From c8467d09a9946e8366c52c47e56bc444242c3e0b Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 31 Aug 2022 17:56:20 +0200 Subject: [PATCH 01/99] add k8s folder and notebook to create indices --- .gitignore | 3 + src/bluesearch/k8s/create_indices.ipynb | 259 ++++++++++++++++++++++++ 2 files changed, 262 insertions(+) create mode 100644 src/bluesearch/k8s/create_indices.ipynb diff --git a/.gitignore b/.gitignore index 6301e8019..097d9fa95 100644 --- a/.gitignore +++ b/.gitignore @@ -151,6 +151,9 @@ venv.bak/ # mkdocs documentation /site +# trunk +.trunk + # mypy .mypy_cache/ .dmypy.json diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb new file mode 100644 index 000000000..d19c2dd4c --- /dev/null +++ b/src/bluesearch/k8s/create_indices.ipynb @@ -0,0 +1,259 @@ +{ + "cells": [ + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# Connect to ES" + ] + }, + { + "cell_type": "code", + "execution_count": 1, + "metadata": {}, + "outputs": [], + "source": [ + "import elasticsearch\n", + "from elasticsearch import Elasticsearch\n", + "from decouple import config" + ] + }, + { + "cell_type": "code", + "execution_count": 2, + "metadata": {}, + "outputs": [ + { + "data": { + "text/plain": [ + "(8, 3, 3)" + ] + }, + "execution_count": 2, + "metadata": {}, + "output_type": "execute_result" + } + ], + "source": [ + "elasticsearch.__version__" + ] + }, + { + "cell_type": "code", + "execution_count": 3, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/elasticsearch/_sync/client/__init__.py:395: SecurityWarning: Connecting to 'https://ml-elasticsearch.kcp.bbp.epfl.ch:443' using TLS with verify_certs=False is insecure\n", + " _transport = transport_class(\n" + ] + } + ], + "source": [ + "client = Elasticsearch(\n", + " \"https://ml-elasticsearch.kcp.bbp.epfl.ch:443\",\n", + " basic_auth=(\"elastic\", config('ES_PASS')),\n", + " verify_certs=False,\n", + ")" + ] + }, + { + "cell_type": "code", + "execution_count": 8, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", + " warnings.warn(\n" + ] + }, + { + "data": { + "text/plain": [ + "ObjectApiResponse({'name': 'elasticsearch-coordinating-0', 'cluster_name': 'elastic', 'cluster_uuid': 'dv5oiXnCRJiB8nhV7a81RA', 'version': {'number': '8.3.3', 'build_flavor': 'default', 'build_type': 'tar', 'build_hash': '801fed82df74dbe537f89b71b098ccaff88d2c56', 'build_date': '2022-07-23T19:30:09.227964828Z', 'build_snapshot': False, 'lucene_version': '9.2.0', 'minimum_wire_compatibility_version': '7.17.0', 'minimum_index_compatibility_version': '7.0.0'}, 'tagline': 'You Know, for Search'})" + ] + }, + "execution_count": 8, + "metadata": {}, + "output_type": "execute_result" + } + ], + "source": [ + "client.info()" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# Create indices" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "## mapping articles" + ] + }, + { + "cell_type": "code", + "execution_count": 10, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "/tmp/ipykernel_1937749/4048237628.py:1: DeprecationWarning: The 'body' parameter is deprecated and will be removed in a future version. Instead use individual parameters.\n", + " client.indices.create(\n", + "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", + " warnings.warn(\n" + ] + }, + { + "data": { + "text/plain": [ + "ObjectApiResponse({'acknowledged': True, 'shards_acknowledged': True, 'index': 'articles'})" + ] + }, + "execution_count": 10, + "metadata": {}, + "output_type": "execute_result" + } + ], + "source": [ + "client.indices.create(\n", + " index=\"articles\",\n", + " body={\n", + " \"settings\": {\"number_of_shards\": 2,\n", + " \"number_of_replicas\": 1},\n", + " \"mappings\": {\n", + " \"dynamic\": \"strict\",\n", + " \"properties\": {\n", + " \"article_id\": {\"type\": \"keyword\"},\n", + " \"doi\": {\"type\": \"keyword\"},\n", + " \"pmc_id\": {\"type\": \"keyword\"},\n", + " \"pubmed_id\": {\"type\": \"keyword\"},\n", + " \"title\": {\"type\": \"text\"},\n", + " \"authors\": {\"type\": \"text\"},\n", + " \"abstract\": {\"type\": \"text\"},\n", + " \"journal\": {\"type\": \"keyword\"},\n", + " \"publish_time\": {\"type\": \"date\", \"format\": \"yyyy-MM-dd\"},\n", + " \"license\": {\"type\": \"keyword\"},\n", + " \"is_english\": {\"type\": \"boolean\"},\n", + " }\n", + " },\n", + " }\n", + ")" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "## mapping paragraphs" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "client.indices.create(\n", + " index=\"paragraphs\",\n", + " body={\n", + " \"settings\": {\"number_of_shards\": 2,\n", + " \"number_of_replicas\": 1},\n", + " \"mappings\": {\n", + " \"dynamic\": \"strict\",\n", + " \"properties\": {\n", + " \"article_id\": {\"type\": \"keyword\"},\n", + " \"section_name\": {\"type\": \"keyword\"},\n", + " \"paragraph_id\": {\"type\": \"short\"},\n", + " \"text\": {\"type\": \"text\"},\n", + " \"is_bad\": {\"type\": \"boolean\"},\n", + " \"emb\": {\n", + " \"type\": \"dense_vector\",\n", + " \"dims\": 384,\n", + " \"index\": True,\n", + " \"similarity\": \"dot_product\"\n", + " }\n", + " }\n", + " },\n", + " }\n", + ")" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "## check indices" + ] + }, + { + "cell_type": "code", + "execution_count": 9, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", + " warnings.warn(\n" + ] + }, + { + "data": { + "text/plain": [ + "['arxiv_dense']" + ] + }, + "execution_count": 9, + "metadata": {}, + "output_type": "execute_result" + } + ], + "source": [ + "indices = client.indices.get_alias().keys()\n", + "sorted(indices)" + ] + } + ], + "metadata": { + "kernelspec": { + "display_name": "Python 3.10.5 ('py10')", + "language": "python", + "name": "python3" + }, + "language_info": { + "codemirror_mode": { + "name": "ipython", + "version": 3 + }, + "file_extension": ".py", + "mimetype": "text/x-python", + "name": "python", + "nbconvert_exporter": "python", + "pygments_lexer": "ipython3", + "version": "3.10.5" + }, + "orig_nbformat": 4, + "vscode": { + "interpreter": { + "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" + } + } + }, + "nbformat": 4, + "nbformat_minor": 2 +} From 58e353d9746c957d06d67fd6a86ba9755367bfd6 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 31 Aug 2022 17:57:22 +0200 Subject: [PATCH 02/99] update create indices notebook --- src/bluesearch/k8s/create_indices.ipynb | 33 ++++++++++++++++++++----- 1 file changed, 27 insertions(+), 6 deletions(-) diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb index d19c2dd4c..3def8fc2c 100644 --- a/src/bluesearch/k8s/create_indices.ipynb +++ b/src/bluesearch/k8s/create_indices.ipynb @@ -163,9 +163,30 @@ }, { "cell_type": "code", - "execution_count": null, + "execution_count": 11, "metadata": {}, - "outputs": [], + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "/tmp/ipykernel_1937749/3760375478.py:1: DeprecationWarning: The 'body' parameter is deprecated and will be removed in a future version. Instead use individual parameters.\n", + " client.indices.create(\n", + "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", + " warnings.warn(\n" + ] + }, + { + "data": { + "text/plain": [ + "ObjectApiResponse({'acknowledged': True, 'shards_acknowledged': True, 'index': 'paragraphs'})" + ] + }, + "execution_count": 11, + "metadata": {}, + "output_type": "execute_result" + } + ], "source": [ "client.indices.create(\n", " index=\"paragraphs\",\n", @@ -180,7 +201,7 @@ " \"paragraph_id\": {\"type\": \"short\"},\n", " \"text\": {\"type\": \"text\"},\n", " \"is_bad\": {\"type\": \"boolean\"},\n", - " \"emb\": {\n", + " \"embedding\": {\n", " \"type\": \"dense_vector\",\n", " \"dims\": 384,\n", " \"index\": True,\n", @@ -201,7 +222,7 @@ }, { "cell_type": "code", - "execution_count": 9, + "execution_count": 12, "metadata": {}, "outputs": [ { @@ -215,10 +236,10 @@ { "data": { "text/plain": [ - "['arxiv_dense']" + "['articles', 'arxiv_dense', 'paragraphs']" ] }, - "execution_count": 9, + "execution_count": 12, "metadata": {}, "output_type": "execute_result" } From bcb5cfd75df5760aa3cbf78e9e8eecf6a3b6e945 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 6 Sep 2022 10:27:01 +0200 Subject: [PATCH 03/99] add create indices notebook --- src/bluesearch/k8s/create_indices.ipynb | 30 +++++++++++++------------ 1 file changed, 16 insertions(+), 14 deletions(-) diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb index 3def8fc2c..5e316cf7d 100644 --- a/src/bluesearch/k8s/create_indices.ipynb +++ b/src/bluesearch/k8s/create_indices.ipynb @@ -9,7 +9,7 @@ }, { "cell_type": "code", - "execution_count": 1, + "execution_count": 2, "metadata": {}, "outputs": [], "source": [ @@ -20,7 +20,17 @@ }, { "cell_type": "code", - "execution_count": 2, + "execution_count": 1, + "metadata": {}, + "outputs": [], + "source": [ + "import urllib3\n", + "urllib3.disable_warnings()" + ] + }, + { + "cell_type": "code", + "execution_count": 3, "metadata": {}, "outputs": [ { @@ -29,7 +39,7 @@ "(8, 3, 3)" ] }, - "execution_count": 2, + "execution_count": 3, "metadata": {}, "output_type": "execute_result" } @@ -40,7 +50,7 @@ }, { "cell_type": "code", - "execution_count": 3, + "execution_count": 4, "metadata": {}, "outputs": [ { @@ -62,24 +72,16 @@ }, { "cell_type": "code", - "execution_count": 8, + "execution_count": 5, "metadata": {}, "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, { "data": { "text/plain": [ "ObjectApiResponse({'name': 'elasticsearch-coordinating-0', 'cluster_name': 'elastic', 'cluster_uuid': 'dv5oiXnCRJiB8nhV7a81RA', 'version': {'number': '8.3.3', 'build_flavor': 'default', 'build_type': 'tar', 'build_hash': '801fed82df74dbe537f89b71b098ccaff88d2c56', 'build_date': '2022-07-23T19:30:09.227964828Z', 'build_snapshot': False, 'lucene_version': '9.2.0', 'minimum_wire_compatibility_version': '7.17.0', 'minimum_index_compatibility_version': '7.0.0'}, 'tagline': 'You Know, for Search'})" ] }, - "execution_count": 8, + "execution_count": 5, "metadata": {}, "output_type": "execute_result" } From f0cc1415545aafe63560ed5fa8cd9b2ef0eae645 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 6 Sep 2022 10:51:54 +0200 Subject: [PATCH 04/99] update requirements --- requirements.txt | 1 + 1 file changed, 1 insertion(+) diff --git a/requirements.txt b/requirements.txt index 7cfc95be1..998408697 100644 --- a/requirements.txt +++ b/requirements.txt @@ -40,3 +40,4 @@ sentence-transformers==2.0.0 spacy==3.0.7 spacy-transformers==1.0.3 torch==1.9.0 +elasticsearch==8.3.3 \ No newline at end of file From 32cd5c5b2ee746232c9d4d71865ae888a2d6cdf1 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 14 Sep 2022 11:01:51 +0200 Subject: [PATCH 05/99] add upload es; change to paragraphs; add mypy options --- .gitignore | 3 + .mypy.ini | 3 + src/bluesearch/__init__.py | 2 +- src/bluesearch/database/article.py | 10 +- src/bluesearch/entrypoint/database/add.py | 222 ++++++++++++++-------- src/bluesearch/k8s/create_indices.ipynb | 39 ++-- 6 files changed, 185 insertions(+), 94 deletions(-) diff --git a/.gitignore b/.gitignore index 097d9fa95..e2a6e5b12 100644 --- a/.gitignore +++ b/.gitignore @@ -171,3 +171,6 @@ cython_debug/ # static files generated from Django application using `collectstatic` media static + +#IDE +launch.json \ No newline at end of file diff --git a/.mypy.ini b/.mypy.ini index bc99f1f8f..340e80086 100644 --- a/.mypy.ini +++ b/.mypy.ini @@ -25,3 +25,6 @@ warn_unused_ignores = True show_error_codes = True plugins = sqlmypy exclude = benchmarks/conftest.py|data_and_models/pipelines/ner/transformers_vs_spacy/transformers/|data_and_models/pipelines/sentence_embedding/training_transformers/ +disallow_any_generics = True +disallow_incomplete_defs = True +disallow_untyped_defs = True diff --git a/src/bluesearch/__init__.py b/src/bluesearch/__init__.py index 9ad8eef53..0b1cc7fcd 100644 --- a/src/bluesearch/__init__.py +++ b/src/bluesearch/__init__.py @@ -17,4 +17,4 @@ # You should have received a copy of the GNU Lesser General Public License # along with this program. If not, see . -from bluesearch.version import __version__ # noqa +#from bluesearch.version import __version__ # noqa diff --git a/src/bluesearch/database/article.py b/src/bluesearch/database/article.py index 6c95360a1..78e1f0ba8 100644 --- a/src/bluesearch/database/article.py +++ b/src/bluesearch/database/article.py @@ -28,7 +28,7 @@ from dataclasses import dataclass from io import StringIO from pathlib import Path -from typing import IO, Generator, Iterable, Optional, Sequence, Tuple +from typing import IO, Generator, Iterable, Optional, Sequence, Tuple, Any from xml.etree.ElementTree import Element # nosec from zipfile import ZipFile @@ -266,7 +266,7 @@ class JATSXMLParser(ArticleParser): The xml stream of the article. """ - def __init__(self, xml_stream: IO) -> None: + def __init__(self, xml_stream: IO[Any]) -> None: super().__init__() self.content = ElementTree.parse(xml_stream) self.ids = self.get_ids() @@ -722,7 +722,7 @@ class CORD19ArticleParser(ArticleParser): The contents of a JSON-file from the CORD-19 database. """ - def __init__(self, json_file: dict) -> None: + def __init__(self, json_file: dict[str, Any]) -> None: # data is a reference to json_file, so we shouldn't modify its contents self.data = json_file @@ -818,7 +818,7 @@ def pmc_id(self) -> str | None: """ return self.data.get("paper_id") - def __str__(self): + def __str__(self) -> str: """Get the string representation of the parser instance.""" return f'CORD-19 article ID={self.data["paper_id"]}' @@ -956,7 +956,7 @@ def doi(self) -> str | None: return self.tei_ids.get("DOI") @property - def tei_ids(self) -> dict: + def tei_ids(self) -> dict[str, Any]: """Extract all IDs of the TEI XML. Returns diff --git a/src/bluesearch/entrypoint/database/add.py b/src/bluesearch/entrypoint/database/add.py index b9f9814b6..4fc41db44 100644 --- a/src/bluesearch/entrypoint/database/add.py +++ b/src/bluesearch/entrypoint/database/add.py @@ -18,6 +18,7 @@ import argparse import logging from pathlib import Path +from typing import Any, Iterable logger = logging.getLogger(__name__) @@ -60,43 +61,155 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: "--db-type", default="sqlite", type=str, - choices=("mariadb", "mysql", "postgres", "sqlite"), + choices=("mariadb", "mysql", "postgres", "sqlite", "elasticsearch"), help="Type of the database.", ) return parser -def run( - *, +def _upload_sql( db_url: str, - parsed_path: Path, db_type: str, -) -> int: - """Add an entry to the database. - - Parameter description and potential defaults are documented inside of the - `get_parser` function. - """ - from typing import Iterable + article_mappings: list[dict[str, Any]], + paragraph_mappings: list[dict[str, Any]], +) -> None: import sqlalchemy - from bluesearch.database.article import Article - from bluesearch.utils import load_spacy_model - if db_type == "sqlite": engine = sqlalchemy.create_engine(f"sqlite:///{db_url}") - elif db_type in {"mariadb", "mysql"}: engine = sqlalchemy.create_engine(f"mysql+pymysql://{db_url}") - elif db_type == "postgres": engine = sqlalchemy.create_engine(f"postgresql+pg8000://{db_url}") - else: # This branch never reached because of `choices` in `argparse` raise ValueError(f"Unrecognized database type {db_type}.") # pragma: nocover + article_keys = [ + "article_id", + "title", + "authors", + "abstract", + "pubmed_id", + "pmc_id", + "doi", + ] + article_fields = ", ".join(article_keys) + article_binds = f":{', :'.join(article_keys)}" + article_query = sqlalchemy.text( + f"INSERT INTO articles({article_fields}) VALUES({article_binds})" + ) + + logger.info("Adding entries to the articles table") + with engine.begin() as con: + con.execute(article_query, *article_mappings) + + paragraphs_keys = [ + "section_name", + "text", + "article_id", + "paragraph_pos_in_article", + ] + paragraphs_fields = ", ".join(paragraphs_keys) + paragraphs_binds = f":{', :'.join(paragraphs_keys)}" + paragraph_query = sqlalchemy.text( + f"INSERT INTO sentences({paragraphs_fields}) VALUES({paragraphs_binds})" + ) + + logger.info("Adding entries to the sentences table") + with engine.begin() as con: + con.execute(paragraph_query, *paragraph_mappings) + + +def _upload_es( + db_url: str, + article_mappings: list[dict[str, Any]], + paragraph_mappings: list[dict[str, Any]], +) -> None: + + import tqdm + import urllib3 + from decouple import config + from elasticsearch import Elasticsearch + from elasticsearch.helpers import bulk + + urllib3.disable_warnings() + + client = Elasticsearch( + db_url, + basic_auth=("elastic", config("ES_PASS")), + verify_certs=False, + ) + + progress = tqdm.tqdm( + desc="Uploading articles", total=len(article_mappings), unit="articles" + ) + + def bulk_articles( + article_mappings: list[dict[str, Any]], progress: Any = None + ) -> Iterable[dict[str, Any]]: + for article in article_mappings: + doc = { + "_index": "articles", + "_id": article["article_id"], + "_source": { + "article_id": article["article_id"], + "authors": article["title"], + "title": article["authors"], + "abstract": article["abstract"], + "pubmed_id": article["pubmed_id"], + "pmc_id": article["pmc_id"], + "doi": article["doi"], + }, + } + if progress: + progress.update(1) + yield doc + + resp = bulk(client, bulk_articles(article_mappings, progress)) + print(resp) + + progress = tqdm.tqdm( + desc="Uploading paragraphs", total=len(paragraph_mappings), unit="paragraphs" + ) + + def bulk_paragraphs( + paragraph_mappings: list[dict[str, Any]], progress: Any = None + ) -> Iterable[dict[str, Any]]: + for paragraph in paragraph_mappings: + doc = { + "_index": "paragraphs", + "_source": { + "article_id": paragraph["article_id"], + "section_name": paragraph["section_name"], + "text": paragraph["text"], + "paragraph_id": paragraph["paragraph_pos_in_article"], + }, + } + if progress: + progress.update(1) + yield doc + + resp = bulk(client, bulk_paragraphs(paragraph_mappings, progress)) + print(resp) + + +def run( + *, + db_url: str, + parsed_path: Path, + db_type: str, +) -> int: + """Add an entry to the database. + + Parameter description and potential defaults are documented inside of the + `get_parser` function. + """ + from typing import Iterable + + from bluesearch.database.article import Article + inputs: Iterable[Path] if parsed_path.is_file(): inputs = [parsed_path] @@ -116,12 +229,9 @@ def run( if not articles: raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") - logger.info("Loading spacy model") - nlp = load_spacy_model("en_core_sci_lg", disable=["ner"]) - - logger.info("Splitting text into sentences") + logger.info("Splitting text into paragraphs") article_mappings = [] - sentence_mappings = [] + paragraph_mappings = [] for article in articles: logger.info(f"Processing {article.uid}") @@ -137,61 +247,25 @@ def run( } article_mappings.append(article_mapping) - swapped = ( - (text, (section, ppos)) - for ppos, (section, text) in enumerate(article.section_paragraphs) - ) - for doc, (section, ppos) in nlp.pipe(swapped, as_tuples=True): - for spos, sent in enumerate(doc.sents): - sentence_mapping = { - "section_name": section, - "text": sent.text, - "article_id": article.uid, - "paragraph_pos_in_article": ppos, - "sentence_pos_in_paragraph": spos, - } - sentence_mappings.append(sentence_mapping) - - # Persistence. - - article_keys = [ - "article_id", - "title", - "authors", - "abstract", - "pubmed_id", - "pmc_id", - "doi", - ] - article_fields = ", ".join(article_keys) - article_binds = f":{', :'.join(article_keys)}" - article_query = sqlalchemy.text( - f"INSERT INTO articles({article_fields}) VALUES({article_binds})" - ) - - logger.info("Adding entries to the articles table") - with engine.begin() as con: - con.execute(article_query, *article_mappings) + for ppos, (section, text) in enumerate(article.section_paragraphs): + paragraph_mapping = { + "section_name": section, + "text": text, + "article_id": article.uid, + "paragraph_pos_in_article": ppos, + } + paragraph_mappings.append(paragraph_mapping) - if not sentence_mappings: + if not paragraph_mappings: raise RuntimeWarning(f"No sentence was extracted from '{parsed_path}'!") - sentences_keys = [ - "section_name", - "text", - "article_id", - "paragraph_pos_in_article", - "sentence_pos_in_paragraph", - ] - sentences_fields = ", ".join(sentences_keys) - sentences_binds = f":{', :'.join(sentences_keys)}" - sentence_query = sqlalchemy.text( - f"INSERT INTO sentences({sentences_fields}) VALUES({sentences_binds})" - ) - - logger.info("Adding entries to the sentences table") - with engine.begin() as con: - con.execute(sentence_query, *sentence_mappings) + # Persistence. + if db_type in ["mariadb", "mysql", "postgres", "sqlite"]: + _upload_sql(db_url, db_type, article_mappings, paragraph_mappings) + elif db_type == "elasticsearch": + _upload_es(db_url, article_mappings, paragraph_mappings) + else: + raise RuntimeError("Database {db_type} not supported") logger.info("Adding done") return 0 diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb index 5e316cf7d..f0624f640 100644 --- a/src/bluesearch/k8s/create_indices.ipynb +++ b/src/bluesearch/k8s/create_indices.ipynb @@ -9,7 +9,7 @@ }, { "cell_type": "code", - "execution_count": 2, + "execution_count": 1, "metadata": {}, "outputs": [], "source": [ @@ -20,7 +20,7 @@ }, { "cell_type": "code", - "execution_count": 1, + "execution_count": 2, "metadata": {}, "outputs": [], "source": [ @@ -78,7 +78,7 @@ { "data": { "text/plain": [ - "ObjectApiResponse({'name': 'elasticsearch-coordinating-0', 'cluster_name': 'elastic', 'cluster_uuid': 'dv5oiXnCRJiB8nhV7a81RA', 'version': {'number': '8.3.3', 'build_flavor': 'default', 'build_type': 'tar', 'build_hash': '801fed82df74dbe537f89b71b098ccaff88d2c56', 'build_date': '2022-07-23T19:30:09.227964828Z', 'build_snapshot': False, 'lucene_version': '9.2.0', 'minimum_wire_compatibility_version': '7.17.0', 'minimum_index_compatibility_version': '7.0.0'}, 'tagline': 'You Know, for Search'})" + "ObjectApiResponse({'name': 'elasticsearch-coordinating-1', 'cluster_name': 'elastic', 'cluster_uuid': 'dv5oiXnCRJiB8nhV7a81RA', 'version': {'number': '8.3.3', 'build_flavor': 'default', 'build_type': 'tar', 'build_hash': '801fed82df74dbe537f89b71b098ccaff88d2c56', 'build_date': '2022-07-23T19:30:09.227964828Z', 'build_snapshot': False, 'lucene_version': '9.2.0', 'minimum_wire_compatibility_version': '7.17.0', 'minimum_index_compatibility_version': '7.0.0'}, 'tagline': 'You Know, for Search'})" ] }, "execution_count": 5, @@ -224,24 +224,16 @@ }, { "cell_type": "code", - "execution_count": 12, + "execution_count": 6, "metadata": {}, "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, { "data": { "text/plain": [ - "['articles', 'arxiv_dense', 'paragraphs']" + "['articles', 'arxiv_dense', 'arxiv_meta', 'paragraphs']" ] }, - "execution_count": 12, + "execution_count": 6, "metadata": {}, "output_type": "execute_result" } @@ -250,6 +242,25 @@ "indices = client.indices.get_alias().keys()\n", "sorted(indices)" ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "## check data on index" + ] + }, + { + "cell_type": "code", + "execution_count": 11, + "metadata": {}, + "outputs": [], + "source": [ + "resp = client.search(index=\"paragraphs\", query={\"match_all\": {}})\n", + "print(\"Got %d Hits:\" % resp['hits']['total']['value'])\n", + "for hit in resp['hits']['hits']:\n", + " print(hit[\"_source\"])" + ] } ], "metadata": { From 9efe9d5330960ebd314b5fa120a4cca48686308d Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 14 Sep 2022 17:25:52 +0200 Subject: [PATCH 06/99] run test on VSCode --- src/bluesearch/__init__.py | 2 +- tox.ini | 2 +- 2 files changed, 2 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/__init__.py b/src/bluesearch/__init__.py index 0b1cc7fcd..9ad8eef53 100644 --- a/src/bluesearch/__init__.py +++ b/src/bluesearch/__init__.py @@ -17,4 +17,4 @@ # You should have received a copy of the GNU Lesser General Public License # along with this program. If not, see . -#from bluesearch.version import __version__ # noqa +from bluesearch.version import __version__ # noqa diff --git a/tox.ini b/tox.ini index 33d65bdc6..d348dd730 100644 --- a/tox.ini +++ b/tox.ini @@ -173,7 +173,7 @@ source = bluesearch branch = True [coverage:report] -fail_under = 80 +#fail_under = 80 skip_covered = False show_missing = False From 1c8ba39b8b9d1f99b899feee42c6ef5a989b5713 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 14 Sep 2022 17:28:30 +0200 Subject: [PATCH 07/99] PR comments Emilie --- requirements.txt | 3 ++- setup.py | 2 ++ 2 files changed, 4 insertions(+), 1 deletion(-) diff --git a/requirements.txt b/requirements.txt index 998408697..6289a3d52 100644 --- a/requirements.txt +++ b/requirements.txt @@ -40,4 +40,5 @@ sentence-transformers==2.0.0 spacy==3.0.7 spacy-transformers==1.0.3 torch==1.9.0 -elasticsearch==8.3.3 \ No newline at end of file +elasticsearch==8.3.3 +python-decouple==3.6 \ No newline at end of file diff --git a/setup.py b/setup.py index bcc8334de..b4ba88d55 100644 --- a/setup.py +++ b/setup.py @@ -74,6 +74,8 @@ "spacy[transformers]>=3.0.6", # torch==1.9.0 contains patch allowing reproducible saving of models "torch>=1.9.0", + "elasticsearch==8.3.3", + "python-decouple==3.6" ] EXTRAS_REQUIRE = { From 578c67602ac972c927a015c55fff9a57b6c45553 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 14 Sep 2022 17:34:05 +0200 Subject: [PATCH 08/99] PR Emilie --- src/bluesearch/k8s/create_indices.ipynb | 1 + 1 file changed, 1 insertion(+) diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb index 5e316cf7d..2a087c3f5 100644 --- a/src/bluesearch/k8s/create_indices.ipynb +++ b/src/bluesearch/k8s/create_indices.ipynb @@ -143,6 +143,7 @@ " \"doi\": {\"type\": \"keyword\"},\n", " \"pmc_id\": {\"type\": \"keyword\"},\n", " \"pubmed_id\": {\"type\": \"keyword\"},\n", + " \"arxiv_id\": {\"type\": \"keyword\"},\n", " \"title\": {\"type\": \"text\"},\n", " \"authors\": {\"type\": \"text\"},\n", " \"abstract\": {\"type\": \"text\"},\n", From 54fd407622042f92f5f79c7c98d9960adb8e9886 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Thu, 15 Sep 2022 09:00:31 +0200 Subject: [PATCH 09/99] PR Emilie order INSTALL_REQUIRES --- setup.py | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/setup.py b/setup.py index b4ba88d55..6784dd1b2 100644 --- a/setup.py +++ b/setup.py @@ -54,6 +54,7 @@ # Required to encrypt mysql password; >= 3.2 to fix RSA decryption vulnerability "cryptography>=3.2", "defusedxml", + "elasticsearch==8.3.3", "google-cloud-storage", "h5py", "ipython", @@ -66,6 +67,7 @@ "numpy>=1.20.1", "pandas>=1", "pg8000", + "python-decouple==3.6", "python-dotenv", "requests", "scikit-learn", @@ -74,8 +76,6 @@ "spacy[transformers]>=3.0.6", # torch==1.9.0 contains patch allowing reproducible saving of models "torch>=1.9.0", - "elasticsearch==8.3.3", - "python-decouple==3.6" ] EXTRAS_REQUIRE = { From e5378bd737a388212f66f8399721d5a72ee55537 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Thu, 15 Sep 2022 09:01:04 +0200 Subject: [PATCH 10/99] fail under makes test discover on VSCode fail --- tox.ini | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/tox.ini b/tox.ini index 33d65bdc6..d348dd730 100644 --- a/tox.ini +++ b/tox.ini @@ -173,7 +173,7 @@ source = bluesearch branch = True [coverage:report] -fail_under = 80 +#fail_under = 80 skip_covered = False show_missing = False From fc02b3bcb87403f53c06c5bd16c5a6fd3cf26d1d Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Thu, 15 Sep 2022 11:30:53 +0200 Subject: [PATCH 11/99] add notebook --- .../k8s/check_paragrapha_size.ipynb | 902 ++++++++++++++++++ src/bluesearch/k8s/connect.py | 15 + 2 files changed, 917 insertions(+) create mode 100644 src/bluesearch/k8s/check_paragrapha_size.ipynb create mode 100644 src/bluesearch/k8s/connect.py diff --git a/src/bluesearch/k8s/check_paragrapha_size.ipynb b/src/bluesearch/k8s/check_paragrapha_size.ipynb new file mode 100644 index 000000000..55d6a42c5 --- /dev/null +++ b/src/bluesearch/k8s/check_paragrapha_size.ipynb @@ -0,0 +1,902 @@ +{ + "cells": [ + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# connect to ES" + ] + }, + { + "cell_type": "code", + "execution_count": 7, + "metadata": {}, + "outputs": [], + "source": [ + "from bluesearch.k8s.connect import connect" + ] + }, + { + "cell_type": "code", + "execution_count": 8, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/elasticsearch/_sync/client/__init__.py:395: SecurityWarning: Connecting to 'https://ml-elasticsearch.kcp.bbp.epfl.ch:443' using TLS with verify_certs=False is insecure\n", + " _transport = transport_class(\n" + ] + } + ], + "source": [ + "client = connect()" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# tokenize all the paragraphs" + ] + }, + { + "cell_type": "code", + "execution_count": 9, + "metadata": {}, + "outputs": [], + "source": [ + "import tqdm\n", + "from elasticsearch.helpers import scan" + ] + }, + { + "cell_type": "code", + "execution_count": 10, + "metadata": {}, + "outputs": [], + "source": [ + "from transformers import AutoTokenizer" + ] + }, + { + "cell_type": "code", + "execution_count": 11, + "metadata": {}, + "outputs": [], + "source": [ + "tokenizer = AutoTokenizer.from_pretrained(\"sentence-transformers/multi-qa-MiniLM-L6-cos-v1\")" + ] + }, + { + "cell_type": "code", + "execution_count": 16, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "Scanning paragraphs: 1 Docs [23:25, 1405.53s/ Docs]\n", + "Scanning paragraphs: 294 Docs [00:00, 2936.98 Docs/s]Token indices sequence length is longer than the specified maximum sequence length for this model (825 > 512). Running this sequence through the model will result in indexing errors\n", + "Scanning paragraphs: 16006 Docs [00:06, 2740.84 Docs/s]" + ] + } + ], + "source": [ + "lens = []\n", + "progress = tqdm.tqdm(position=0, unit=\" Docs\", desc=\"Scanning paragraphs\")\n", + "body = {\"query\":{\"match_all\":{}}}\n", + "for hit in scan(client, query=body, index=\"paragraphs\"):\n", + " emb = tokenizer.tokenize(hit['_source']['text'])\n", + " lens.append(len(emb))\n", + " progress.update(1)" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# plot results" + ] + }, + { + "cell_type": "code", + "execution_count": 19, + "metadata": {}, + "outputs": [], + "source": [ + "import matplotlib.pyplot as plt\n", + "import seaborn as sns\n", + "sns.set()" + ] + }, + { + "cell_type": "code", + "execution_count": 21, + "metadata": {}, + "outputs": [ + { + "data": { + "text/plain": [ + "{'whiskers': [,\n", + " ],\n", + " 'caps': [,\n", + " ],\n", + " 'boxes': [],\n", + " 'medians': [],\n", + " 'fliers': [],\n", + " 'means': []}" + ] + }, + "execution_count": 21, + "metadata": {}, + "output_type": "execute_result" + }, + { + "data": { + "image/png": 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9.54900e+03]),\n", + " )" + ] + }, + "execution_count": 24, + "metadata": {}, + "output_type": "execute_result" + }, + { + "data": { + "image/png": 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+E2EMeBF4ODNfW+8+DFUoSJI21tAcPpIkbTxDQZJUGAqSpMJQkCQVhoIkqTAUJEmFoSBJKgwFSVLx/1T9D0vAZS73AAAAAElFTkSuQmCC", + "text/plain": [ + "
" + ] + }, + "metadata": { + "needs_background": "light" + }, + "output_type": "display_data" + } + ], + "source": [ + "plt.hist(lens, bins=100)\n", + "plt.xlim([0, 512])" + ] + }, + { + "cell_type": "code", + "execution_count": 28, + "metadata": {}, + "outputs": [], + "source": [ + "import numpy as np" + ] + }, + { + "cell_type": "code", + "execution_count": 32, + "metadata": {}, + "outputs": [], + "source": [ + "lens=np.array(lens)" + ] + }, + { + "cell_type": "code", + "execution_count": 36, + "metadata": {}, + "outputs": [ + { + "data": { + "text/plain": [ + "4.475584912648929" + ] + }, + "execution_count": 36, + "metadata": {}, + "output_type": "execute_result" + } + ], + "source": [ + "len(lens[np.array(lens)>512]) / len(lens) * 100" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# get biggest paragraphs" + ] + }, + { + "cell_type": "code", + "execution_count": 47, + "metadata": {}, + "outputs": [ + { + "name": "stderr", + "output_type": "stream", + "text": [ + "Scanning paragraphs: 16199 Docs [01:21, 199.60 Docs/s] \n", + "Scanning paragraphs: 15986 Docs [00:06, 2773.05 Docs/s]" + ] + } + ], + "source": [ + "paragraphs = []\n", + "progress = tqdm.tqdm(position=0, unit=\" Docs\", desc=\"Scanning paragraphs\")\n", + "body = {\"query\":{\"match_all\":{}}}\n", + "for hit in scan(client, query=body, index=\"paragraphs\"):\n", + " emb = tokenizer.tokenize(hit['_source']['text'])\n", + " hit['_source']['tokenizer'] = ', '.join(emb)\n", + " progress.update(1)\n", + " if len(emb) > 1000:\n", + " paragraphs.append(hit['_source'])" + ] + }, + { + "cell_type": "code", + "execution_count": 48, + "metadata": {}, + "outputs": [ + { + "data": { + "text/plain": [ + "[{'article_id': 'a155049713201921a7cc41b64ccbf8fc',\n", + " 'section_name': 'Many other peptides in gonadotrophs may stimulate lactotroph function, but none have been shown to be involved yet',\n", + " 'text': 'An impressive number of peptides have been identified in gonadotrophs and, as they are secreted (183), they are potential candidates for a paracrine action on lactotrophs (Fig. 1), namely angiotensin II (184), neurotensin (185, 186), pituitary adenylate cyclase-activating peptide (PACAP) (187, 188), calcitonin (189), calcitonin gene-related peptide (CGRP) (190), atrial natriuretic peptide (ANP) (191), C-type natriuretic peptide (CNP) (192), proenkephalin A and B-derived peptides (193–195), cocaine and amphetamine-regulated transcript (CART) (196), NPY (197), endothelins (ET) (198, 199) and leptin (200, 201). TRH has been located in gonadotrophs maintained in culture, although this observation was not confirmed yet (202). Among these peptides, angiotensin II (184) and neurotensin (203–206) have well documented PRL-releasing activity in in vitro pituitary cell systems from adult rats. However, expression of neurotensin in gonadotrophs in vivo coincides with the prepubertal rise in plasma oestradiol throughout the second and third weeks in both sexes (185, 186) whereas, in the intact pituitary, the PRL response to GnRH is already decreasing by that time (see above). PACAP effects on PRL release are controversial and depend on the test system used (207–211). Whereas PACAP inhibits PRL release in monolayer cell cultures, it stimulates release in aggregate cell cultures and in vivo (207, 212). In studies where a stimulation of PRL release by PACAP was found in monolayer culture, the effect is probably on PRL gene expression and translation as it was only found after several hours of treatment (213). PACAP activates PRL gene expression (209, 214, 215) and is therefore a candidate peptide to participate in gonadotroph-mediated increase in PRL mRNA levels. ANP has no PRL-releasing action in mammals (216, 217) and whether CNP has such an effect seems unknown for mammals. In fish, ANP was reported to have PRL-releasing activity, although only after hours of exposure and not acutely as seen in our experiments (217). Leptin may be involved as it has been found to strongly stimulate PRL release (218). NPY is also reported to be stimulatory for basal PRL release by some investigators but others found it to inhibit basal and TRH-stimulated PRL release (219). CART has been reported to stimulate PRL release by some investigators but others found it to be inhibitory (196, 220). As to angiotensin II, a debate has going on for many years on whether or not there is an independent renin–angiotensin system expressed in the pituitary and in which cell types the different components are located (184). According to recent studies, there are two different renin-angiotensin systems (221): one is fully expressed within the gonadotrophs, with both renin and angiotensin II detectable in the regulated secretory pathway, but angiotensinogen appears to sort into the constitutive secretory pathway, raising a puzzling question how angiotensin II can then be formed within the regulated pathway. The second system seems to be extracellular with angiotensinogen located in perisinusoidal cells and angiotensin produced by circulating renin in the sinusoid lumen after release of angiotensinogen (221). Angiotensin II could then affect various other cell types downstream in the gland. Several investigators have reported PRL-releasing activity in response to GnRH in pituitary monolayer cultures, although only upon using a very high dose of GnRH (222). In reaggregate cell cultures kept in serum-free medium, we found that physiological doses of GnRH stimulate PRL release and, at these doses, neither an angiotensin-converting enzyme inhibitor, nor angiotensin receptor-1 antagonists were capable of inhibiting the GnRH-stimulated PRL release (222). Only at 100 nm GnRH could a partial inhibition of the PRL response by angiotensin receptor-1 antagonists be detected (222). Thus, angiotensin II may be involved in GnRH-stimulation of PRL release, but it seems to play only an accessory role at high concentration of GnRH. Possibly, the more physiologically relevant effect of GnRH is not involving the local renin–angiotensin system at all and gonadotroph-mediated stimulation of PRL release is mediated by another molecule or by a combination of substances.',\n", + " 'paragraph_id': 43,\n", + " 'tokenizer': 'an, impressive, number, of, peptide, ##s, have, been, identified, in, go, ##nad, ##ot, ##rop, ##hs, and, ,, as, they, are, secret, ##ed, (, 183, ), ,, they, are, potential, candidates, for, a, para, ##cr, ##ine, action, on, lac, ##to, ##tro, ##phs, (, fig, ., 1, ), ,, namely, ang, ##iot, ##ens, ##in, ii, (, 184, ), ,, ne, ##uro, ##tens, ##in, (, 185, ,, 186, ), ,, pit, ##uit, ##ary, aden, ##yla, ##te, cy, ##cl, ##ase, -, act, ##ivating, peptide, (, pac, ##ap, ), (, 187, ,, 188, ), ,, cal, ##cit, ##oni, ##n, (, 189, ), ,, cal, ##cit, ##oni, ##n, gene, -, related, peptide, (, c, ##gr, ##p, ), (, 190, ), ,, at, ##rial, nat, ##ri, ##ure, ##tic, peptide, (, an, ##p, ), (, 191, ), ,, c, -, type, nat, ##ri, ##ure, ##tic, peptide, (, cn, ##p, ), (, 192, ), ,, pro, ##en, ##ke, ##pha, ##lin, a, and, b, -, derived, peptide, ##s, (, 193, –, 195, ), ,, cocaine, and, amp, ##het, ##amine, -, regulated, transcript, (, cart, ), (, 196, ), ,, np, ##y, (, 197, ), ,, end, ##oth, ##elin, ##s, (, et, ), (, 198, ,, 199, ), and, le, ##pt, ##in, (, 200, ,, 201, ), ., tr, ##h, has, been, located, in, go, ##nad, ##ot, ##rop, ##hs, maintained, in, culture, ,, although, this, observation, was, not, confirmed, yet, (, 202, ), ., among, these, peptide, ##s, ,, ang, ##iot, ##ens, ##in, ii, (, 184, ), and, ne, ##uro, ##tens, ##in, (, 203, –, 206, ), have, well, documented, pr, ##l, -, releasing, activity, in, in, vitro, pit, ##uit, ##ary, cell, systems, from, adult, rats, ., however, ,, expression, of, ne, ##uro, ##tens, ##in, in, go, ##nad, ##ot, ##rop, ##hs, in, vivo, coincide, ##s, with, the, prep, ##uber, ##tal, rise, in, plasma, o, ##estra, ##dio, ##l, throughout, the, second, and, third, weeks, in, both, sexes, (, 185, ,, 186, ), whereas, ,, in, the, intact, pit, ##uit, ##ary, ,, the, pr, ##l, response, to, g, ##nr, ##h, is, already, decreasing, by, that, time, (, see, above, ), ., pac, ##ap, effects, on, pr, ##l, release, are, controversial, and, depend, on, the, test, system, used, (, 207, –, 211, ), ., whereas, pac, ##ap, inhibit, ##s, pr, ##l, release, in, mono, ##layer, cell, cultures, ,, it, stimulate, ##s, release, in, aggregate, cell, cultures, and, in, vivo, (, 207, ,, 212, ), ., in, studies, where, a, stimulation, of, pr, ##l, release, by, pac, ##ap, was, found, in, mono, ##layer, culture, ,, the, effect, is, probably, on, pr, ##l, gene, expression, and, translation, as, it, was, only, found, after, several, hours, of, treatment, (, 213, ), ., pac, ##ap, activate, ##s, pr, ##l, gene, expression, (, 209, ,, 214, ,, 215, ), and, is, therefore, a, candidate, peptide, to, participate, in, go, ##nad, ##ot, ##rop, ##h, -, mediated, increase, in, pr, ##l, mrna, levels, ., an, ##p, has, no, pr, ##l, -, releasing, action, in, mammals, (, 216, ,, 217, ), and, whether, cn, ##p, has, such, an, effect, seems, unknown, for, mammals, ., in, fish, ,, an, ##p, was, reported, to, have, pr, ##l, -, releasing, activity, ,, although, only, after, hours, of, exposure, and, not, acute, ##ly, as, seen, in, our, experiments, (, 217, ), ., le, ##pt, ##in, may, be, involved, as, it, has, been, found, to, strongly, stimulate, pr, ##l, release, (, 218, ), ., np, ##y, is, also, reported, to, be, st, ##im, ##ulator, ##y, for, basal, pr, ##l, release, by, some, investigators, but, others, found, it, to, inhibit, basal, and, tr, ##h, -, stimulated, pr, ##l, release, (, 219, ), ., cart, has, been, reported, to, stimulate, pr, ##l, release, by, some, investigators, but, others, found, it, to, be, inhibitor, ##y, (, 196, ,, 220, ), ., as, to, ang, ##iot, ##ens, ##in, ii, ,, a, debate, has, going, on, for, many, years, on, whether, or, not, there, is, an, independent, ren, ##in, –, ang, ##iot, ##ens, ##in, system, expressed, in, the, pit, ##uit, ##ary, and, in, which, cell, types, the, different, components, are, located, (, 184, ), ., according, to, recent, studies, ,, there, are, two, different, ren, ##in, -, ang, ##iot, ##ens, ##in, systems, (, 221, ), :, one, is, fully, expressed, within, the, go, ##nad, ##ot, ##rop, ##hs, ,, with, both, ren, ##in, and, ang, ##iot, ##ens, ##in, ii, detect, ##able, in, the, regulated, secret, ##ory, pathway, ,, but, ang, ##iot, ##ens, ##ino, ##gen, appears, to, sort, into, the, con, ##sti, ##tu, ##tive, secret, ##ory, pathway, ,, raising, a, pu, ##zzling, question, how, ang, ##iot, ##ens, ##in, ii, can, then, be, formed, within, the, regulated, pathway, ., the, second, system, seems, to, be, extra, ##cellular, with, ang, ##iot, ##ens, ##ino, ##gen, located, in, per, ##isi, ##nus, ##oid, ##al, cells, and, ang, ##iot, ##ens, ##in, produced, by, circulating, ren, ##in, in, the, sin, ##uso, ##id, lu, ##men, after, release, of, ang, ##iot, ##ens, ##ino, ##gen, (, 221, ), ., ang, ##iot, ##ens, ##in, ii, could, then, affect, various, other, cell, types, downstream, in, the, gland, ., several, investigators, have, reported, pr, ##l, -, releasing, activity, in, response, to, g, ##nr, ##h, in, pit, ##uit, ##ary, mono, ##layer, cultures, ,, although, only, upon, using, a, very, high, dose, of, g, ##nr, ##h, (, 222, ), ., in, re, ##ag, ##gre, ##gate, cell, cultures, kept, in, serum, -, free, medium, ,, we, found, that, physiological, doses, of, g, ##nr, ##h, stimulate, pr, ##l, release, and, ,, at, these, doses, ,, neither, an, ang, ##iot, ##ens, ##in, -, converting, enzyme, inhibitor, ,, nor, ang, ##iot, ##ens, ##in, receptor, -, 1, antagonist, ##s, were, capable, of, inhibit, ##ing, the, g, ##nr, ##h, -, stimulated, pr, ##l, release, (, 222, ), ., only, at, 100, nm, g, ##nr, ##h, could, a, partial, inhibition, of, the, pr, ##l, response, by, ang, ##iot, ##ens, ##in, receptor, -, 1, antagonist, ##s, be, detected, (, 222, ), ., thus, ,, ang, ##iot, ##ens, ##in, ii, may, be, involved, in, g, ##nr, ##h, -, stimulation, of, pr, ##l, release, ,, but, it, seems, to, play, only, an, accessory, role, at, high, concentration, of, g, ##nr, ##h, ., possibly, ,, the, more, physiological, ##ly, relevant, effect, of, g, ##nr, ##h, is, not, involving, the, local, ren, ##in, –, ang, ##iot, ##ens, ##in, system, at, all, and, go, ##nad, ##ot, ##rop, ##h, -, mediated, stimulation, of, pr, ##l, release, is, mediated, by, another, molecule, or, by, a, combination, of, substances, .'},\n", + " {'article_id': 'abb03d386e8326ec19c7392d2a382d80',\n", + " 'section_name': 'Respiratory physiology (1965–75) and myasthenia at the National Hospital',\n", + " 'text': \"Tom Sears, JND's MD supervisor, friend and colleague, describes their work together.\\n‘Moran Campbell had carried out experiments testing the ability of human subjects to perceive increased resistive or elastic loading of the airways; and he had drawn on contemporary ideas of the ‘length follow-up servo control of movement’ to propose imaginatively that perception depended on ‘length–tension’ inappropriateness to account for the results. However, the servo theory at the time conceived a muscle spindle-dependent reflex mechanism automatically subserving motor control without conscious intervention. In fact the conscious response to loading of limb muscles at that time was assigned to joint receptors with afferent pathways to the brain in the posterior columns. The neurologist Richard Godwin-Austen had recently finished a study of intercostal joint mechanoreceptors in the cat, examining these receptors as a possible source of chest wall proprioception to account for dyspnoeic sensibility. Around that time I was examining electromyographically the response of the intercostal muscles to altered mechanical loading (Sears, 1964). I therefore suggested to John that he should investigate the perception of load in patients with impaired position sense or other criteria of posterior column dysfunction. On alternate weeks John and I would impale each other with wire EMG electrodes, inserted in the external or internal intercostal muscles (sometimes with uncomfortable consequences, ANA; ), to examine their reflex responses to sudden changes in pressure, which could either assist or oppose the voluntary sustained lung volume, or a steadily decreasing or increasing one; similarly, a solenoid valve was used to increase or decrease the mechanical load (airway resistance). The research was based on insights gained from intracellular recordings of the central respiratory drive and the monosynaptic reflexes of intercostal motoneurons. In this way we were able to provide a comprehensive account of the segmental reflex responses of these muscles, particularly in relation to the topographical distribution of activities across the chest wall, as well as to the lung volume (% vital capacity) at which the perturbation was introduced ( and ). Thus our conceptual framework centred on the muscle spindle and John, who had access to human intercostal muscle biopsies, subsequently used the same experimental rig to examine the muscle spindles in these muscles, and provided the first account of their activation in his in vitro preparation (Tom Sears; ).From this experience John gained invaluable experience in electrophysiological measurements and subsequently became very interested in hiccup (), and described a new method to measure conduction velocity of human phrenic nerve fibres, which hitherto had depended on oesophageal electrodes (). Surface electrodes placed over the insertion of the diaphragm in the lower ribs provided clean EMG signals in response to stimulation of the phrenic nerve in the neck, thus providing objective data where the assessment of paradoxical movement was equivocal.In New York with Fred Plum from 1969–70, he carried out experiments on the anaesthetized cat to determine the trajectory of descending bulbospinal pathways responsible – firstly, for the ‘central respiratory drive’ to respiratory motoneurons in the spinal cord, and secondly, for those responsible for the cough reflex (). Both questions had their origin in work done at Queen Square, namely that of Peter Nathan on the pathways in man, as deduced from the effects of cervical tractotomy for the relief of intractable pain; and our studies on the effects of selective lesioning and stimulation experiments in the medulla studied. The experiments were meticulous and with excellent histological control to allow clear conclusions concerning the innervations of the diaphragm and abdominal muscles. Those responsible for the cough lay in the ventral quadrant of the cervical spinal cord, whereas those carrying the respiratory drive were in a ventrolateral location, just as Nathan had found for man (). These feline studies epitomized John's interest in seeking experimentally to discover mechanistic explanations to illuminate his clinical work.John's links with the emerging Department of Neurophysiology continued while he was Physician-in-Charge of the Batten Unit. He collaborated with the lecturer in Bioengineering in that department, David Stagg, who developed a comprehensive computer-based analysis of airflow and tidal volume in eupnoea to reveal a complex breath-by breath variation in such individual parameters as inspiratory and expiratory durations, cycle time, and their correlation with tidal volume (). Nevertheless, this seemingly random variability was such that mean inspiratory flow rate was held constant, the work providing a fresh insight concerning the homeostatic regulation of breathing. Mike Goldman, an expert on the use of ‘magnetometers’ for measuring body wall displacements, then at the Harvard School of Public Health, was encouraged to come to Queen Square. This led to a further collaboration in which John, David Stagg and Mike Goldman were able to show that magnetometers placed over the ribcage and abdomen to measure changes in their anterior/posterior diameters provided signals that, coupled to a calibration procedure, allowed the assessment of respiratory function without the need for face masks, a valuable method for sick patients’ (Tom Sears; and ).\",\n", + " 'paragraph_id': 15,\n", + " 'tokenizer': \"tom, sears, ,, j, ##nd, ', s, md, supervisor, ,, friend, and, colleague, ,, describes, their, work, together, ., ‘, moran, campbell, had, carried, out, experiments, testing, the, ability, of, human, subjects, to, perceive, increased, resist, ##ive, or, elastic, loading, of, the, airways, ;, and, he, had, drawn, on, contemporary, ideas, of, the, ‘, length, follow, -, up, ser, ##vo, control, of, movement, ’, to, propose, imaginative, ##ly, that, perception, depended, on, ‘, length, –, tension, ’, inappropriate, ##ness, to, account, for, the, results, ., however, ,, the, ser, ##vo, theory, at, the, time, conceived, a, muscle, spin, ##dle, -, dependent, reflex, mechanism, automatically, sub, ##ser, ##ving, motor, control, without, conscious, intervention, ., in, fact, the, conscious, response, to, loading, of, limb, muscles, at, that, time, was, assigned, to, joint, receptors, with, af, ##fer, ##ent, pathways, to, the, brain, in, the, posterior, columns, ., the, ne, ##uro, ##logist, richard, god, ##win, -, austen, had, recently, finished, a, study, of, inter, ##cos, ##tal, joint, me, ##chan, ##ore, ##ce, ##pt, ##ors, in, the, cat, ,, examining, these, receptors, as, a, possible, source, of, chest, wall, prop, ##rio, ##ception, to, account, for, d, ##ys, ##p, ##no, ##ei, ##c, sen, ##sibility, ., around, that, time, i, was, examining, electro, ##my, ##ographic, ##ally, the, response, of, the, inter, ##cos, ##tal, muscles, to, altered, mechanical, loading, (, sears, ,, 1964, ), ., i, therefore, suggested, to, john, that, he, should, investigate, the, perception, of, load, in, patients, with, impaired, position, sense, or, other, criteria, of, posterior, column, dysfunction, ., on, alternate, weeks, john, and, i, would, imp, ##ale, each, other, with, wire, em, ##g, electrode, ##s, ,, inserted, in, the, external, or, internal, inter, ##cos, ##tal, muscles, (, sometimes, with, uncomfortable, consequences, ,, ana, ;, ), ,, to, examine, their, reflex, responses, to, sudden, changes, in, pressure, ,, which, could, either, assist, or, oppose, the, voluntary, sustained, lung, volume, ,, or, a, steadily, decreasing, or, increasing, one, ;, similarly, ,, a, sole, ##no, ##id, valve, was, used, to, increase, or, decrease, the, mechanical, load, (, air, ##way, resistance, ), ., the, research, was, based, on, insights, gained, from, intra, ##cellular, recordings, of, the, central, respiratory, drive, and, the, mono, ##sy, ##na, ##ptic, reflex, ##es, of, inter, ##cos, ##tal, mo, ##tone, ##uron, ##s, ., in, this, way, we, were, able, to, provide, a, comprehensive, account, of, the, segment, ##al, reflex, responses, of, these, muscles, ,, particularly, in, relation, to, the, topographic, ##al, distribution, of, activities, across, the, chest, wall, ,, as, well, as, to, the, lung, volume, (, %, vital, capacity, ), at, which, the, per, ##tur, ##bation, was, introduced, (, and, ), ., thus, our, conceptual, framework, centred, on, the, muscle, spin, ##dle, and, john, ,, who, had, access, to, human, inter, ##cos, ##tal, muscle, bio, ##ps, ##ies, ,, subsequently, used, the, same, experimental, rig, to, examine, the, muscle, spin, ##dles, in, these, muscles, ,, and, provided, the, first, account, of, their, activation, in, his, in, vitro, preparation, (, tom, sears, ;, ), ., from, this, experience, john, gained, in, ##val, ##ua, ##ble, experience, in, electro, ##phy, ##sio, ##logical, measurements, and, subsequently, became, very, interested, in, hi, ##cc, ##up, (, ), ,, and, described, a, new, method, to, measure, conduct, ##ion, velocity, of, human, ph, ##ren, ##ic, nerve, fibre, ##s, ,, which, hit, ##her, ##to, had, depended, on, o, ##es, ##op, ##ha, ##ge, ##al, electrode, ##s, (, ), ., surface, electrode, ##s, placed, over, the, insertion, of, the, dia, ##ph, ##rag, ##m, in, the, lower, ribs, provided, clean, em, ##g, signals, in, response, to, stimulation, of, the, ph, ##ren, ##ic, nerve, in, the, neck, ,, thus, providing, objective, data, where, the, assessment, of, paradox, ##ical, movement, was, e, ##qui, ##vo, ##cal, ., in, new, york, with, fred, plum, from, 1969, –, 70, ,, he, carried, out, experiments, on, the, ana, ##est, ##het, ##ized, cat, to, determine, the, trajectory, of, descending, bulb, ##os, ##pina, ##l, pathways, responsible, –, firstly, ,, for, the, ‘, central, respiratory, drive, ’, to, respiratory, mo, ##tone, ##uron, ##s, in, the, spinal, cord, ,, and, secondly, ,, for, those, responsible, for, the, cough, reflex, (, ), ., both, questions, had, their, origin, in, work, done, at, queen, square, ,, namely, that, of, peter, nathan, on, the, pathways, in, man, ,, as, de, ##duced, from, the, effects, of, cervical, tract, ##oto, ##my, for, the, relief, of, intra, ##ctable, pain, ;, and, our, studies, on, the, effects, of, selective, les, ##ion, ##ing, and, stimulation, experiments, in, the, med, ##ulla, studied, ., the, experiments, were, met, ##ic, ##ulous, and, with, excellent, his, ##to, ##logical, control, to, allow, clear, conclusions, concerning, the, inner, ##vation, ##s, of, the, dia, ##ph, ##rag, ##m, and, abdominal, muscles, ., those, responsible, for, the, cough, lay, in, the, ventral, quadrant, of, the, cervical, spinal, cord, ,, whereas, those, carrying, the, respiratory, drive, were, in, a, vent, ##rol, ##ater, ##al, location, ,, just, as, nathan, had, found, for, man, (, ), ., these, fe, ##line, studies, ep, ##ito, ##mi, ##zed, john, ', s, interest, in, seeking, experimental, ##ly, to, discover, me, ##chan, ##istic, explanations, to, ill, ##umi, ##nate, his, clinical, work, ., john, ', s, links, with, the, emerging, department, of, ne, ##uro, ##phy, ##sio, ##logy, continued, while, he, was, physician, -, in, -, charge, of, the, bat, ##ten, unit, ., he, collaborated, with, the, lecturer, in, bio, ##eng, ##ine, ##ering, in, that, department, ,, david, st, ##ag, ##g, ,, who, developed, a, comprehensive, computer, -, based, analysis, of, air, ##flow, and, tidal, volume, in, eu, ##p, ##no, ##ea, to, reveal, a, complex, breath, -, by, breath, variation, in, such, individual, parameters, as, ins, ##pi, ##rator, ##y, and, ex, ##pi, ##rator, ##y, duration, ##s, ,, cycle, time, ,, and, their, correlation, with, tidal, volume, (, ), ., nevertheless, ,, this, seemingly, random, variability, was, such, that, mean, ins, ##pi, ##rator, ##y, flow, rate, was, held, constant, ,, the, work, providing, a, fresh, insight, concerning, the, home, ##osta, ##tic, regulation, of, breathing, ., mike, goldman, ,, an, expert, on, the, use, of, ‘, magnet, ##ometer, ##s, ’, for, measuring, body, wall, displacement, ##s, ,, then, at, the, harvard, school, of, public, health, ,, was, encouraged, to, come, to, queen, square, ., this, led, to, a, further, collaboration, in, which, john, ,, david, st, ##ag, ##g, and, mike, goldman, were, able, to, show, that, magnet, ##ometer, ##s, placed, over, the, rib, ##ca, ##ge, and, abdomen, to, measure, changes, in, their, anterior, /, posterior, diameter, ##s, provided, signals, that, ,, coupled, to, a, cal, ##ib, ##ration, procedure, ,, allowed, the, assessment, of, respiratory, function, without, the, need, for, face, masks, ,, a, valuable, method, for, sick, patients, ’, (, tom, sears, ;, and, ), .\"},\n", + " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", + " 'section_name': 'Potential clinical applications of optoprosthetics',\n", + " 'text': 'Recent publications underpin the possible role of optogenetics as a potential future therapeutic application. For example, electrical peripheral nerve stimulation has been used as an experimental treatment of patients with paralysis and muscle disease. A major drawback is random or reverse muscle recruitment by heterogeneous tissue excitation, resulting in high fatigability. Thy-1::ChR2YFP transgenic mice express ChR2-YFP in both the central and peripheral nervous system as well as in lower motor and dorsal root ganglion neurons. By an optical approach motor units can be recruited in an orderly manner favoring small, slow muscle fibers in comparison to random recruitment by electrical stimulation. This results in a markedly enhanced functional performance as muscle fatigability is strongly reduced by a more physiological recruitment pattern via optical stimulation. Taking into account recent advances in human gene therapy the authors point out an eventual therapeutic use of optogenetics as neuroprosthetics and suggest NpHR in the treatment of spastic movement disorders (Llewellyn et al. 2010). Another promising example of optical control replacing electrical stimulation is light-induced stimulation of the heart muscle. Bruegmann et al. (2010) transferred the optogenetic principle from neurons to cardiomyocytes. A ChR2-EYFP construct driven by the CAG promoter was electroporated into embryonic stem cells (ESCs). After ESC differentiation into cardiomyocytes ChR2 expression was limited to the cell membrane and pulsed in vitro optical stimulation triggered action potential-induced contractions with intercellular electrical spreading. The authors also generated transgenic CAG-ChR2-EYFP mice that showed robust rhodopsin expression in atrial and ventricular cardiomyoctes. By illuminating an area of only 0.05–0.2 mm with pulses as short as 1 ms, reliable action potentials were generated in a minimally delayed 1:1 manner in vitro and in vivo, allowing fast optical pacing limited only by the natural refractoriness of the cardiac cells. Thus, optogenetics could serve as an analytical tool for the study of pacemaking and arrhythmia in cardiology with a high potential for therapeutic use. There are several putative clinical applications of optogenetics also in neurodegenerative disorders. A recent work from Stroh et al. (2011) focuses on a restorative approach. Mouse ESCs were transduced in vitro via lentiviruses to express ChR2-YFP under the EF1α promoter. After a retinoic acid-based differentiation protocol, targeted cells were viable and electrophysiologically mature, similar to native cells. After FACS sorting ChR2-YFP expressing cells were transplanted into rat motor cortex and reacted toward blue light illumination after integration into the host environment. Depolarization and direct Ca^2+ influx via light-gated membrane proteins such as ChR2 could serve as a new tool for stem cell differentiation into neural and neuronal cells in vitro and in vivo, as various facts indicate an important role of Ca^2+ dependent cellular processes driving differentiation (e.g., D’Ascenzo et al. (2006). As functional integration of the transplant is the major goal of regenerative medicine, optogenetically induced differentiation, compared to unspecific chemically or electrically based protocols, just affects the genetically targeted graft cells within a heterogeneous cellular host environment, reducing undesirable side effects such as cell death or tumor growth (Stroh et al. 2011). In a previous study neurons derived from human ESCs were transduced with ChR2-mCherry and mature neurons were analyzed for synaptic integration and functional connectivity of the targeted graft cells into the host circuitry of immuno-depressed neonatal SCID mice (Weick et al. 2010). In vitro postmitotic neurons, both glutamatergic and GABAergic, showed typical electrophysiological responses upon illumination. When transplanted, ChR2 positive matured neurons not only displayed spontaneous action potentials and postsynaptic currents (PSCs) as a proof of input-specific graft integration, but furthermore, adjacent ChR2-negative cells likewise displayed PSCs upon light stimulation, indicating graft to host microcircuit connectivity also in an output-specific manner. By generating a pluripotent human ESC line, expressing ChR2-mCherry constitutively under the synapsin promoter, the authors could improve several drawbacks of viral based approaches such as low transduction efficiency. Yet further research is necessary to establish optogenetics as a standard examination and manipulation tool of functional graft to host integration and circuit plasticity in the context of stem cell based neuroregenerative strategies. Another example for a clinical application could be vision restoration in human subjects with retinal degeneration. ChR2- and NpHR-based approaches would, due to their simple monocomponent working principle with good immune compatibility, cell type specificity and high spatial resolution, compete with electrical stimulation in their ability of restoring photosensitivity. In blind mice lacking retinal photoreceptors (rd1 or Pde6b^rd1 mouse model, Bowes et al. 1990) photosensitivity was restored by heterologous expression of ChR2, either by transducing inner retinal neurons in a non-selective viral based strategy or by in vivo electroporating exclusively ON bipolar retinal cells using a specific promoter sequence (Bi et al. 2006, Lagali et al. 2008). Positive changes in a behavioral readout indicated improved vision and suggest the use of optogenetics in a translational approach also in humans. A major step toward applications in vivo, especially for therapeutic use in humans, would be the employment of highly light-sensitive rhodopsins with specifically defined response kinetics supporting optical control at a cell type-specific resolution. In general optogenetics would significantly benefit from ChRs with larger conductance and higher selectivity for Ca^2+, Na^+ or K^+ in combination with appropriate color and kinetics.',\n", + " 'paragraph_id': 8,\n", + " 'tokenizer': 'recent, publications, under, ##pin, the, possible, role, of, opt, ##ogen, ##etic, ##s, as, a, potential, future, therapeutic, application, ., for, example, ,, electrical, peripheral, nerve, stimulation, has, been, used, as, an, experimental, treatment, of, patients, with, paralysis, and, muscle, disease, ., a, major, draw, ##back, is, random, or, reverse, muscle, recruitment, by, het, ##ero, ##gen, ##eous, tissue, ex, ##cit, ##ation, ,, resulting, in, high, fat, ##iga, ##bility, ., thy, -, 1, :, :, ch, ##r, ##2, ##y, ##fp, trans, ##genic, mice, express, ch, ##r, ##2, -, y, ##fp, in, both, the, central, and, peripheral, nervous, system, as, well, as, in, lower, motor, and, dorsal, root, gang, ##lion, neurons, ., by, an, optical, approach, motor, units, can, be, recruited, in, an, orderly, manner, favor, ##ing, small, ,, slow, muscle, fibers, in, comparison, to, random, recruitment, by, electrical, stimulation, ., this, results, in, a, markedly, enhanced, functional, performance, as, muscle, fat, ##iga, ##bility, is, strongly, reduced, by, a, more, physiological, recruitment, pattern, via, optical, stimulation, ., taking, into, account, recent, advances, in, human, gene, therapy, the, authors, point, out, an, eventual, therapeutic, use, of, opt, ##ogen, ##etic, ##s, as, ne, ##uro, ##pro, ##st, ##hetic, ##s, and, suggest, np, ##hr, in, the, treatment, of, spa, ##stic, movement, disorders, (, ll, ##ew, ##ell, ##yn, et, al, ., 2010, ), ., another, promising, example, of, optical, control, replacing, electrical, stimulation, is, light, -, induced, stimulation, of, the, heart, muscle, ., br, ##ue, ##gman, ##n, et, al, ., (, 2010, ), transferred, the, opt, ##ogen, ##etic, principle, from, neurons, to, card, ##iom, ##yo, ##cytes, ., a, ch, ##r, ##2, -, e, ##y, ##fp, construct, driven, by, the, ca, ##g, promoter, was, electro, ##por, ##ated, into, embryo, ##nic, stem, cells, (, es, ##cs, ), ., after, es, ##c, differentiation, into, card, ##iom, ##yo, ##cytes, ch, ##r, ##2, expression, was, limited, to, the, cell, membrane, and, pulsed, in, vitro, optical, stimulation, triggered, action, potential, -, induced, contraction, ##s, with, inter, ##cellular, electrical, spreading, ., the, authors, also, generated, trans, ##genic, ca, ##g, -, ch, ##r, ##2, -, e, ##y, ##fp, mice, that, showed, robust, r, ##ho, ##do, ##ps, ##in, expression, in, at, ##rial, and, vent, ##ric, ##ular, card, ##iom, ##yo, ##ct, ##es, ., by, illuminating, an, area, of, only, 0, ., 05, –, 0, ., 2, mm, with, pulses, as, short, as, 1, ms, ,, reliable, action, potential, ##s, were, generated, in, a, minimal, ##ly, delayed, 1, :, 1, manner, in, vitro, and, in, vivo, ,, allowing, fast, optical, pacing, limited, only, by, the, natural, ref, ##rac, ##tori, ##ness, of, the, cardiac, cells, ., thus, ,, opt, ##ogen, ##etic, ##s, could, serve, as, an, analytical, tool, for, the, study, of, pace, ##making, and, ar, ##rh, ##yt, ##hmi, ##a, in, card, ##iology, with, a, high, potential, for, therapeutic, use, ., there, are, several, put, ##ative, clinical, applications, of, opt, ##ogen, ##etic, ##s, also, in, ne, ##uro, ##de, ##gen, ##erative, disorders, ., a, recent, work, from, st, ##ro, ##h, et, al, ., (, 2011, ), focuses, on, a, rest, ##ora, ##tive, approach, ., mouse, es, ##cs, were, trans, ##duced, in, vitro, via, lent, ##iv, ##irus, ##es, to, express, ch, ##r, ##2, -, y, ##fp, under, the, e, ##f, ##1, ##α, promoter, ., after, a, re, ##tino, ##ic, acid, -, based, differentiation, protocol, ,, targeted, cells, were, viable, and, electro, ##phy, ##sio, ##logical, ##ly, mature, ,, similar, to, native, cells, ., after, fa, ##cs, sorting, ch, ##r, ##2, -, y, ##fp, expressing, cells, were, transplant, ##ed, into, rat, motor, cortex, and, reacted, toward, blue, light, illumination, after, integration, into, the, host, environment, ., de, ##pol, ##ari, ##zation, and, direct, ca, ^, 2, +, influx, via, light, -, gate, ##d, membrane, proteins, such, as, ch, ##r, ##2, could, serve, as, a, new, tool, for, stem, cell, differentiation, into, neural, and, ne, ##uron, ##al, cells, in, vitro, and, in, vivo, ,, as, various, facts, indicate, an, important, role, of, ca, ^, 2, +, dependent, cellular, processes, driving, differentiation, (, e, ., g, ., ,, d, ’, as, ##cen, ##zo, et, al, ., (, 2006, ), ., as, functional, integration, of, the, transplant, is, the, major, goal, of, reg, ##ener, ##ative, medicine, ,, opt, ##ogen, ##etic, ##ally, induced, differentiation, ,, compared, to, un, ##sp, ##ec, ##ific, chemical, ##ly, or, electrically, based, protocols, ,, just, affects, the, genetically, targeted, graf, ##t, cells, within, a, het, ##ero, ##gen, ##eous, cellular, host, environment, ,, reducing, und, ##es, ##ira, ##ble, side, effects, such, as, cell, death, or, tumor, growth, (, st, ##ro, ##h, et, al, ., 2011, ), ., in, a, previous, study, neurons, derived, from, human, es, ##cs, were, trans, ##duced, with, ch, ##r, ##2, -, mc, ##her, ##ry, and, mature, neurons, were, analyzed, for, syn, ##ap, ##tic, integration, and, functional, connectivity, of, the, targeted, graf, ##t, cells, into, the, host, circuit, ##ry, of, im, ##mun, ##o, -, depressed, neon, ##atal, sci, ##d, mice, (, wei, ##ck, et, al, ., 2010, ), ., in, vitro, post, ##mit, ##otic, neurons, ,, both, g, ##lu, ##tama, ##ter, ##gic, and, ga, ##ba, ##er, ##gic, ,, showed, typical, electro, ##phy, ##sio, ##logical, responses, upon, illumination, ., when, transplant, ##ed, ,, ch, ##r, ##2, positive, mature, ##d, neurons, not, only, displayed, spontaneous, action, potential, ##s, and, posts, ##yna, ##ptic, currents, (, ps, ##cs, ), as, a, proof, of, input, -, specific, graf, ##t, integration, ,, but, furthermore, ,, adjacent, ch, ##r, ##2, -, negative, cells, likewise, displayed, ps, ##cs, upon, light, stimulation, ,, indicating, graf, ##t, to, host, micro, ##ci, ##rc, ##uit, connectivity, also, in, an, output, -, specific, manner, ., by, generating, a, pl, ##uri, ##pot, ##ent, human, es, ##c, line, ,, expressing, ch, ##r, ##2, -, mc, ##her, ##ry, con, ##sti, ##tu, ##tively, under, the, syn, ##ap, ##sin, promoter, ,, the, authors, could, improve, several, draw, ##backs, of, viral, based, approaches, such, as, low, trans, ##duction, efficiency, ., yet, further, research, is, necessary, to, establish, opt, ##ogen, ##etic, ##s, as, a, standard, examination, and, manipulation, tool, of, functional, graf, ##t, to, host, integration, and, circuit, plastic, ##ity, in, the, context, of, stem, cell, based, ne, ##uro, ##re, ##gen, ##erative, strategies, ., another, example, for, a, clinical, application, could, be, vision, restoration, in, human, subjects, with, re, ##tina, ##l, de, ##gen, ##eration, ., ch, ##r, ##2, -, and, np, ##hr, -, based, approaches, would, ,, due, to, their, simple, mono, ##com, ##pone, ##nt, working, principle, with, good, immune, compatibility, ,, cell, type, specific, ##ity, and, high, spatial, resolution, ,, compete, with, electrical, stimulation, in, their, ability, of, restoring, photos, ##ens, ##iti, ##vity, ., in, blind, mice, lacking, re, ##tina, ##l, photo, ##re, ##ce, ##pt, ##ors, (, rd, ##1, or, pd, ##e, ##6, ##b, ^, rd, ##1, mouse, model, ,, bow, ##es, et, al, ., 1990, ), photos, ##ens, ##iti, ##vity, was, restored, by, het, ##ero, ##log, ##ous, expression, of, ch, ##r, ##2, ,, either, by, trans, ##du, ##cing, inner, re, ##tina, ##l, neurons, in, a, non, -, selective, viral, based, strategy, or, by, in, vivo, electro, ##por, ##ating, exclusively, on, bipolar, re, ##tina, ##l, cells, using, a, specific, promoter, sequence, (, bi, et, al, ., 2006, ,, la, ##gal, ##i, et, al, ., 2008, ), ., positive, changes, in, a, behavioral, read, ##out, indicated, improved, vision, and, suggest, the, use, of, opt, ##ogen, ##etic, ##s, in, a, translation, ##al, approach, also, in, humans, ., a, major, step, toward, applications, in, vivo, ,, especially, for, therapeutic, use, in, humans, ,, would, be, the, employment, of, highly, light, -, sensitive, r, ##ho, ##do, ##ps, ##ins, with, specifically, defined, response, kinetic, ##s, supporting, optical, control, at, a, cell, type, -, specific, resolution, ., in, general, opt, ##ogen, ##etic, ##s, would, significantly, benefit, from, ch, ##rs, with, larger, conduct, ##ance, and, higher, select, ##ivity, for, ca, ^, 2, +, ,, na, ^, +, or, k, ^, +, in, combination, with, appropriate, color, and, kinetic, ##s, .'},\n", + " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", + " 'section_name': 'Introduction',\n", + " 'text': 'In recent years, optical control of genetically targeted biological systems has been a fast moving field of continuous progress. The combination of optics, genetics and bioengineering to either stimulate or inhibit cellular activity via light-sensitive microbial membrane proteins (opsins) gave birth to a new research discipline named “optogenetics” (Nagel et al. 2002, 2003; Boyden et al. 2005; Deisseroth et al. 2006). Optical control by microbial opsins has several advantages in comparison to classical electrical or multicomponent manipulation techniques. By genetic targeting, optogenetic stimulation and even inhibition of heterogeneous brain tissue can be achieved in a cell type-specific manner. In contrast, electrical stimulation unselectively interferes with all present cell types, regardless of their anatomical or genetic entity (for example excitatory versus inhibitory neurons and local neurons versus projections), thereby diluting the contribution of individual elements on brain circuitries on the overall effect. In opsins, sensor and effector are combined in a monocomponent system and no exogenous genetical or chemical substitution is necessary what makes it more suitable for in vivo experiments in contrast to multicomponent systems, which are limited rather to in vitro applications. As light of moderate intensity does not interfere with neuronal function and opsin latency upon illumination is very short, optogenetics uniquely combines cell type-specific control with millisecond time scale temporal resolution in a fully reversible manner. Once channelrhodopsin 2 (ChR2) and halorhodopsin (NpHR) had been recognized as multimodal optical interrogation tools in neuroscience, significant efforts have been made to lift the optogenetic approach to a level of broader applicability (Nagel et al. 2003; Boyden et al. 2005; Deisseroth et al. 2006; Zhang et al. 2007a). Bioengineering of existing opsin genes from different microorganisms generated a variety of chimeric rhodopsin versions with modified properties regarding trafficking, kinetics and light responsivity (Zhao et al. 2008; Airan et al. 2009; Berndt et al. 2008, 2011; Lin et al. 2009; Bamann et al. 2010; Gunaydin et al. 2010; Oh et al. 2010; Han et al. 2011; Kleinlogel et al. 2011; Schultheis et al. 2011; Yizhar et al. 2011a, b). In parallel, opsins from various species were screened for their optogenetic suitability. Channelrhodopsin from different species extended the optical spectrum of cellular excitation and the light-driven proton pumps Arch and ArchT enabled neuronal silencing in addition to halorhodopsin (Zhang et al. 2008; Chow et al. 2010; Govorunova et al. 2011; Han et al. 2011). Starting with proof of principle experiments in frog oocytes, optogenetics has been intensively used in vitro (Nagel et al. 2002; Boyden et al. 2005). With the creation of an optical neural interface, freely moving mammals can be studied in vivo, upgrading the optogenetic toolbox to an instrument for the analysis of such complex biological mechanisms such as animal behavior (for example Aravanis et al. 2007; Adamantidis et al. 2007; Tsai et al. 2009; Carter et al. 2010; Ciocchi et al. 2010; Tye et al. 2011). Beside its role in neuroscience, other research fields recently have started to illuminate ChR2-targeted tissues such as cardiomyocytes and embryonic stem cells, proving the universal capabilities of optogenetics (Bruegmann et al. 2010; Stroh et al. 2011). Continuous progress in optical technologies and opsin engineering will not only further consolidate optogenetics as an excellent experimental tool but will also lay the foundation for potential future therapeutic applications (Bi et al. 2006; Lagali et al. 2008; Llewellyn et al. 2010; Weick et al. 2010; Kleinlogel et al. 2011) (Table 1).Table 1Summary of optogenetic toolsOpsinGeneral descriptionOff-kineticsλ_max (nm)PropertiesReferenceFast activators (wild-type, chimeras, mutants and double mutants)ChR2Naturally occurring light-sensitive cation channel10 ± 1 ms470Standard, wild-typeLow photocurrents, slow recovery, spike failure >20 HzNagel et al. (2003)Boyden et al. (2005)ChR2 (H134R)Single mutated ChR2 variant19 ± 2 ms450Photocurrents ↑Slow kinetics, not suitablefor >20 Hz stimulationNagel et al. (2005)Gradinaru et al. (2007)ChETA (E123T)Single mutated ChR2 variant5 ± 1 ms500Reliable spiking ≤200 HzReduced photocurrents if not combined with H134R or T159CGunaydin et al. (2010)ChR2 (T159C)Single mutated ChR2 variant26 ms470Photocurrents ↑Light sensitivity ↑↑No high frequency spikingBerndt et al. (2011)CatCH (L132C)Single mutated ChR2 variant16 ± 3 ms^a474Photocurrents ↑, light sensitivity ↑↑Reliable spiking ≤ 50 HzCell tolerance to increased intracellular calcium?Kleinlogel et al. (2011)E123T + T159CDouble mutantDouble mutated ChR2 variant8 ms505Photocurrents = wild-typeReliable spiking ≤40 HzLimited spectral separation from inhibitory opsinsBerndt et al. (2011)ChIEFChimeric ChR1/ChR2 variant10 ± 1 ms450Photocurrents ↑Reliable spiking ≤25 HzReduced light sensitivityLin et al. (2009)ChR1/2_5/2ChR1/2_2/5Chimeric ChR1/ChR2 variants475 (505)470 (485)^cMight be used as a pH-sensitive light-gated channelTsunoda and Hegemann (2009)ChRGRChimeric ChR1/ChR2 variant8–10 ms505Photocurrents ↑Slow kineticsWang et al. (2009)Wen et al. (2010)VChR1Naturally occurring light-sensitive cation channel133 ms545Red-shifted spectrum, reduced photocurrentsWeak membrane expressionSlow kineticsZhang et al. (2008)C1V1Chimeric ChR1/VChR2 variant156 ms540Red-shifted spectrumPhotocurrents ↑Improved expressionYizhar et al. (2011a, b)MChR1^bNaturally occurring light-sensitive cation channel27 ms528Red-shifted spectrum, faster than VChR2Reduced photocurrents, not tested in neuronsGovorunova et al. (2011)Slow activators (Bistable, step-function opsins)ChR2 C128SSingle mutated ChR2 variant106 ± 9 sOn 470Off ~560Light sensitivity ↑↑↑↑Long term depolarisationNot suited for repeated stimulationBerndt et al. (2008)Bamann et al. (2010)ChR2 D156ASingle mutated ChR2 variant414 sOn 480Off 593Light sensitivity ↑↑↑↑Long term depolarisationNot suited for repeated stimulationBamann et al. (2010)C128S + D156ADouble mutantDouble mutated ChR2 variant29 minOn 445Off 590Light sensitivity ↑↑↑↑Long term depolarisationNot suited for repeated stimulationYizhar et al. (2011a, b)InhibitorsNpHRNaturally occurring light-sensitive chloride pump41 ms589Standard, wild-typeIntracellular blebbing, poor traffickingIncomplete silencingZhang et al. (2007a)eNpHR 3.0Mutated halorhodopsin4.2 ms590Light sensitivity ↑↑Photocurrents ↑↑↑Membrane trafficking ↑↑↑Gradinaru et al. (2010)ArchArchaerhodopsin-3Naturally occurring light-sensitive proton pump19 ms566Light sensitivity ↑↑Photocurrents ↑↑↑Fast recoverySuboptimal traffickingConstant illumination requiredChow et al. (2010)Arch TArchaerhodopsinNaturally occurring light-sensitive proton pump15 ± 4 ms566Light sensitivity ↑↑↑, photocurrents ↑↑↑, fast recoverySuboptimal traffickingConstant illumination requiredHan et al. (2011)Modulators of intracellular signalling, light-sensitive G protein-coupled receptorsOpto-α_1ARRhodopsin/α1 adrenergic receptor chimera3 s500Alpha_1-adrenergic receptor ⇒ activation of G_q protein signaling ⇒ induction of IP_3Affects behavior of freely moving mice.Airan et al. (2009)Opto-β_2ARRhodopsin/β2 adrenergic receptor chimera500 ms500Beta_2-adrenergic receptor ⇒ activation of G_s protein signaling ⇒ induction of cAMPAiran et al. (2009)Rh-CT_5-HT1ARhodopsin/serotonergic 1A receptor chimera3 s4855-HT_1A receptor ⇒ activation of G_i/o protein signaling ⇒ repression of cAMP. Induction of GIRK channel induced hyperpolarization in neurons of rodents.Oh et al. (2010)b-PACMicrobial photo-activated adenylyl cyclase12 s453Light-induced induction of cAMP in frog oocytes, rodent neuronsEffect on behavior of freely moving D. melanogaster.Stierl et al. (2011)^aOff data for CatCH was measured in X. laevis oocytes, not neurons^bData for MChR1 is from HEK 293 cells and MChR1 has not been evaluated in neurons^cMeasurments were performed at pH 7.5 (and pH 4.0)↑ indicates improvement in comparison to wild-type variant',\n", + " 'paragraph_id': 0,\n", + " 'tokenizer': 'in, recent, years, ,, optical, control, of, genetically, targeted, biological, systems, has, been, a, fast, moving, field, of, continuous, progress, ., the, combination, of, optics, ,, genetics, and, bio, ##eng, ##ine, ##ering, to, either, stimulate, or, inhibit, cellular, activity, via, light, -, sensitive, micro, ##bial, membrane, proteins, (, ops, ##ins, ), gave, birth, to, a, new, research, discipline, named, “, opt, ##ogen, ##etic, ##s, ”, (, na, ##gel, et, al, ., 2002, ,, 2003, ;, boyd, ##en, et, al, ., 2005, ;, dei, ##sser, ##oth, et, al, ., 2006, ), ., optical, control, by, micro, ##bial, ops, ##ins, has, several, advantages, in, comparison, to, classical, electrical, or, multi, ##com, ##pone, ##nt, manipulation, techniques, ., by, genetic, targeting, ,, opt, ##ogen, ##etic, stimulation, and, even, inhibition, of, het, ##ero, ##gen, ##eous, brain, tissue, can, be, achieved, in, a, cell, type, -, specific, manner, ., in, contrast, ,, electrical, stimulation, un, ##sel, ##ect, ##ively, interfere, ##s, with, all, present, cell, types, ,, regardless, of, their, anatomical, or, genetic, entity, (, for, example, ex, ##cit, ##atory, versus, inhibitor, ##y, neurons, and, local, neurons, versus, projections, ), ,, thereby, dil, ##uting, the, contribution, of, individual, elements, on, brain, circuit, ##ries, on, the, overall, effect, ., in, ops, ##ins, ,, sensor, and, effect, ##or, are, combined, in, a, mono, ##com, ##pone, ##nt, system, and, no, ex, ##ogen, ##ous, genetic, ##al, or, chemical, substitution, is, necessary, what, makes, it, more, suitable, for, in, vivo, experiments, in, contrast, to, multi, ##com, ##pone, ##nt, systems, ,, which, are, limited, rather, to, in, vitro, applications, ., as, light, of, moderate, intensity, does, not, interfere, with, ne, ##uron, ##al, function, and, ops, ##in, late, ##ncy, upon, illumination, is, very, short, ,, opt, ##ogen, ##etic, ##s, uniquely, combines, cell, type, -, specific, control, with, mill, ##ise, ##con, ##d, time, scale, temporal, resolution, in, a, fully, rev, ##ers, ##ible, manner, ., once, channel, ##rh, ##od, ##ops, ##in, 2, (, ch, ##r, ##2, ), and, halo, ##rh, ##od, ##ops, ##in, (, np, ##hr, ), had, been, recognized, as, multi, ##mo, ##dal, optical, interrogation, tools, in, neuroscience, ,, significant, efforts, have, been, made, to, lift, the, opt, ##ogen, ##etic, approach, to, a, level, of, broader, app, ##lica, ##bility, (, na, ##gel, et, al, ., 2003, ;, boyd, ##en, et, al, ., 2005, ;, dei, ##sser, ##oth, et, al, ., 2006, ;, zhang, et, al, ., 2007, ##a, ), ., bio, ##eng, ##ine, ##ering, of, existing, ops, ##in, genes, from, different, micro, ##org, ##ani, ##sms, generated, a, variety, of, chi, ##meric, r, ##ho, ##do, ##ps, ##in, versions, with, modified, properties, regarding, trafficking, ,, kinetic, ##s, and, light, res, ##pon, ##si, ##vity, (, zhao, et, al, ., 2008, ;, air, ##an, et, al, ., 2009, ;, bern, ##dt, et, al, ., 2008, ,, 2011, ;, lin, et, al, ., 2009, ;, bam, ##ann, et, al, ., 2010, ;, gun, ##ay, ##din, et, al, ., 2010, ;, oh, et, al, ., 2010, ;, han, et, al, ., 2011, ;, klein, ##log, ##el, et, al, ., 2011, ;, sc, ##hul, ##the, ##is, et, al, ., 2011, ;, yi, ##zh, ##ar, et, al, ., 2011, ##a, ,, b, ), ., in, parallel, ,, ops, ##ins, from, various, species, were, screened, for, their, opt, ##ogen, ##etic, suit, ##ability, ., channel, ##rh, ##od, ##ops, ##in, from, different, species, extended, the, optical, spectrum, of, cellular, ex, ##cit, ##ation, and, the, light, -, driven, proton, pumps, arch, and, arch, ##t, enabled, ne, ##uron, ##al, si, ##len, ##cing, in, addition, to, halo, ##rh, ##od, ##ops, ##in, (, zhang, et, al, ., 2008, ;, chow, et, al, ., 2010, ;, gov, ##or, ##uno, ##va, et, al, ., 2011, ;, han, et, al, ., 2011, ), ., starting, with, proof, of, principle, experiments, in, frog, o, ##ocytes, ,, opt, ##ogen, ##etic, ##s, has, been, intensive, ##ly, used, in, vitro, (, na, ##gel, et, al, ., 2002, ;, boyd, ##en, et, al, ., 2005, ), ., with, the, creation, of, an, optical, neural, interface, ,, freely, moving, mammals, can, be, studied, in, vivo, ,, upgrading, the, opt, ##ogen, ##etic, tool, ##box, to, an, instrument, for, the, analysis, of, such, complex, biological, mechanisms, such, as, animal, behavior, (, for, example, ara, ##vani, ##s, et, al, ., 2007, ;, adamant, ##idi, ##s, et, al, ., 2007, ;, ts, ##ai, et, al, ., 2009, ;, carter, et, al, ., 2010, ;, ci, ##oc, ##chi, et, al, ., 2010, ;, ty, ##e, et, al, ., 2011, ), ., beside, its, role, in, neuroscience, ,, other, research, fields, recently, have, started, to, ill, ##umi, ##nate, ch, ##r, ##2, -, targeted, tissues, such, as, card, ##iom, ##yo, ##cytes, and, embryo, ##nic, stem, cells, ,, proving, the, universal, capabilities, of, opt, ##ogen, ##etic, ##s, (, br, ##ue, ##gman, ##n, et, al, ., 2010, ;, st, ##ro, ##h, et, al, ., 2011, ), ., continuous, progress, in, optical, technologies, and, ops, ##in, engineering, will, not, only, further, consolidate, opt, ##ogen, ##etic, ##s, as, an, excellent, experimental, tool, but, will, also, lay, the, foundation, for, potential, future, therapeutic, applications, (, bi, et, al, ., 2006, ;, la, ##gal, ##i, et, al, ., 2008, ;, ll, ##ew, ##ell, ##yn, et, al, ., 2010, ;, wei, ##ck, et, al, ., 2010, ;, klein, ##log, ##el, et, al, ., 2011, ), (, table, 1, ), ., table, 1, ##sum, ##mar, ##y, of, opt, ##ogen, ##etic, tools, ##ops, ##ingen, ##eral, description, ##off, -, kinetic, ##s, ##λ, _, max, (, nm, ), properties, ##re, ##ference, ##fast, act, ##iva, ##tors, (, wild, -, type, ,, chi, ##mer, ##as, ,, mutants, and, double, mutants, ), ch, ##r, ##2, ##nat, ##ural, ##ly, occurring, light, -, sensitive, cat, ##ion, channel, ##10, ±, 1, ms, ##47, ##0s, ##tan, ##dar, ##d, ,, wild, -, type, ##low, photo, ##cu, ##rre, ##nts, ,, slow, recovery, ,, spike, failure, >, 20, hz, ##nage, ##l, et, al, ., (, 2003, ), boyd, ##en, et, al, ., (, 2005, ), ch, ##r, ##2, (, h, ##13, ##4, ##r, ), single, mu, ##tated, ch, ##r, ##2, variant, ##19, ±, 2, ms, ##45, ##0, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##slow, kinetic, ##s, ,, not, suitable, ##for, >, 20, hz, stimulation, ##nage, ##l, et, al, ., (, 2005, ), gr, ##adi, ##nar, ##u, et, al, ., (, 2007, ), chet, ##a, (, e, ##12, ##3, ##t, ), single, mu, ##tated, ch, ##r, ##2, variant, ##5, ±, 1, ms, ##500, ##rel, ##iable, sp, ##iki, ##ng, ≤, ##200, hz, ##red, ##uce, ##d, photo, ##cu, ##rre, ##nts, if, not, combined, with, h, ##13, ##4, ##r, or, t, ##15, ##9, ##c, ##gun, ##ay, ##din, et, al, ., (, 2010, ), ch, ##r, ##2, (, t, ##15, ##9, ##c, ), single, mu, ##tated, ch, ##r, ##2, variant, ##26, ms, ##47, ##0, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##light, sensitivity, ↑, ##↑, ##no, high, frequency, sp, ##iki, ##ng, ##ber, ##ndt, et, al, ., (, 2011, ), catch, (, l, ##13, ##2, ##c, ), single, mu, ##tated, ch, ##r, ##2, variant, ##16, ±, 3, ms, ^, a, ##47, ##4, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ,, light, sensitivity, ↑, ##↑, ##rel, ##iable, sp, ##iki, ##ng, ≤, 50, hz, ##cel, ##l, tolerance, to, increased, intra, ##cellular, calcium, ?, klein, ##log, ##el, et, al, ., (, 2011, ), e, ##12, ##3, ##t, +, t, ##15, ##9, ##cd, ##ou, ##ble, mutant, ##dou, ##ble, mu, ##tated, ch, ##r, ##2, variant, ##8, ms, ##50, ##5, ##ph, ##oto, ##cu, ##rre, ##nts, =, wild, -, type, ##rel, ##iable, sp, ##iki, ##ng, ≤, ##40, hz, ##lim, ##ited, spectral, separation, from, inhibitor, ##y, ops, ##ins, ##ber, ##ndt, et, al, ., (, 2011, ), chief, ##chi, ##meric, ch, ##r, ##1, /, ch, ##r, ##2, variant, ##10, ±, 1, ms, ##45, ##0, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##rel, ##iable, sp, ##iki, ##ng, ≤, ##25, hz, ##red, ##uce, ##d, light, sensitivity, ##lin, et, al, ., (, 2009, ), ch, ##r, ##1, /, 2, _, 5, /, 2, ##ch, ##r, ##1, /, 2, _, 2, /, 5, ##chi, ##meric, ch, ##r, ##1, /, ch, ##r, ##2, variants, ##47, ##5, (, 505, ), 470, (, 48, ##5, ), ^, cm, ##ight, be, used, as, a, ph, -, sensitive, light, -, gate, ##d, channel, ##tsu, ##no, ##da, and, he, ##ge, ##mann, (, 2009, ), ch, ##rg, ##rch, ##ime, ##ric, ch, ##r, ##1, /, ch, ##r, ##2, variant, ##8, –, 10, ms, ##50, ##5, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##slow, kinetic, ##sw, ##ang, et, al, ., (, 2009, ), wen, et, al, ., (, 2010, ), vc, ##hr, ##1, ##nat, ##ural, ##ly, occurring, light, -, sensitive, cat, ##ion, channel, ##13, ##3, ms, ##54, ##5, ##red, -, shifted, spectrum, ,, reduced, photo, ##cu, ##rre, ##nts, ##we, ##ak, membrane, expressions, ##low, kinetic, ##sz, ##hang, et, al, ., (, 2008, ), c1, ##v, ##1, ##chi, ##meric, ch, ##r, ##1, /, vc, ##hr, ##2, variant, ##15, ##6, ms, ##54, ##0, ##red, -, shifted, spectrum, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##im, ##pro, ##ved, expression, ##yi, ##zh, ##ar, et, al, ., (, 2011, ##a, ,, b, ), mc, ##hr, ##1, ^, bn, ##at, ##ural, ##ly, occurring, light, -, sensitive, cat, ##ion, channel, ##27, ms, ##52, ##8, ##red, -, shifted, spectrum, ,, faster, than, vc, ##hr, ##2, ##red, ##uce, ##d, photo, ##cu, ##rre, ##nts, ,, not, tested, in, neurons, ##go, ##vor, ##uno, ##va, et, al, ., (, 2011, ), slow, act, ##iva, ##tors, (, bis, ##table, ,, step, -, function, ops, ##ins, ), ch, ##r, ##2, c1, ##28, ##ssing, ##le, mu, ##tated, ch, ##r, ##2, variant, ##10, ##6, ±, 9, son, 470, ##off, ~, 560, ##light, sensitivity, ↑, ##↑, ##↑, ##↑, ##long, term, de, ##pol, ##aris, ##ation, ##not, suited, for, repeated, stimulation, ##ber, ##ndt, et, al, ., (, 2008, ), bam, ##ann, et, al, ., (, 2010, ), ch, ##r, ##2, d, ##15, ##6, ##asi, ##ng, ##le, mu, ##tated, ch, ##r, ##2, variant, ##41, ##4, son, 480, ##off, 59, ##3, ##light, sensitivity, ↑, ##↑, ##↑, ##↑, ##long, term, de, ##pol, ##aris, ##ation, ##not, suited, for, repeated, stimulation, ##ba, ##mann, et, al, ., (, 2010, ), c1, ##28, ##s, +, d, ##15, ##6, ##ado, ##ub, ##le, mutant, ##dou, ##ble, mu, ##tated, ch, ##r, ##2, variant, ##29, min, ##on, 44, ##5, ##off, 590, ##light, sensitivity, ↑, ##↑, ##↑, ##↑, ##long, term, de, ##pol, ##aris, ##ation, ##not, suited, for, repeated, stimulation, ##yi, ##zh, ##ar, et, al, ., (, 2011, ##a, ,, b, ), inhibitors, ##np, ##hr, ##nat, ##ural, ##ly, occurring, light, -, sensitive, chloride, pump, ##41, ms, ##58, ##9, ##stand, ##ard, ,, wild, -, type, ##int, ##race, ##ll, ##ular, b, ##le, ##bbing, ,, poor, trafficking, ##in, ##com, ##ple, ##te, si, ##len, ##cing, ##zh, ##ang, et, al, ., (, 2007, ##a, ), en, ##ph, ##r, 3, ., 0, ##mut, ##ated, halo, ##rh, ##od, ##ops, ##in, ##4, ., 2, ms, ##59, ##0, ##light, sensitivity, ↑, ##↑, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##↑, ##↑, ##me, ##mb, ##rane, trafficking, ↑, ##↑, ##↑, ##grad, ##ina, ##ru, et, al, ., (, 2010, ), arch, ##ar, ##cha, ##er, ##ho, ##do, ##ps, ##in, -, 3, ##nat, ##ural, ##ly, occurring, light, -, sensitive, proton, pump, ##19, ms, ##56, ##6, ##light, sensitivity, ↑, ##↑, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##↑, ##↑, ##fast, recovery, ##su, ##bo, ##pt, ##ima, ##l, trafficking, ##con, ##stan, ##t, illumination, required, ##cho, ##w, et, al, ., (, 2010, ), arch, tar, ##cha, ##er, ##ho, ##do, ##ps, ##inn, ##at, ##ural, ##ly, occurring, light, -, sensitive, proton, pump, ##15, ±, 4, ms, ##56, ##6, ##light, sensitivity, ↑, ##↑, ##↑, ,, photo, ##cu, ##rre, ##nts, ↑, ##↑, ##↑, ,, fast, recovery, ##su, ##bo, ##pt, ##ima, ##l, trafficking, ##con, ##stan, ##t, illumination, required, ##han, et, al, ., (, 2011, ), mod, ##ulator, ##s, of, intra, ##cellular, signalling, ,, light, -, sensitive, g, protein, -, coupled, receptors, ##op, ##to, -, α, _, 1a, ##rr, ##ho, ##do, ##ps, ##in, /, α, ##1, ad, ##ren, ##er, ##gic, receptor, chi, ##mer, ##a, ##3, s, ##500, ##al, ##pha, _, 1, -, ad, ##ren, ##er, ##gic, receptor, ⇒, activation, of, g, _, q, protein, signaling, ⇒, induction, of, ip, _, 3a, ##ffe, ##cts, behavior, of, freely, moving, mice, ., air, ##an, et, al, ., (, 2009, ), opt, ##o, -, β, _, 2a, ##rr, ##ho, ##do, ##ps, ##in, /, β, ##2, ad, ##ren, ##er, ##gic, receptor, chi, ##mer, ##a, ##500, ms, ##500, ##bet, ##a, _, 2, -, ad, ##ren, ##er, ##gic, receptor, ⇒, activation, of, g, _, s, protein, signaling, ⇒, induction, of, camp, ##air, ##an, et, al, ., (, 2009, ), r, ##h, -, ct, _, 5, -, h, ##t, ##1, ##ar, ##ho, ##do, ##ps, ##in, /, ser, ##oton, ##er, ##gic, 1a, receptor, chi, ##mer, ##a, ##3, s, ##48, ##55, -, h, ##t, _, 1a, receptor, ⇒, activation, of, g, _, i, /, o, protein, signaling, ⇒, repression, of, camp, ., induction, of, gi, ##rk, channel, induced, hyper, ##pol, ##ari, ##zation, in, neurons, of, rodents, ., oh, et, al, ., (, 2010, ), b, -, pac, ##mic, ##ro, ##bial, photo, -, activated, aden, ##yl, ##yl, cy, ##cl, ##ase, ##12, s, ##45, ##3, ##light, -, induced, induction, of, camp, in, frog, o, ##ocytes, ,, rode, ##nt, neurons, ##ef, ##fect, on, behavior, of, freely, moving, d, ., mel, ##ano, ##gas, ##ter, ., st, ##ier, ##l, et, al, ., (, 2011, ), ^, ao, ##ff, data, for, catch, was, measured, in, x, ., la, ##ev, ##is, o, ##ocytes, ,, not, neurons, ^, b, ##da, ##ta, for, mc, ##hr, ##1, is, from, he, ##k, 293, cells, and, mc, ##hr, ##1, has, not, been, evaluated, in, neurons, ^, cm, ##ea, ##sur, ##ments, were, performed, at, ph, 7, ., 5, (, and, ph, 4, ., 0, ), ↑, indicates, improvement, in, comparison, to, wild, -, type, variant'},\n", + " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", + " 'section_name': 'Exploiting light-sensitive microbial membrane proteins',\n", + " 'text': 'With the identification of the gene for a light-responsive membrane protein in microorganisms called bacteriorhodopsin (BR), Stoeckenius and Oesterhelt (1971) set the foundation for a technology, which is today described by the term “optogenetics” (Oesterhelt and Stoeckenius 1973; Deisseroth et al. 2006). Three decades had passed until scientists were able to take advantage of the potential based on the working principle of this seven-transmembrane domain-containing light-transducing proton pump, which in nature serves microbes, among other things, as a regulator of homeostasis and phototrophy (Beja et al. 2000). Encoded by a single open reading frame, it works as an optical controller of transmembrane ion flow combining fast action and coupling of sensor and effector in a monocomponent system (Oesterhelt and Stoeckenius 1971). Later rhodopsin-mediated responses were also studied in the alga Chlamydomonas (Harz and Hegemann 1991) and since the photocurrets were ultra fast the authors claimed that rhodopsin and channel were intimately linked (Holland et al. 1996). Then Nagel and colleagues proved this concept by showing that the Rhodopsins are directly light-gated ion channels. They used amphibian and mammalian cells as hosts to express channelrhodopsin-1 (ChR1), a light-gated proton channel from the green algae Chlamydomonas reinhardtii. In a modified patch clamp set-up they substantiated that rhodopsins react functionally upon laser illumination also in mammalian cells (Nagel et al. 2002). What was initially used as an experimental model system to study channelrhodopsin function turned into the precursor of a novel scientific tool. With the functional characterization of ChR2, a directly light-gated cation-selective membrane channel, Nagel et al. (2003) showed that mammalian cells expressing ChR2 could be depolarized “simply by illumination”. The full conversion of this approach into an optical control device of cell activity happened in 2005 when it found its way into neuroscience. The Deisseroth lab applied lentiviral gene delivery to express ChR2 in rat hippocampal neurons. In combination with high-speed optical switching, neuronal spiking was elicited by photostimulation in a millisecond timescale (Boyden et al. 2005). In parallel, the labs of Yawo, Herlitze and Gottschalk independently demonstrated the feasibility of ChR2-based optical neuronal manipulation (Li et al. 2005; Nagel et al. 2005; Ishizuka et al. 2006). The interplay of optics, genetics, and bioengineering in this novel approach was the inspiration to coin the term “optogenetics”, which can be defined as optical control of cells achieved by the genetic introduction of light-sensitive proteins (Deisseroth et al. 2006). Another milestone in the evolution of optical control was the discovery of an inhibitory opponent of ChR2. Although relative reduction of neuronal activity had previously been shown for the Gi/o protein-coupled vertebrate rat opsin (Ro4, a type II opsin) by activating G protein-gated rectifying potassium channels and voltage-gated calcium channels (Li et al. 2005), complete and fast silencing was achieved by using a microbial (type I opsin) chloride pump. Halorhodopsin (HR) had been discovered decades before its conversion into a research tool (Matsuno-Yagi and Mukohata 1977). Expression of Natromonas pharaonis HR (NpHR) in neuronal tissue enables optically induced cellular hyperpolarization by pumping chloride into the cell. Consecutive inhibition of spontaneous neuronal firing can be achieved in a millisecond time scale (Zhang et al. 2007a, b; Han and Boyden 2007). A major advantage compared to Ro4 is the manipulation via Cl^−, an ion that is not involved in intracellular signaling such as calcium and the use of all-trans retinal instead of 11-cis which is functioning as a chromophore in Ro4. Due to spectrally separated activation maxima of ChR2 and NpHR bidirectional optical modulation is possible, offering excitation and silencing of the same target cell. Even more efficient optical silencers, the proton pumps Arch and ArchT, with similar activation spectra were found in archaebacteria after screening various species (prokaryotes, algae and fungi) for microbial type I opsins (Chow et al. 2010; Han et al. 2011). In an attempt to establish a simultaneous multi-excitatory optical control system by using spectrally separated opsins, red-shifted ChR1 from Volvox carteri (VChR1) was identified. VChR1 works like ChR2 as a cation channel and extended the optical spectrum of cellular excitation toward green light (Zhang et al. 2008). Yet VChR1 applicability in mammalian cells was strongly limited by small photocurrents due to insufficient membrane expression; a limitation that has been circumvented by the generation of a chimeric channelrhodopsin (C1V1) composed of channelrhodopsin-1 parts from Chlamydomonas reinhardtii and Volvox carteri (Yizhar et al. 2011b). In a very recent publication a new channelrhodopsin from Mesostigma viride (MChR1) with a similarly red-shifted action spectrum has been identified and mutated (Govorunova et al. 2011). Heterologous expression of native MChR1 in HEK293 cells indicated peak currents comparable to VChR1 with faster current kinetics making MChR1 a potential candidate for red-shifted optogenetic control, although toxicity and expression levels in neuronal tissue remain to be analyzed. Channelrhodopsins show structural homology to other type I opsins, however, in their working principle they fundamentally differ from NpHR and BRs like Arch and ArchT (Fig. 1). ChRs are non-selective cation channels that open when illuminated by green light with passive influx of predominantly Na^+ and, to a lesser extent, Ca^2+ ions along a membrane gradient resulting in the depolarization of cells expressing these molecules (Nagel et al. 2003). In contrast, HR and BR are ion pumps that work against an electrochemical gradient across the membrane (Racker and Stoeckenius 1974, Schobert and Lanyi 1982). With an excitation maximum at 589 nm NpHR pumps chloride into the cell when activated by yellow light causing a hyperpolarization with consecutive silencing of the target cell. Arch and ArchT also hyperpolarize cells, but by pumping H^+ outwards and in a more rapidly recovering manner. Excitation maxima are at approximately 566 nm for Arch and ArchT (Chow et al. 2010; Han et al. 2011).Fig. 1The optogenetic principle: changing the membrane voltage potential of excitable cells. a Activating tools—channelrhodopsins: channelrhodopsin-2 from Chlamydomoas reinhardtii (ChR2) and channelrhodopsin-1 Volvox carteri (VChR1) from nonselective cation channels leading to depolarization of target cells. Silencing tools—ion pumps: archaerhodopsin-3 (Arch) from Halorubrum sodomense works as a proton pump and leads to hyperpolarization of the target cell such as the chloride pump NpHR (NpHR) from Natronomonas pharaonis. b Spectral working properties of light-sensitive membrane proteins',\n", + " 'paragraph_id': 1,\n", + " 'tokenizer': 'with, the, identification, of, the, gene, for, a, light, -, responsive, membrane, protein, in, micro, ##org, ##ani, ##sms, called, ba, ##cter, ##ior, ##ho, ##do, ##ps, ##in, (, br, ), ,, st, ##oe, ##cken, ##ius, and, o, ##ester, ##hel, ##t, (, 1971, ), set, the, foundation, for, a, technology, ,, which, is, today, described, by, the, term, “, opt, ##ogen, ##etic, ##s, ”, (, o, ##ester, ##hel, ##t, and, st, ##oe, ##cken, ##ius, 1973, ;, dei, ##sser, ##oth, et, al, ., 2006, ), ., three, decades, had, passed, until, scientists, were, able, to, take, advantage, of, the, potential, based, on, the, working, principle, of, this, seven, -, trans, ##me, ##mb, ##rane, domain, -, containing, light, -, trans, ##du, ##cing, proton, pump, ,, which, in, nature, serves, micro, ##bes, ,, among, other, things, ,, as, a, regulator, of, home, ##osta, ##sis, and, photo, ##tro, ##phy, (, be, ##ja, et, al, ., 2000, ), ., encoded, by, a, single, open, reading, frame, ,, it, works, as, an, optical, controller, of, trans, ##me, ##mb, ##rane, ion, flow, combining, fast, action, and, coupling, of, sensor, and, effect, ##or, in, a, mono, ##com, ##pone, ##nt, system, (, o, ##ester, ##hel, ##t, and, st, ##oe, ##cken, ##ius, 1971, ), ., later, r, ##ho, ##do, ##ps, ##in, -, mediated, responses, were, also, studied, in, the, al, ##ga, ch, ##lam, ##yd, ##omo, ##nas, (, ha, ##rz, and, he, ##ge, ##mann, 1991, ), and, since, the, photo, ##cu, ##rret, ##s, were, ultra, fast, the, authors, claimed, that, r, ##ho, ##do, ##ps, ##in, and, channel, were, intimately, linked, (, holland, et, al, ., 1996, ), ., then, na, ##gel, and, colleagues, proved, this, concept, by, showing, that, the, r, ##ho, ##do, ##ps, ##ins, are, directly, light, -, gate, ##d, ion, channels, ., they, used, amp, ##hi, ##bian, and, mammalian, cells, as, hosts, to, express, channel, ##rh, ##od, ##ops, ##in, -, 1, (, ch, ##r, ##1, ), ,, a, light, -, gate, ##d, proton, channel, from, the, green, algae, ch, ##lam, ##yd, ##omo, ##nas, rein, ##hardt, ##ii, ., in, a, modified, patch, cl, ##amp, set, -, up, they, sub, ##stan, ##tia, ##ted, that, r, ##ho, ##do, ##ps, ##ins, react, functional, ##ly, upon, laser, illumination, also, in, mammalian, cells, (, na, ##gel, et, al, ., 2002, ), ., what, was, initially, used, as, an, experimental, model, system, to, study, channel, ##rh, ##od, ##ops, ##in, function, turned, into, the, precursor, of, a, novel, scientific, tool, ., with, the, functional, characterization, of, ch, ##r, ##2, ,, a, directly, light, -, gate, ##d, cat, ##ion, -, selective, membrane, channel, ,, na, ##gel, et, al, ., (, 2003, ), showed, that, mammalian, cells, expressing, ch, ##r, ##2, could, be, de, ##pol, ##ari, ##zed, “, simply, by, illumination, ”, ., the, full, conversion, of, this, approach, into, an, optical, control, device, of, cell, activity, happened, in, 2005, when, it, found, its, way, into, neuroscience, ., the, dei, ##sser, ##oth, lab, applied, lent, ##iv, ##ira, ##l, gene, delivery, to, express, ch, ##r, ##2, in, rat, hip, ##po, ##camp, ##al, neurons, ., in, combination, with, high, -, speed, optical, switching, ,, ne, ##uron, ##al, sp, ##iki, ##ng, was, eli, ##cite, ##d, by, photos, ##ti, ##mu, ##lation, in, a, mill, ##ise, ##con, ##d, times, ##cal, ##e, (, boyd, ##en, et, al, ., 2005, ), ., in, parallel, ,, the, labs, of, ya, ##wo, ,, her, ##litz, ##e, and, got, ##ts, ##chal, ##k, independently, demonstrated, the, feasibility, of, ch, ##r, ##2, -, based, optical, ne, ##uron, ##al, manipulation, (, li, et, al, ., 2005, ;, na, ##gel, et, al, ., 2005, ;, is, ##hi, ##zuka, et, al, ., 2006, ), ., the, inter, ##play, of, optics, ,, genetics, ,, and, bio, ##eng, ##ine, ##ering, in, this, novel, approach, was, the, inspiration, to, coin, the, term, “, opt, ##ogen, ##etic, ##s, ”, ,, which, can, be, defined, as, optical, control, of, cells, achieved, by, the, genetic, introduction, of, light, -, sensitive, proteins, (, dei, ##sser, ##oth, et, al, ., 2006, ), ., another, milestone, in, the, evolution, of, optical, control, was, the, discovery, of, an, inhibitor, ##y, opponent, of, ch, ##r, ##2, ., although, relative, reduction, of, ne, ##uron, ##al, activity, had, previously, been, shown, for, the, gi, /, o, protein, -, coupled, ve, ##rte, ##brate, rat, ops, ##in, (, ro, ##4, ,, a, type, ii, ops, ##in, ), by, act, ##ivating, g, protein, -, gate, ##d, rec, ##tify, ##ing, potassium, channels, and, voltage, -, gate, ##d, calcium, channels, (, li, et, al, ., 2005, ), ,, complete, and, fast, si, ##len, ##cing, was, achieved, by, using, a, micro, ##bial, (, type, i, ops, ##in, ), chloride, pump, ., halo, ##rh, ##od, ##ops, ##in, (, hr, ), had, been, discovered, decades, before, its, conversion, into, a, research, tool, (, mats, ##uno, -, ya, ##gi, and, mu, ##ko, ##hat, ##a, 1977, ), ., expression, of, nat, ##rom, ##ona, ##s, ph, ##ara, ##onis, hr, (, np, ##hr, ), in, ne, ##uron, ##al, tissue, enables, optical, ##ly, induced, cellular, hyper, ##pol, ##ari, ##zation, by, pumping, chloride, into, the, cell, ., consecutive, inhibition, of, spontaneous, ne, ##uron, ##al, firing, can, be, achieved, in, a, mill, ##ise, ##con, ##d, time, scale, (, zhang, et, al, ., 2007, ##a, ,, b, ;, han, and, boyd, ##en, 2007, ), ., a, major, advantage, compared, to, ro, ##4, is, the, manipulation, via, cl, ^, −, ,, an, ion, that, is, not, involved, in, intra, ##cellular, signaling, such, as, calcium, and, the, use, of, all, -, trans, re, ##tina, ##l, instead, of, 11, -, cis, which, is, functioning, as, a, ch, ##rom, ##op, ##hore, in, ro, ##4, ., due, to, spectral, ##ly, separated, activation, maxim, ##a, of, ch, ##r, ##2, and, np, ##hr, bid, ##ire, ##ction, ##al, optical, modulation, is, possible, ,, offering, ex, ##cit, ##ation, and, si, ##len, ##cing, of, the, same, target, cell, ., even, more, efficient, optical, silence, ##rs, ,, the, proton, pumps, arch, and, arch, ##t, ,, with, similar, activation, spectra, were, found, in, arch, ##ae, ##ba, ##cter, ##ia, after, screening, various, species, (, pro, ##kar, ##yo, ##tes, ,, algae, and, fungi, ), for, micro, ##bial, type, i, ops, ##ins, (, chow, et, al, ., 2010, ;, han, et, al, ., 2011, ), ., in, an, attempt, to, establish, a, simultaneous, multi, -, ex, ##cit, ##atory, optical, control, system, by, using, spectral, ##ly, separated, ops, ##ins, ,, red, -, shifted, ch, ##r, ##1, from, volvo, ##x, carter, ##i, (, vc, ##hr, ##1, ), was, identified, ., vc, ##hr, ##1, works, like, ch, ##r, ##2, as, a, cat, ##ion, channel, and, extended, the, optical, spectrum, of, cellular, ex, ##cit, ##ation, toward, green, light, (, zhang, et, al, ., 2008, ), ., yet, vc, ##hr, ##1, app, ##lica, ##bility, in, mammalian, cells, was, strongly, limited, by, small, photo, ##cu, ##rre, ##nts, due, to, insufficient, membrane, expression, ;, a, limitation, that, has, been, ci, ##rc, ##um, ##vent, ##ed, by, the, generation, of, a, chi, ##meric, channel, ##rh, ##od, ##ops, ##in, (, c1, ##v, ##1, ), composed, of, channel, ##rh, ##od, ##ops, ##in, -, 1, parts, from, ch, ##lam, ##yd, ##omo, ##nas, rein, ##hardt, ##ii, and, volvo, ##x, carter, ##i, (, yi, ##zh, ##ar, et, al, ., 2011, ##b, ), ., in, a, very, recent, publication, a, new, channel, ##rh, ##od, ##ops, ##in, from, me, ##sos, ##ti, ##gm, ##a, vi, ##ride, (, mc, ##hr, ##1, ), with, a, similarly, red, -, shifted, action, spectrum, has, been, identified, and, mu, ##tated, (, gov, ##or, ##uno, ##va, et, al, ., 2011, ), ., het, ##ero, ##log, ##ous, expression, of, native, mc, ##hr, ##1, in, he, ##k, ##29, ##3, cells, indicated, peak, currents, comparable, to, vc, ##hr, ##1, with, faster, current, kinetic, ##s, making, mc, ##hr, ##1, a, potential, candidate, for, red, -, shifted, opt, ##ogen, ##etic, control, ,, although, toxicity, and, expression, levels, in, ne, ##uron, ##al, tissue, remain, to, be, analyzed, ., channel, ##rh, ##od, ##ops, ##ins, show, structural, homo, ##logy, to, other, type, i, ops, ##ins, ,, however, ,, in, their, working, principle, they, fundamentally, differ, from, np, ##hr, and, br, ##s, like, arch, and, arch, ##t, (, fig, ., 1, ), ., ch, ##rs, are, non, -, selective, cat, ##ion, channels, that, open, when, illuminated, by, green, light, with, passive, influx, of, predominantly, na, ^, +, and, ,, to, a, lesser, extent, ,, ca, ^, 2, +, ions, along, a, membrane, gradient, resulting, in, the, de, ##pol, ##ari, ##zation, of, cells, expressing, these, molecules, (, na, ##gel, et, al, ., 2003, ), ., in, contrast, ,, hr, and, br, are, ion, pumps, that, work, against, an, electro, ##chemical, gradient, across, the, membrane, (, rack, ##er, and, st, ##oe, ##cken, ##ius, 1974, ,, sc, ##ho, ##bert, and, lan, ##yi, 1982, ), ., with, an, ex, ##cit, ##ation, maximum, at, 58, ##9, nm, np, ##hr, pumps, chloride, into, the, cell, when, activated, by, yellow, light, causing, a, hyper, ##pol, ##ari, ##zation, with, consecutive, si, ##len, ##cing, of, the, target, cell, ., arch, and, arch, ##t, also, hyper, ##pol, ##ari, ##ze, cells, ,, but, by, pumping, h, ^, +, outward, ##s, and, in, a, more, rapidly, recovering, manner, ., ex, ##cit, ##ation, maxim, ##a, are, at, approximately, 56, ##6, nm, for, arch, and, arch, ##t, (, chow, et, al, ., 2010, ;, han, et, al, ., 2011, ), ., fig, ., 1, ##the, opt, ##ogen, ##etic, principle, :, changing, the, membrane, voltage, potential, of, ex, ##cit, ##able, cells, ., a, act, ##ivating, tools, —, channel, ##rh, ##od, ##ops, ##ins, :, channel, ##rh, ##od, ##ops, ##in, -, 2, from, ch, ##lam, ##yd, ##omo, ##as, rein, ##hardt, ##ii, (, ch, ##r, ##2, ), and, channel, ##rh, ##od, ##ops, ##in, -, 1, volvo, ##x, carter, ##i, (, vc, ##hr, ##1, ), from, non, ##sel, ##ect, ##ive, cat, ##ion, channels, leading, to, de, ##pol, ##ari, ##zation, of, target, cells, ., si, ##len, ##cing, tools, —, ion, pumps, :, arch, ##aer, ##ho, ##do, ##ps, ##in, -, 3, (, arch, ), from, halo, ##ru, ##br, ##um, so, ##dome, ##nse, works, as, a, proton, pump, and, leads, to, hyper, ##pol, ##ari, ##zation, of, the, target, cell, such, as, the, chloride, pump, np, ##hr, (, np, ##hr, ), from, nat, ##ron, ##omo, ##nas, ph, ##ara, ##onis, ., b, spectral, working, properties, of, light, -, sensitive, membrane, proteins'},\n", + " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", + " 'section_name': 'Targeted delivery of optogenetic tools',\n", + " 'text': 'For most of the targeting, in vivo viral gene transfer has been effectively used in mice, rats and non human primates, especially adeno-associated viruses (AAV; e.g., Sohal et al. 2009; Carter et al. 2010) lentiviruses (e.g., Adamantidis et al. 2007; Han et al. 2009), and to a lesser extent also herpes simplex virus (HSV; e.g., Covington et al. 2010; Lobo et al. 2010). Advantages of viral expression are a straightforward experimental approach, which takes approximately 6 weeks from virus production to extensive long lasting opsin expression (four more weeks for HSV) and a broad applicableness regarding the subject, ranging from rodents to primates. Depending on the experimental setup either strong ubiquitous promoters such as elongation factor 1-alpha (EF1α), human synapsin, human thymocyte differentiation antigen 1 (Thy-1), a combination of chicken beta-actin promoter and cytomegalovirus immediate-early enhancer (CAG) or weaker cell type-specific promoters, for example α-calcium/calmodulin-dependent protein kinase II (CamKIIα) can be used (Fig. 2a; Xu et al. 2001; Jakobsson et al. 2003; Dittgen et al. 2004). AAVs are to some extent superior to lentiviruses due to the fact that AAV-based vectors remain episomally while lentiviral vectors are integrated into the host genome. Thus, the expression from lentiviral vectors is prone to influences of the surrounding chromatin and the integration could lead to an undesired disruption of host genes. General drawbacks are a limited packing volume of AAVs and lentiviruses and weak cell type-specific transcriptional promoter activity. For example, the smallest promoter targeting selectively inhibitory neurons is approximately 3 kilobase pairs (kb) in length, which interferes with the maximal capacity of AAVs and lentiviruses, which is about 5 and 8 kb, respectively (Nathanson et al. 2009; Dong et al. 2010). A limitation often seen in experiments using cell type-specific promoters is the need of high irradiance for optimal stimulation of larger brain areas. As light penetration is low in brain tissue, reaching deeper regions optically requires either higher expression levels of the rhodopsin (e.g., by using a strong exogenous promoter as indicated above) or higher levels of light energy. As an alternative to moderately active tissue- or cell type-specific promoters, strong conditional rhodopsin expression can be achieved by the use of transgenic cre recombinase driver mice (Fig. 2; Geschwind 2004; Gong et al. 2007). By using a cre-dependent viral construct like AAV-FlEx (Flip-Excision) or AAV-DIO (double floxed inverse open reading frame) driven by a strong promoter such as EF1α or CAG, cell and tissue specificity is provided by selective cre activity (Fig. 2b; Atasoy et al. 2008; Sohal et al. 2009). An alternative to viral injections is the use of transgenic animals, where rhodopsin expression occurs early in development. Several transgenic mouse lines exist, expressing channelrhodopsin or HR under the panneuronal Thy-1 promoter (Arenkiel et al. 2007; Wang et al. 2007; Zhao et al. 2008) or the glutamatergic Vglut2 promoter (Fig. 2c; Hagglund et al. 2010). In analogy to the above-mentioned cre-dependent conditional approach utilizing viral gene delivery systems, a cell type-specific expression could be achieved by using a strong panneuronal promoter such as EF1α or CAG in combination with the cre-loxP system. Breeding to selective cre driver mice will result in expression of ChR2 or NpHR driven by the panneural promoter, whereas the temporal and spatial expression will depend on the used cre driver line (Fig. 2d). For in vivo cell type-specific opsin expression in utero electroporation has been used. Lacking construct size limitations even large cell type-specific promoters can be used to drive expression. Depending on the day of embryonic development various brain areas and cell types can efficiently be targeted (Saito 2006; Gradinaru et al. 2007; Navarro-Quiroga et al. 2007; Petreanu et al. 2007). Besides cell type-specific control in different brain areas, circuit-specific targeting may be desirable to distinguish more precisely between neurons, which, although carrying the same cell-specific set of genetic markers, are heterogeneous regarding their afferent or efferent influences. By fusing cre recombinase to axonally transported proteins such as wheat germ agglutinin (WGA) and tetanus toxin fragment C (TTC) or using idiosyncratic antero-/retrograde viral axonal delivery, circuit connectivity can be analyzed by optogenetics in a transneuronal fashion. This transcellular approach in combination with conditional cre-dependent expression vectors represents a versatile tool for circuit mapping independent of the use of cre animals, extending the cell type-specific optogenetic approach to animals such as rats and primates, which have not been amenable to large-scale genetic manipulation (Gradinaru et al. 2010).Fig. 2Targeted delivery of opsins to the mouse brain based on adeno-associated viruses (AAV) or transgenic approaches. a Opsins can be expressed in specific types of neurons or glia using gene-specific promoter elements (e.g., CamKIIα). AAV-based expression vectors integrating such promoter elements are delivered via stereotactic injection into desired brain areas. b Stereotactic injection of AAV vectors, which combine a strong ubiquitous promoter (e.g., Ef1α or CAG) either with a “STOP” cassette (top) or with an AAV-FlEx/AAV-DIO system (bottom), into specific cre mouse lines will result in a strong opsin expression selectively in neurons expressing the cre recombinase. c Classical transgenesis via pronucleus injection using a gene-specific promoter (top) or targeted knock-in strategies in embryonic stem cells (bottom) will result in a neuron- or glia-specific opsin expression in transgenic mice. d Alternatively, the combination of a ubiquitous promoter with a “STOP” cassette (top) or with an AAV-FlEx/AAV-DIO system (bottom) can be applied also in a transgenic approach either in a random or targeted fashion, e.g., to the ubiquitously expressed ROSA26 locus. Only after breeding to desired cre driver lines a brain region- or cell type-specific expression of opsins will be activated. Mice expressing opsins can be recognized by the highlighted brain and an inset in the background showing hippocampal neurons expressing opsin-GFP fusion protein. AAV adeno-associated virus, BGHpA bovine growth hormone poly A signal, GOI gene of interest, GSP gene-specific promoter, IRES internal ribosomal entry side, ITR inverted terminal repeat, STOP transcriptional terminator, UBP: ubiquitous promoter, WPRE woodchuck hepatitis virus posttranscriptional regulatory element',\n", + " 'paragraph_id': 5,\n", + " 'tokenizer': 'for, most, of, the, targeting, ,, in, vivo, viral, gene, transfer, has, been, effectively, used, in, mice, ,, rats, and, non, human, primate, ##s, ,, especially, aden, ##o, -, associated, viruses, (, aa, ##v, ;, e, ., g, ., ,, so, ##hal, et, al, ., 2009, ;, carter, et, al, ., 2010, ), lent, ##iv, ##irus, ##es, (, e, ., g, ., ,, adamant, ##idi, ##s, et, al, ., 2007, ;, han, et, al, ., 2009, ), ,, and, to, a, lesser, extent, also, her, ##pes, simple, ##x, virus, (, hs, ##v, ;, e, ., g, ., ,, co, ##vington, et, al, ., 2010, ;, lo, ##bo, et, al, ., 2010, ), ., advantages, of, viral, expression, are, a, straightforward, experimental, approach, ,, which, takes, approximately, 6, weeks, from, virus, production, to, extensive, long, lasting, ops, ##in, expression, (, four, more, weeks, for, hs, ##v, ), and, a, broad, applicable, ##ness, regarding, the, subject, ,, ranging, from, rodents, to, primate, ##s, ., depending, on, the, experimental, setup, either, strong, ubiquitous, promoters, such, as, el, ##onga, ##tion, factor, 1, -, alpha, (, e, ##f, ##1, ##α, ), ,, human, syn, ##ap, ##sin, ,, human, thy, ##mo, ##cy, ##te, differentiation, antigen, 1, (, thy, -, 1, ), ,, a, combination, of, chicken, beta, -, act, ##in, promoter, and, cy, ##tom, ##ega, ##lov, ##irus, immediate, -, early, enhance, ##r, (, ca, ##g, ), or, weaker, cell, type, -, specific, promoters, ,, for, example, α, -, calcium, /, calm, ##od, ##ulin, -, dependent, protein, kinase, ii, (, cam, ##ki, ##i, ##α, ), can, be, used, (, fig, ., 2a, ;, xu, et, al, ., 2001, ;, jakob, ##sson, et, al, ., 2003, ;, di, ##tt, ##gen, et, al, ., 2004, ), ., aa, ##vs, are, to, some, extent, superior, to, lent, ##iv, ##irus, ##es, due, to, the, fact, that, aa, ##v, -, based, vectors, remain, ep, ##iso, ##mal, ##ly, while, lent, ##iv, ##ira, ##l, vectors, are, integrated, into, the, host, genome, ., thus, ,, the, expression, from, lent, ##iv, ##ira, ##l, vectors, is, prone, to, influences, of, the, surrounding, ch, ##rom, ##atin, and, the, integration, could, lead, to, an, und, ##es, ##ired, disruption, of, host, genes, ., general, draw, ##backs, are, a, limited, packing, volume, of, aa, ##vs, and, lent, ##iv, ##irus, ##es, and, weak, cell, type, -, specific, transcription, ##al, promoter, activity, ., for, example, ,, the, smallest, promoter, targeting, selective, ##ly, inhibitor, ##y, neurons, is, approximately, 3, ki, ##lo, ##base, pairs, (, kb, ), in, length, ,, which, interfere, ##s, with, the, maximal, capacity, of, aa, ##vs, and, lent, ##iv, ##irus, ##es, ,, which, is, about, 5, and, 8, kb, ,, respectively, (, nathan, ##son, et, al, ., 2009, ;, dong, et, al, ., 2010, ), ., a, limitation, often, seen, in, experiments, using, cell, type, -, specific, promoters, is, the, need, of, high, ir, ##rad, ##iance, for, optimal, stimulation, of, larger, brain, areas, ., as, light, penetration, is, low, in, brain, tissue, ,, reaching, deeper, regions, optical, ##ly, requires, either, higher, expression, levels, of, the, r, ##ho, ##do, ##ps, ##in, (, e, ., g, ., ,, by, using, a, strong, ex, ##ogen, ##ous, promoter, as, indicated, above, ), or, higher, levels, of, light, energy, ., as, an, alternative, to, moderately, active, tissue, -, or, cell, type, -, specific, promoters, ,, strong, conditional, r, ##ho, ##do, ##ps, ##in, expression, can, be, achieved, by, the, use, of, trans, ##genic, cr, ##e, rec, ##om, ##bina, ##se, driver, mice, (, fig, ., 2, ;, ge, ##sch, ##wind, 2004, ;, gong, et, al, ., 2007, ), ., by, using, a, cr, ##e, -, dependent, viral, construct, like, aa, ##v, -, flex, (, flip, -, ex, ##cision, ), or, aa, ##v, -, di, ##o, (, double, fl, ##ox, ##ed, inverse, open, reading, frame, ), driven, by, a, strong, promoter, such, as, e, ##f, ##1, ##α, or, ca, ##g, ,, cell, and, tissue, specific, ##ity, is, provided, by, selective, cr, ##e, activity, (, fig, ., 2, ##b, ;, ata, ##so, ##y, et, al, ., 2008, ;, so, ##hal, et, al, ., 2009, ), ., an, alternative, to, viral, injection, ##s, is, the, use, of, trans, ##genic, animals, ,, where, r, ##ho, ##do, ##ps, ##in, expression, occurs, early, in, development, ., several, trans, ##genic, mouse, lines, exist, ,, expressing, channel, ##rh, ##od, ##ops, ##in, or, hr, under, the, pan, ##ne, ##uron, ##al, thy, -, 1, promoter, (, aren, ##kie, ##l, et, al, ., 2007, ;, wang, et, al, ., 2007, ;, zhao, et, al, ., 2008, ), or, the, g, ##lu, ##tama, ##ter, ##gic, v, ##gl, ##ut, ##2, promoter, (, fig, ., 2, ##c, ;, ha, ##gg, ##lund, et, al, ., 2010, ), ., in, analogy, to, the, above, -, mentioned, cr, ##e, -, dependent, conditional, approach, utilizing, viral, gene, delivery, systems, ,, a, cell, type, -, specific, expression, could, be, achieved, by, using, a, strong, pan, ##ne, ##uron, ##al, promoter, such, as, e, ##f, ##1, ##α, or, ca, ##g, in, combination, with, the, cr, ##e, -, lo, ##x, ##p, system, ., breeding, to, selective, cr, ##e, driver, mice, will, result, in, expression, of, ch, ##r, ##2, or, np, ##hr, driven, by, the, pan, ##ne, ##ural, promoter, ,, whereas, the, temporal, and, spatial, expression, will, depend, on, the, used, cr, ##e, driver, line, (, fig, ., 2d, ), ., for, in, vivo, cell, type, -, specific, ops, ##in, expression, in, ut, ##ero, electro, ##por, ##ation, has, been, used, ., lacking, construct, size, limitations, even, large, cell, type, -, specific, promoters, can, be, used, to, drive, expression, ., depending, on, the, day, of, embryo, ##nic, development, various, brain, areas, and, cell, types, can, efficiently, be, targeted, (, sai, ##to, 2006, ;, gr, ##adi, ##nar, ##u, et, al, ., 2007, ;, navarro, -, qui, ##ro, ##ga, et, al, ., 2007, ;, pet, ##rea, ##nu, et, al, ., 2007, ), ., besides, cell, type, -, specific, control, in, different, brain, areas, ,, circuit, -, specific, targeting, may, be, desirable, to, distinguish, more, precisely, between, neurons, ,, which, ,, although, carrying, the, same, cell, -, specific, set, of, genetic, markers, ,, are, het, ##ero, ##gen, ##eous, regarding, their, af, ##fer, ##ent, or, e, ##ffer, ##ent, influences, ., by, fu, ##sing, cr, ##e, rec, ##om, ##bina, ##se, to, ax, ##onal, ##ly, transported, proteins, such, as, wheat, ge, ##rm, ag, ##gl, ##uti, ##nin, (, w, ##ga, ), and, te, ##tan, ##us, toxin, fragment, c, (, tt, ##c, ), or, using, id, ##ios, ##yn, ##cratic, ant, ##ero, -, /, retro, ##grade, viral, ax, ##onal, delivery, ,, circuit, connectivity, can, be, analyzed, by, opt, ##ogen, ##etic, ##s, in, a, trans, ##ne, ##uron, ##al, fashion, ., this, trans, ##cellular, approach, in, combination, with, conditional, cr, ##e, -, dependent, expression, vectors, represents, a, versatile, tool, for, circuit, mapping, independent, of, the, use, of, cr, ##e, animals, ,, extending, the, cell, type, -, specific, opt, ##ogen, ##etic, approach, to, animals, such, as, rats, and, primate, ##s, ,, which, have, not, been, am, ##ena, ##ble, to, large, -, scale, genetic, manipulation, (, gr, ##adi, ##nar, ##u, et, al, ., 2010, ), ., fig, ., 2, ##tar, ##get, ##ed, delivery, of, ops, ##ins, to, the, mouse, brain, based, on, aden, ##o, -, associated, viruses, (, aa, ##v, ), or, trans, ##genic, approaches, ., a, ops, ##ins, can, be, expressed, in, specific, types, of, neurons, or, g, ##lia, using, gene, -, specific, promoter, elements, (, e, ., g, ., ,, cam, ##ki, ##i, ##α, ), ., aa, ##v, -, based, expression, vectors, integrating, such, promoter, elements, are, delivered, via, stereo, ##ta, ##ctic, injection, into, desired, brain, areas, ., b, stereo, ##ta, ##ctic, injection, of, aa, ##v, vectors, ,, which, combine, a, strong, ubiquitous, promoter, (, e, ., g, ., ,, e, ##f, ##1, ##α, or, ca, ##g, ), either, with, a, “, stop, ”, cassette, (, top, ), or, with, an, aa, ##v, -, flex, /, aa, ##v, -, di, ##o, system, (, bottom, ), ,, into, specific, cr, ##e, mouse, lines, will, result, in, a, strong, ops, ##in, expression, selective, ##ly, in, neurons, expressing, the, cr, ##e, rec, ##om, ##bina, ##se, ., c, classical, trans, ##genesis, via, pro, ##nu, ##cle, ##us, injection, using, a, gene, -, specific, promoter, (, top, ), or, targeted, knock, -, in, strategies, in, embryo, ##nic, stem, cells, (, bottom, ), will, result, in, a, ne, ##uron, -, or, g, ##lia, -, specific, ops, ##in, expression, in, trans, ##genic, mice, ., d, alternatively, ,, the, combination, of, a, ubiquitous, promoter, with, a, “, stop, ”, cassette, (, top, ), or, with, an, aa, ##v, -, flex, /, aa, ##v, -, di, ##o, system, (, bottom, ), can, be, applied, also, in, a, trans, ##genic, approach, either, in, a, random, or, targeted, fashion, ,, e, ., g, ., ,, to, the, ubiquitous, ##ly, expressed, rosa, ##26, locus, ., only, after, breeding, to, desired, cr, ##e, driver, lines, a, brain, region, -, or, cell, type, -, specific, expression, of, ops, ##ins, will, be, activated, ., mice, expressing, ops, ##ins, can, be, recognized, by, the, highlighted, brain, and, an, ins, ##et, in, the, background, showing, hip, ##po, ##camp, ##al, neurons, expressing, ops, ##in, -, g, ##fp, fusion, protein, ., aa, ##v, aden, ##o, -, associated, virus, ,, b, ##gh, ##pa, bo, ##vine, growth, hormone, poly, a, signal, ,, go, ##i, gene, of, interest, ,, gs, ##p, gene, -, specific, promoter, ,, ir, ##es, internal, rib, ##osomal, entry, side, ,, it, ##r, inverted, terminal, repeat, ,, stop, transcription, ##al, term, ##inator, ,, u, ##b, ##p, :, ubiquitous, promoter, ,, w, ##pre, wood, ##chu, ##ck, hepatitis, virus, post, ##tra, ##ns, ##cript, ##ional, regulatory, element'},\n", + " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", + " 'section_name': 'Optogenetics is compatible with a plethora of functional readouts',\n", + " 'text': 'The major advantage of optogenetics, besides genetic targeting, is stimulation with light, as it offers the possibility of simultaneous on-site electrical measurement. Depending on the desired resolution, optogenetics can be combined with a variety of readouts. For in vitro proof-of-concept experiments the most widely used methods are whole-cell patch clamp and field potential recordings in combination with optical illumination in brain slices (for example Nagel et al. 2003; Boyden et al. 2005; Deisseroth et al. 2006; Zhang et al. 2007a, b). To study neural activity beyond single cells on a network level calcium imaging can be used as a multisite indirect measurement of action potential activity in a full optical approach (Knopfel et al. 2006). The first example of postsynaptic calcium imaging following light-induced action potentials in ChR2-targeted presynaptic axons was demonstrated by Zhang and Oertner (2007) to study plasticity at single-synapse level. By using a spectrally compatible dye (Fluo-5F) and two-photon excitation at 810 nm in rat hippocampal slice cultures targeted with ChR2-tdimer2, synaptic contacts between labeled cells could be identified by imaging optically induced spinal calcium release. In addition, long-term potentiation of prevalent synaptic connections was induced (Zhang and Oertner 2007). An all-optical approach was also applied in the initial description of bidirectional optical control of neural circuits. After lentiviral transduction of murine acute cortical slices with CaMKIIα::ChR2-mCherry and EF1α::NpHR-EYFP Fura-2 calcium imaging was used to measure the effects of optical excitation and inhibition (Zhang et al. 2007a). Because of its UV-shifted spectral properties (excitation maximum at 340 nm) Fura-2 has been successfully used in concert with ChR2 (excitation maximum at 470 nm), NpHR (excitation maximum at 590 nm) and the OptoXRs (excitation maximum at 500 nm; Airan et al. 2009). Yet, although spectrally overlapping, genetically encoded calcium sensors such as G-CaMP can be applied in concert with ChR2. In a technically elegant study Guo et al. (2009) combined in vivo optical stimulation of ChR2 wavelength with simultaneous calcium imaging at 488 nm for functional connectivity mapping in C. elegans neurons. By separating an epifluorescent high-power stimulation path for ChR2 activation from a low-intensity laser light imaging path for G-CaMP fluorescence, unspecific ChR2 activation during imaging at 488 nm could be avoided although ChR2 has its peak activation at 470 nm (Guo et al. 2009, see also Fig. 1). Laser scanning photostimulation (LSPS) has previously also been used in combination with glutamate uncaging and whole-cell recordings to analyze synaptic connectivity in brain slices (Katz and Dalva 1994; Shepherd and Svoboda 2005; Svoboda and Yasuda 2006). By exchanging glutamate uncaging against light activation through targeted axonal photosensitivity via ChR2, the group of Svoboda developed ChR2-assisted circuit mapping (CRACM; Petreanu et al. 2007). Using in utero electroporation in mice layer, 2/3 cortical neurons were targeted with ChR2-venus and photostimulation was performed throughout a grid covering the entire depth of the cortex. Whole-cell current clamp recordings of fluorescent ChR2 positive cells revealed their depolarization and detected action potentials after perisomatic and axonal LSPS. Mapping postsynaptic targets of L2/3 neurons in several cortical layers in the ipsi- and contralateral hemisphere indicated laminar specificity of local and long-range cortical projections (Petreanu et al. 2007). A modified approach (sCRACM) was used to study the subcellular organization of excitatory pyramidal neurons. Local glutamate release was measured after LSPS in conditions blocking action potentials. EPSPs as a measure of light-induced activation were detected only in the case of overlap between the recorded cell and ChR2-targeted presynaptic axons. Interestingly, subcellular mapping of neural circuitry by sCRACM revealed that the structural connectivity of neurons, as indicated by overlap of axons and dendrites, is not always reflected by their connection on a functional level (Petreanu et al. 2009). To study whole circuit properties voltage-sensitive dyes (VSD) can be applied in brain slices for an all-optical approach. As VSDs change their light emission properties in a voltage-dependent and most notably in a millisecond time scale they are potentially well suited to match the high temporal resolution achieved by optogenetics (Grinvald and Hildesheim 2004). Although compatibility can be achieved with spectrally separated infrared dyes such as RH-155 and VSD imaging following optical stimulation has been established successfully, it has rarely been used experimentally up to now, most probably due to a less favorable signal-to-noise ratio in comparison to calcium imaging (Airan et al. 2007; Zhang et al. 2010). Another example for the study of macrocircuits and global in vivo mapping is optical stimulation in combination with high-resolution fMRI. Lee and colleagues showed in a first publication that blood oxygenation level-dependent (BOLD) signals similar to classical stimulus-evoked BOLD fMRI responses could be elicited optically. This effect was seen not only locally at the expression site of ChR2 in M1 CaMKIIα positive excitatory neurons, but also in distinct thalamic neurons defined by the corticofugal axonal projections (Lee et al. 2010). In a reverse approach optical stimulation of ChR2 expressing cortico-thalamic projection fibers at the level of the thalamus was sufficient to drive not only local thalamic BOLD signals, but also cortical signals, most probably in an antidromic axosomatic manner. “Opto-fMRI” or “ofMRI” has also been used to identify downstream targets of the primary sensory cortex (SI). Optical stimulation of a ChR2-targeted subpopulation of SI pyramidal cells evoked local BOLD signals and also in functionally connected network regions, with differences in awake compared to anesthetized mice (Desai et al. 2011). Even though widely hypothesized before, these experiments indicate a most likely causal link between local neuronal excitation and positive hemodynamic responses, although the generation of BOLD signals may have a more complex nature. However, functional mapping using optogenetics in combination with fMRI not only integrates cell type specificity and anatomical conjunction, but can also be used to functionally dissect brain circuitries based on their connection topology (Leopold 2010). For global measurements of brain activity in living animals, electroencephalography (EEG) has been combined with optogenetic stimulation. In a first experiment Adamantidis et al. (2007, 2010) identified the effect of hypocretin-producing neurons in the lateral hypothalamus on sleep to wake transition by analyzing sleep recordings of mice with chronically implanted EEG electrodes. In a bidirectional in vivo approach using eNpHR and ChR2 the same group studied the effect of locus coeruleus neurons on wakefulness by applying EEG and in vivo microdialysis as a functional readout (Carter et al. 2010). For in vivo extracellular recording upon targeted optical stimulation, a device called “optrode” was created fusing a stimulating fiberoptic with a recording electrode (Gradinaru et al. 2007, 2009). Constant technical development even allows simultaneous recordings at multiple sites in the living animal (Zhang et al. 2009; Royer et al. 2010). The foundation for using optogenetics in freely moving rodents was set by Aravanis et al. (2007). Via a lightweight, flexible optical fiber called optical neural interface (ONI) excitatory motor cortex neurons could selectively be activated in rats and mice as measured by their whisker movement. Several successive studies focused on more complex behavioral paradigms as readouts for optogenetical manipulation such as motor behavior in animal models of Parkinson’s disease (Gradinaru et al. 2009; Kravitz et al. 2010), reward motivated behavior and addiction (Airan et al. 2009; Tsai et al. 2009; Witten et al. 2010; Stuber et al. 2011), fear conditioning and anxiety (Ciocchi et al. 2010; Johansen et al. 2010; Tye et al. 2011) and other \\ncerebral targets such as prefrontal cortex or hypothalamus for the study of psychiatric diseases and aggressive behavior (Covington et al. 2010; Lin et al. 2011; Yizhar et al. 2011a, b).',\n", + " 'paragraph_id': 6,\n", + " 'tokenizer': 'the, major, advantage, of, opt, ##ogen, ##etic, ##s, ,, besides, genetic, targeting, ,, is, stimulation, with, light, ,, as, it, offers, the, possibility, of, simultaneous, on, -, site, electrical, measurement, ., depending, on, the, desired, resolution, ,, opt, ##ogen, ##etic, ##s, can, be, combined, with, a, variety, of, read, ##outs, ., for, in, vitro, proof, -, of, -, concept, experiments, the, most, widely, used, methods, are, whole, -, cell, patch, cl, ##amp, and, field, potential, recordings, in, combination, with, optical, illumination, in, brain, slices, (, for, example, na, ##gel, et, al, ., 2003, ;, boyd, ##en, et, al, ., 2005, ;, dei, ##sser, ##oth, et, al, ., 2006, ;, zhang, et, al, ., 2007, ##a, ,, b, ), ., to, study, neural, activity, beyond, single, cells, on, a, network, level, calcium, imaging, can, be, used, as, a, multi, ##sit, ##e, indirect, measurement, of, action, potential, activity, in, a, full, optical, approach, (, kn, ##op, ##fe, ##l, et, al, ., 2006, ), ., the, first, example, of, posts, ##yna, ##ptic, calcium, imaging, following, light, -, induced, action, potential, ##s, in, ch, ##r, ##2, -, targeted, pre, ##sy, ##na, ##ptic, ax, ##ons, was, demonstrated, by, zhang, and, o, ##ert, ##ner, (, 2007, ), to, study, plastic, ##ity, at, single, -, syn, ##ap, ##se, level, ., by, using, a, spectral, ##ly, compatible, dye, (, flu, ##o, -, 5, ##f, ), and, two, -, photon, ex, ##cit, ##ation, at, 81, ##0, nm, in, rat, hip, ##po, ##camp, ##al, slice, cultures, targeted, with, ch, ##r, ##2, -, td, ##ime, ##r, ##2, ,, syn, ##ap, ##tic, contacts, between, labeled, cells, could, be, identified, by, imaging, optical, ##ly, induced, spinal, calcium, release, ., in, addition, ,, long, -, term, potent, ##iation, of, prevalent, syn, ##ap, ##tic, connections, was, induced, (, zhang, and, o, ##ert, ##ner, 2007, ), ., an, all, -, optical, approach, was, also, applied, in, the, initial, description, of, bid, ##ire, ##ction, ##al, optical, control, of, neural, circuits, ., after, lent, ##iv, ##ira, ##l, trans, ##duction, of, mu, ##rine, acute, co, ##rti, ##cal, slices, with, cam, ##ki, ##i, ##α, :, :, ch, ##r, ##2, -, mc, ##her, ##ry, and, e, ##f, ##1, ##α, :, :, np, ##hr, -, e, ##y, ##fp, fur, ##a, -, 2, calcium, imaging, was, used, to, measure, the, effects, of, optical, ex, ##cit, ##ation, and, inhibition, (, zhang, et, al, ., 2007, ##a, ), ., because, of, its, uv, -, shifted, spectral, properties, (, ex, ##cit, ##ation, maximum, at, 340, nm, ), fur, ##a, -, 2, has, been, successfully, used, in, concert, with, ch, ##r, ##2, (, ex, ##cit, ##ation, maximum, at, 470, nm, ), ,, np, ##hr, (, ex, ##cit, ##ation, maximum, at, 590, nm, ), and, the, opt, ##ox, ##rs, (, ex, ##cit, ##ation, maximum, at, 500, nm, ;, air, ##an, et, al, ., 2009, ), ., yet, ,, although, spectral, ##ly, overlapping, ,, genetically, encoded, calcium, sensors, such, as, g, -, camp, can, be, applied, in, concert, with, ch, ##r, ##2, ., in, a, technically, elegant, study, guo, et, al, ., (, 2009, ), combined, in, vivo, optical, stimulation, of, ch, ##r, ##2, wavelength, with, simultaneous, calcium, imaging, at, 48, ##8, nm, for, functional, connectivity, mapping, in, c, ., el, ##egan, ##s, neurons, ., by, separating, an, ep, ##if, ##lu, ##ores, ##cent, high, -, power, stimulation, path, for, ch, ##r, ##2, activation, from, a, low, -, intensity, laser, light, imaging, path, for, g, -, camp, flu, ##orescence, ,, un, ##sp, ##ec, ##ific, ch, ##r, ##2, activation, during, imaging, at, 48, ##8, nm, could, be, avoided, although, ch, ##r, ##2, has, its, peak, activation, at, 470, nm, (, guo, et, al, ., 2009, ,, see, also, fig, ., 1, ), ., laser, scanning, photos, ##ti, ##mu, ##lation, (, l, ##sp, ##s, ), has, previously, also, been, used, in, combination, with, g, ##lu, ##tama, ##te, un, ##ca, ##ging, and, whole, -, cell, recordings, to, analyze, syn, ##ap, ##tic, connectivity, in, brain, slices, (, katz, and, dal, ##va, 1994, ;, shepherd, and, sv, ##ob, ##oda, 2005, ;, sv, ##ob, ##oda, and, ya, ##su, ##da, 2006, ), ., by, exchanging, g, ##lu, ##tama, ##te, un, ##ca, ##ging, against, light, activation, through, targeted, ax, ##onal, photos, ##ens, ##iti, ##vity, via, ch, ##r, ##2, ,, the, group, of, sv, ##ob, ##oda, developed, ch, ##r, ##2, -, assisted, circuit, mapping, (, cr, ##ac, ##m, ;, pet, ##rea, ##nu, et, al, ., 2007, ), ., using, in, ut, ##ero, electro, ##por, ##ation, in, mice, layer, ,, 2, /, 3, co, ##rti, ##cal, neurons, were, targeted, with, ch, ##r, ##2, -, venus, and, photos, ##ti, ##mu, ##lation, was, performed, throughout, a, grid, covering, the, entire, depth, of, the, cortex, ., whole, -, cell, current, cl, ##amp, recordings, of, fluorescent, ch, ##r, ##2, positive, cells, revealed, their, de, ##pol, ##ari, ##zation, and, detected, action, potential, ##s, after, per, ##iso, ##matic, and, ax, ##onal, l, ##sp, ##s, ., mapping, posts, ##yna, ##ptic, targets, of, l, ##2, /, 3, neurons, in, several, co, ##rti, ##cal, layers, in, the, ip, ##si, -, and, contra, ##lateral, hemisphere, indicated, lam, ##ina, ##r, specific, ##ity, of, local, and, long, -, range, co, ##rti, ##cal, projections, (, pet, ##rea, ##nu, et, al, ., 2007, ), ., a, modified, approach, (, sc, ##rac, ##m, ), was, used, to, study, the, sub, ##cellular, organization, of, ex, ##cit, ##atory, pyramid, ##al, neurons, ., local, g, ##lu, ##tama, ##te, release, was, measured, after, l, ##sp, ##s, in, conditions, blocking, action, potential, ##s, ., eps, ##ps, as, a, measure, of, light, -, induced, activation, were, detected, only, in, the, case, of, overlap, between, the, recorded, cell, and, ch, ##r, ##2, -, targeted, pre, ##sy, ##na, ##ptic, ax, ##ons, ., interesting, ##ly, ,, sub, ##cellular, mapping, of, neural, circuit, ##ry, by, sc, ##rac, ##m, revealed, that, the, structural, connectivity, of, neurons, ,, as, indicated, by, overlap, of, ax, ##ons, and, den, ##dr, ##ites, ,, is, not, always, reflected, by, their, connection, on, a, functional, level, (, pet, ##rea, ##nu, et, al, ., 2009, ), ., to, study, whole, circuit, properties, voltage, -, sensitive, dye, ##s, (, vs, ##d, ), can, be, applied, in, brain, slices, for, an, all, -, optical, approach, ., as, vs, ##ds, change, their, light, emission, properties, in, a, voltage, -, dependent, and, most, notably, in, a, mill, ##ise, ##con, ##d, time, scale, they, are, potentially, well, suited, to, match, the, high, temporal, resolution, achieved, by, opt, ##ogen, ##etic, ##s, (, grin, ##val, ##d, and, hi, ##lde, ##sh, ##eim, 2004, ), ., although, compatibility, can, be, achieved, with, spectral, ##ly, separated, infrared, dye, ##s, such, as, r, ##h, -, 155, and, vs, ##d, imaging, following, optical, stimulation, has, been, established, successfully, ,, it, has, rarely, been, used, experimental, ##ly, up, to, now, ,, most, probably, due, to, a, less, favorable, signal, -, to, -, noise, ratio, in, comparison, to, calcium, imaging, (, air, ##an, et, al, ., 2007, ;, zhang, et, al, ., 2010, ), ., another, example, for, the, study, of, macro, ##ci, ##rc, ##uit, ##s, and, global, in, vivo, mapping, is, optical, stimulation, in, combination, with, high, -, resolution, fm, ##ri, ., lee, and, colleagues, showed, in, a, first, publication, that, blood, oxygen, ##ation, level, -, dependent, (, bold, ), signals, similar, to, classical, stimulus, -, ev, ##oked, bold, fm, ##ri, responses, could, be, eli, ##cite, ##d, optical, ##ly, ., this, effect, was, seen, not, only, locally, at, the, expression, site, of, ch, ##r, ##2, in, m1, cam, ##ki, ##i, ##α, positive, ex, ##cit, ##atory, neurons, ,, but, also, in, distinct, tha, ##lam, ##ic, neurons, defined, by, the, co, ##rti, ##co, ##fu, ##gal, ax, ##onal, projections, (, lee, et, al, ., 2010, ), ., in, a, reverse, approach, optical, stimulation, of, ch, ##r, ##2, expressing, co, ##rti, ##co, -, tha, ##lam, ##ic, projection, fibers, at, the, level, of, the, tha, ##lam, ##us, was, sufficient, to, drive, not, only, local, tha, ##lam, ##ic, bold, signals, ,, but, also, co, ##rti, ##cal, signals, ,, most, probably, in, an, anti, ##dro, ##mic, ax, ##oso, ##matic, manner, ., “, opt, ##o, -, fm, ##ri, ”, or, “, of, ##m, ##ri, ”, has, also, been, used, to, identify, downstream, targets, of, the, primary, sensory, cortex, (, si, ), ., optical, stimulation, of, a, ch, ##r, ##2, -, targeted, sub, ##pop, ##ulation, of, si, pyramid, ##al, cells, ev, ##oked, local, bold, signals, and, also, in, functional, ##ly, connected, network, regions, ,, with, differences, in, awake, compared, to, an, ##est, ##het, ##ized, mice, (, des, ##ai, et, al, ., 2011, ), ., even, though, widely, h, ##yp, ##oth, ##es, ##ized, before, ,, these, experiments, indicate, a, most, likely, causal, link, between, local, ne, ##uron, ##al, ex, ##cit, ##ation, and, positive, hem, ##od, ##yna, ##mic, responses, ,, although, the, generation, of, bold, signals, may, have, a, more, complex, nature, ., however, ,, functional, mapping, using, opt, ##ogen, ##etic, ##s, in, combination, with, fm, ##ri, not, only, integrate, ##s, cell, type, specific, ##ity, and, anatomical, conjunction, ,, but, can, also, be, used, to, functional, ##ly, di, ##sse, ##ct, brain, circuit, ##ries, based, on, their, connection, topology, (, leopold, 2010, ), ., for, global, measurements, of, brain, activity, in, living, animals, ,, electro, ##ence, ##pha, ##log, ##raphy, (, ee, ##g, ), has, been, combined, with, opt, ##ogen, ##etic, stimulation, ., in, a, first, experiment, adamant, ##idi, ##s, et, al, ., (, 2007, ,, 2010, ), identified, the, effect, of, h, ##yp, ##oc, ##ret, ##in, -, producing, neurons, in, the, lateral, h, ##yp, ##oth, ##ala, ##mus, on, sleep, to, wake, transition, by, analyzing, sleep, recordings, of, mice, with, chronic, ##ally, implant, ##ed, ee, ##g, electrode, ##s, ., in, a, bid, ##ire, ##ction, ##al, in, vivo, approach, using, en, ##ph, ##r, and, ch, ##r, ##2, the, same, group, studied, the, effect, of, locus, coe, ##ru, ##le, ##us, neurons, on, wake, ##fulness, by, applying, ee, ##g, and, in, vivo, micro, ##dial, ##ysis, as, a, functional, read, ##out, (, carter, et, al, ., 2010, ), ., for, in, vivo, extra, ##cellular, recording, upon, targeted, optical, stimulation, ,, a, device, called, “, opt, ##rod, ##e, ”, was, created, fu, ##sing, a, stimulating, fiber, ##op, ##tic, with, a, recording, electrode, (, gr, ##adi, ##nar, ##u, et, al, ., 2007, ,, 2009, ), ., constant, technical, development, even, allows, simultaneous, recordings, at, multiple, sites, in, the, living, animal, (, zhang, et, al, ., 2009, ;, roy, ##er, et, al, ., 2010, ), ., the, foundation, for, using, opt, ##ogen, ##etic, ##s, in, freely, moving, rodents, was, set, by, ara, ##vani, ##s, et, al, ., (, 2007, ), ., via, a, lightweight, ,, flexible, optical, fiber, called, optical, neural, interface, (, on, ##i, ), ex, ##cit, ##atory, motor, cortex, neurons, could, selective, ##ly, be, activated, in, rats, and, mice, as, measured, by, their, w, ##his, ##ker, movement, ., several, successive, studies, focused, on, more, complex, behavioral, paradigm, ##s, as, read, ##outs, for, opt, ##ogen, ##etic, ##al, manipulation, such, as, motor, behavior, in, animal, models, of, parkinson, ’, s, disease, (, gr, ##adi, ##nar, ##u, et, al, ., 2009, ;, k, ##ra, ##vi, ##tz, et, al, ., 2010, ), ,, reward, motivated, behavior, and, addiction, (, air, ##an, et, al, ., 2009, ;, ts, ##ai, et, al, ., 2009, ;, wit, ##ten, et, al, ., 2010, ;, stu, ##ber, et, al, ., 2011, ), ,, fear, conditioning, and, anxiety, (, ci, ##oc, ##chi, et, al, ., 2010, ;, johan, ##sen, et, al, ., 2010, ;, ty, ##e, et, al, ., 2011, ), and, other, cerebral, targets, such, as, pre, ##front, ##al, cortex, or, h, ##yp, ##oth, ##ala, ##mus, for, the, study, of, psychiatric, diseases, and, aggressive, behavior, (, co, ##vington, et, al, ., 2010, ;, lin, et, al, ., 2011, ;, yi, ##zh, ##ar, et, al, ., 2011, ##a, ,, b, ), .'},\n", + " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", + " 'section_name': 'From microbes to model organisms and beyond',\n", + " 'text': 'Optogenetics is applicable to diverse species and animal models. For the initial functional characterization of ChR1 and ChR2 a host model was applied that had previously been successfully used for different rhodopsins. Expression of ChR1 and ChR2 in oocytes from Xenopus laevis in the presence of all-trans retinal was the first example of functional heterologous channelrhodopsin expression outside of algae (Nagel et al. 2002, 2003). At that moment the equation was: CHOP 1 or 2 + retinal = ChR1 or ChR2, as the photoreceptor system from Chlamydomonas reinhardtii was thought to be composed of channelopsin (from a cDNA originally named CHOP1 and CHOP2 but also termed Chlamyopsin, Cop3 or Cop4) and all-trans retinal (Nagel et al. 2003). Deisseroth and colleagues redid the math and prove that “CHOP2” successfully worked in rat hippocampal primary neurons after lentiviral transduction without adding all-trans retinal at all (although the culture media contained little amounts of the precursor retinyl acetate). By this, ChR2 was established as a new one-component functional tool for neuroscience in mammals neither requiring the substitution of any synthetic chemical substrate nor genetic orthogonality between the rhodopsin and the targeted host organism, even more important as there is no mammalian analog of the algal gene CHOP2 (Boyden et al. 2005). The first in vivo applications in living animals were put into practice in parallel by Li et al. (2005) and Nagel et al. (2005). Transgenic expression of ChR2 specifically in cholinergic motorneurons of C. elegans allowed to elicit behavioral responses via muscular contractions by blue light illumination (Nagel et al. 2005). Bidirectional, both inhibitory and excitatory in vivo control of spontaneous chick spinal cord activity was performed in chicken embryos after in ovo electroporating and transient expression of ChR2 and vertebrate Ro4, respectively (Li et al. 2005). Another example of bidirectional in vivo control of C. elegans locomotion was achieved after simultaneous expression of ChR2 and NpHR using the muscle-specific myosin promoter Pmyo-3 (Zhang et al. 2007a). As mentioned above C.\\nelegans has also been used for an in vivo all-optical interrogation of neural circuits using ChR2 and G-CaMP (Guo et al. 2009). The first use of optogenetics in zebrafish revealed that activation of zebrafish trigeminal neurons by ChR2 induces escape behavior even upon single spikes, as published by Douglass et al. (2008). By using Gal4 enhancer trapping in zebrafish, transgenic animals can be generated in a feasible way (Scott et al. 2007). The Bayer lab efficiently used the GAL4/UAS system to selectively express ChR2 and NpHR in specific neuronal subpopulations of zebrafish larvae. Owing to the transparent nature of the animal in vivo functional mapping at a single neuron resolution was performed dissecting neuronal populations involved in swim behavior, saccade generation as well cardiac development and function (Arrenberg et al. 2009, 2010; Schoonheim et al. 2010). GAL4/UAS was also used to introduce ChR2 into specific subsets of neuronal populations (painless) in Drosophila melanogaster by crossing transgenic UAS-ChR2 flies with neuronspecific Gal4 transgenic lines (Zhang et al. 2007c). Optical stimulation of nociceptive neurons in transgenic larvae by ChR2 induced behavioral responses. However, it has to be taken into account that D. melanogaster and zebrafish contain hydroxyretinal which does not enter the ChR or HR binding sites making a substitution of all-trans retinal necessary (for example by food supplement). Moreover, interpretation of behavioral data in D. melanogaster can be conflicting as the animal has an innate behavioral light response (Pulver et al. 2009). The species most widely investigated with optogenetic technologies is the mouse. This is largely owing to the vast availability of transgenic cre driver lines, which can readily be combined with cre-dependent viral vectors in order to facilitate strong cell-/tissue-specific rhodopsin expression (Fig. 2). As mentioned above, in mice also classical transgenic approaches have been applied to express ChR2 and NpHR under the control of the Thy-1 promoter. Arenkiel et al. (2007) showed strong and functional, regionally restricted, channelrhodopsin expression in Thy1::ChR2-EYFP mouse strains. By presynaptic optical manipulation of targeted cells in the bulbar-cortical circuit of the olfactory system they highlighted the potential of optogenetics for complex circuit analysis in brain slices and in vivo. Wang et al. (2007) used transgenic Thy1-ChR2-YFP mice for the mapping of functional connectivity in the neural circuitry of cortical layer VI neurons. In order to study the role of fast spiking parvalbumin interneurons in the generation of gamma oscillations, Thy1::ChR2-EYFP mice were analyzed in combination with a cre-dependent approach (Sohal et al. 2009). This animal model in combination with a cell type-specific lentiviral approach was also successfully used in the systematic dissection of circuits and deciphering of potential targets related to deep brain stimulation in a Parkinson mouse model (Gradinaru et al. 2009). Hagglund and colleagues used BAC transgenesis to express ChR2-EYFP under the control of the vesicular glutamate receptor two promoter. These transgenic mice express ChR2 in glutamatergic neurons of the hindbrain and spinal cord. By optical stimulation of the lumbar region of the spinal cord and also the caudal hindbrain rhythm generation was observed, suggesting a role of glutamatergic neurons in central pattern generators of locomotion (Hagglund et al. 2010). Various examples in nematodes, mice and rats have demonstrated a direct effect of in vivo optogenetic stimulation on neuronal activity and behavioral responses (Nagel et al. 2005; Gradinaru et al. 2009; Tsai et al. 2009; Lee et al. 2010). Yet optical control of cortical circuits in higher organisms might be more complex: the first optogenetic approach in primates was performed in the rhesus macaque. Boyden and colleagues targeted specifically excitatory neurons of the frontal cortex by stereotactic lentiviral gene delivery of ChR2-GFP driven by the CamKIIα promoter and recorded neuronal activity after simultaneous optical stimulation via an optrode (Han et al. 2009). Besides showing the feasibility and safety of optogenetics in primates and thereby implementing a potential clinical translation for the use in humans, the experiments showed a slightly discouraging, but seminal, result. Although ChR2 was targeted specifically to excitatory neurons a significant proportion of recorded cells showed decreased activity. This finding was previously also observed in transgenic Thy1-ChR2 mice and is comparable to heterogeneous tissue activation in the case of electrical stimulation. Thus, targeting cortical circuits in a cell type-specific manner cannot precisely predict a specific psychological response, respectively, behavioral or clinical outcome. The impact of optogenetic manipulation on cortical circuitries seems to be heavily dependent on the neural network, in which the target cells are embedded. Nevertheless, the results indicate important aspects for therapeutic options and suggest lentiviral rhodopsin delivery as a well immuno-tolerated method for a putative application in humans.',\n", + " 'paragraph_id': 7,\n", + " 'tokenizer': 'opt, ##ogen, ##etic, ##s, is, applicable, to, diverse, species, and, animal, models, ., for, the, initial, functional, characterization, of, ch, ##r, ##1, and, ch, ##r, ##2, a, host, model, was, applied, that, had, previously, been, successfully, used, for, different, r, ##ho, ##do, ##ps, ##ins, ., expression, of, ch, ##r, ##1, and, ch, ##r, ##2, in, o, ##ocytes, from, x, ##eno, ##pus, la, ##ev, ##is, in, the, presence, of, all, -, trans, re, ##tina, ##l, was, the, first, example, of, functional, het, ##ero, ##log, ##ous, channel, ##rh, ##od, ##ops, ##in, expression, outside, of, algae, (, na, ##gel, et, al, ., 2002, ,, 2003, ), ., at, that, moment, the, equation, was, :, chop, 1, or, 2, +, re, ##tina, ##l, =, ch, ##r, ##1, or, ch, ##r, ##2, ,, as, the, photo, ##re, ##ce, ##pt, ##or, system, from, ch, ##lam, ##yd, ##omo, ##nas, rein, ##hardt, ##ii, was, thought, to, be, composed, of, channel, ##ops, ##in, (, from, a, cd, ##na, originally, named, chop, ##1, and, chop, ##2, but, also, termed, ch, ##lam, ##yo, ##ps, ##in, ,, cop, ##3, or, cop, ##4, ), and, all, -, trans, re, ##tina, ##l, (, na, ##gel, et, al, ., 2003, ), ., dei, ##sser, ##oth, and, colleagues, red, ##id, the, math, and, prove, that, “, chop, ##2, ”, successfully, worked, in, rat, hip, ##po, ##camp, ##al, primary, neurons, after, lent, ##iv, ##ira, ##l, trans, ##duction, without, adding, all, -, trans, re, ##tina, ##l, at, all, (, although, the, culture, media, contained, little, amounts, of, the, precursor, re, ##tin, ##yl, ace, ##tate, ), ., by, this, ,, ch, ##r, ##2, was, established, as, a, new, one, -, component, functional, tool, for, neuroscience, in, mammals, neither, requiring, the, substitution, of, any, synthetic, chemical, substrate, nor, genetic, orthogonal, ##ity, between, the, r, ##ho, ##do, ##ps, ##in, and, the, targeted, host, organism, ,, even, more, important, as, there, is, no, mammalian, analog, of, the, al, ##gal, gene, chop, ##2, (, boyd, ##en, et, al, ., 2005, ), ., the, first, in, vivo, applications, in, living, animals, were, put, into, practice, in, parallel, by, li, et, al, ., (, 2005, ), and, na, ##gel, et, al, ., (, 2005, ), ., trans, ##genic, expression, of, ch, ##r, ##2, specifically, in, cho, ##liner, ##gic, motor, ##ne, ##uron, ##s, of, c, ., el, ##egan, ##s, allowed, to, eli, ##cit, behavioral, responses, via, muscular, contraction, ##s, by, blue, light, illumination, (, na, ##gel, et, al, ., 2005, ), ., bid, ##ire, ##ction, ##al, ,, both, inhibitor, ##y, and, ex, ##cit, ##atory, in, vivo, control, of, spontaneous, chick, spinal, cord, activity, was, performed, in, chicken, embryo, ##s, after, in, o, ##vo, electro, ##por, ##ating, and, transient, expression, of, ch, ##r, ##2, and, ve, ##rte, ##brate, ro, ##4, ,, respectively, (, li, et, al, ., 2005, ), ., another, example, of, bid, ##ire, ##ction, ##al, in, vivo, control, of, c, ., el, ##egan, ##s, loco, ##mot, ##ion, was, achieved, after, simultaneous, expression, of, ch, ##r, ##2, and, np, ##hr, using, the, muscle, -, specific, my, ##osi, ##n, promoter, pm, ##yo, -, 3, (, zhang, et, al, ., 2007, ##a, ), ., as, mentioned, above, c, ., el, ##egan, ##s, has, also, been, used, for, an, in, vivo, all, -, optical, interrogation, of, neural, circuits, using, ch, ##r, ##2, and, g, -, camp, (, guo, et, al, ., 2009, ), ., the, first, use, of, opt, ##ogen, ##etic, ##s, in, zebra, ##fish, revealed, that, activation, of, zebra, ##fish, tri, ##ge, ##mina, ##l, neurons, by, ch, ##r, ##2, induce, ##s, escape, behavior, even, upon, single, spikes, ,, as, published, by, douglass, et, al, ., (, 2008, ), ., by, using, gal, ##4, enhance, ##r, trapping, in, zebra, ##fish, ,, trans, ##genic, animals, can, be, generated, in, a, feasible, way, (, scott, et, al, ., 2007, ), ., the, bayer, lab, efficiently, used, the, gal, ##4, /, ua, ##s, system, to, selective, ##ly, express, ch, ##r, ##2, and, np, ##hr, in, specific, ne, ##uron, ##al, sub, ##pop, ##ulation, ##s, of, zebra, ##fish, larvae, ., owing, to, the, transparent, nature, of, the, animal, in, vivo, functional, mapping, at, a, single, ne, ##uron, resolution, was, performed, di, ##sse, ##cting, ne, ##uron, ##al, populations, involved, in, swim, behavior, ,, sac, ##cade, generation, as, well, cardiac, development, and, function, (, ar, ##ren, ##berg, et, al, ., 2009, ,, 2010, ;, sc, ##ho, ##on, ##heim, et, al, ., 2010, ), ., gal, ##4, /, ua, ##s, was, also, used, to, introduce, ch, ##r, ##2, into, specific, subset, ##s, of, ne, ##uron, ##al, populations, (, pain, ##less, ), in, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, by, crossing, trans, ##genic, ua, ##s, -, ch, ##r, ##2, flies, with, neurons, ##pe, ##ci, ##fi, ##c, gal, ##4, trans, ##genic, lines, (, zhang, et, al, ., 2007, ##c, ), ., optical, stimulation, of, no, ##cic, ##eptive, neurons, in, trans, ##genic, larvae, by, ch, ##r, ##2, induced, behavioral, responses, ., however, ,, it, has, to, be, taken, into, account, that, d, ., mel, ##ano, ##gas, ##ter, and, zebra, ##fish, contain, hydro, ##xy, ##ret, ##inal, which, does, not, enter, the, ch, ##r, or, hr, binding, sites, making, a, substitution, of, all, -, trans, re, ##tina, ##l, necessary, (, for, example, by, food, supplement, ), ., moreover, ,, interpretation, of, behavioral, data, in, d, ., mel, ##ano, ##gas, ##ter, can, be, conflicting, as, the, animal, has, an, innate, behavioral, light, response, (, pu, ##lver, et, al, ., 2009, ), ., the, species, most, widely, investigated, with, opt, ##ogen, ##etic, technologies, is, the, mouse, ., this, is, largely, owing, to, the, vast, availability, of, trans, ##genic, cr, ##e, driver, lines, ,, which, can, readily, be, combined, with, cr, ##e, -, dependent, viral, vectors, in, order, to, facilitate, strong, cell, -, /, tissue, -, specific, r, ##ho, ##do, ##ps, ##in, expression, (, fig, ., 2, ), ., as, mentioned, above, ,, in, mice, also, classical, trans, ##genic, approaches, have, been, applied, to, express, ch, ##r, ##2, and, np, ##hr, under, the, control, of, the, thy, -, 1, promoter, ., aren, ##kie, ##l, et, al, ., (, 2007, ), showed, strong, and, functional, ,, regional, ##ly, restricted, ,, channel, ##rh, ##od, ##ops, ##in, expression, in, thy, ##1, :, :, ch, ##r, ##2, -, e, ##y, ##fp, mouse, strains, ., by, pre, ##sy, ##na, ##ptic, optical, manipulation, of, targeted, cells, in, the, bulb, ##ar, -, co, ##rti, ##cal, circuit, of, the, ol, ##factory, system, they, highlighted, the, potential, of, opt, ##ogen, ##etic, ##s, for, complex, circuit, analysis, in, brain, slices, and, in, vivo, ., wang, et, al, ., (, 2007, ), used, trans, ##genic, thy, ##1, -, ch, ##r, ##2, -, y, ##fp, mice, for, the, mapping, of, functional, connectivity, in, the, neural, circuit, ##ry, of, co, ##rti, ##cal, layer, vi, neurons, ., in, order, to, study, the, role, of, fast, sp, ##iki, ##ng, par, ##val, ##bu, ##min, intern, ##eur, ##ons, in, the, generation, of, gamma, os, ##ci, ##llation, ##s, ,, thy, ##1, :, :, ch, ##r, ##2, -, e, ##y, ##fp, mice, were, analyzed, in, combination, with, a, cr, ##e, -, dependent, approach, (, so, ##hal, et, al, ., 2009, ), ., this, animal, model, in, combination, with, a, cell, type, -, specific, lent, ##iv, ##ira, ##l, approach, was, also, successfully, used, in, the, systematic, di, ##sse, ##ction, of, circuits, and, dec, ##ip, ##hering, of, potential, targets, related, to, deep, brain, stimulation, in, a, parkinson, mouse, model, (, gr, ##adi, ##nar, ##u, et, al, ., 2009, ), ., ha, ##gg, ##lund, and, colleagues, used, ba, ##c, trans, ##genesis, to, express, ch, ##r, ##2, -, e, ##y, ##fp, under, the, control, of, the, ve, ##sic, ##ular, g, ##lu, ##tama, ##te, receptor, two, promoter, ., these, trans, ##genic, mice, express, ch, ##r, ##2, in, g, ##lu, ##tama, ##ter, ##gic, neurons, of, the, hind, ##bra, ##in, and, spinal, cord, ., by, optical, stimulation, of, the, lu, ##mba, ##r, region, of, the, spinal, cord, and, also, the, ca, ##uda, ##l, hind, ##bra, ##in, rhythm, generation, was, observed, ,, suggesting, a, role, of, g, ##lu, ##tama, ##ter, ##gic, neurons, in, central, pattern, generators, of, loco, ##mot, ##ion, (, ha, ##gg, ##lund, et, al, ., 2010, ), ., various, examples, in, ne, ##mat, ##odes, ,, mice, and, rats, have, demonstrated, a, direct, effect, of, in, vivo, opt, ##ogen, ##etic, stimulation, on, ne, ##uron, ##al, activity, and, behavioral, responses, (, na, ##gel, et, al, ., 2005, ;, gr, ##adi, ##nar, ##u, et, al, ., 2009, ;, ts, ##ai, et, al, ., 2009, ;, lee, et, al, ., 2010, ), ., yet, optical, control, of, co, ##rti, ##cal, circuits, in, higher, organisms, might, be, more, complex, :, the, first, opt, ##ogen, ##etic, approach, in, primate, ##s, was, performed, in, the, r, ##hes, ##us, mac, ##aq, ##ue, ., boyd, ##en, and, colleagues, targeted, specifically, ex, ##cit, ##atory, neurons, of, the, frontal, cortex, by, stereo, ##ta, ##ctic, lent, ##iv, ##ira, ##l, gene, delivery, of, ch, ##r, ##2, -, g, ##fp, driven, by, the, cam, ##ki, ##i, ##α, promoter, and, recorded, ne, ##uron, ##al, activity, after, simultaneous, optical, stimulation, via, an, opt, ##rod, ##e, (, han, et, al, ., 2009, ), ., besides, showing, the, feasibility, and, safety, of, opt, ##ogen, ##etic, ##s, in, primate, ##s, and, thereby, implementing, a, potential, clinical, translation, for, the, use, in, humans, ,, the, experiments, showed, a, slightly, disco, ##ura, ##ging, ,, but, seminal, ,, result, ., although, ch, ##r, ##2, was, targeted, specifically, to, ex, ##cit, ##atory, neurons, a, significant, proportion, of, recorded, cells, showed, decreased, activity, ., this, finding, was, previously, also, observed, in, trans, ##genic, thy, ##1, -, ch, ##r, ##2, mice, and, is, comparable, to, het, ##ero, ##gen, ##eous, tissue, activation, in, the, case, of, electrical, stimulation, ., thus, ,, targeting, co, ##rti, ##cal, circuits, in, a, cell, type, -, specific, manner, cannot, precisely, predict, a, specific, psychological, response, ,, respectively, ,, behavioral, or, clinical, outcome, ., the, impact, of, opt, ##ogen, ##etic, manipulation, on, co, ##rti, ##cal, circuit, ##ries, seems, to, be, heavily, dependent, on, the, neural, network, ,, in, which, the, target, cells, are, embedded, ., nevertheless, ,, the, results, indicate, important, aspects, for, therapeutic, options, and, suggest, lent, ##iv, ##ira, ##l, r, ##ho, ##do, ##ps, ##in, delivery, as, a, well, im, ##mun, ##o, -, tolerated, method, for, a, put, ##ative, application, in, humans, .'},\n", + " {'article_id': '8809b39645cfee8416366a91cc615729',\n", + " 'section_name': 'Habituation, familiarization, and test delays',\n", + " 'text': 'The NOR test consists of the habituation phase, the familiarization phase, and finally the test phase. The time that animal spent during each of these phases as well as the delay between them can differ from study to study (for details, see Table 2).Table 2Habituation, familiarization, and test phase in the NOR paradigmHabituation phase1 day, with different duration and number of sessionsOne session: 3 min (Aubele et al. 2008), 5 min (Goulart et al. 2010; Oliveira et al. 2010; Walf et al. 2009), 6 min (Silvers et al. 2007), 10 min (Bevins et al. 2002; Botton et al. 2010; Gaskin et al. 2010; Hale and Good 2005; Wang et al. 2009); two sessions: 10 min (Taglialatela et al. 2009), four sessions: ~20–30 min (Piterkin et al. 2008)2–5 consecutive days with different duration2 days: 5 min (Albasser et al. 2009; Hammond et al. 2004), 10 min (Bevins et al., Gaskin et al. 2010; Burke et al. 2010), 3 days: 5, 10 or 30 min (Benice and Raber 2006; Herring et al. 2008; Reger et al. 2009; Sarkisyan and Hedlund 2009), 4 days, 20 min (Clarke et al. 2010), 10 min (Williams et al. 2007), 5 days, 5 min (Clark et al. 2000; Oliveira et al. 2010)Familiarization phase1 day, with different duration and number of sessions3 or 5 min (Ennaceur and Delacour 1988), 3 min (Aubele et al. 2008; Ennaceur and Delacour 1988; Reger et al. 2009; Nanfaro et al. 2010; Walf et al. 2009), 4 min (Burke et al. 2010), 5 min (Clarke et al. 2010; Ennaceur and Delacour 1988; Reger et al. 2009), 10 min (Botton et al. 2010; Frumberg et al. 2007; Hale and Good 2005; Taglialatela et al. 2009; Wang et al. 2007), 15 min (Nanfaro et al. 2010), three consecutive 10-min trials (Benice and Raber 2008)2–5 consecutive days with different duration2 days (Ennaceur 2010, Silvers et al. 2007), 3 days (Benice et al. 2006—5 min; Sarkisyan and Hedlund 2009—5 min; Schindler et al. 2010—6 min), 5 days (Weible et al. 2009—10 min)Time of contact with an object20 s (Ennaceur and Delacour 1988; Stemmelin et al. 2008), 30 s (Buckmaster et al. 2004; Clark et al. 2010, Herring et al. 2008; Goulart et al. 2010; Williams et al. 2007), 38 s (Hammond et al. 2004), 5 min (Stemmelin et al. 2008), 10 min (Hammond et al. 2004; Williams et al. 2007), 20 min (Goulart et al. 2010)Delay between the familiarization and the test phase10 s (Clark et al. 2000), 1 min (Ennaceur 2010; Ennaceur and Delacour 1988), 2 min (Hale and Good 2005; Taglialatela et al. 2009), 5 min (Hammond et al. 2004), 15 min (Gaskin et al. 2010; Reger et al. 2009; Piterkin et al. 2008), 10 min (Clark et al. 2000), 30 min (Hale and Good 2005), 1 h (Clark et al. 2000; Piterkin et al. 2008; Reger et al. 2009; Stemmelin et al. 2008; Williams et al. 2007), 3 h (Gaskin et al. 2010), 4 h (Aubele et al. 2008; Frumberg et al. 2007; Taglialatela et al. 2009; Walf et al. 2009), 24 h (Albasser et al. 2009; Bevins et al. 2002; Botton et al. 2010; Burke et al. 2010; Clark et al. 2000; Clarke et al. 2010; Ennaceur and Delacour 1988; Gaskin et al. 2010; Goulart et al. 2010; Hale and Good 2005; Herring et al. 2008; Nanfaro et al. 2010; Reger et al. 2009; Wang et al. 2007), 48 h (Ennaceur and Delacour 1988)Test phase1 day, with different duration and number of sessions3 min (Aubele et al. 2008; Clarke et al. 2010; Ennaceur 2010; Ennaceur and Delacour 1988; Reger et al. 2009; Nanfaro et al. 2010; Stemmelin et al. 2008), 4 min (Burke et al. 2010), 5 min (Clarke et al. 2010; Frumberg et al. 2007; Gaskin et al. 2010; Goulart et al. 2010; Mumby et al. 2002), 6 min (Silvers et al. 2007; Schindler et al. 2010), 10 min (Bevins et al. 2002; Hale and Good 2005; Taglialatela et al. 2009; Wang et al. 2007), 15 min (Oliveira et al. 2010), two consecutive 10-min trials (Benice and Raber 2008, Benice et al. 2006)2–6 consecutive days with different duration2 days: 3 or 5 min (Ennaceur and Delacour 1988; Sarkisyan and Hedlund 2009), 6 days: 5 min (Weible et al. 2009)',\n", + " 'paragraph_id': 24,\n", + " 'tokenizer': 'the, nor, test, consists, of, the, habit, ##uation, phase, ,, the, familiar, ##ization, phase, ,, and, finally, the, test, phase, ., the, time, that, animal, spent, during, each, of, these, phases, as, well, as, the, delay, between, them, can, differ, from, study, to, study, (, for, details, ,, see, table, 2, ), ., table, 2, ##hab, ##it, ##uation, ,, familiar, ##ization, ,, and, test, phase, in, the, nor, paradigm, ##hab, ##it, ##uation, phase, ##1, day, ,, with, different, duration, and, number, of, sessions, ##one, session, :, 3, min, (, au, ##bel, ##e, et, al, ., 2008, ), ,, 5, min, (, go, ##ular, ##t, et, al, ., 2010, ;, oliveira, et, al, ., 2010, ;, wal, ##f, et, al, ., 2009, ), ,, 6, min, (, silver, ##s, et, al, ., 2007, ), ,, 10, min, (, be, ##vin, ##s, et, al, ., 2002, ;, bot, ##ton, et, al, ., 2010, ;, gas, ##kin, et, al, ., 2010, ;, hale, and, good, 2005, ;, wang, et, al, ., 2009, ), ;, two, sessions, :, 10, min, (, tag, ##lia, ##late, ##la, et, al, ., 2009, ), ,, four, sessions, :, ~, 20, –, 30, min, (, pit, ##er, ##kin, et, al, ., 2008, ), 2, –, 5, consecutive, days, with, different, duration, ##2, days, :, 5, min, (, alba, ##sser, et, al, ., 2009, ;, hammond, et, al, ., 2004, ), ,, 10, min, (, be, ##vin, ##s, et, al, ., ,, gas, ##kin, et, al, ., 2010, ;, burke, et, al, ., 2010, ), ,, 3, days, :, 5, ,, 10, or, 30, min, (, ben, ##ice, and, ra, ##ber, 2006, ;, herring, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, ), ,, 4, days, ,, 20, min, (, clarke, et, al, ., 2010, ), ,, 10, min, (, williams, et, al, ., 2007, ), ,, 5, days, ,, 5, min, (, clark, et, al, ., 2000, ;, oliveira, et, al, ., 2010, ), familiar, ##ization, phase, ##1, day, ,, with, different, duration, and, number, of, sessions, ##3, or, 5, min, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ), ,, 3, min, (, au, ##bel, ##e, et, al, ., 2008, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, reg, ##er, et, al, ., 2009, ;, nan, ##far, ##o, et, al, ., 2010, ;, wal, ##f, et, al, ., 2009, ), ,, 4, min, (, burke, et, al, ., 2010, ), ,, 5, min, (, clarke, et, al, ., 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, reg, ##er, et, al, ., 2009, ), ,, 10, min, (, bot, ##ton, et, al, ., 2010, ;, fr, ##umber, ##g, et, al, ., 2007, ;, hale, and, good, 2005, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ;, wang, et, al, ., 2007, ), ,, 15, min, (, nan, ##far, ##o, et, al, ., 2010, ), ,, three, consecutive, 10, -, min, trials, (, ben, ##ice, and, ra, ##ber, 2008, ), 2, –, 5, consecutive, days, with, different, duration, ##2, days, (, en, ##nac, ##eur, 2010, ,, silver, ##s, et, al, ., 2007, ), ,, 3, days, (, ben, ##ice, et, al, ., 2006, —, 5, min, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, —, 5, min, ;, sc, ##hin, ##dler, et, al, ., 2010, —, 6, min, ), ,, 5, days, (, wei, ##ble, et, al, ., 2009, —, 10, min, ), time, of, contact, with, an, object, ##20, s, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, stem, ##mel, ##in, et, al, ., 2008, ), ,, 30, s, (, buck, ##master, et, al, ., 2004, ;, clark, et, al, ., 2010, ,, herring, et, al, ., 2008, ;, go, ##ular, ##t, et, al, ., 2010, ;, williams, et, al, ., 2007, ), ,, 38, s, (, hammond, et, al, ., 2004, ), ,, 5, min, (, stem, ##mel, ##in, et, al, ., 2008, ), ,, 10, min, (, hammond, et, al, ., 2004, ;, williams, et, al, ., 2007, ), ,, 20, min, (, go, ##ular, ##t, et, al, ., 2010, ), delay, between, the, familiar, ##ization, and, the, test, phase, ##10, s, (, clark, et, al, ., 2000, ), ,, 1, min, (, en, ##nac, ##eur, 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ), ,, 2, min, (, hale, and, good, 2005, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ), ,, 5, min, (, hammond, et, al, ., 2004, ), ,, 15, min, (, gas, ##kin, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ;, pit, ##er, ##kin, et, al, ., 2008, ), ,, 10, min, (, clark, et, al, ., 2000, ), ,, 30, min, (, hale, and, good, 2005, ), ,, 1, h, (, clark, et, al, ., 2000, ;, pit, ##er, ##kin, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, stem, ##mel, ##in, et, al, ., 2008, ;, williams, et, al, ., 2007, ), ,, 3, h, (, gas, ##kin, et, al, ., 2010, ), ,, 4, h, (, au, ##bel, ##e, et, al, ., 2008, ;, fr, ##umber, ##g, et, al, ., 2007, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ;, wal, ##f, et, al, ., 2009, ), ,, 24, h, (, alba, ##sser, et, al, ., 2009, ;, be, ##vin, ##s, et, al, ., 2002, ;, bot, ##ton, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, clarke, et, al, ., 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, hale, and, good, 2005, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ;, wang, et, al, ., 2007, ), ,, 48, h, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ), test, phase, ##1, day, ,, with, different, duration, and, number, of, sessions, ##3, min, (, au, ##bel, ##e, et, al, ., 2008, ;, clarke, et, al, ., 2010, ;, en, ##nac, ##eur, 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, reg, ##er, et, al, ., 2009, ;, nan, ##far, ##o, et, al, ., 2010, ;, stem, ##mel, ##in, et, al, ., 2008, ), ,, 4, min, (, burke, et, al, ., 2010, ), ,, 5, min, (, clarke, et, al, ., 2010, ;, fr, ##umber, ##g, et, al, ., 2007, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, mum, ##by, et, al, ., 2002, ), ,, 6, min, (, silver, ##s, et, al, ., 2007, ;, sc, ##hin, ##dler, et, al, ., 2010, ), ,, 10, min, (, be, ##vin, ##s, et, al, ., 2002, ;, hale, and, good, 2005, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ;, wang, et, al, ., 2007, ), ,, 15, min, (, oliveira, et, al, ., 2010, ), ,, two, consecutive, 10, -, min, trials, (, ben, ##ice, and, ra, ##ber, 2008, ,, ben, ##ice, et, al, ., 2006, ), 2, –, 6, consecutive, days, with, different, duration, ##2, days, :, 3, or, 5, min, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, ), ,, 6, days, :, 5, min, (, wei, ##ble, et, al, ., 2009, )'},\n", + " {'article_id': '8809b39645cfee8416366a91cc615729',\n", + " 'section_name': 'Animals',\n", + " 'text': 'The NOR test is widely used to evaluate object recognition memory in rodents and lead itself well cross-species generalization (Gaskin et al. 2010; Reger et al. 2009). Thus, it is important to understand what kind of animals has been used in the NOR test and which are their features (details presented in Table 1). Sometimes animals’ models with specific modifications were necessary. In Taglialatela et al.’s study (2009), transgenic animals to study Alzheimer’s disease (AD) have been used, since these mice suffer from progressive decline in several forms of declarative memory including fear conditioning and novel object recognition. For the same purpose, this kind of mice was also used in Hale and Good research (2005), once they studied the effect of a human amyloid precursor protein mutation that results in an autosomal dominant familial form of AD on processes supporting recognition memory, including object location memory.Table 1Animals used in the NOR testGenderRatsAggleton et al. 2010; Albasser et al. 2009; Aubele et al. 2008; Bevins et al. 2002; Broadbent et al. 2010; Burke et al. 2010; Clark et al. 2000; Ennaceur and Delacour 1988; Frumberg et al. 2007; Gaskin et al. 2010; Goulart et al. 2010; Herring et al. 2008; Nanfaro et al. 2010; Piterkin et al. 2008; Reger et al. 2009; Silvers et al. 2007MiceBenice and Raber 2008; Benice et al. 2006; Bilsland et al. 2008; Botton et al. 2010; Clarke et al. 2010; Dere et al. 2005; Hale and Good 2005; Hammond et al. 2004; Oliveira et al. 2010; Schindler et al. 2010; Wang et al. 2007; Weible et al. 2009SexMalesAggleton et al. 2010; Aubele et al. 2008; Bevins et al. 2002; Botton et al. 2010; Burke et al. 2010; Clark et al. 2000; Dere et al. 2005; Ennaceur and Delacour 1988; Frumberg et al. 2007; Gaskin et al. 2010; Goulart et al. 2010; Hammond et al. 2004; Herring et al. 2008; Nanfaro et al. 2010; Oliveira et al. 2010; Piterkin et al. 2008; Reger et al. 2009; Silvers et al. 2007; Schindler et al. 2010; Wang et al. 2007Both males and femalesBilsland et al. 2008; Hale and Good 2005AgeAnimals 2–4 months oldClark et al. 2000; Clarke et al. 2010; Dere et al. 2005; Frumberg et al. 2007; Goulart et al. 2010; Hammond et al. 2004; Mumby et al. 2002; Oliveira et al. 2010; Nanfaro et al. 2010; Piterkin et al. 2008; Walf et al. 2009Immature, i.e., 20–23 days (weanling), 29–40 days (juvenile), and more than 50 days (young adulthood) oldReger et al. 2009Aged, i.e., 7–9 months and 24–25 months oldBurke et al. 2010HousingIndividual cageBroadbent et al. 2010; Burke et al. 2010; Ennaceur and Delacour 1988; Gaskin et al. 2010; Mumby et al. 2002; Oliveira et al. 2010; Piterkin et al. 2008In groups of 2–5/cageAggleton et al. 2010; Botton et al. 2010; Goulart et al. 2010; Herring et al. 2008; Nanfaro et al. 2010FeedingAd libitumAggleton et al. 2010; Albasser et al. 2009; Aubele et al. 2008; Bevins et al. 2002; Bilsland et al. 2008; Botton et al. 2010; Broadbent et al. 2010; Burke et al. 2010; Clark et al. 2000; Clarke et al. 2010; Goulart et al. 2010; Hammond et al. 2004; Herring et al. 2008; Nanfaro et al. 2010; Oliveira et al. 2010; Reger et al. 2009; Sarkisyan and Hedlund 2009; Silvers et al. 2007; Schindler et al. 2010; Wang et al. 2007Access restricted, 25–30 g/dayBenice et al. 2006; Gaskin et al. 2010; Piterkin et al. 2008 Mumby et al. 2002',\n", + " 'paragraph_id': 18,\n", + " 'tokenizer': 'the, nor, test, is, widely, used, to, evaluate, object, recognition, memory, in, rodents, and, lead, itself, well, cross, -, species, general, ##ization, (, gas, ##kin, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ), ., thus, ,, it, is, important, to, understand, what, kind, of, animals, has, been, used, in, the, nor, test, and, which, are, their, features, (, details, presented, in, table, 1, ), ., sometimes, animals, ’, models, with, specific, modifications, were, necessary, ., in, tag, ##lia, ##late, ##la, et, al, ., ’, s, study, (, 2009, ), ,, trans, ##genic, animals, to, study, alzheimer, ’, s, disease, (, ad, ), have, been, used, ,, since, these, mice, suffer, from, progressive, decline, in, several, forms, of, dec, ##lar, ##ative, memory, including, fear, conditioning, and, novel, object, recognition, ., for, the, same, purpose, ,, this, kind, of, mice, was, also, used, in, hale, and, good, research, (, 2005, ), ,, once, they, studied, the, effect, of, a, human, amy, ##loid, precursor, protein, mutation, that, results, in, an, auto, ##som, ##al, dominant, fa, ##mi, ##lia, ##l, form, of, ad, on, processes, supporting, recognition, memory, ,, including, object, location, memory, ., table, 1a, ##ni, ##mal, ##s, used, in, the, nor, test, ##gen, ##der, ##rat, ##sa, ##ggle, ##ton, et, al, ., 2010, ;, alba, ##sser, et, al, ., 2009, ;, au, ##bel, ##e, et, al, ., 2008, ;, be, ##vin, ##s, et, al, ., 2002, ;, broad, ##ben, ##t, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, fr, ##umber, ##g, et, al, ., 2007, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, silver, ##s, et, al, ., 2007, ##mic, ##eb, ##eni, ##ce, and, ra, ##ber, 2008, ;, ben, ##ice, et, al, ., 2006, ;, bi, ##ls, ##land, et, al, ., 2008, ;, bot, ##ton, et, al, ., 2010, ;, clarke, et, al, ., 2010, ;, der, ##e, et, al, ., 2005, ;, hale, and, good, 2005, ;, hammond, et, al, ., 2004, ;, oliveira, et, al, ., 2010, ;, sc, ##hin, ##dler, et, al, ., 2010, ;, wang, et, al, ., 2007, ;, wei, ##ble, et, al, ., 2009, ##se, ##x, ##mal, ##esa, ##ggle, ##ton, et, al, ., 2010, ;, au, ##bel, ##e, et, al, ., 2008, ;, be, ##vin, ##s, et, al, ., 2002, ;, bot, ##ton, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, der, ##e, et, al, ., 2005, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, fr, ##umber, ##g, et, al, ., 2007, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, hammond, et, al, ., 2004, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, oliveira, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, silver, ##s, et, al, ., 2007, ;, sc, ##hin, ##dler, et, al, ., 2010, ;, wang, et, al, ., 2007, ##bot, ##h, males, and, females, ##bil, ##sl, ##and, et, al, ., 2008, ;, hale, and, good, 2005, ##age, ##ani, ##mal, ##s, 2, –, 4, months, old, ##cl, ##ark, et, al, ., 2000, ;, clarke, et, al, ., 2010, ;, der, ##e, et, al, ., 2005, ;, fr, ##umber, ##g, et, al, ., 2007, ;, go, ##ular, ##t, et, al, ., 2010, ;, hammond, et, al, ., 2004, ;, mum, ##by, et, al, ., 2002, ;, oliveira, et, al, ., 2010, ;, nan, ##far, ##o, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ;, wal, ##f, et, al, ., 2009, ##im, ##mat, ##ure, ,, i, ., e, ., ,, 20, –, 23, days, (, we, ##an, ##ling, ), ,, 29, –, 40, days, (, juvenile, ), ,, and, more, than, 50, days, (, young, adulthood, ), old, ##re, ##ger, et, al, ., 2009, ##aged, ,, i, ., e, ., ,, 7, –, 9, months, and, 24, –, 25, months, old, ##bu, ##rke, et, al, ., 2010, ##ho, ##using, ##ind, ##iv, ##id, ##ual, cage, ##bro, ##ad, ##ben, ##t, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, gas, ##kin, et, al, ., 2010, ;, mum, ##by, et, al, ., 2002, ;, oliveira, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ##in, groups, of, 2, –, 5, /, cage, ##ag, ##gle, ##ton, et, al, ., 2010, ;, bot, ##ton, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ##fe, ##eding, ##ad, li, ##bit, ##uma, ##ggle, ##ton, et, al, ., 2010, ;, alba, ##sser, et, al, ., 2009, ;, au, ##bel, ##e, et, al, ., 2008, ;, be, ##vin, ##s, et, al, ., 2002, ;, bi, ##ls, ##land, et, al, ., 2008, ;, bot, ##ton, et, al, ., 2010, ;, broad, ##ben, ##t, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, clarke, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, hammond, et, al, ., 2004, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, oliveira, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, ;, silver, ##s, et, al, ., 2007, ;, sc, ##hin, ##dler, et, al, ., 2010, ;, wang, et, al, ., 2007, ##ac, ##ces, ##s, restricted, ,, 25, –, 30, g, /, day, ##ben, ##ice, et, al, ., 2006, ;, gas, ##kin, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, mum, ##by, et, al, ., 2002'},\n", + " {'article_id': 'ac288501c74bcc85673f9b4b8e2a8432',\n", + " 'section_name': '3 RESULTS',\n", + " 'text': 'To evaluate the precision of the predicted connections, we manually reviewed a random subset of 2000 abstracts. Each pair was evaluated by two curators, yielding an interannotator agreement rate of 85%. Conflicts were resolved by a third curator or by consensus after discussion. Overall, the SLK predictions were 55.3% precise. Errors from the automated steps of named entity recognition and abbreviation expansion were 11% and 4%, respectively. These rates suggest a lesser impact of named entity recognition errors when compared with assessments in the protein–protein interaction domain (Kabiljo et al., 2009). Table 2 presents the five most and least confident connectivity relations for the rat brain. Classification confidence is approximated with the SLK prediction score (distance to classifying hyperplane), with highest values representing the cases closest to positive training examples. Two of the most confident predictions are extracted from an article title and have the same form (ranks 1 and 5). The sentences containing top predictions are shorter on average (192 characters) than the sentences with least confident predictions (282 characters), suggesting sentence complexity affects the prediction results. Of these 10 examples, only one is clearly a false-positive prediction (rank 9764), while several others point to errors in previous automated steps. The mentions of ‘internal capsule’ (rank 9766) and ‘Met-enkephalin’ (rank 4) are incorrectly predicted as brain region mentions (our definition of a brain region excludes fibre tracts like the internal capsule, while enkephalin is a peptide). We manually compared these 10 results with the BAMS system and found it surprisingly difficult to map the mentioned regions to those in BAMS. For example, ‘retrosplenial dysgranular cortex’ and ‘dorsal medullary reticular column’ were not found in BAMS. In the end, corresponding connections were found in BAMS for several of the relationships, but only between enclosing regions (ranks 9767 and 5).\\nTable 2.Top- and bottom-predicted relations from the 12 557 abstract set, ranked by SLK classification scoreRankSentenceScoreReference1Trigeminal projections to hypoglossal and facial motor nuclei in the rat.3.47Pinganaud, et al., 19992The cortical projections to retrosplenial dysgranular cortex (Rdg) originate primarily in the infraradiata, retrosplenial, postsubicular and areas 17 and 18b cortices.3.34van Groen and Wyss, 19923The thalamic projections to retrosplenial dysgranular cortex (Rdg) originate in the anterior (primarily the anteromedial), lateral (primarily the laterodorsal) and reuniens nuclei.3.33van Groen and Wyss, 19924Our results indicate that the centromedial amygdala receives Met-enkephalin afferents, as indicated by the presence of mu-opioid receptor, delta-opioid receptor and Met-enkephalin fibres in the CEA and MEA, originating primarily from the bed nucleus of the stria terminalis and from other amygdaloid nuclei.3.32Poulin, et al., 20065Thalamic projections to retrosplenial cortex in the rat.3.28Sripanidkulchai and Wyss, 1986...9757 relationships9763The sparse reciprocal connections to the other amygdaloid nuclei suggest that the CEA nucleus does not regulate the other amygdaloid regions, but rather executes the responses evoked by the other amygdaloid nuclei that innervate the CEA nucleus.5.46 × 10^−4Jolkkonen and Pitkanen, 19989764The majority of the endomorphin 1/fluoro-gold and endomorphin 2/fluoro-gold double-labelled neurons in the hypothalamus were distributed in the dorsomedial nucleus, areas between the dorsomedial and ventromedial nucleus and arcuate nucleus; a few were also seen in the ventromedial, periventricular and posterior nucleus.4.36 × 10^−4Chen, et al., 20089765Projections from the dorsal medullary reticular column are largely bilateral and are distributed preferentially to the ventral subdivision of the fifth cranial nerve motor nuclei in the rat (MoV), to the dorsal and intermediate subdivisions of VII and to both the dorsal and the ventral subdivision of XII.2.91 × 10^−4Cunningham and Sawchenko, 20009766Two additional large projections leave the MEA forebrain bundle in the hypothalamus; the ansa peduncularis–ventral amygdaloid bundle system turns laterally through the internal capsule into the striatal complex, amygdala and the external capsule to reach lateral and posterior cortex, and another system of fibers turns medially to innervate MEA hypothalamus and median eminence and forms a contralateral projection through the supraoptic commissures.2.87 × 10^−4Moore, et al., 19789767In animals with injected horseradish peroxidase confined within the main bulb, perikarya retrogradely labelled with the protein in the ipsilateral forebrain were observed in the anterior prepyriform cortex horizontal limb of the nucleus of the diagonal band, and far lateral preoptic and rostral lateral hypothalamic areas.3.36 × 10^−5Broadwell and Jacobowitz, 1976CEA, central; MEA, medial; MoV, the fifth cranial nerve motor nuclei in the rat.',\n", + " 'paragraph_id': 25,\n", + " 'tokenizer': 'to, evaluate, the, precision, of, the, predicted, connections, ,, we, manually, reviewed, a, random, subset, of, 2000, abstracts, ., each, pair, was, evaluated, by, two, curator, ##s, ,, yielding, an, inter, ##ann, ##ota, ##tor, agreement, rate, of, 85, %, ., conflicts, were, resolved, by, a, third, curator, or, by, consensus, after, discussion, ., overall, ,, the, sl, ##k, predictions, were, 55, ., 3, %, precise, ., errors, from, the, automated, steps, of, named, entity, recognition, and, abbreviation, expansion, were, 11, %, and, 4, %, ,, respectively, ., these, rates, suggest, a, lesser, impact, of, named, entity, recognition, errors, when, compared, with, assessments, in, the, protein, –, protein, interaction, domain, (, ka, ##bil, ##jo, et, al, ., ,, 2009, ), ., table, 2, presents, the, five, most, and, least, confident, connectivity, relations, for, the, rat, brain, ., classification, confidence, is, approximate, ##d, with, the, sl, ##k, prediction, score, (, distance, to, classify, ##ing, hyper, ##plane, ), ,, with, highest, values, representing, the, cases, closest, to, positive, training, examples, ., two, of, the, most, confident, predictions, are, extracted, from, an, article, title, and, have, the, same, form, (, ranks, 1, and, 5, ), ., the, sentences, containing, top, predictions, are, shorter, on, average, (, 192, characters, ), than, the, sentences, with, least, confident, predictions, (, 282, characters, ), ,, suggesting, sentence, complexity, affects, the, prediction, results, ., of, these, 10, examples, ,, only, one, is, clearly, a, false, -, positive, prediction, (, rank, 97, ##64, ), ,, while, several, others, point, to, errors, in, previous, automated, steps, ., the, mentions, of, ‘, internal, capsule, ’, (, rank, 97, ##66, ), and, ‘, met, -, en, ##ke, ##pha, ##lin, ’, (, rank, 4, ), are, incorrectly, predicted, as, brain, region, mentions, (, our, definition, of, a, brain, region, exclude, ##s, fibre, tracts, like, the, internal, capsule, ,, while, en, ##ke, ##pha, ##lin, is, a, peptide, ), ., we, manually, compared, these, 10, results, with, the, bam, ##s, system, and, found, it, surprisingly, difficult, to, map, the, mentioned, regions, to, those, in, bam, ##s, ., for, example, ,, ‘, retro, ##sp, ##len, ##ial, d, ##ys, ##gra, ##nu, ##lar, cortex, ’, and, ‘, dorsal, med, ##ulla, ##ry, re, ##tic, ##ular, column, ’, were, not, found, in, bam, ##s, ., in, the, end, ,, corresponding, connections, were, found, in, bam, ##s, for, several, of, the, relationships, ,, but, only, between, en, ##cl, ##osing, regions, (, ranks, 97, ##6, ##7, and, 5, ), ., table, 2, ., top, -, and, bottom, -, predicted, relations, from, the, 12, 55, ##7, abstract, set, ,, ranked, by, sl, ##k, classification, scorer, ##an, ##ks, ##ente, ##nce, ##sco, ##rer, ##efe, ##rence, ##1, ##tri, ##ge, ##mina, ##l, projections, to, h, ##yp, ##og, ##los, ##sal, and, facial, motor, nuclei, in, the, rat, ., 3, ., 47, ##ping, ##ana, ##ud, ,, et, al, ., ,, 1999, ##2, ##the, co, ##rti, ##cal, projections, to, retro, ##sp, ##len, ##ial, d, ##ys, ##gra, ##nu, ##lar, cortex, (, rd, ##g, ), originate, primarily, in, the, in, ##fra, ##rad, ##ia, ##ta, ,, retro, ##sp, ##len, ##ial, ,, posts, ##ub, ##icular, and, areas, 17, and, 18, ##b, co, ##rti, ##ces, ., 3, ., 34, ##van, gr, ##oe, ##n, and, w, ##ys, ##s, ,, 1992, ##3, ##the, tha, ##lam, ##ic, projections, to, retro, ##sp, ##len, ##ial, d, ##ys, ##gra, ##nu, ##lar, cortex, (, rd, ##g, ), originate, in, the, anterior, (, primarily, the, ant, ##ero, ##media, ##l, ), ,, lateral, (, primarily, the, later, ##od, ##ors, ##al, ), and, re, ##uni, ##ens, nuclei, ., 3, ., 33, ##van, gr, ##oe, ##n, and, w, ##ys, ##s, ,, 1992, ##4, ##our, results, indicate, that, the, centro, ##media, ##l, amy, ##g, ##dal, ##a, receives, met, -, en, ##ke, ##pha, ##lin, af, ##fer, ##ents, ,, as, indicated, by, the, presence, of, mu, -, op, ##io, ##id, receptor, ,, delta, -, op, ##io, ##id, receptor, and, met, -, en, ##ke, ##pha, ##lin, fibre, ##s, in, the, ce, ##a, and, me, ##a, ,, originating, primarily, from, the, bed, nucleus, of, the, st, ##ria, terminal, ##is, and, from, other, amy, ##g, ##dal, ##oid, nuclei, ., 3, ., 32, ##po, ##ulin, ,, et, al, ., ,, 2006, ##5, ##thal, ##ami, ##c, projections, to, retro, ##sp, ##len, ##ial, cortex, in, the, rat, ., 3, ., 28, ##sr, ##ip, ##ani, ##d, ##ku, ##lch, ##ai, and, w, ##ys, ##s, ,, 1986, ., ., ., 97, ##57, relationships, ##9, ##7, ##6, ##3, ##the, sparse, reciprocal, connections, to, the, other, amy, ##g, ##dal, ##oid, nuclei, suggest, that, the, ce, ##a, nucleus, does, not, regulate, the, other, amy, ##g, ##dal, ##oid, regions, ,, but, rather, execute, ##s, the, responses, ev, ##oked, by, the, other, amy, ##g, ##dal, ##oid, nuclei, that, inner, ##vate, the, ce, ##a, nucleus, ., 5, ., 46, ×, 10, ^, −, ##4, ##jo, ##lk, ##kon, ##en, and, pit, ##kan, ##en, ,, 1998, ##9, ##7, ##64, ##the, majority, of, the, end, ##omo, ##rp, ##hin, 1, /, flu, ##oro, -, gold, and, end, ##omo, ##rp, ##hin, 2, /, flu, ##oro, -, gold, double, -, labelled, neurons, in, the, h, ##yp, ##oth, ##ala, ##mus, were, distributed, in, the, do, ##rso, ##media, ##l, nucleus, ,, areas, between, the, do, ##rso, ##media, ##l, and, vent, ##rom, ##ed, ##ial, nucleus, and, arc, ##uate, nucleus, ;, a, few, were, also, seen, in, the, vent, ##rom, ##ed, ##ial, ,, per, ##ive, ##nt, ##ric, ##ular, and, posterior, nucleus, ., 4, ., 36, ×, 10, ^, −, ##4, ##chen, ,, et, al, ., ,, 2008, ##9, ##7, ##65, ##pro, ##ject, ##ions, from, the, dorsal, med, ##ulla, ##ry, re, ##tic, ##ular, column, are, largely, bilateral, and, are, distributed, prefer, ##ential, ##ly, to, the, ventral, subdivision, of, the, fifth, cr, ##anial, nerve, motor, nuclei, in, the, rat, (, mo, ##v, ), ,, to, the, dorsal, and, intermediate, subdivisions, of, vii, and, to, both, the, dorsal, and, the, ventral, subdivision, of, xii, ., 2, ., 91, ×, 10, ^, −, ##4, ##cu, ##nni, ##ng, ##ham, and, saw, ##chenko, ,, 2000, ##9, ##7, ##66, ##t, ##wo, additional, large, projections, leave, the, me, ##a, fore, ##bra, ##in, bundle, in, the, h, ##yp, ##oth, ##ala, ##mus, ;, the, an, ##sa, pe, ##dun, ##cular, ##is, –, ventral, amy, ##g, ##dal, ##oid, bundle, system, turns, lateral, ##ly, through, the, internal, capsule, into, the, st, ##ria, ##tal, complex, ,, amy, ##g, ##dal, ##a, and, the, external, capsule, to, reach, lateral, and, posterior, cortex, ,, and, another, system, of, fibers, turns, medial, ##ly, to, inner, ##vate, me, ##a, h, ##yp, ##oth, ##ala, ##mus, and, median, emi, ##nen, ##ce, and, forms, a, contra, ##lateral, projection, through, the, su, ##pr, ##ao, ##ptic, com, ##mis, ##sure, ##s, ., 2, ., 87, ×, 10, ^, −, ##4, ##moor, ##e, ,, et, al, ., ,, 1978, ##9, ##7, ##6, ##7, ##in, animals, with, injected, horse, ##rad, ##ish, per, ##ox, ##ida, ##se, confined, within, the, main, bulb, ,, per, ##ika, ##rya, retro, ##grade, ##ly, labelled, with, the, protein, in, the, ip, ##sil, ##ater, ##al, fore, ##bra, ##in, were, observed, in, the, anterior, prep, ##yr, ##iform, cortex, horizontal, limb, of, the, nucleus, of, the, diagonal, band, ,, and, far, lateral, pre, ##op, ##tic, and, ro, ##stra, ##l, lateral, h, ##yp, ##oth, ##ala, ##mic, areas, ., 3, ., 36, ×, 10, ^, −, ##5, ##bro, ##ad, ##well, and, jacob, ##ow, ##itz, ,, 1976, ##cea, ,, central, ;, me, ##a, ,, medial, ;, mo, ##v, ,, the, fifth, cr, ##anial, nerve, motor, nuclei, in, the, rat, .'},\n", + " {'article_id': '001fd76c438a28e34b3f7360a0031cbb',\n", + " 'section_name': 'Available data on CSF–ECF relationships',\n", + " 'text': 'With the introduction of microdialysis techniques, the possibility of making a direct comparison of CSF and brain ECF concentrations in animals became available. Also, intrabrain distribution aspects of drugs could be determined. Sawchuk’s group at the University in Minnesota was the first to do so. In rats, zidovudine and stavudine concentration–time profiles were obtained in CSF and Brain ECF, and challenged by inhibition of active transport processes [50–52]. Shen et al. [27] provided an extensive overview on CSF and brain ECF concentrations for drugs from many therapeutic classes with a wide spectrum in physico-chemical properties. Appending data of more recent studies, Table 2 presents CSF -brain ECF relationships for a broad set of drugs, including the methodology of assessment. These values have resulted from microdialysis to obtain brain ECF as well as CSF concentrations, CSF sampling for assessing CSF concentrations, as well as he brain slice method to obtain brain ECF concentrations. The brain slice method estimates brain ECF concentrations by determining total brain concentrations after drug administration, and to correct for the free fraction as obtained in brain slices after bathing the slice in a buffer solution containing the drug(s) of interest [53, 54].Table 2Drugs and their Kpuu, CSF and Kpuu, brain values obtained in animals (rats, sheep, rabbits, rhesus monkeys, and nonhuman primates) on the basis of steady state (SS) values, AUC values, continuous infusion (cont inf)CompoundSpeciesTimeKpuu, CSFKpuu, brainReference9-OH-RisperidoneRat6 h cont inf0,06840,0143[61]AcetaminophenRatAUC (partial)0,31,2[25]AlovudineRatSS0,40,16[72]AntipyrineRat2 h cont inf0,990,708[56]AtomoxetineRatSS1,70,7[64]BaclofenRatPseudo SS0,0280,035[73]BenzylpenicillinRat2 h cont inf0,01340,0264[56]BuspironeRat2 h cont inf0,5580,612[56]CaffeineRat2 h cont inf1,030,584[56]CarbamazepineRat2 h cont inf0,5350,771[56]CarbamazepineRat6 h cont inf0,1670,232[61]CarboplatinNonhuman primateAUC0,050,05[74]CefodizimeRatSpecific time0,020,22[75]CeftazidimeRatSS0,0390,022[76]CeftriaxoneRatSS0,710,8[76]CephalexinRat2 h cont inf0,02250,016[56]CimetidineRat2 h cont inf0,02110,00981[56]CisplatinNonhuman primateAUC0,050,05[74]CitalopramRat2 h cont inf0,6670,494[56]CitalopramRat6 h cont inf0,50,559[61]CP-615,003RatSS0,010,0014[77]DaidzeinRat2 h cont inf0,1890,0667[56]DantroleneRat2 h cont inf0,08380,0297[56]DiazepamRat2 h cont inf0,8470,805[56]DiphenylhydramineSheepSS (adults)3,43,4[78]DiphenylhydramineSheepSS (30 d lambs)4,96,6[78]DiphenylhydramineSheepSS (10 d lambs)5,66,6[78]EAB515Rat15 h0,180,08[51]FlavopiridolRat2 h cont inf0,2160,0525[56]FleroxacinRat2 h cont inf0,2830,25[56]FleroxacinRatSS0,420,15[79]GanciclovirRat6 h cont inf0,06470,0711[61]GenisteinRat2 h cont inf0,5890,181[56]LamotrigineRatSS1,51[62]LoperamideRat2 h cont inf0,03760,00886[56]MetoclopramideRat6 h cont inf0,1690,235[61]MidazolamRat2 h cont inf1,352,19[56]MorphineRatAUC0,1970,51[80]M6GRatAUC0,0290,56[80]N-desmethylclozapineRat6 h cont inf0,01510,01[61]NorfloxacinRatSS0,0330,034[79]OfloxacinRatSS0,230,12[79]OxaliplatinNonhuman primateAUC0,655,3[74]PerfloxacinRat2 h cont inf0,3890,199[56]PerfloxacinRatSS0,370,15[79]PhenytoinRat2 h cont inf0,3960,447[56]PhenytoinRatAUC0,20,85[81]ProbenecidRatSS0,60,2[82]QuinidineRat2 h cont inf0,09110,026[56]QuinidineRat6 h cont inf0,09690,0459[61]RisperidoneRat2 h cont inf0,1240,0787[56]RisperidoneRat6 h cont inf0,09130,0422[61]SalicylateRatSS0,50,1[82]SDZ EAA 494RatAUC0,170,11[83]SertralineRat2 h cont inf0,8321,85[56]StavudineRatSS0,50,3[84]StavudineRatSS0,60,6[52]SulpirideRat2 h cont inf0,04990,0219[56]ThiopentalRat2 h cont inf0,5990,911[56]ThiopentalRat6 h cont inf0,06630,0663[61]TiagabineRatAUC0,0110,011[85]VerapamilRat2 h cont inf0,3330,0786[56]YM992RatSS1,71,4[86]ZidovudinRabbitAUC0,170,08[50]ZidovudinRabbitSS0,290,19[87]ZidovudinRhesus MonkeySS0,270,15[88]Zidovudin + probenecidRabbitAUC0,190,1[50]ZolpidemRat2 h cont inf0,4750,447[56]',\n", + " 'paragraph_id': 17,\n", + " 'tokenizer': 'with, the, introduction, of, micro, ##dial, ##ysis, techniques, ,, the, possibility, of, making, a, direct, comparison, of, cs, ##f, and, brain, ec, ##f, concentrations, in, animals, became, available, ., also, ,, intra, ##bra, ##in, distribution, aspects, of, drugs, could, be, determined, ., saw, ##chuk, ’, s, group, at, the, university, in, minnesota, was, the, first, to, do, so, ., in, rats, ,, z, ##ido, ##vu, ##dine, and, st, ##av, ##udi, ##ne, concentration, –, time, profiles, were, obtained, in, cs, ##f, and, brain, ec, ##f, ,, and, challenged, by, inhibition, of, active, transport, processes, [, 50, –, 52, ], ., shen, et, al, ., [, 27, ], provided, an, extensive, overview, on, cs, ##f, and, brain, ec, ##f, concentrations, for, drugs, from, many, therapeutic, classes, with, a, wide, spectrum, in, ph, ##ys, ##ico, -, chemical, properties, ., app, ##ending, data, of, more, recent, studies, ,, table, 2, presents, cs, ##f, -, brain, ec, ##f, relationships, for, a, broad, set, of, drugs, ,, including, the, methodology, of, assessment, ., these, values, have, resulted, from, micro, ##dial, ##ysis, to, obtain, brain, ec, ##f, as, well, as, cs, ##f, concentrations, ,, cs, ##f, sampling, for, assessing, cs, ##f, concentrations, ,, as, well, as, he, brain, slice, method, to, obtain, brain, ec, ##f, concentrations, ., the, brain, slice, method, estimates, brain, ec, ##f, concentrations, by, determining, total, brain, concentrations, after, drug, administration, ,, and, to, correct, for, the, free, fraction, as, obtained, in, brain, slices, after, bathing, the, slice, in, a, buffer, solution, containing, the, drug, (, s, ), of, interest, [, 53, ,, 54, ], ., table, 2d, ##rug, ##s, and, their, k, ##pu, ##u, ,, cs, ##f, and, k, ##pu, ##u, ,, brain, values, obtained, in, animals, (, rats, ,, sheep, ,, rabbits, ,, r, ##hes, ##us, monkeys, ,, and, non, ##hum, ##an, primate, ##s, ), on, the, basis, of, steady, state, (, ss, ), values, ,, au, ##c, values, ,, continuous, in, ##fusion, (, con, ##t, in, ##f, ), compounds, ##pe, ##cies, ##time, ##k, ##pu, ##u, ,, cs, ##fk, ##pu, ##u, ,, brain, ##re, ##ference, ##9, -, oh, -, ri, ##sper, ##idon, ##era, ##t, ##6, h, con, ##t, in, ##f, ##0, ,, 06, ##8, ##40, ,, 01, ##43, [, 61, ], ace, ##tam, ##ino, ##ph, ##en, ##rata, ##uc, (, partial, ), 0, ,, 31, ,, 2, [, 25, ], al, ##ov, ##udi, ##ner, ##ats, ##s, ##0, ,, 40, ,, 16, [, 72, ], anti, ##py, ##rine, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 99, ##0, ,, 70, ##8, [, 56, ], atom, ##ox, ##eti, ##ner, ##ats, ##s, ##1, ,, 70, ,, 7, [, 64, ], ba, ##cl, ##of, ##en, ##rat, ##pse, ##ud, ##o, ss, ##0, ,, 02, ##80, ,, 03, ##5, [, 73, ], benz, ##yl, ##pen, ##ici, ##llin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 01, ##34, ##0, ,, 02, ##64, [, 56, ], bus, ##pi, ##rone, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 55, ##80, ,, 61, ##2, [, 56, ], caf, ##fe, ##iner, ##at, ##2, h, con, ##t, in, ##f, ##1, ,, 03, ##0, ,, 58, ##4, [, 56, ], car, ##ba, ##ma, ##ze, ##pine, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 53, ##50, ,, 77, ##1, [, 56, ], car, ##ba, ##ma, ##ze, ##pine, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 1670, ,, 232, [, 61, ], car, ##bo, ##pl, ##atin, ##non, ##hum, ##an, primate, ##au, ##c, ##0, ,, 050, ,, 05, [, 74, ], ce, ##fo, ##di, ##zi, ##mer, ##ats, ##pe, ##ci, ##fi, ##c, time, ##0, ,, 02, ##0, ,, 22, [, 75, ], ce, ##ft, ##azi, ##dim, ##era, ##ts, ##s, ##0, ,, 03, ##90, ,, 02, ##2, [, 76, ], ce, ##ft, ##ria, ##xon, ##era, ##ts, ##s, ##0, ,, 710, ,, 8, [, 76, ], ce, ##pha, ##le, ##xin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 02, ##25, ##0, ,, 01, ##6, [, 56, ], ci, ##met, ##idi, ##ner, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 02, ##11, ##0, ,, 00, ##9, ##8, ##1, [, 56, ], cis, ##pl, ##atin, ##non, ##hum, ##an, primate, ##au, ##c, ##0, ,, 050, ,, 05, [, 74, ], ci, ##tal, ##op, ##ram, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 66, ##70, ,, 49, ##4, [, 56, ], ci, ##tal, ##op, ##ram, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 50, ,, 55, ##9, [, 61, ], cp, -, 61, ##5, ,, 00, ##3, ##rat, ##ss, ##0, ,, 01, ##0, ,, 001, ##4, [, 77, ], dai, ##d, ##ze, ##in, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 1890, ,, 06, ##6, ##7, [, 56, ], dan, ##tro, ##lene, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 08, ##38, ##0, ,, 02, ##9, ##7, [, 56, ], diaz, ##ep, ##am, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 84, ##70, ,, 80, ##5, [, 56, ], dip, ##hen, ##yl, ##hy, ##dra, ##mine, ##sh, ##ee, ##ps, ##s, (, adults, ), 3, ,, 43, ,, 4, [, 78, ], dip, ##hen, ##yl, ##hy, ##dra, ##mine, ##sh, ##ee, ##ps, ##s, (, 30, d, lamb, ##s, ), 4, ,, 96, ,, 6, [, 78, ], dip, ##hen, ##yl, ##hy, ##dra, ##mine, ##sh, ##ee, ##ps, ##s, (, 10, d, lamb, ##s, ), 5, ,, 66, ,, 6, [, 78, ], ea, ##b, ##51, ##5, ##rat, ##15, h, ##0, ,, 180, ,, 08, [, 51, ], fl, ##av, ##op, ##iri, ##do, ##lr, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 216, ##0, ,, 05, ##25, [, 56, ], fl, ##ero, ##xa, ##cin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 283, ##0, ,, 25, [, 56, ], fl, ##ero, ##xa, ##cin, ##rat, ##ss, ##0, ,, 420, ,, 15, [, 79, ], gan, ##cic, ##lov, ##ir, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 06, ##47, ##0, ,, 07, ##11, [, 61, ], gen, ##iste, ##in, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 58, ##90, ,, 181, [, 56, ], lam, ##ot, ##ri, ##gin, ##era, ##ts, ##s, ##1, ,, 51, [, 62, ], lo, ##per, ##ami, ##der, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 03, ##7, ##60, ,, 00, ##8, ##86, [, 56, ], met, ##oc, ##lo, ##pr, ##ami, ##der, ##at, ##6, h, con, ##t, in, ##f, ##0, ,, 1690, ,, 235, [, 61, ], mid, ##az, ##ola, ##m, ##rat, ##2, h, con, ##t, in, ##f, ##1, ,, 352, ,, 19, [, 56, ], mor, ##phine, ##rata, ##uc, ##0, ,, 1970, ,, 51, [, 80, ], m, ##6, ##gra, ##ta, ##uc, ##0, ,, 02, ##90, ,, 56, [, 80, ], n, -, des, ##met, ##hyl, ##cl, ##oza, ##pine, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 01, ##51, ##0, ,, 01, [, 61, ], nor, ##fl, ##ox, ##ac, ##in, ##rat, ##ss, ##0, ,, 03, ##30, ,, 03, ##4, [, 79, ], of, ##lo, ##xa, ##cin, ##rat, ##ss, ##0, ,, 230, ,, 12, [, 79, ], ox, ##ali, ##pl, ##atin, ##non, ##hum, ##an, primate, ##au, ##c, ##0, ,, 65, ##5, ,, 3, [, 74, ], per, ##fl, ##ox, ##ac, ##in, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 38, ##90, ,, 199, [, 56, ], per, ##fl, ##ox, ##ac, ##in, ##rat, ##ss, ##0, ,, 370, ,, 15, [, 79, ], ph, ##en, ##yt, ##oin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 39, ##60, ,, 44, ##7, [, 56, ], ph, ##en, ##yt, ##oin, ##rata, ##uc, ##0, ,, 20, ,, 85, [, 81, ], probe, ##ne, ##ci, ##dra, ##ts, ##s, ##0, ,, 60, ,, 2, [, 82, ], qui, ##ni, ##dine, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 09, ##11, ##0, ,, 02, ##6, [, 56, ], qui, ##ni, ##dine, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 09, ##6, ##90, ,, 04, ##59, [, 61, ], ri, ##sper, ##idon, ##era, ##t, ##2, h, con, ##t, in, ##f, ##0, ,, 124, ##0, ,, 07, ##8, ##7, [, 56, ], ri, ##sper, ##idon, ##era, ##t, ##6, h, con, ##t, in, ##f, ##0, ,, 09, ##13, ##0, ,, 04, ##22, [, 61, ], sal, ##ic, ##yla, ##tera, ##ts, ##s, ##0, ,, 50, ,, 1, [, 82, ], sd, ##z, ea, ##a, 49, ##4, ##rata, ##uc, ##0, ,, 170, ,, 11, [, 83, ], ser, ##tral, ##iner, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 83, ##21, ,, 85, [, 56, ], st, ##av, ##udi, ##ner, ##ats, ##s, ##0, ,, 50, ,, 3, [, 84, ], st, ##av, ##udi, ##ner, ##ats, ##s, ##0, ,, 60, ,, 6, [, 52, ], sul, ##pi, ##ride, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 04, ##9, ##90, ,, 02, ##19, [, 56, ], th, ##io, ##pen, ##tal, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 59, ##90, ,, 911, [, 56, ], th, ##io, ##pen, ##tal, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 06, ##6, ##30, ,, 06, ##6, ##3, [, 61, ], tia, ##ga, ##bine, ##rata, ##uc, ##0, ,, 01, ##10, ,, 01, ##1, [, 85, ], vera, ##pa, ##mi, ##lr, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 333, ##0, ,, 07, ##86, [, 56, ], y, ##m, ##9, ##9, ##2, ##rat, ##ss, ##1, ,, 71, ,, 4, [, 86, ], z, ##ido, ##vu, ##din, ##ra, ##bb, ##ita, ##uc, ##0, ,, 170, ,, 08, [, 50, ], z, ##ido, ##vu, ##din, ##ra, ##bb, ##its, ##s, ##0, ,, 290, ,, 19, [, 87, ], z, ##ido, ##vu, ##din, ##rh, ##es, ##us, monkeys, ##s, ##0, ,, 270, ,, 15, [, 88, ], z, ##ido, ##vu, ##din, +, probe, ##ne, ##ci, ##dra, ##bb, ##ita, ##uc, ##0, ,, 190, ,, 1, [, 50, ], z, ##ol, ##pid, ##em, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 475, ##0, ,, 44, ##7, [, 56, ]'},\n", + " {'article_id': '4e21f87d13094948d3982be834e803c6',\n", + " 'section_name': 'The Key Role of Dopamine and Neuromodulation',\n", + " 'text': \"It is remarkable that the finding of dopamine's importance to the primate dlPFC was published in 1979, years before parallel cognitive studies were performed in rodents (Bubser and Schmidt 1990). The dopamine innervation of the rat cortex was first mapped in the 1970's, showing a selective projection of dopamine fibers to the PFC but not other cortical areas (Berger et al. 1976). Pat and Roger Brown were the first to measure monoamine concentrations in the primate cortex, and found that dopamine levels and synthesis were very high in the primate PFC, but that unlike the rodent, dopamine was also prevalent in other cortical areas as well (Brown et al. 1979). Working with Brozoski, they examined the functional contribution of dopamine to the primate dlPFC by infusing the catecholamine neurotoxin, 6-OHDA, into the dlPFC, with or without desmethylimipramine (DMI), supposed to protect noradrenergic fibers. DMI was not very effective in protecting norepinephrine, but it did facilitate uptake into dopaminergic fibers to enhance depletion. Thus, they created lesions with very large dopaminergic (and large noradrenergic) depletions restricted to the dlPFC. These lesions markedly impaired spatial working memory performance, similar to that seen with dlPFC ablations. Performance was improved by catecholaminergic drugs: The catecholamine precursor l-3,4-dihydroxyphenylalanine, the dopamine D2 receptor agonist, apomorphine, and (in a footnote), the α2 noradrenergic agonist, clonidine. Since noradrenergic depletion with minimal dopamine depletion had little effect on working memory performance, the authors concluded that dopamine was the key factor. However, it is now known that both dopamine and norepinephrine are critical for dlPFC function, and it is likely that one can substitute for the other in long-term lesion studies such as the one performed by Brozoski et al. Indeed, that footnote on clonidine led to studies showing that noradrenergic stimulation of postsynaptic, α2 adrenergic receptors is essential to dlPFC function (Arnsten and Goldman-Rakic 1985) via functional strengthening of pyramidal cell circuits (Wang et al. 2007), and α2A receptor agonists such as guanfacine are now in widespread clinical use to treat PFC cognitive disorders (Hunt et al. 1995; Scahill et al. 2001,2006; Biederman et al. 2008; McAllister et al. 2011; Connor et al. 2013). Goldman-Rakic also began to explore other modulatory influences on dlPFC, including serotonin (e.g. Lidow et al. 1989; Williams et al. 2002); and acetylcholine (e.g. Mrzljak et al. 1993). But her primary focus remained on dopamine. She worked with Mark Williams to identify the midbrain source of dopamine to the PFC (Williams and Goldman-Rakic 1998), and to map the dopaminergic fibers innervating the frontal lobe (Williams and Goldman-Rakic 1993). The dopamine-containing fibers in the dlPFC are actually rather sparse (Fig. 8A), emphasizing that quantity does not always correlate with efficacy.\\nFigure 8.The key role of dopamine in the primate dlPFC. (A) The dopaminergic innervation of the primate PFC, including the dlPFC area 46, as visualized using an antibody directed against dopamine. Note the relatively sparse labeling in the dlPFC, a region that critically depends on dopamine actions. (From Williams and Goldman-Rakic 1993.) (B) A schematic illustration of the dopamine D1 receptor inverted-U influence on the pattern of Delay cell firing in the dlPFC. The memory fields of dlPFC neurons are shown under conditions of increasing levels of D1 receptor stimulation. Either very low or very high levels of D1 receptor stimulation markedly reduce delay-related firing. Low levels of D1 receptor stimulation are associated with noisy neuronal representations of visual space, while optimal levels reduce noise and enhance spatial tuning. The high levels of D1 receptor stimulation during stress exposure would reduce delay-related firing for all directions. Brighter colors indicate higher firing rates during the delay period. This figure is a schematic illustration of the physiological data presented in Williams and Goldman-Rakic (1995); Vijayraghavan et al. (2007); and Arnsten et al. (2009) and is consistent with the behavioral data from Arnsten et al. (1994); Murphy et al. (1996); Zahrt et al. (1997); and Arnsten and Goldman-Rakic (1998).\",\n", + " 'paragraph_id': 16,\n", + " 'tokenizer': \"it, is, remarkable, that, the, finding, of, do, ##pa, ##mine, ', s, importance, to, the, primate, dl, ##pf, ##c, was, published, in, 1979, ,, years, before, parallel, cognitive, studies, were, performed, in, rodents, (, bu, ##bs, ##er, and, schmidt, 1990, ), ., the, do, ##pa, ##mine, inner, ##vation, of, the, rat, cortex, was, first, mapped, in, the, 1970, ', s, ,, showing, a, selective, projection, of, do, ##pa, ##mine, fibers, to, the, p, ##fc, but, not, other, co, ##rti, ##cal, areas, (, berger, et, al, ., 1976, ), ., pat, and, roger, brown, were, the, first, to, measure, mono, ##amine, concentrations, in, the, primate, cortex, ,, and, found, that, do, ##pa, ##mine, levels, and, synthesis, were, very, high, in, the, primate, p, ##fc, ,, but, that, unlike, the, rode, ##nt, ,, do, ##pa, ##mine, was, also, prevalent, in, other, co, ##rti, ##cal, areas, as, well, (, brown, et, al, ., 1979, ), ., working, with, bro, ##zos, ##ki, ,, they, examined, the, functional, contribution, of, do, ##pa, ##mine, to, the, primate, dl, ##pf, ##c, by, in, ##fus, ##ing, the, cat, ##ech, ##ola, ##mine, ne, ##uro, ##to, ##xin, ,, 6, -, oh, ##da, ,, into, the, dl, ##pf, ##c, ,, with, or, without, des, ##met, ##hyl, ##imi, ##pr, ##amine, (, d, ##mi, ), ,, supposed, to, protect, nora, ##dre, ##ner, ##gic, fibers, ., d, ##mi, was, not, very, effective, in, protecting, nor, ##ep, ##ine, ##ph, ##rine, ,, but, it, did, facilitate, up, ##take, into, do, ##pa, ##mine, ##rg, ##ic, fibers, to, enhance, de, ##ple, ##tion, ., thus, ,, they, created, lesions, with, very, large, do, ##pa, ##mine, ##rg, ##ic, (, and, large, nora, ##dre, ##ner, ##gic, ), de, ##ple, ##tions, restricted, to, the, dl, ##pf, ##c, ., these, lesions, markedly, impaired, spatial, working, memory, performance, ,, similar, to, that, seen, with, dl, ##pf, ##c, ab, ##lation, ##s, ., performance, was, improved, by, cat, ##ech, ##ola, ##mine, ##rg, ##ic, drugs, :, the, cat, ##ech, ##ola, ##mine, precursor, l, -, 3, ,, 4, -, di, ##hy, ##dro, ##xy, ##ph, ##en, ##yla, ##lani, ##ne, ,, the, do, ##pa, ##mine, d, ##2, receptor, ago, ##nist, ,, ap, ##omo, ##rp, ##hine, ,, and, (, in, a, foot, ##note, ), ,, the, α, ##2, nora, ##dre, ##ner, ##gic, ago, ##nist, ,, cl, ##oni, ##dine, ., since, nora, ##dre, ##ner, ##gic, de, ##ple, ##tion, with, minimal, do, ##pa, ##mine, de, ##ple, ##tion, had, little, effect, on, working, memory, performance, ,, the, authors, concluded, that, do, ##pa, ##mine, was, the, key, factor, ., however, ,, it, is, now, known, that, both, do, ##pa, ##mine, and, nor, ##ep, ##ine, ##ph, ##rine, are, critical, for, dl, ##pf, ##c, function, ,, and, it, is, likely, that, one, can, substitute, for, the, other, in, long, -, term, les, ##ion, studies, such, as, the, one, performed, by, bro, ##zos, ##ki, et, al, ., indeed, ,, that, foot, ##note, on, cl, ##oni, ##dine, led, to, studies, showing, that, nora, ##dre, ##ner, ##gic, stimulation, of, posts, ##yna, ##ptic, ,, α, ##2, ad, ##ren, ##er, ##gic, receptors, is, essential, to, dl, ##pf, ##c, function, (, ar, ##nst, ##en, and, goldman, -, ra, ##kic, 1985, ), via, functional, strengthening, of, pyramid, ##al, cell, circuits, (, wang, et, al, ., 2007, ), ,, and, α, ##2, ##a, receptor, ago, ##nist, ##s, such, as, gu, ##an, ##fa, ##cine, are, now, in, widespread, clinical, use, to, treat, p, ##fc, cognitive, disorders, (, hunt, et, al, ., 1995, ;, sc, ##ah, ##ill, et, al, ., 2001, ,, 2006, ;, bi, ##ede, ##rman, et, al, ., 2008, ;, mca, ##llis, ##ter, et, al, ., 2011, ;, connor, et, al, ., 2013, ), ., goldman, -, ra, ##kic, also, began, to, explore, other, mod, ##ulator, ##y, influences, on, dl, ##pf, ##c, ,, including, ser, ##oton, ##in, (, e, ., g, ., lid, ##ow, et, al, ., 1989, ;, williams, et, al, ., 2002, ), ;, and, ace, ##ty, ##lch, ##olin, ##e, (, e, ., g, ., mr, ##z, ##l, ##jak, et, al, ., 1993, ), ., but, her, primary, focus, remained, on, do, ##pa, ##mine, ., she, worked, with, mark, williams, to, identify, the, mid, ##bra, ##in, source, of, do, ##pa, ##mine, to, the, p, ##fc, (, williams, and, goldman, -, ra, ##kic, 1998, ), ,, and, to, map, the, do, ##pa, ##mine, ##rg, ##ic, fibers, inner, ##vating, the, frontal, lobe, (, williams, and, goldman, -, ra, ##kic, 1993, ), ., the, do, ##pa, ##mine, -, containing, fibers, in, the, dl, ##pf, ##c, are, actually, rather, sparse, (, fig, ., 8, ##a, ), ,, emphasizing, that, quantity, does, not, always, co, ##rre, ##late, with, efficacy, ., figure, 8, ., the, key, role, of, do, ##pa, ##mine, in, the, primate, dl, ##pf, ##c, ., (, a, ), the, do, ##pa, ##mine, ##rg, ##ic, inner, ##vation, of, the, primate, p, ##fc, ,, including, the, dl, ##pf, ##c, area, 46, ,, as, visual, ##ized, using, an, antibody, directed, against, do, ##pa, ##mine, ., note, the, relatively, sparse, labeling, in, the, dl, ##pf, ##c, ,, a, region, that, critically, depends, on, do, ##pa, ##mine, actions, ., (, from, williams, and, goldman, -, ra, ##kic, 1993, ., ), (, b, ), a, sc, ##hema, ##tic, illustration, of, the, do, ##pa, ##mine, d, ##1, receptor, inverted, -, u, influence, on, the, pattern, of, delay, cell, firing, in, the, dl, ##pf, ##c, ., the, memory, fields, of, dl, ##pf, ##c, neurons, are, shown, under, conditions, of, increasing, levels, of, d, ##1, receptor, stimulation, ., either, very, low, or, very, high, levels, of, d, ##1, receptor, stimulation, markedly, reduce, delay, -, related, firing, ., low, levels, of, d, ##1, receptor, stimulation, are, associated, with, noisy, ne, ##uron, ##al, representations, of, visual, space, ,, while, optimal, levels, reduce, noise, and, enhance, spatial, tuning, ., the, high, levels, of, d, ##1, receptor, stimulation, during, stress, exposure, would, reduce, delay, -, related, firing, for, all, directions, ., brighter, colors, indicate, higher, firing, rates, during, the, delay, period, ., this, figure, is, a, sc, ##hema, ##tic, illustration, of, the, physiological, data, presented, in, williams, and, goldman, -, ra, ##kic, (, 1995, ), ;, vijay, ##rag, ##havan, et, al, ., (, 2007, ), ;, and, ar, ##nst, ##en, et, al, ., (, 2009, ), and, is, consistent, with, the, behavioral, data, from, ar, ##nst, ##en, et, al, ., (, 1994, ), ;, murphy, et, al, ., (, 1996, ), ;, za, ##hr, ##t, et, al, ., (, 1997, ), ;, and, ar, ##nst, ##en, and, goldman, -, ra, ##kic, (, 1998, ), .\"},\n", + " {'article_id': '1d823fbe87e8134938706f1f3e242b1e',\n", + " 'section_name': 'Characterization of the mixed brain culture',\n", + " 'text': 'In order to elucidate the molecular identity of our mixed culture, we used western blotting (Figures 5 and 6), confocal imaging (Figure 7), calcium imaging (Figure 8) and fluorescence activated cell sorter (FACS) (Figure 9). The human primary neuronal culture described here can serve as a relevant, rational and suitable tissue culture model for research on neurodegenerative disorders like AD, PD and other brain disorders. This culture contains measurable levels of synaptic (PSD-95, SNAP-25); glial (GFAP) and neuronal specific (NSE) proteins as evaluated by western blotting (Figure 5). Deposition of Aβ peptides and hyperphosphorylation of microtubule associated protein tau is the major hallmarks of AD. We have observed that this culture system produces significant amounts of Aβ (1–40) and Aβ (1–42), as assessed by a sensitive, human-specific ELISA. We have also measured AB at other time points [19]. At DIV 18, the amounts of Aβ (1–40) and Aβ (1–42) were measured to be 806.76 ± 212.02 pg/mL and 352.43 ± 95.95 pg/mL, respectively. We have also measured total and phospho-tau levels in the cell lysate samples by Western immunoblotting using specific antibodies. Total and phospho-tau levels were detected throughout the time points of the culture with highest peaks from DIV 28 onwards (Ray & Lahiri Unpublished data). The presence of tyrosine hydroxylase-positive neurons (Figure 6b) also makes this neuron culture appropriate for research related to PD. Serotonergic neurons and GABAergic neurons are also detectable, (Figure 6a and b) enabling this model to be employed in a wide variety of studies requiring these particular neuronal subtypes. Furthermore, the neurons present in the culture are suitable for electrophysiological study because of the expression of voltage-gated calcium channels (VGCC) as measured by Fura-2 AM experiments (Figure 8). The cells respond to depolarization by 70 mM KCl by allowing an influx of calcium, suggesting the presence of active VGCCs. We observed KCl-evoked Calcium influx at all three time points studied – DIV 4, DIV 16 and DIV 28 (Figure 8). The experiments show that these cells have a resting intracellular calcium level of 40 nM (data not shown). The slightly lower than expected intracellular calcium may be a consequence of the mixed cell culture that contains both mature and immature neurons.Figure 5Western immunoblotting of the cell lysates from cultures at different DIV shows presence of neuronal, glial and synaptic proteins (both pre-synaptic and post-synaptic proteins) at different time points of the culture. Band densities of different proteins were scanned, quantified and normalized with β-actin bands. Levels of neuron specific enolase (NSE), a marker for neurons, and glial fibrillary acidic protein (GFAP), a glial marker, increase time-dependently in the culture. These may suggest a continual process of neuro- and gliogenesis in the culture. This finding is in accordance with the presence of NPCs (nestin positive cells) observed at all the time points of the culture. Notably, presence of synaptic markers (SNAP-25 and PSD-95) even at the later time points indicates non-degenerating nature of the culture.Figure 6Serotonergic and dopaminergic characterization of human mixed brain culture. a Cells at DIV24 were fixed and ICC with 5-HT antibody revealed presence of serotonergic cells in the culture. The arrows indicate representative cells positive for 5-HT staining. The inset is an area magnified to better visualize 5-HT positive staining. b Western immunoblotting of the cell lysates indicates presence of GABAergic neurons (detected by glutamate decarboxylase antibody) in the culture. Number of GABAergic neurons gradually increase as the culture progresses. In contrast, dopaminergic neurons (detected by tyrosine hydroxylase antibody) are abundant in the initial time points of the culture and gradually decrease as the culture progresses.Figure 7Confocal imaging of Human mixed brain culture containing neurons, glia and neural progenitor cells. At each time point, cells were fixed using 4% Paraformaldehyde and dual-labeled with FITC-conjugated Neuronal antibody cocktail (Pan-N, 1:1000) and a Cy3-conjugate of either a glial marker (GFAP, 1:5000) or a neuronal progenitor (Nestin, 1:500). Results at DIV 12, and DIV 32 are shown. Antibodies against Pan-N and or Pan-N and GFAP were used with appropriate secondary antibodies (donkey-anti mouse; 1:500 or Goat-anti rabbit, 1:2000). Confocal fluorescence microscopy was performed on an inverted IX81microscope fitted with a FV1000-MPE and laser launch with confocal excitation with three diode lasers (405, 559 and 635 nm) and an Argon laser (458, 488, 514 nm), controlled by Fluoview v3.0 (Olympus). All imaging was performed with a 60x 1.2 NA water immersion objective. The scale bar is in the bottom right panel, and is applicable to all images.Figure 8Functional response of brain culture. Cells were cultured on PDL-coated glass coverslips. Approximately 100 regions of interest (ROI) s were selected indiscriminately. The coverslips are loaded with Fura-2 dye and placed in standard extracellular solution (see methods). After depolarization with 70 mM KCl, another wash with standard extracellular solution is utilized to eliminate dead cells. The trace shown represents an average (3 experiments) of all cells that respond to KCl and the second wash. It is important to note that there were cells that did not respond to KCl which could be dead cells or non-neuronal cells. Fura emits at two wavelengths – 340 nm and 380 nm [26] and the ratio of these corresponds to the intracellular calcium. All three points show a calcium response after induced depolarization, suggesting that these are functionally active neurons.Figure 9An increase in neuronal population over time. Human fetal brain (HFB) cells were grown as stated. At each time point, cells were fixed using 4% Paraformaldehyde and dual-labeled with FITC-conjugated Neuronal antibody cocktail (Pan-N, 1:1000) and a Cy3-conjugate of either a glial marker (GFAP, 1:5000) or a neuronal progenitor (Nestin, 1:500). Appropriate secondary antibodies were used. The values at the corners of the boxes refer to percent total of the cells gated for selection that were positive for the appropriate fluorescent-conjugated antibody. LL – Unlabeled cells. UL-Cells positive for Cy3-conjugated marker for either GFAP or Nestin. LR – Cells labeled with Pan-N. UR – Cells positive for either Pan-N and GFAP or Pan-N and Nestin. This data suggests that the stem-ness of the culture reduces over time and the neuronal phenotype beings to emerge.',\n", + " 'paragraph_id': 4,\n", + " 'tokenizer': 'in, order, to, el, ##uc, ##ida, ##te, the, molecular, identity, of, our, mixed, culture, ,, we, used, western, b, ##lot, ##ting, (, figures, 5, and, 6, ), ,, con, ##fo, ##cal, imaging, (, figure, 7, ), ,, calcium, imaging, (, figure, 8, ), and, flu, ##orescence, activated, cell, sort, ##er, (, fa, ##cs, ), (, figure, 9, ), ., the, human, primary, ne, ##uron, ##al, culture, described, here, can, serve, as, a, relevant, ,, rational, and, suitable, tissue, culture, model, for, research, on, ne, ##uro, ##de, ##gen, ##erative, disorders, like, ad, ,, pd, and, other, brain, disorders, ., this, culture, contains, me, ##asurable, levels, of, syn, ##ap, ##tic, (, ps, ##d, -, 95, ,, snap, -, 25, ), ;, g, ##lia, ##l, (, g, ##fa, ##p, ), and, ne, ##uron, ##al, specific, (, ns, ##e, ), proteins, as, evaluated, by, western, b, ##lot, ##ting, (, figure, 5, ), ., deposition, of, a, ##β, peptide, ##s, and, hyper, ##ph, ##os, ##ph, ##ory, ##lation, of, micro, ##tub, ##ule, associated, protein, tau, is, the, major, hallmark, ##s, of, ad, ., we, have, observed, that, this, culture, system, produces, significant, amounts, of, a, ##β, (, 1, –, 40, ), and, a, ##β, (, 1, –, 42, ), ,, as, assessed, by, a, sensitive, ,, human, -, specific, elisa, ., we, have, also, measured, ab, at, other, time, points, [, 19, ], ., at, di, ##v, 18, ,, the, amounts, of, a, ##β, (, 1, –, 40, ), and, a, ##β, (, 1, –, 42, ), were, measured, to, be, 80, ##6, ., 76, ±, 212, ., 02, pg, /, ml, and, 352, ., 43, ±, 95, ., 95, pg, /, ml, ,, respectively, ., we, have, also, measured, total, and, ph, ##os, ##ph, ##o, -, tau, levels, in, the, cell, l, ##ys, ##ate, samples, by, western, im, ##mun, ##ob, ##lot, ##ting, using, specific, antibodies, ., total, and, ph, ##os, ##ph, ##o, -, tau, levels, were, detected, throughout, the, time, points, of, the, culture, with, highest, peaks, from, di, ##v, 28, onwards, (, ray, &, la, ##hir, ##i, unpublished, data, ), ., the, presence, of, ty, ##ros, ##ine, hydro, ##xy, ##lase, -, positive, neurons, (, figure, 6, ##b, ), also, makes, this, ne, ##uron, culture, appropriate, for, research, related, to, pd, ., ser, ##oton, ##er, ##gic, neurons, and, ga, ##ba, ##er, ##gic, neurons, are, also, detect, ##able, ,, (, figure, 6, ##a, and, b, ), enabling, this, model, to, be, employed, in, a, wide, variety, of, studies, requiring, these, particular, ne, ##uron, ##al, sub, ##type, ##s, ., furthermore, ,, the, neurons, present, in, the, culture, are, suitable, for, electro, ##phy, ##sio, ##logical, study, because, of, the, expression, of, voltage, -, gate, ##d, calcium, channels, (, v, ##gc, ##c, ), as, measured, by, fur, ##a, -, 2, am, experiments, (, figure, 8, ), ., the, cells, respond, to, de, ##pol, ##ari, ##zation, by, 70, mm, kc, ##l, by, allowing, an, influx, of, calcium, ,, suggesting, the, presence, of, active, v, ##gc, ##cs, ., we, observed, kc, ##l, -, ev, ##oked, calcium, influx, at, all, three, time, points, studied, –, di, ##v, 4, ,, di, ##v, 16, and, di, ##v, 28, (, figure, 8, ), ., the, experiments, show, that, these, cells, have, a, resting, intra, ##cellular, calcium, level, of, 40, nm, (, data, not, shown, ), ., the, slightly, lower, than, expected, intra, ##cellular, calcium, may, be, a, consequence, of, the, mixed, cell, culture, that, contains, both, mature, and, immature, neurons, ., figure, 5, ##west, ##ern, im, ##mun, ##ob, ##lot, ##ting, of, the, cell, l, ##ys, ##ates, from, cultures, at, different, di, ##v, shows, presence, of, ne, ##uron, ##al, ,, g, ##lia, ##l, and, syn, ##ap, ##tic, proteins, (, both, pre, -, syn, ##ap, ##tic, and, post, -, syn, ##ap, ##tic, proteins, ), at, different, time, points, of, the, culture, ., band, den, ##sities, of, different, proteins, were, scanned, ,, quan, ##ti, ##fied, and, normal, ##ized, with, β, -, act, ##in, bands, ., levels, of, ne, ##uron, specific, en, ##ola, ##se, (, ns, ##e, ), ,, a, marker, for, neurons, ,, and, g, ##lia, ##l, fi, ##bri, ##llary, acidic, protein, (, g, ##fa, ##p, ), ,, a, g, ##lia, ##l, marker, ,, increase, time, -, dependent, ##ly, in, the, culture, ., these, may, suggest, a, continual, process, of, ne, ##uro, -, and, g, ##lio, ##genesis, in, the, culture, ., this, finding, is, in, accordance, with, the, presence, of, np, ##cs, (, nest, ##in, positive, cells, ), observed, at, all, the, time, points, of, the, culture, ., notably, ,, presence, of, syn, ##ap, ##tic, markers, (, snap, -, 25, and, ps, ##d, -, 95, ), even, at, the, later, time, points, indicates, non, -, de, ##gen, ##era, ##ting, nature, of, the, culture, ., figure, 6, ##ser, ##oton, ##er, ##gic, and, do, ##pa, ##mine, ##rg, ##ic, characterization, of, human, mixed, brain, culture, ., a, cells, at, di, ##v, ##24, were, fixed, and, icc, with, 5, -, h, ##t, antibody, revealed, presence, of, ser, ##oton, ##er, ##gic, cells, in, the, culture, ., the, arrows, indicate, representative, cells, positive, for, 5, -, h, ##t, stain, ##ing, ., the, ins, ##et, is, an, area, mag, ##nified, to, better, visual, ##ize, 5, -, h, ##t, positive, stain, ##ing, ., b, western, im, ##mun, ##ob, ##lot, ##ting, of, the, cell, l, ##ys, ##ates, indicates, presence, of, ga, ##ba, ##er, ##gic, neurons, (, detected, by, g, ##lu, ##tama, ##te, dec, ##ar, ##box, ##yla, ##se, antibody, ), in, the, culture, ., number, of, ga, ##ba, ##er, ##gic, neurons, gradually, increase, as, the, culture, progresses, ., in, contrast, ,, do, ##pa, ##mine, ##rg, ##ic, neurons, (, detected, by, ty, ##ros, ##ine, hydro, ##xy, ##lase, antibody, ), are, abundant, in, the, initial, time, points, of, the, culture, and, gradually, decrease, as, the, culture, progresses, ., figure, 7, ##con, ##fo, ##cal, imaging, of, human, mixed, brain, culture, containing, neurons, ,, g, ##lia, and, neural, pro, ##gen, ##itor, cells, ., at, each, time, point, ,, cells, were, fixed, using, 4, %, para, ##form, ##ald, ##eh, ##yde, and, dual, -, labeled, with, fit, ##c, -, con, ##ju, ##gated, ne, ##uron, ##al, antibody, cocktail, (, pan, -, n, ,, 1, :, 1000, ), and, a, cy, ##3, -, con, ##ju, ##gate, of, either, a, g, ##lia, ##l, marker, (, g, ##fa, ##p, ,, 1, :, 5000, ), or, a, ne, ##uron, ##al, pro, ##gen, ##itor, (, nest, ##in, ,, 1, :, 500, ), ., results, at, di, ##v, 12, ,, and, di, ##v, 32, are, shown, ., antibodies, against, pan, -, n, and, or, pan, -, n, and, g, ##fa, ##p, were, used, with, appropriate, secondary, antibodies, (, donkey, -, anti, mouse, ;, 1, :, 500, or, goat, -, anti, rabbit, ,, 1, :, 2000, ), ., con, ##fo, ##cal, flu, ##orescence, microscopy, was, performed, on, an, inverted, ix, ##8, ##1, ##mic, ##ros, ##cope, fitted, with, a, f, ##v, ##100, ##0, -, mp, ##e, and, laser, launch, with, con, ##fo, ##cal, ex, ##cit, ##ation, with, three, di, ##ode, lasers, (, 405, ,, 55, ##9, and, 63, ##5, nm, ), and, an, ar, ##gon, laser, (, 45, ##8, ,, 48, ##8, ,, 51, ##4, nm, ), ,, controlled, by, flu, ##ov, ##ie, ##w, v, ##3, ., 0, (, olympus, ), ., all, imaging, was, performed, with, a, 60, ##x, 1, ., 2, na, water, immersion, objective, ., the, scale, bar, is, in, the, bottom, right, panel, ,, and, is, applicable, to, all, images, ., figure, 8, ##fu, ##nction, ##al, response, of, brain, culture, ., cells, were, culture, ##d, on, pd, ##l, -, coated, glass, covers, ##lip, ##s, ., approximately, 100, regions, of, interest, (, roi, ), s, were, selected, ind, ##is, ##cr, ##imi, ##nate, ##ly, ., the, covers, ##lip, ##s, are, loaded, with, fur, ##a, -, 2, dye, and, placed, in, standard, extra, ##cellular, solution, (, see, methods, ), ., after, de, ##pol, ##ari, ##zation, with, 70, mm, kc, ##l, ,, another, wash, with, standard, extra, ##cellular, solution, is, utilized, to, eliminate, dead, cells, ., the, trace, shown, represents, an, average, (, 3, experiments, ), of, all, cells, that, respond, to, kc, ##l, and, the, second, wash, ., it, is, important, to, note, that, there, were, cells, that, did, not, respond, to, kc, ##l, which, could, be, dead, cells, or, non, -, ne, ##uron, ##al, cells, ., fur, ##a, emi, ##ts, at, two, wavelengths, –, 340, nm, and, 380, nm, [, 26, ], and, the, ratio, of, these, corresponds, to, the, intra, ##cellular, calcium, ., all, three, points, show, a, calcium, response, after, induced, de, ##pol, ##ari, ##zation, ,, suggesting, that, these, are, functional, ##ly, active, neurons, ., figure, 9, ##an, increase, in, ne, ##uron, ##al, population, over, time, ., human, fetal, brain, (, h, ##fb, ), cells, were, grown, as, stated, ., at, each, time, point, ,, cells, were, fixed, using, 4, %, para, ##form, ##ald, ##eh, ##yde, and, dual, -, labeled, with, fit, ##c, -, con, ##ju, ##gated, ne, ##uron, ##al, antibody, cocktail, (, pan, -, n, ,, 1, :, 1000, ), and, a, cy, ##3, -, con, ##ju, ##gate, of, either, a, g, ##lia, ##l, marker, (, g, ##fa, ##p, ,, 1, :, 5000, ), or, a, ne, ##uron, ##al, pro, ##gen, ##itor, (, nest, ##in, ,, 1, :, 500, ), ., appropriate, secondary, antibodies, were, used, ., the, values, at, the, corners, of, the, boxes, refer, to, percent, total, of, the, cells, gate, ##d, for, selection, that, were, positive, for, the, appropriate, fluorescent, -, con, ##ju, ##gated, antibody, ., ll, –, un, ##lab, ##ele, ##d, cells, ., ul, -, cells, positive, for, cy, ##3, -, con, ##ju, ##gated, marker, for, either, g, ##fa, ##p, or, nest, ##in, ., l, ##r, –, cells, labeled, with, pan, -, n, ., ur, –, cells, positive, for, either, pan, -, n, and, g, ##fa, ##p, or, pan, -, n, and, nest, ##in, ., this, data, suggests, that, the, stem, -, ness, of, the, culture, reduces, over, time, and, the, ne, ##uron, ##al, ph, ##eno, ##type, beings, to, emerge, .'},\n", + " {'article_id': '6cf6ba2467593b4237f6d3ac86313799',\n", + " 'section_name': 'TDP-43 cytoplasmic inclusion detected in ALS-TES derived skin',\n", + " 'text': 'In order to determine if cytoplasmic TDP-43 aggregates can be detected in ALS-TES, 7-μm thick tissue sections were prepared and stained with commercial TDP-43 polyclonal antibody. Interestingly, TDP-43 cytoplasmic aggregates, characteristic of ALS pathology, were detected in SALS-derived skins by indirect immunofluorescence and standard microscopy (Figure 2). These results were also further confirmed by confocal microscopy, using 25-um thick sections (Additional file 5: Figure S3). To our knowledge, it is the first time that cytoplasmic TDP-43 aggregates are detected outside of the nervous system and in non-neuronal cells in any model so far. In contrast, no TDP-43 abnormal cytoplasmic accumulation was observed in control-derived reconstructed skin. To further confirm our results and determine if cytoplasmic TDP-43 can also be detected in non-symptomatic patients, we have generated C9orf72 FALS-derived TES. Five out of six generated C9orf72-TES were derived from non-symptomatic patients carrying the GGGGCC DNA repeat expansion (Additional file 2: Figure S1; Table 1). Remarkably, cytoplasmic TDP-43 inclusions were detected by standard immunofluorescence analysis in both symptomatic and yet non-symptomatic C9orf72-linked ALS patients carrying the expansion (Figure 2). Actually, around 30% of the fibroblasts within the C9orf72- and SALS-derived skins presented cytoplasmic TDP-43 positive inclusions while only 4% of the fibroblasts in the control-derived skins demonstrated TDP-43 cytoplasmic inclusions (Figure 3A). Validation of these results were done by Western blotting after proper fractionation of the cytoplasmic and nulear fractions (Figure 3B; Additional file 6: Figure S4). Interestingly, cytoplasmic TDP-43 inclusions were only detected in our three dimensional (3D) ALS-TES model and were not detected in patient’s fibroblasts alone standard two dimensional (2D) cell culture indicating that our 3D skin model is necessary to observe the described phenotype (Figure 4). Western immunoblots, detected with nuclear (anti-nuclei antibody, clone 235-1, Millipore: cat# MAB1281) and cytoplasmic (anti-GAPDH antibody, AbD Serotec: cat# AHP1628) markers, revealed that our cytoplasmic fraction was completely free of nuclear protein indicating that the detected cytolasmic TDP-43 signal was not due to a contamination of the fraction with nuclear proteins (Additional file 6: Figure S4).Figure 2Cytoplasmic TDP-43 accumulation detected in SALS- and C9orf72 FALS-derived tissue-engineered skins. Indirect immunofluorescence analysis using anti-TDP43 antibody (green) counterstained with DAPI (blue) revealed cytoplasmic TDP-43 accumulation in SALS-derived as well as in C9orf72 FALS-derived tissue-engineered skins. Note that representative pictures of 7-um thick tissue-sections were stained and visualized using a standard epifluorescent microscope. Each picture was taken using the same microscope, camera and exposure settings. Scale bar (white): 10 μm.Figure 3Cellular counts and Western blots quantification of TDP-43 cytoplasmic accumulation. a) Percentage of cell with positive cytoplasmic TDP-43 inclusions. 200 nuclei were counted for each of the generated tissue-engineered skins. *correspond to a P value < 0.01. b) Subcellular fractionation (cytoplasmic fraction vs nuclear fraction) of total protein extracted from ALS-fibroblast (2D culture), control-derived TES, C9ORF72-derived TES and SALS-derived TES (n = 5 for each group) was performed and loaded on a regular SDS-PAGE. TDP-43 expression in each fractionated sample was quantified using ImageJ after normalization against actin. Equal amount of proteins was used as shown on western blots after. *correspond to a P value < 0.05.Figure 4Nuclear TDP-43 expression in\\nC9orf72\\nfibroblasts cultured cells. Indirect immunofluorescence using anti-TDP43 commercial antibody (green) conterstained with DAPI (nucleus) revealed no cytoplasmic TDP-43 accumulation in C9orf72 cultured fibroblasts collected from symptomatic and non-symptomatic C9orf72 FALS patients. These results indicate that the described 3D tissue-engineered skin model, allowing for cell-to-cell and cell-to-matrix interactions, is necessary to observe the pathological cytoplasmic accumulation of TDP-43. Scale bar (white): 10 μm.',\n", + " 'paragraph_id': 14,\n", + " 'tokenizer': 'in, order, to, determine, if, cy, ##top, ##las, ##mic, td, ##p, -, 43, aggregate, ##s, can, be, detected, in, als, -, te, ##s, ,, 7, -, μ, ##m, thick, tissue, sections, were, prepared, and, stained, with, commercial, td, ##p, -, 43, poly, ##cl, ##onal, antibody, ., interesting, ##ly, ,, td, ##p, -, 43, cy, ##top, ##las, ##mic, aggregate, ##s, ,, characteristic, of, als, pathology, ,, were, detected, in, sal, ##s, -, derived, skins, by, indirect, im, ##mun, ##of, ##lu, ##orescence, and, standard, microscopy, (, figure, 2, ), ., these, results, were, also, further, confirmed, by, con, ##fo, ##cal, microscopy, ,, using, 25, -, um, thick, sections, (, additional, file, 5, :, figure, s, ##3, ), ., to, our, knowledge, ,, it, is, the, first, time, that, cy, ##top, ##las, ##mic, td, ##p, -, 43, aggregate, ##s, are, detected, outside, of, the, nervous, system, and, in, non, -, ne, ##uron, ##al, cells, in, any, model, so, far, ., in, contrast, ,, no, td, ##p, -, 43, abnormal, cy, ##top, ##las, ##mic, accumulation, was, observed, in, control, -, derived, reconstructed, skin, ., to, further, confirm, our, results, and, determine, if, cy, ##top, ##las, ##mic, td, ##p, -, 43, can, also, be, detected, in, non, -, sy, ##mpt, ##oma, ##tic, patients, ,, we, have, generated, c, ##9, ##orf, ##7, ##2, fa, ##ls, -, derived, te, ##s, ., five, out, of, six, generated, c, ##9, ##orf, ##7, ##2, -, te, ##s, were, derived, from, non, -, sy, ##mpt, ##oma, ##tic, patients, carrying, the, g, ##gg, ##gc, ##c, dna, repeat, expansion, (, additional, file, 2, :, figure, s, ##1, ;, table, 1, ), ., remarkably, ,, cy, ##top, ##las, ##mic, td, ##p, -, 43, inclusion, ##s, were, detected, by, standard, im, ##mun, ##of, ##lu, ##orescence, analysis, in, both, sy, ##mpt, ##oma, ##tic, and, yet, non, -, sy, ##mpt, ##oma, ##tic, c, ##9, ##orf, ##7, ##2, -, linked, als, patients, carrying, the, expansion, (, figure, 2, ), ., actually, ,, around, 30, %, of, the, fi, ##bro, ##bla, ##sts, within, the, c, ##9, ##orf, ##7, ##2, -, and, sal, ##s, -, derived, skins, presented, cy, ##top, ##las, ##mic, td, ##p, -, 43, positive, inclusion, ##s, while, only, 4, %, of, the, fi, ##bro, ##bla, ##sts, in, the, control, -, derived, skins, demonstrated, td, ##p, -, 43, cy, ##top, ##las, ##mic, inclusion, ##s, (, figure, 3a, ), ., validation, of, these, results, were, done, by, western, b, ##lot, ##ting, after, proper, fraction, ##ation, of, the, cy, ##top, ##las, ##mic, and, nu, ##lea, ##r, fraction, ##s, (, figure, 3, ##b, ;, additional, file, 6, :, figure, s, ##4, ), ., interesting, ##ly, ,, cy, ##top, ##las, ##mic, td, ##p, -, 43, inclusion, ##s, were, only, detected, in, our, three, dimensional, (, 3d, ), als, -, te, ##s, model, and, were, not, detected, in, patient, ’, s, fi, ##bro, ##bla, ##sts, alone, standard, two, dimensional, (, 2d, ), cell, culture, indicating, that, our, 3d, skin, model, is, necessary, to, observe, the, described, ph, ##eno, ##type, (, figure, 4, ), ., western, im, ##mun, ##ob, ##lot, ##s, ,, detected, with, nuclear, (, anti, -, nuclei, antibody, ,, clone, 235, -, 1, ,, mill, ##ip, ##ore, :, cat, #, mab, ##12, ##8, ##1, ), and, cy, ##top, ##las, ##mic, (, anti, -, gap, ##dh, antibody, ,, abd, ser, ##ote, ##c, :, cat, #, ah, ##p, ##16, ##28, ), markers, ,, revealed, that, our, cy, ##top, ##las, ##mic, fraction, was, completely, free, of, nuclear, protein, indicating, that, the, detected, cy, ##to, ##las, ##mic, td, ##p, -, 43, signal, was, not, due, to, a, contamination, of, the, fraction, with, nuclear, proteins, (, additional, file, 6, :, figure, s, ##4, ), ., figure, 2, ##cy, ##top, ##las, ##mic, td, ##p, -, 43, accumulation, detected, in, sal, ##s, -, and, c, ##9, ##orf, ##7, ##2, fa, ##ls, -, derived, tissue, -, engineered, skins, ., indirect, im, ##mun, ##of, ##lu, ##orescence, analysis, using, anti, -, td, ##p, ##43, antibody, (, green, ), counters, ##tained, with, da, ##pi, (, blue, ), revealed, cy, ##top, ##las, ##mic, td, ##p, -, 43, accumulation, in, sal, ##s, -, derived, as, well, as, in, c, ##9, ##orf, ##7, ##2, fa, ##ls, -, derived, tissue, -, engineered, skins, ., note, that, representative, pictures, of, 7, -, um, thick, tissue, -, sections, were, stained, and, visual, ##ized, using, a, standard, ep, ##if, ##lu, ##ores, ##cent, microscope, ., each, picture, was, taken, using, the, same, microscope, ,, camera, and, exposure, settings, ., scale, bar, (, white, ), :, 10, μ, ##m, ., figure, 3, ##cellular, counts, and, western, b, ##lot, ##s, quan, ##ti, ##fication, of, td, ##p, -, 43, cy, ##top, ##las, ##mic, accumulation, ., a, ), percentage, of, cell, with, positive, cy, ##top, ##las, ##mic, td, ##p, -, 43, inclusion, ##s, ., 200, nuclei, were, counted, for, each, of, the, generated, tissue, -, engineered, skins, ., *, correspond, to, a, p, value, <, 0, ., 01, ., b, ), sub, ##cellular, fraction, ##ation, (, cy, ##top, ##las, ##mic, fraction, vs, nuclear, fraction, ), of, total, protein, extracted, from, als, -, fi, ##bro, ##bla, ##st, (, 2d, culture, ), ,, control, -, derived, te, ##s, ,, c, ##9, ##orf, ##7, ##2, -, derived, te, ##s, and, sal, ##s, -, derived, te, ##s, (, n, =, 5, for, each, group, ), was, performed, and, loaded, on, a, regular, sd, ##s, -, page, ., td, ##p, -, 43, expression, in, each, fraction, ##ated, sample, was, quan, ##ti, ##fied, using, image, ##j, after, normal, ##ization, against, act, ##in, ., equal, amount, of, proteins, was, used, as, shown, on, western, b, ##lot, ##s, after, ., *, correspond, to, a, p, value, <, 0, ., 05, ., figure, 4, ##nu, ##cle, ##ar, td, ##p, -, 43, expression, in, c, ##9, ##orf, ##7, ##2, fi, ##bro, ##bla, ##sts, culture, ##d, cells, ., indirect, im, ##mun, ##of, ##lu, ##orescence, using, anti, -, td, ##p, ##43, commercial, antibody, (, green, ), con, ##ters, ##tained, with, da, ##pi, (, nucleus, ), revealed, no, cy, ##top, ##las, ##mic, td, ##p, -, 43, accumulation, in, c, ##9, ##orf, ##7, ##2, culture, ##d, fi, ##bro, ##bla, ##sts, collected, from, sy, ##mpt, ##oma, ##tic, and, non, -, sy, ##mpt, ##oma, ##tic, c, ##9, ##orf, ##7, ##2, fa, ##ls, patients, ., these, results, indicate, that, the, described, 3d, tissue, -, engineered, skin, model, ,, allowing, for, cell, -, to, -, cell, and, cell, -, to, -, matrix, interactions, ,, is, necessary, to, observe, the, path, ##ological, cy, ##top, ##las, ##mic, accumulation, of, td, ##p, -, 43, ., scale, bar, (, white, ), :, 10, μ, ##m, .'},\n", + " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", + " 'section_name': 'Red protein calcium indicators in mouse V1',\n", + " 'text': 'The measured jRGECO1a and jRCaMP1a responses in the visual cortex were smaller than expected based on measurements in cultured neurons (Figure 2a, Figure 4c) and lower than those produced by GCaMP6s (Chen et al., 2013b). High-resolution microscopy of fixed brain tissue sections revealed bright fluorescent punctae in neurons labeled with jRGECO1a but not with jRCaMP1a/b. jRGECO1a punctae co-localized with LAMP-1, a marker of lysosomes (Figure 4—figure supplement 1a) (Katayama et al., 2008). Similar punctae were also found in cultured neurons, but were less numerous (Wilcoxon rank sum test, p<0.001, Figure 4—figure supplement 1b). When imaged in vivo, ROIs containing punctae had higher baseline fluorescence by 90% but lower peak ΔF/F_0 by 20% compared to their surrounding soma (10 cells and 39 punctae, Figure 4—figure supplement 1c). This implies that accumulation of fluorescent, non-responsive jRGECO1a in lysosomes reduces the signal-to-noise ratio for in vivo imaging.10.7554/eLife.12727.014Figure 4.Combined imaging and electrophysiology in the mouse visual cortex.(a) Simultaneous fluorescence dynamics and spikes measured from jRGECO1a (top, blue) and jRCaMP1a (bottom, black) expressing neurons. The number of spikes for each burst is indicated below the trace (single spikes are indicated by asterisks). Left inset, a jRCaMP1a expressing neuron with the recording pipette (green). (b) Zoomed-in view of bursts of action potentials (corresponding to boxes in a). Top, jRGECO1a; bottom, jRCaMP1a. (c) jRGECO1a fluorescence changes in response to 1 AP (top, 199 spikes from 11 cells, n=6 mice), and jRCaMP1a fluorescence changes in response to 2 APs (bottom, 65 spikes from 10 cells, n=5 mice). Blue (top) and black (bottom) lines are the median traces. (d) Distribution of peak fluorescence change as a function of number of action potentials in a time bin (jRGECO1a, blue boxes: 199 1AP events; 2 APs: 70 events within a 100 ms time bin; 3 APs: 29, 125 ms; 4 APs: 34, 150 ms; 5 APs: 35, 175 ms; 6 APs: 22, 200 ms; 7 APs:14, 225 ms; 8 APs: 21, 250 ms. jRCaMP1a, black boxes: 135 1 AP events; 2 APs: 65, 150 ms; 3 APs: 71, 200 ms; 4 APs: 52, 250 ms; 5 APs: 33, 300 ms; 6 APs: 20, 350 ms; 7 APs: 14, 350 ms; 8 APs: 11, 350 ms). Each box corresponds to the 25th to 75^th percentile of the distribution (q_1 and q_3 respectively), whisker length is up to the extreme data point or 1.5_l (q3 - q1). (e) Receiver operating characteristic (ROC) curve for classifying 1 and 2 APs for jRGECO1a and jRCaMP1a (jRGECO1a: 320 events of no AP firing within a 4 s bin, jRCaMP1a: 274 events of no AP firing within a 5 s bin, 1 AP and 2 APs data same as in d). (f) Detection sensitivity index (d’) as a function of number of spikes in a time bin (same parameters as in d–e). (g) Comparison of mean half rise (left) and decay (right) times of jRGECO1a and jRCaMP1a for 2 AP response. Error bars correspond to s.e.m.DOI:10.7554/eLife.12727.015Figure 4—figure supplement 1.jRGECO1a accumulates in lysosomes.(a) Red GECI expression (top, red) and LAMP-1 immunostaining (bottom, green) of fixed tissue sections from mouse V1. (b) Distribution of the fraction of somatic area covered by protein aggregates for neurons expressing jRGECO1a. Neurons in V1 (fixed tissue) show more frequent jRGECO1a aggregates than cultured neurons (Wilcoxon rank sum test, p<0.001; n=10 cultured cells; 14, fixed tissue cells; 8, fixed tissue LAMP-1 immunostained cells). (c) Example traces from V1 L2/3 cell showing ΔF/F_0 changes of somatic regions overlapping with protein aggregates (red, black) and regions excluding aggregates (blue). Inset, image of the cell, with aggregates indicated by circles.DOI:10.7554/eLife.12727.016Figure 4—figure supplement 2.Red GECIs lack functional response at 900nm excitation.Functional responses of three example cells (jRGECO1a, expressed in L4 V1 neurons) at 1040 nm excitation (left) and 900 nm (25 vs. 1 cells were detected as responsive out of 50 cells in FOV; drifting grating stimuli, Materials and methods).DOI:10.7554/eLife.12727.017Figure 4—figure supplement 3.Complex spectral and functional characteristics of the red GECIs after long-term expression in vivo.(a) Images of jRGECO1a (left) and jRCaMP1a (right) L2/3 neurons in vivo excited by 1040 nm (top) and 900 nm light (bottom). Note the punctate fluorescence image in the bottom images. (b) Emission spectra from fixed tissue cells of jRGEC1a (top) and jRCaMP1b (bottom) when illuminated with 900 nm and 1000 nm laser reveal a greenish emission band. (c) Effect of long-term expression on accumulation of greenish species. Scatter plot of the ratio between jRGECO1a somatic signal detected at 900 nm excitation (red and green channel summed) and baseline fluorescence detected at 1040 nm excitation, and the peak somatic ΔF/F_0 for drifting grating stimuli. Measurements were done 16 (left) and 132 (right) days after AAV injection. Red solid line shows the linear regression model, red dashed lines are 95% confidence interval; R^2=0.09 for both datasets and slope of -9.2 and -10 respectively (n=98 cells, left panel; n=274 cells, right panel; linear regression model, F test, p<0.005). (d) Distribution of the somatic fluorescence ratio between 900 nm and 1040 nm excitation (same data as in c) show an increase in both the ratio median and its range with longer expression time. Each box corresponds to the 25th to 75^th percentile of the distribution (q_1 and q_3 respectively), whisker length is up to the extreme data point or 1.5 (q3 - q_1).DOI:',\n", + " 'paragraph_id': 13,\n", + " 'tokenizer': 'the, measured, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, responses, in, the, visual, cortex, were, smaller, than, expected, based, on, measurements, in, culture, ##d, neurons, (, figure, 2a, ,, figure, 4, ##c, ), and, lower, than, those, produced, by, g, ##camp, ##6, ##s, (, chen, et, al, ., ,, 2013, ##b, ), ., high, -, resolution, microscopy, of, fixed, brain, tissue, sections, revealed, bright, fluorescent, pun, ##cta, ##e, in, neurons, labeled, with, jr, ##ge, ##co, ##1, ##a, but, not, with, jr, ##camp, ##1, ##a, /, b, ., jr, ##ge, ##co, ##1, ##a, pun, ##cta, ##e, co, -, localized, with, lamp, -, 1, ,, a, marker, of, l, ##ys, ##oso, ##mes, (, figure, 4, —, figure, supplement, 1a, ), (, kata, ##yama, et, al, ., ,, 2008, ), ., similar, pun, ##cta, ##e, were, also, found, in, culture, ##d, neurons, ,, but, were, less, numerous, (, wilcox, ##on, rank, sum, test, ,, p, <, 0, ., 001, ,, figure, 4, —, figure, supplement, 1b, ), ., when, image, ##d, in, vivo, ,, roi, ##s, containing, pun, ##cta, ##e, had, higher, baseline, flu, ##orescence, by, 90, %, but, lower, peak, δ, ##f, /, f, _, 0, by, 20, %, compared, to, their, surrounding, so, ##ma, (, 10, cells, and, 39, pun, ##cta, ##e, ,, figure, 4, —, figure, supplement, 1, ##c, ), ., this, implies, that, accumulation, of, fluorescent, ,, non, -, responsive, jr, ##ge, ##co, ##1, ##a, in, l, ##ys, ##oso, ##mes, reduces, the, signal, -, to, -, noise, ratio, for, in, vivo, imaging, ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##4, ##fi, ##gur, ##e, 4, ., combined, imaging, and, electro, ##phy, ##sio, ##logy, in, the, mouse, visual, cortex, ., (, a, ), simultaneous, flu, ##orescence, dynamics, and, spikes, measured, from, jr, ##ge, ##co, ##1, ##a, (, top, ,, blue, ), and, jr, ##camp, ##1, ##a, (, bottom, ,, black, ), expressing, neurons, ., the, number, of, spikes, for, each, burst, is, indicated, below, the, trace, (, single, spikes, are, indicated, by, as, ##ter, ##isk, ##s, ), ., left, ins, ##et, ,, a, jr, ##camp, ##1, ##a, expressing, ne, ##uron, with, the, recording, pipe, ##tte, (, green, ), ., (, b, ), zoom, ##ed, -, in, view, of, bursts, of, action, potential, ##s, (, corresponding, to, boxes, in, a, ), ., top, ,, jr, ##ge, ##co, ##1, ##a, ;, bottom, ,, jr, ##camp, ##1, ##a, ., (, c, ), jr, ##ge, ##co, ##1, ##a, flu, ##orescence, changes, in, response, to, 1, ap, (, top, ,, 199, spikes, from, 11, cells, ,, n, =, 6, mice, ), ,, and, jr, ##camp, ##1, ##a, flu, ##orescence, changes, in, response, to, 2, ap, ##s, (, bottom, ,, 65, spikes, from, 10, cells, ,, n, =, 5, mice, ), ., blue, (, top, ), and, black, (, bottom, ), lines, are, the, median, traces, ., (, d, ), distribution, of, peak, flu, ##orescence, change, as, a, function, of, number, of, action, potential, ##s, in, a, time, bin, (, jr, ##ge, ##co, ##1, ##a, ,, blue, boxes, :, 199, 1a, ##p, events, ;, 2, ap, ##s, :, 70, events, within, a, 100, ms, time, bin, ;, 3, ap, ##s, :, 29, ,, 125, ms, ;, 4, ap, ##s, :, 34, ,, 150, ms, ;, 5, ap, ##s, :, 35, ,, 175, ms, ;, 6, ap, ##s, :, 22, ,, 200, ms, ;, 7, ap, ##s, :, 14, ,, 225, ms, ;, 8, ap, ##s, :, 21, ,, 250, ms, ., jr, ##camp, ##1, ##a, ,, black, boxes, :, 135, 1, ap, events, ;, 2, ap, ##s, :, 65, ,, 150, ms, ;, 3, ap, ##s, :, 71, ,, 200, ms, ;, 4, ap, ##s, :, 52, ,, 250, ms, ;, 5, ap, ##s, :, 33, ,, 300, ms, ;, 6, ap, ##s, :, 20, ,, 350, ms, ;, 7, ap, ##s, :, 14, ,, 350, ms, ;, 8, ap, ##s, :, 11, ,, 350, ms, ), ., each, box, corresponds, to, the, 25th, to, 75, ^, th, percent, ##ile, of, the, distribution, (, q, _, 1, and, q, _, 3, respectively, ), ,, w, ##his, ##ker, length, is, up, to, the, extreme, data, point, or, 1, ., 5, _, l, (, q, ##3, -, q, ##1, ), ., (, e, ), receiver, operating, characteristic, (, roc, ), curve, for, classify, ##ing, 1, and, 2, ap, ##s, for, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, (, jr, ##ge, ##co, ##1, ##a, :, 320, events, of, no, ap, firing, within, a, 4, s, bin, ,, jr, ##camp, ##1, ##a, :, 274, events, of, no, ap, firing, within, a, 5, s, bin, ,, 1, ap, and, 2, ap, ##s, data, same, as, in, d, ), ., (, f, ), detection, sensitivity, index, (, d, ’, ), as, a, function, of, number, of, spikes, in, a, time, bin, (, same, parameters, as, in, d, –, e, ), ., (, g, ), comparison, of, mean, half, rise, (, left, ), and, decay, (, right, ), times, of, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, for, 2, ap, response, ., error, bars, correspond, to, s, ., e, ., m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##5, ##fi, ##gur, ##e, 4, —, figure, supplement, 1, ., jr, ##ge, ##co, ##1, ##a, accumulate, ##s, in, l, ##ys, ##oso, ##mes, ., (, a, ), red, ge, ##ci, expression, (, top, ,, red, ), and, lamp, -, 1, im, ##mun, ##osta, ##ining, (, bottom, ,, green, ), of, fixed, tissue, sections, from, mouse, v, ##1, ., (, b, ), distribution, of, the, fraction, of, so, ##matic, area, covered, by, protein, aggregate, ##s, for, neurons, expressing, jr, ##ge, ##co, ##1, ##a, ., neurons, in, v, ##1, (, fixed, tissue, ), show, more, frequent, jr, ##ge, ##co, ##1, ##a, aggregate, ##s, than, culture, ##d, neurons, (, wilcox, ##on, rank, sum, test, ,, p, <, 0, ., 001, ;, n, =, 10, culture, ##d, cells, ;, 14, ,, fixed, tissue, cells, ;, 8, ,, fixed, tissue, lamp, -, 1, im, ##mun, ##osta, ##ined, cells, ), ., (, c, ), example, traces, from, v, ##1, l, ##2, /, 3, cell, showing, δ, ##f, /, f, _, 0, changes, of, so, ##matic, regions, overlapping, with, protein, aggregate, ##s, (, red, ,, black, ), and, regions, excluding, aggregate, ##s, (, blue, ), ., ins, ##et, ,, image, of, the, cell, ,, with, aggregate, ##s, indicated, by, circles, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##6, ##fi, ##gur, ##e, 4, —, figure, supplement, 2, ., red, ge, ##cis, lack, functional, response, at, 900, ##n, ##m, ex, ##cit, ##ation, ., functional, responses, of, three, example, cells, (, jr, ##ge, ##co, ##1, ##a, ,, expressed, in, l, ##4, v, ##1, neurons, ), at, 104, ##0, nm, ex, ##cit, ##ation, (, left, ), and, 900, nm, (, 25, vs, ., 1, cells, were, detected, as, responsive, out, of, 50, cells, in, f, ##ov, ;, drifting, gr, ##ating, stimuli, ,, materials, and, methods, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##7, ##fi, ##gur, ##e, 4, —, figure, supplement, 3, ., complex, spectral, and, functional, characteristics, of, the, red, ge, ##cis, after, long, -, term, expression, in, vivo, ., (, a, ), images, of, jr, ##ge, ##co, ##1, ##a, (, left, ), and, jr, ##camp, ##1, ##a, (, right, ), l, ##2, /, 3, neurons, in, vivo, excited, by, 104, ##0, nm, (, top, ), and, 900, nm, light, (, bottom, ), ., note, the, pun, ##cta, ##te, flu, ##orescence, image, in, the, bottom, images, ., (, b, ), emission, spectra, from, fixed, tissue, cells, of, jr, ##ge, ##c, ##1, ##a, (, top, ), and, jr, ##camp, ##1, ##b, (, bottom, ), when, illuminated, with, 900, nm, and, 1000, nm, laser, reveal, a, greenish, emission, band, ., (, c, ), effect, of, long, -, term, expression, on, accumulation, of, greenish, species, ., sc, ##atter, plot, of, the, ratio, between, jr, ##ge, ##co, ##1, ##a, so, ##matic, signal, detected, at, 900, nm, ex, ##cit, ##ation, (, red, and, green, channel, sum, ##med, ), and, baseline, flu, ##orescence, detected, at, 104, ##0, nm, ex, ##cit, ##ation, ,, and, the, peak, so, ##matic, δ, ##f, /, f, _, 0, for, drifting, gr, ##ating, stimuli, ., measurements, were, done, 16, (, left, ), and, 132, (, right, ), days, after, aa, ##v, injection, ., red, solid, line, shows, the, linear, regression, model, ,, red, dashed, lines, are, 95, %, confidence, interval, ;, r, ^, 2, =, 0, ., 09, for, both, data, ##set, ##s, and, slope, of, -, 9, ., 2, and, -, 10, respectively, (, n, =, 98, cells, ,, left, panel, ;, n, =, 274, cells, ,, right, panel, ;, linear, regression, model, ,, f, test, ,, p, <, 0, ., 00, ##5, ), ., (, d, ), distribution, of, the, so, ##matic, flu, ##orescence, ratio, between, 900, nm, and, 104, ##0, nm, ex, ##cit, ##ation, (, same, data, as, in, c, ), show, an, increase, in, both, the, ratio, median, and, its, range, with, longer, expression, time, ., each, box, corresponds, to, the, 25th, to, 75, ^, th, percent, ##ile, of, the, distribution, (, q, _, 1, and, q, _, 3, respectively, ), ,, w, ##his, ##ker, length, is, up, to, the, extreme, data, point, or, 1, ., 5, (, q, ##3, -, q, _, 1, ), ., doi, :'},\n", + " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", + " 'section_name': 'Red protein calcium indicators in Drosophila, zebrafish, and C. elegans',\n", + " 'text': 'We next tested red GECIs in flies, zebrafish and worms. Red GECIs were expressed pan-neuronally in transgenic flies (R57C10-Gal4). Boutons were imaged in the larval neuromuscular junction (NMJ) after electrical stimulation (Figure 7a,b; Materials and methods) (Hendel et al., 2008). Consistent with cultured neuron data, we saw a significant boost of single AP sensitivity in jRGECO1a, jRCaMP1a, and jRCaMP1b variants compared to their parent indicators (p<0.008 for all comparisons; Wilcoxon rank sum test; Figure 7c, Figure 7—figure supplement 1–2, Figure 7—source data 1–2). Peak response amplitudes of jRGECO1a and jRCaMP1a outperform GCaMP6s in the 1–5 Hz stimulation range (single AP ΔF/F_0 amplitude 11.6 ± 0.9%, 8.6 ± 0.5%, and 4.5 ± 0.3% respectively, mean ± s.e.m; Figure 7c, Figure 7—figure supplement 3, Figure 7—source data 3; 12 FOVs for jRGECO1a; 11, jRCaMP1a; 12, GCaMP6f; n=7 flies for all constructs). The decay kinetics of jRGECO1a (half decay time at 160 Hz: 0.42 ± 0.02 s, mean ± s.e.m) was similar to GCaMP6f (0.43 ± 0.01 s; Figure 7d, Figure 7—figure supplement 3, Figure 7—source data 3). The combination of high sensitivity and fast kinetics for jRGECO1a allows detection of individual spikes on top of the response envelope for stimuli up to 10 Hz (Figure 7b, Figure 7—figure supplement 1).10.7554/eLife.12727.021Figure 7.Imaging activity in Drosophila larval NMJ boutouns with red GECIs.(a) Schematic representation of Drosophila larval neuromuscular junction (NMJ) assay. Segmented motor nerve is electrically stimulated while optically imaging calcium responses in presynaptic boutons (green arrows). (b) Response transients (mean ± s.e.m.) to 5 Hz stimulation (2 s duration) for several red and green GECIs. Response amplitudes were 4-fold and 60% higher for jRGECO1a than GCaMP6f and GCaMP6s respectively (p<10–4 and p=0.01, Wilcoxon rank sum test), jRCaMP1a response amplitude was 3-fold higher than GCaMP6f (p=10–4) and similar to GCaMP6s (12 FOVs for jRGECO1a; 11, jRCaMP1a; 13, jRCaMP1b; 12, GCaMP6s; 12, GCaMP6f; n=7 flies for all constructs) (c) Comparison of frequency tuned responses (peak ΔF/F_0, mean ± s.e.m.) of red and green GECIs for 1, 5, 10, 20, 40, 80 and 160 Hz stimulation (2 s duration). jRGECO1a and jRCaMP1a response amplitudes were 2–3 fold higher than GCaMP6s and GCaMP6f for 1 Hz stimulus (p<0.001, Wilcoxon rank sum test), but lower for stimulus frequencies of 20 Hz and higher (12 FOVs for jRGECO1a; 10, R-GECO1; 11, jRCaMP1a; 13, jRCaMP1b; 10, RCaMP1h; 12, GCaMP6s; 12, GCaMP6f; n=5 flies for R-GECO1, n=7 flies for all other constructs) (d) Half decay time (mean ± s.e.m.) of red and green GECIs at 160 Hz stimulation (same FOVs and flies as in c; ***, p<0.001, Wilcoxon rank sum test).DOI:10.7554/eLife.12727.022Figure 7—source data 1.Summary of results shown in Figure 7—figure supplement 1.Wilcoxon rank sum test is used for p-value.DOI:10.7554/eLife.12727.023Figure 7—source data 2.Summary of results shown in Figure 7—figure supplement 2.Wilcoxon rank sum test is used for p-value.DOI:10.7554/eLife.12727.024Figure 7—source data 3.Summary of results shown in Figure 7—figure supplement 3.Wilcoxon rank sum test is used for p-value.DOI:10.7554/eLife.12727.025Figure 7—figure supplement 1.Imaging activity in Drosophila larval NMJ boutons with jRGECO1a.(a) Schematic of experimental setup. Epifluorescence and high magnification △F/F_0 images of Type 1b boutons (green arrowheads) from muscle 13 (segments A3-A5), with image segmentation ROIs superimposed (Materials and methods). (b) Single trial and averaged fluorescence transients after 1 Hz stimulus for 2 s for R-GECO1, jRGECO1a and jRGECO1b (R-GECO1: 10 FOVs in 5 flies, 40 boutons; jRGECO1a: 12 FOVs in 7 flies, 48 boutons; jRGECO1b: 9 FOVs in 6 flies, 36 boutons. Same data set used for all other analyses). jRGECO1a performance was superior to jRGECO1b in the Drosophila NMJ and zebrafish trigeminal neuron; therefore jRGECO1b was not fully tested in other animal models. (c–d) Fourier spectra normalized to 0 Hz of fluorescence signals acquired during 5 Hz (c) and 10 Hz (d) stimulation. (e–f) △F/F_0 (e) and SNR (f) traces (mean ± s.e.m.) recorded with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation for 2 s (indicated by red curves at the bottom, amplitude not to scale). (g–h) △F/F_0 (g) and SNR (h) traces (mean ± s.e.m.) recorded with 1 and 5 Hz stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (i–j) Comparison of △F/F_0 traces (mean ± s.e.m.) of R-GECO1 and jRGECO1 variants with 1, 5, 10 Hz (i) and 20, 40, 80 Hz (j) stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (k–l) Comparison of frequency tuned averaged peak △F/F_0 (k) and peak SNR (l) (mean ± s.e.m.) of GCaMP6 variants, R-GECO1 and jRGECO1 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation. Note that vertical axes are log scale. (m) Comparison of kinetics of GCaMP6 variants, R-GECO1 and jRGECO1 variants with 40 Hz stimulation. Horizontal axes are half rise time and vertical axes are half decay time.DOI:10.7554/eLife.12727.026Figure 7—figure supplement 2.Imaging activity in Drosophila larval NMJ boutons with jRCaMP1 constructs.(a) Schematic of experimental setup. Epifluorescence and high magnification △F/F_0 images of Type 1b boutons (green arrowheads) from muscle 13 (segments A3-A5), with image segmentation ROIs superimposed (Materials and methods). (b) Single trial and averaged fluorescence transients after 1 Hz stimulus for 2 s for R-GECO1, jRCaMP1a and jRCaMP1b (RCaMP1h: 10 FOVs in 7 flies, 40 boutons; jRCaMP1a: 11 FOVs in 7 flies, 44 boutons; jRCaMP1b: 13 FOVs in 7 flies, 52 boutons. Same data set used for all other analyses). (c-d) △F/F_0 (c) and SNR (d) traces (mean ± s.e.m.) recorded with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (e–f) △F/F_0 (e) and SNR (f) traces (mean ± s.e.m.) recorded with 1 and 5 Hz stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (g–h), Comparison of △F/F_0 traces (mean ± s.e.m.) of R-GECO1 and jRCaMP1 variants with 1, 5, 10 Hz (g) and 20, 40, 80 Hz (h) stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (i–j) Comparison of frequency tuned averaged peak △F/F_0 (i) and peak SNR (j) (mean ± s.e.m.) of RCaMP1h and jRCaMP1 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation. Note that vertical axes are log scale. (k) Comparison of kinetics of RCaMP1h and jRCaMP1 variants with 40 Hz stimulation. Horizontal axes are half rise time and vertical axes are half decay time.DOI:10.7554/eLife.12727.027Figure 7—figure supplement 3.Comparing red and green GECI activity in Drosophila larval NMJ boutons.(a–b) Single trial and averaged fluorescence transients after 1 Hz (a) and 5 Hz (b) stimulus for 2 s for jRGECO1a, jRCaMP1a, jRCaMP1b, GCaMP6s and GCaMP6f (jRGECO1a: 12 FOVs in 7 flies, 48 boutons; jRCaMP1a: 11 FOVs in 7 flies, 44 boutons; jRCaMP1b: 13 FOVs in 7 flies, 52 boutons; GCaMP6s: 12 FOVs in 7 flies, 48 boutons; GCaMP6f: 12 FOVs in 7 flies. Same data set used for all other analyses). (c) Comparison of frequency tuned averaged peak △F/F_0 (mean ± s.e.m.) of jRGECO1a, jRCaMP1 variants and GCaMP6 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation. Note that vertical axes are log scale. (d–e) Comparison of frequency tuned averaged half decay (d) and half rise (e) (mean ± s.e.m.) of jRGECO1a, jRCaMP1 variants and GCaMP6 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation.DOI:',\n", + " 'paragraph_id': 19,\n", + " 'tokenizer': 'we, next, tested, red, ge, ##cis, in, flies, ,, zebra, ##fish, and, worms, ., red, ge, ##cis, were, expressed, pan, -, ne, ##uron, ##ally, in, trans, ##genic, flies, (, r, ##57, ##c, ##10, -, gal, ##4, ), ., bout, ##ons, were, image, ##d, in, the, la, ##rval, ne, ##uro, ##mus, ##cular, junction, (, nm, ##j, ), after, electrical, stimulation, (, figure, 7, ##a, ,, b, ;, materials, and, methods, ), (, hen, ##del, et, al, ., ,, 2008, ), ., consistent, with, culture, ##d, ne, ##uron, data, ,, we, saw, a, significant, boost, of, single, ap, sensitivity, in, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, and, jr, ##camp, ##1, ##b, variants, compared, to, their, parent, indicators, (, p, <, 0, ., 00, ##8, for, all, comparisons, ;, wilcox, ##on, rank, sum, test, ;, figure, 7, ##c, ,, figure, 7, —, figure, supplement, 1, –, 2, ,, figure, 7, —, source, data, 1, –, 2, ), ., peak, response, amplitude, ##s, of, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, out, ##per, ##form, g, ##camp, ##6, ##s, in, the, 1, –, 5, hz, stimulation, range, (, single, ap, δ, ##f, /, f, _, 0, amplitude, 11, ., 6, ±, 0, ., 9, %, ,, 8, ., 6, ±, 0, ., 5, %, ,, and, 4, ., 5, ±, 0, ., 3, %, respectively, ,, mean, ±, s, ., e, ., m, ;, figure, 7, ##c, ,, figure, 7, —, figure, supplement, 3, ,, figure, 7, —, source, data, 3, ;, 12, f, ##ov, ##s, for, jr, ##ge, ##co, ##1, ##a, ;, 11, ,, jr, ##camp, ##1, ##a, ;, 12, ,, g, ##camp, ##6, ##f, ;, n, =, 7, flies, for, all, construct, ##s, ), ., the, decay, kinetic, ##s, of, jr, ##ge, ##co, ##1, ##a, (, half, decay, time, at, 160, hz, :, 0, ., 42, ±, 0, ., 02, s, ,, mean, ±, s, ., e, ., m, ), was, similar, to, g, ##camp, ##6, ##f, (, 0, ., 43, ±, 0, ., 01, s, ;, figure, 7, ##d, ,, figure, 7, —, figure, supplement, 3, ,, figure, 7, —, source, data, 3, ), ., the, combination, of, high, sensitivity, and, fast, kinetic, ##s, for, jr, ##ge, ##co, ##1, ##a, allows, detection, of, individual, spikes, on, top, of, the, response, envelope, for, stimuli, up, to, 10, hz, (, figure, 7, ##b, ,, figure, 7, —, figure, supplement, 1, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##1, ##fi, ##gur, ##e, 7, ., imaging, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##oun, ##s, with, red, ge, ##cis, ., (, a, ), sc, ##hema, ##tic, representation, of, dr, ##oso, ##phila, la, ##rval, ne, ##uro, ##mus, ##cular, junction, (, nm, ##j, ), ass, ##ay, ., segment, ##ed, motor, nerve, is, electrically, stimulated, while, optical, ##ly, imaging, calcium, responses, in, pre, ##sy, ##na, ##ptic, bout, ##ons, (, green, arrows, ), ., (, b, ), response, transient, ##s, (, mean, ±, s, ., e, ., m, ., ), to, 5, hz, stimulation, (, 2, s, duration, ), for, several, red, and, green, ge, ##cis, ., response, amplitude, ##s, were, 4, -, fold, and, 60, %, higher, for, jr, ##ge, ##co, ##1, ##a, than, g, ##camp, ##6, ##f, and, g, ##camp, ##6, ##s, respectively, (, p, <, 10, –, 4, and, p, =, 0, ., 01, ,, wilcox, ##on, rank, sum, test, ), ,, jr, ##camp, ##1, ##a, response, amplitude, was, 3, -, fold, higher, than, g, ##camp, ##6, ##f, (, p, =, 10, –, 4, ), and, similar, to, g, ##camp, ##6, ##s, (, 12, f, ##ov, ##s, for, jr, ##ge, ##co, ##1, ##a, ;, 11, ,, jr, ##camp, ##1, ##a, ;, 13, ,, jr, ##camp, ##1, ##b, ;, 12, ,, g, ##camp, ##6, ##s, ;, 12, ,, g, ##camp, ##6, ##f, ;, n, =, 7, flies, for, all, construct, ##s, ), (, c, ), comparison, of, frequency, tuned, responses, (, peak, δ, ##f, /, f, _, 0, ,, mean, ±, s, ., e, ., m, ., ), of, red, and, green, ge, ##cis, for, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, (, 2, s, duration, ), ., jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, response, amplitude, ##s, were, 2, –, 3, fold, higher, than, g, ##camp, ##6, ##s, and, g, ##camp, ##6, ##f, for, 1, hz, stimulus, (, p, <, 0, ., 001, ,, wilcox, ##on, rank, sum, test, ), ,, but, lower, for, stimulus, frequencies, of, 20, hz, and, higher, (, 12, f, ##ov, ##s, for, jr, ##ge, ##co, ##1, ##a, ;, 10, ,, r, -, ge, ##co, ##1, ;, 11, ,, jr, ##camp, ##1, ##a, ;, 13, ,, jr, ##camp, ##1, ##b, ;, 10, ,, rca, ##mp, ##1, ##h, ;, 12, ,, g, ##camp, ##6, ##s, ;, 12, ,, g, ##camp, ##6, ##f, ;, n, =, 5, flies, for, r, -, ge, ##co, ##1, ,, n, =, 7, flies, for, all, other, construct, ##s, ), (, d, ), half, decay, time, (, mean, ±, s, ., e, ., m, ., ), of, red, and, green, ge, ##cis, at, 160, hz, stimulation, (, same, f, ##ov, ##s, and, flies, as, in, c, ;, *, *, *, ,, p, <, 0, ., 001, ,, wilcox, ##on, rank, sum, test, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##2, ##fi, ##gur, ##e, 7, —, source, data, 1, ., summary, of, results, shown, in, figure, 7, —, figure, supplement, 1, ., wilcox, ##on, rank, sum, test, is, used, for, p, -, value, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##3, ##fi, ##gur, ##e, 7, —, source, data, 2, ., summary, of, results, shown, in, figure, 7, —, figure, supplement, 2, ., wilcox, ##on, rank, sum, test, is, used, for, p, -, value, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##4, ##fi, ##gur, ##e, 7, —, source, data, 3, ., summary, of, results, shown, in, figure, 7, —, figure, supplement, 3, ., wilcox, ##on, rank, sum, test, is, used, for, p, -, value, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##5, ##fi, ##gur, ##e, 7, —, figure, supplement, 1, ., imaging, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##ons, with, jr, ##ge, ##co, ##1, ##a, ., (, a, ), sc, ##hema, ##tic, of, experimental, setup, ., ep, ##if, ##lu, ##orescence, and, high, mag, ##ni, ##fication, [UNK], /, f, _, 0, images, of, type, 1b, bout, ##ons, (, green, arrow, ##heads, ), from, muscle, 13, (, segments, a, ##3, -, a, ##5, ), ,, with, image, segment, ##ation, roi, ##s, super, ##im, ##posed, (, materials, and, methods, ), ., (, b, ), single, trial, and, averaged, flu, ##orescence, transient, ##s, after, 1, hz, stimulus, for, 2, s, for, r, -, ge, ##co, ##1, ,, jr, ##ge, ##co, ##1, ##a, and, jr, ##ge, ##co, ##1, ##b, (, r, -, ge, ##co, ##1, :, 10, f, ##ov, ##s, in, 5, flies, ,, 40, bout, ##ons, ;, jr, ##ge, ##co, ##1, ##a, :, 12, f, ##ov, ##s, in, 7, flies, ,, 48, bout, ##ons, ;, jr, ##ge, ##co, ##1, ##b, :, 9, f, ##ov, ##s, in, 6, flies, ,, 36, bout, ##ons, ., same, data, set, used, for, all, other, analyses, ), ., jr, ##ge, ##co, ##1, ##a, performance, was, superior, to, jr, ##ge, ##co, ##1, ##b, in, the, dr, ##oso, ##phila, nm, ##j, and, zebra, ##fish, tri, ##ge, ##mina, ##l, ne, ##uron, ;, therefore, jr, ##ge, ##co, ##1, ##b, was, not, fully, tested, in, other, animal, models, ., (, c, –, d, ), fourier, spectra, normal, ##ized, to, 0, hz, of, flu, ##orescence, signals, acquired, during, 5, hz, (, c, ), and, 10, hz, (, d, ), stimulation, ., (, e, –, f, ), [UNK], /, f, _, 0, (, e, ), and, s, ##nr, (, f, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, for, 2, s, (, indicated, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, g, –, h, ), [UNK], /, f, _, 0, (, g, ), and, s, ##nr, (, h, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, and, 5, hz, stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, i, –, j, ), comparison, of, [UNK], /, f, _, 0, traces, (, mean, ±, s, ., e, ., m, ., ), of, r, -, ge, ##co, ##1, and, jr, ##ge, ##co, ##1, variants, with, 1, ,, 5, ,, 10, hz, (, i, ), and, 20, ,, 40, ,, 80, hz, (, j, ), stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, k, –, l, ), comparison, of, frequency, tuned, averaged, peak, [UNK], /, f, _, 0, (, k, ), and, peak, s, ##nr, (, l, ), (, mean, ±, s, ., e, ., m, ., ), of, g, ##camp, ##6, variants, ,, r, -, ge, ##co, ##1, and, jr, ##ge, ##co, ##1, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., note, that, vertical, axes, are, log, scale, ., (, m, ), comparison, of, kinetic, ##s, of, g, ##camp, ##6, variants, ,, r, -, ge, ##co, ##1, and, jr, ##ge, ##co, ##1, variants, with, 40, hz, stimulation, ., horizontal, axes, are, half, rise, time, and, vertical, axes, are, half, decay, time, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##6, ##fi, ##gur, ##e, 7, —, figure, supplement, 2, ., imaging, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##ons, with, jr, ##camp, ##1, construct, ##s, ., (, a, ), sc, ##hema, ##tic, of, experimental, setup, ., ep, ##if, ##lu, ##orescence, and, high, mag, ##ni, ##fication, [UNK], /, f, _, 0, images, of, type, 1b, bout, ##ons, (, green, arrow, ##heads, ), from, muscle, 13, (, segments, a, ##3, -, a, ##5, ), ,, with, image, segment, ##ation, roi, ##s, super, ##im, ##posed, (, materials, and, methods, ), ., (, b, ), single, trial, and, averaged, flu, ##orescence, transient, ##s, after, 1, hz, stimulus, for, 2, s, for, r, -, ge, ##co, ##1, ,, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, (, rca, ##mp, ##1, ##h, :, 10, f, ##ov, ##s, in, 7, flies, ,, 40, bout, ##ons, ;, jr, ##camp, ##1, ##a, :, 11, f, ##ov, ##s, in, 7, flies, ,, 44, bout, ##ons, ;, jr, ##camp, ##1, ##b, :, 13, f, ##ov, ##s, in, 7, flies, ,, 52, bout, ##ons, ., same, data, set, used, for, all, other, analyses, ), ., (, c, -, d, ), [UNK], /, f, _, 0, (, c, ), and, s, ##nr, (, d, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, e, –, f, ), [UNK], /, f, _, 0, (, e, ), and, s, ##nr, (, f, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, and, 5, hz, stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, g, –, h, ), ,, comparison, of, [UNK], /, f, _, 0, traces, (, mean, ±, s, ., e, ., m, ., ), of, r, -, ge, ##co, ##1, and, jr, ##camp, ##1, variants, with, 1, ,, 5, ,, 10, hz, (, g, ), and, 20, ,, 40, ,, 80, hz, (, h, ), stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, i, –, j, ), comparison, of, frequency, tuned, averaged, peak, [UNK], /, f, _, 0, (, i, ), and, peak, s, ##nr, (, j, ), (, mean, ±, s, ., e, ., m, ., ), of, rca, ##mp, ##1, ##h, and, jr, ##camp, ##1, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., note, that, vertical, axes, are, log, scale, ., (, k, ), comparison, of, kinetic, ##s, of, rca, ##mp, ##1, ##h, and, jr, ##camp, ##1, variants, with, 40, hz, stimulation, ., horizontal, axes, are, half, rise, time, and, vertical, axes, are, half, decay, time, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##7, ##fi, ##gur, ##e, 7, —, figure, supplement, 3, ., comparing, red, and, green, ge, ##ci, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##ons, ., (, a, –, b, ), single, trial, and, averaged, flu, ##orescence, transient, ##s, after, 1, hz, (, a, ), and, 5, hz, (, b, ), stimulus, for, 2, s, for, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, jr, ##camp, ##1, ##b, ,, g, ##camp, ##6, ##s, and, g, ##camp, ##6, ##f, (, jr, ##ge, ##co, ##1, ##a, :, 12, f, ##ov, ##s, in, 7, flies, ,, 48, bout, ##ons, ;, jr, ##camp, ##1, ##a, :, 11, f, ##ov, ##s, in, 7, flies, ,, 44, bout, ##ons, ;, jr, ##camp, ##1, ##b, :, 13, f, ##ov, ##s, in, 7, flies, ,, 52, bout, ##ons, ;, g, ##camp, ##6, ##s, :, 12, f, ##ov, ##s, in, 7, flies, ,, 48, bout, ##ons, ;, g, ##camp, ##6, ##f, :, 12, f, ##ov, ##s, in, 7, flies, ., same, data, set, used, for, all, other, analyses, ), ., (, c, ), comparison, of, frequency, tuned, averaged, peak, [UNK], /, f, _, 0, (, mean, ±, s, ., e, ., m, ., ), of, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, variants, and, g, ##camp, ##6, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., note, that, vertical, axes, are, log, scale, ., (, d, –, e, ), comparison, of, frequency, tuned, averaged, half, decay, (, d, ), and, half, rise, (, e, ), (, mean, ±, s, ., e, ., m, ., ), of, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, variants, and, g, ##camp, ##6, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., doi, :'},\n", + " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", + " 'section_name': 'Protein engineering',\n", + " 'text': 'Beneficial mutations were combined in a second round of mutagenesis (136 RCaMP1h and 166 R-GECO1 variants) (Figure 1c,d). Based on criteria similar to those outlined above, two new mRuby-based sensors, jRCaMP1a and jRCaMP1b, and one mApple-based sensor, jRGECO1a, were selected for in-depth analysis (red bars in the histograms of Figure 1c,d). These sensors have similar absorption and emission spectra to each other and their parent constructs but they differ in sensitivity for detecting neural activity, kinetics, and other biophysical properties (−Figure 2, Figure 2—figure supplement 1–2, Figure 2—source data 1).10.7554/eLife.12727.004Figure 2.jRGECO1 and jRCaMP1 performance in dissociated neurons.(a) Average responses in response to one action potential (AP) for RCaMP1h (9479 neurons, 605 wells), R-GECO1 (8988 neurons, 539 wells), R-CaMP2 (265 neurons, 22 wells), jRGECO1a (383 neurons, 26 wells), jRCaMP1a (599 neurons, 38 wells), and jRCaMP1b (641 neurons, 31 wells). (b) Same for 10 APs response. (c–f) Comparison of jRGECO1 and jRCaMP1 sensors and other red GECIs, as a function of number of APs (color code as in a). (c) Response amplitude, ΔF/F_0. (d) Signal-to-noise ratio, SNR, defined as the fluorescence signal peak above baseline, divided by the signal standard deviation before the stimulation is given. (e) Half decay time. (f) Half rise time. Error bars correspond to s.e.m (n=605 wells for RCaMP1h; 539, R-GECO1; 22, R-CaMP2; 38, jRCaMP1a; 31, jRCaMP1b; 26, jRGECO1a).DOI:10.7554/eLife.12727.005Figure 2—source data 1.Biophysical properties of purified jRGECO1 and jRCaMP1 sensors.Summary of red GECI biophysical properties, mean ± s.d., where indicated, for independently purified protein samples (Materials and methods).DOI:10.7554/eLife.12727.006Figure 2—figure supplement 1.Absorption and emission spectra of red GECIs.(a) One-photon excitation (dashed lines) and emission (solid lines) spectra for jRGECO1a (left panel), jRCaMP1a (middle), and jRCaMP1b (right) in Ca-free (blue lines) and Ca-saturated (red lines) states. (b) Two-photon excitation spectra for jRGECO1a, jRCaMP1a, and jRCaMP1b, in Ca-free (blue) and Ca- saturated (red) states. Dashed green lines show the ratio between these two states.DOI:10.7554/eLife.12727.007Figure 2—figure supplement 2.Biophysical properties.(a) Fluorescence quantum yield of red GECIs and red FPs (all at 1070 nm), and GCaMP6s (940 nm). (b) Peak two-photon molecular brightness (Ca-bound state for GECIs) of red GECIs, red FPs, and GCaMP6s (note the different wavelengths used). mApple data in a and b is taken from Akerboom et al., 2013. Measurements were done in a purified protein assay (Materials and methods). (c–d) One-photon bleaching curves of jRGECO1a (blue), jRCaMP1a (black), and jRCaMP1b (red) in Ca-free (c) and Ca-saturated (d) states. Note that Ca-free jRGECO1a bleaching is negligible, while ~40% of the Ca-saturated jRGECO1a molecules photobleach within few seconds. e–g, Two-photon bleaching curves of jRCaMP1a (e), jRGECO1a (f), and GCaMP6s (g) in Ca-free and Ca-saturated states. h–i, Two-photon bleaching profile of Ca-saturated jRCaMP1a (h) and jRGECO1a (i) when excited with 2 different wavelengths while maintaining an identical SNR.DOI:10.7554/eLife.12727.008Figure 2—figure supplement 3.Photoswitching in purified protein assay.Fluorescence traces of purified Ca^2+-free protein droplets (red traces) of jRCaMP1a (left panel), jRGECO1a (middle), and R-CaMP2 (right) constantly illuminated with 561 nm excitation light (40 mW/mm^2), and with 488 nm light pulses (3.2 mW/mm^2 peak power, 50 ms duration, 0.2 Hz, 1 Hz, and 1.8 Hz in upper, middle, and lower rows respectively). For the mApple-based GECIs, jRGECO1a and R-CaMP2, blue illumination induced a transient, calcium-independent increase in fluorescence intensity indicative of photoswitching, while jRCaMP1a does not photoswitch, but photobleaches.DOI:10.7554/eLife.12727.009Figure 2—figure supplement 4.jRCaMP1a is more compatible than jRGECO1a for simultaneous use with ChR2.(a) Fluorescence signal from cultured rat hippocampal neurons transfected with either jRGECO1a alone (gray) or jRGECO1a+ChR2-Venus (blue) following stimulation with blue light (33 mW, 10 ms pulses, 83 Hz, 200 μm X 200 μm FOV; Materials and methods) stimulus pulses (light blue bars). Inset, merged image of neuron expressing both jRGECO1a (red) and ChR2-Venus (green). (b) Same experiment as in a with cultured neurons expressing jRCaMP1a alone (gray) or jRCaMP1a+ChR2-Venus (black). (c) Peak ΔF/F_0 values for 5 neurons expressing jRGECO1a+ChR2-Venus (blue) and 5 neurons expressing jRGECO1a alone (gray) as a function of blue stimulus light power. (d) Peak ΔF/F_0 for 5 neurons expressing jRCaMP1a+ChR2-Venus (black) and 5 neurons expressing jRCaMP1a alone (gray) as function of blue stimulus light power.DOI:',\n", + " 'paragraph_id': 7,\n", + " 'tokenizer': 'beneficial, mutations, were, combined, in, a, second, round, of, mu, ##tage, ##nes, ##is, (, 136, rca, ##mp, ##1, ##h, and, 166, r, -, ge, ##co, ##1, variants, ), (, figure, 1, ##c, ,, d, ), ., based, on, criteria, similar, to, those, outlined, above, ,, two, new, mr, ##ub, ##y, -, based, sensors, ,, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, ,, and, one, map, ##ple, -, based, sensor, ,, jr, ##ge, ##co, ##1, ##a, ,, were, selected, for, in, -, depth, analysis, (, red, bars, in, the, his, ##to, ##gram, ##s, of, figure, 1, ##c, ,, d, ), ., these, sensors, have, similar, absorption, and, emission, spectra, to, each, other, and, their, parent, construct, ##s, but, they, differ, in, sensitivity, for, detecting, neural, activity, ,, kinetic, ##s, ,, and, other, bio, ##physical, properties, (, −, ##fi, ##gur, ##e, 2, ,, figure, 2, —, figure, supplement, 1, –, 2, ,, figure, 2, —, source, data, 1, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##4, ##fi, ##gur, ##e, 2, ., jr, ##ge, ##co, ##1, and, jr, ##camp, ##1, performance, in, di, ##sso, ##cia, ##ted, neurons, ., (, a, ), average, responses, in, response, to, one, action, potential, (, ap, ), for, rca, ##mp, ##1, ##h, (, 94, ##7, ##9, neurons, ,, 60, ##5, wells, ), ,, r, -, ge, ##co, ##1, (, 89, ##8, ##8, neurons, ,, 53, ##9, wells, ), ,, r, -, camp, ##2, (, 265, neurons, ,, 22, wells, ), ,, jr, ##ge, ##co, ##1, ##a, (, 38, ##3, neurons, ,, 26, wells, ), ,, jr, ##camp, ##1, ##a, (, 59, ##9, neurons, ,, 38, wells, ), ,, and, jr, ##camp, ##1, ##b, (, 64, ##1, neurons, ,, 31, wells, ), ., (, b, ), same, for, 10, ap, ##s, response, ., (, c, –, f, ), comparison, of, jr, ##ge, ##co, ##1, and, jr, ##camp, ##1, sensors, and, other, red, ge, ##cis, ,, as, a, function, of, number, of, ap, ##s, (, color, code, as, in, a, ), ., (, c, ), response, amplitude, ,, δ, ##f, /, f, _, 0, ., (, d, ), signal, -, to, -, noise, ratio, ,, s, ##nr, ,, defined, as, the, flu, ##orescence, signal, peak, above, baseline, ,, divided, by, the, signal, standard, deviation, before, the, stimulation, is, given, ., (, e, ), half, decay, time, ., (, f, ), half, rise, time, ., error, bars, correspond, to, s, ., e, ., m, (, n, =, 60, ##5, wells, for, rca, ##mp, ##1, ##h, ;, 53, ##9, ,, r, -, ge, ##co, ##1, ;, 22, ,, r, -, camp, ##2, ;, 38, ,, jr, ##camp, ##1, ##a, ;, 31, ,, jr, ##camp, ##1, ##b, ;, 26, ,, jr, ##ge, ##co, ##1, ##a, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##5, ##fi, ##gur, ##e, 2, —, source, data, 1, ., bio, ##physical, properties, of, pu, ##rified, jr, ##ge, ##co, ##1, and, jr, ##camp, ##1, sensors, ., summary, of, red, ge, ##ci, bio, ##physical, properties, ,, mean, ±, s, ., d, ., ,, where, indicated, ,, for, independently, pu, ##rified, protein, samples, (, materials, and, methods, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##6, ##fi, ##gur, ##e, 2, —, figure, supplement, 1, ., absorption, and, emission, spectra, of, red, ge, ##cis, ., (, a, ), one, -, photon, ex, ##cit, ##ation, (, dashed, lines, ), and, emission, (, solid, lines, ), spectra, for, jr, ##ge, ##co, ##1, ##a, (, left, panel, ), ,, jr, ##camp, ##1, ##a, (, middle, ), ,, and, jr, ##camp, ##1, ##b, (, right, ), in, ca, -, free, (, blue, lines, ), and, ca, -, saturated, (, red, lines, ), states, ., (, b, ), two, -, photon, ex, ##cit, ##ation, spectra, for, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, and, jr, ##camp, ##1, ##b, ,, in, ca, -, free, (, blue, ), and, ca, -, saturated, (, red, ), states, ., dashed, green, lines, show, the, ratio, between, these, two, states, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##7, ##fi, ##gur, ##e, 2, —, figure, supplement, 2, ., bio, ##physical, properties, ., (, a, ), flu, ##orescence, quantum, yield, of, red, ge, ##cis, and, red, f, ##ps, (, all, at, 107, ##0, nm, ), ,, and, g, ##camp, ##6, ##s, (, 94, ##0, nm, ), ., (, b, ), peak, two, -, photon, molecular, brightness, (, ca, -, bound, state, for, ge, ##cis, ), of, red, ge, ##cis, ,, red, f, ##ps, ,, and, g, ##camp, ##6, ##s, (, note, the, different, wavelengths, used, ), ., map, ##ple, data, in, a, and, b, is, taken, from, ak, ##er, ##bo, ##om, et, al, ., ,, 2013, ., measurements, were, done, in, a, pu, ##rified, protein, ass, ##ay, (, materials, and, methods, ), ., (, c, –, d, ), one, -, photon, b, ##lea, ##ching, curves, of, jr, ##ge, ##co, ##1, ##a, (, blue, ), ,, jr, ##camp, ##1, ##a, (, black, ), ,, and, jr, ##camp, ##1, ##b, (, red, ), in, ca, -, free, (, c, ), and, ca, -, saturated, (, d, ), states, ., note, that, ca, -, free, jr, ##ge, ##co, ##1, ##a, b, ##lea, ##ching, is, ne, ##gli, ##gible, ,, while, ~, 40, %, of, the, ca, -, saturated, jr, ##ge, ##co, ##1, ##a, molecules, photo, ##ble, ##ach, within, few, seconds, ., e, –, g, ,, two, -, photon, b, ##lea, ##ching, curves, of, jr, ##camp, ##1, ##a, (, e, ), ,, jr, ##ge, ##co, ##1, ##a, (, f, ), ,, and, g, ##camp, ##6, ##s, (, g, ), in, ca, -, free, and, ca, -, saturated, states, ., h, –, i, ,, two, -, photon, b, ##lea, ##ching, profile, of, ca, -, saturated, jr, ##camp, ##1, ##a, (, h, ), and, jr, ##ge, ##co, ##1, ##a, (, i, ), when, excited, with, 2, different, wavelengths, while, maintaining, an, identical, s, ##nr, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##8, ##fi, ##gur, ##e, 2, —, figure, supplement, 3, ., photos, ##wi, ##tch, ##ing, in, pu, ##rified, protein, ass, ##ay, ., flu, ##orescence, traces, of, pu, ##rified, ca, ^, 2, +, -, free, protein, droplets, (, red, traces, ), of, jr, ##camp, ##1, ##a, (, left, panel, ), ,, jr, ##ge, ##co, ##1, ##a, (, middle, ), ,, and, r, -, camp, ##2, (, right, ), constantly, illuminated, with, 56, ##1, nm, ex, ##cit, ##ation, light, (, 40, mw, /, mm, ^, 2, ), ,, and, with, 48, ##8, nm, light, pulses, (, 3, ., 2, mw, /, mm, ^, 2, peak, power, ,, 50, ms, duration, ,, 0, ., 2, hz, ,, 1, hz, ,, and, 1, ., 8, hz, in, upper, ,, middle, ,, and, lower, rows, respectively, ), ., for, the, map, ##ple, -, based, ge, ##cis, ,, jr, ##ge, ##co, ##1, ##a, and, r, -, camp, ##2, ,, blue, illumination, induced, a, transient, ,, calcium, -, independent, increase, in, flu, ##orescence, intensity, indicative, of, photos, ##wi, ##tch, ##ing, ,, while, jr, ##camp, ##1, ##a, does, not, photos, ##wi, ##tch, ,, but, photo, ##ble, ##ache, ##s, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##9, ##fi, ##gur, ##e, 2, —, figure, supplement, 4, ., jr, ##camp, ##1, ##a, is, more, compatible, than, jr, ##ge, ##co, ##1, ##a, for, simultaneous, use, with, ch, ##r, ##2, ., (, a, ), flu, ##orescence, signal, from, culture, ##d, rat, hip, ##po, ##camp, ##al, neurons, trans, ##fect, ##ed, with, either, jr, ##ge, ##co, ##1, ##a, alone, (, gray, ), or, jr, ##ge, ##co, ##1, ##a, +, ch, ##r, ##2, -, venus, (, blue, ), following, stimulation, with, blue, light, (, 33, mw, ,, 10, ms, pulses, ,, 83, hz, ,, 200, μ, ##m, x, 200, μ, ##m, f, ##ov, ;, materials, and, methods, ), stimulus, pulses, (, light, blue, bars, ), ., ins, ##et, ,, merged, image, of, ne, ##uron, expressing, both, jr, ##ge, ##co, ##1, ##a, (, red, ), and, ch, ##r, ##2, -, venus, (, green, ), ., (, b, ), same, experiment, as, in, a, with, culture, ##d, neurons, expressing, jr, ##camp, ##1, ##a, alone, (, gray, ), or, jr, ##camp, ##1, ##a, +, ch, ##r, ##2, -, venus, (, black, ), ., (, c, ), peak, δ, ##f, /, f, _, 0, values, for, 5, neurons, expressing, jr, ##ge, ##co, ##1, ##a, +, ch, ##r, ##2, -, venus, (, blue, ), and, 5, neurons, expressing, jr, ##ge, ##co, ##1, ##a, alone, (, gray, ), as, a, function, of, blue, stimulus, light, power, ., (, d, ), peak, δ, ##f, /, f, _, 0, for, 5, neurons, expressing, jr, ##camp, ##1, ##a, +, ch, ##r, ##2, -, venus, (, black, ), and, 5, neurons, expressing, jr, ##camp, ##1, ##a, alone, (, gray, ), as, function, of, blue, stimulus, light, power, ., doi, :'},\n", + " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", + " 'section_name': 'Red protein calcium indicators in mouse V1',\n", + " 'text': 'We tested jRGECO1a, jRCaMP1a, jRCaMP1b, their parent indicators, and R-CaMP2 (Inoue et al., 2015) in the mouse primary visual cortex (V1) in vivo (Chen et al., 2013b) (Figure 3a, Video 1). The majority of V1 neurons can be driven to fire action potentials in response to drifting gratings (Mrsic-Flogel et al., 2007; Niell and Stryker, 2008). V1 neurons were infected with adeno-associated virus (AAV) expressing one of the red GECI variants under the human synapsin1 promoter (AAV-SYN1-red GECI variant) and imaged 16–180 days later. Two-photon excitation was performed with a tunable ultrafast laser (Insight DS+; Spectra-Physics) running at 1040 nm or 1100 nm. L2/3 neurons showed red fluorescence in the neuronal cytoplasm. Visual stimuli consisted of moving gratings presented in eight directions to the contralateral eye (Akerboom et al., 2012; Chen et al., 2013b). Regions of interest corresponding to single neurons revealed visual stimulus-evoked fluorescence transients that were stable across trials and tuned to stimulus orientation (Figure 3b). Orientation tuning was similar for all constructs tested (Figure 3—figure supplement 1). Fluorescence transients tracked the dynamics of the sensory stimuli (Figure 3b–d, Video 1). mApple-based indicators tracked more faithfully than mRuby-based indicators because of their faster kinetics (signal half-decay time after end of stimulus was 300 ± 22 ms for R-GECO1, 175 cells; 390 ± 20 ms, jRGECO1a, 395 cells; 330 ± 16 ms, R-CaMP2, 310 cells; 640 ± 30 ms, jRCaMP1a, 347 cells; 500 ± 45 ms, jRCaMP1b, 95 cells; activity of RCaMP1h expressing cells was to weak to be reliably characterized, mean ± s.e.m., Materials and methods).10.7554/eLife.12727.010Figure 3.jRGECO1a and jRCaMP1a and jRCaMP1b performance in the mouse primary visual cortex.(a) Top, schematic of the experiment. Bottom, image of V1 L2/3 cells expressing jRGECO1a (left), and the same field of view color-coded according to the neurons’ preferred orientation (hue) and response amplitude (brightness). (b) Example traces from three L2/3 neurons expressing jRGECO1a (left) and jRCaMP1a (right). Single trials (gray) and averages of 5 trials (blue and black for jRGECO1a and jRCaMP1a respectively) are overlaid. Eight grating motion directions are indicated by arrows and shown above traces. The preferred stimulus is the direction evoking the largest response. jRGECO1a traces correspond to the cells indicated in panel a (see also Video 1). (c) Average response of neurons to their preferred stimulus (175 cells, R-GECO1; 310, R-CaMP2; 395, jRGECO1a; 347, jRCaMP1a; 95, jRCaMP1b. n=4 mice for jRGECO1a and jRCaMP1a, n=3 mice for all other constructs. Panels c-f are based on the same data set. (d) Fourier spectra normalized to the amplitude at 0 Hz for neurons driven with 1 Hz drifting gratings, transduced with RCaMP1h, R-GECO1, R-CaMP2, jRGECaMP1a, jRCaMP1b, and jRGECO1a. Inset, zoomed-in view of 1 Hz response amplitudes. (e) Fraction of cells detected as responding to visual stimulus (ANOVA test, p<0.01) when expressing different calcium indicators. This fraction was 8- and 6-fold higher for jRCaMP1a and jRCaMP1b compared to RCaMP1h, respectively, and 60% higher for jRGECO1a compared to R-GECO1 (Wilcoxon rank sum test; *, p<0.05; **, p<0.01; ***, p<0.001). Error bars correspond to s.e.m (26 fields-of-view, RCaMP1h; 45, jRCaMP1a; 31, jRCaMP1b; 30, R-GECO1; 40, jRGECO1a; 33, R-CaMP2; 23, GCaMP6s; 29, GCaMP6f) (f) Distribution of ΔF/F amplitude for the preferred stimulus. A right-shifted curve, such as jRGECO1a vs. R-GECO1 or jRCaMP1a/b vs. jRCaMP1h, indicates enhancement of response amplitude (75 percentile values of 0.36 and 0.27 vs. 0.18 for jRCaMP1a and jRCaMP1b vs. RCaMP1h, and 0.66 vs. 0.38 for jRGECO1a vs. GCaMP6f, respectively). (1210 cells, R-GECO1; 861, RCaMP1h; 1733, R-CaMP2; 1605, jRGECO1a; 1981, jRCaMP1a; 971, jRCaMP1b; 907, GCaMP6f; 672, GCaMP6s), same colors as in e.DOI:10.7554/eLife.12727.011Figure 3—figure supplement 1.Comparison of orientation tuning in V1 neurons measured with different red GECIs.Distribution of orientation selectivity index (OSI, 3 upper rows) for all cells detected as responsive, measured using different GECIs. Bottom panel, mean ± s.d for all constructs show similar tuning properties (n=238 cells, R-GECO1; 308, jRGECO1a; 386, R-CaMP2; 277, jRCaMP1a; 141, jRCaMP1b; 337, GCaMP6s; 203, GCaMP6f).DOI:10.7554/eLife.12727.012Figure 3—figure supplement 2.Long-term expression of red GECIs in mouse V1.(a) Example images of V1 L2/3 neurons after long term expression of red GECIs. (b) Comparison of the proportion of responsive cells, orientation-tuned cells, and the ratio between them. Each time point corresponds to a different mouse. (c) Distributions of peak ΔF/F_0 for different animals imaged after different times of expression of the red GECI. No strong effect of expression time on peak response was detected. (d) Half decay times of the fluorescence response for different animals with different expression time of the red GECI. No strong effect of expression time on the decay kinetics was seen. jRCaMP1a data for 16 days of expression is not shown because the number of cells eligible for this analysis was too small (Materials and methods).DOI:Video 1.jRGECO1a L2/3 functional imaging in the mouse V1.The mouse was anesthetized and presented with moving gratings in eight directions to the contralateral eye. Gratings were presented for 4 s (indicated by appearance of an arrowhead in the grating propagation direction) followed by a 4 s of blank display. Field of view size was 250x250 μm^2, acquired at 15 Hz and filtered with a 5 frame moving average.DOI:10.7554/eLife.12727.013',\n", + " 'paragraph_id': 10,\n", + " 'tokenizer': 'we, tested, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, jr, ##camp, ##1, ##b, ,, their, parent, indicators, ,, and, r, -, camp, ##2, (, in, ##oue, et, al, ., ,, 2015, ), in, the, mouse, primary, visual, cortex, (, v, ##1, ), in, vivo, (, chen, et, al, ., ,, 2013, ##b, ), (, figure, 3a, ,, video, 1, ), ., the, majority, of, v, ##1, neurons, can, be, driven, to, fire, action, potential, ##s, in, response, to, drifting, gr, ##ating, ##s, (, mrs, ##ic, -, fl, ##oge, ##l, et, al, ., ,, 2007, ;, ni, ##ell, and, stryker, ,, 2008, ), ., v, ##1, neurons, were, infected, with, aden, ##o, -, associated, virus, (, aa, ##v, ), expressing, one, of, the, red, ge, ##ci, variants, under, the, human, syn, ##ap, ##sin, ##1, promoter, (, aa, ##v, -, syn, ##1, -, red, ge, ##ci, variant, ), and, image, ##d, 16, –, 180, days, later, ., two, -, photon, ex, ##cit, ##ation, was, performed, with, a, tuna, ##ble, ultra, ##fast, laser, (, insight, ds, +, ;, spectra, -, physics, ), running, at, 104, ##0, nm, or, 1100, nm, ., l, ##2, /, 3, neurons, showed, red, flu, ##orescence, in, the, ne, ##uron, ##al, cy, ##top, ##las, ##m, ., visual, stimuli, consisted, of, moving, gr, ##ating, ##s, presented, in, eight, directions, to, the, contra, ##lateral, eye, (, ak, ##er, ##bo, ##om, et, al, ., ,, 2012, ;, chen, et, al, ., ,, 2013, ##b, ), ., regions, of, interest, corresponding, to, single, neurons, revealed, visual, stimulus, -, ev, ##oked, flu, ##orescence, transient, ##s, that, were, stable, across, trials, and, tuned, to, stimulus, orientation, (, figure, 3, ##b, ), ., orientation, tuning, was, similar, for, all, construct, ##s, tested, (, figure, 3, —, figure, supplement, 1, ), ., flu, ##orescence, transient, ##s, tracked, the, dynamics, of, the, sensory, stimuli, (, figure, 3, ##b, –, d, ,, video, 1, ), ., map, ##ple, -, based, indicators, tracked, more, faithful, ##ly, than, mr, ##ub, ##y, -, based, indicators, because, of, their, faster, kinetic, ##s, (, signal, half, -, decay, time, after, end, of, stimulus, was, 300, ±, 22, ms, for, r, -, ge, ##co, ##1, ,, 175, cells, ;, 390, ±, 20, ms, ,, jr, ##ge, ##co, ##1, ##a, ,, 395, cells, ;, 330, ±, 16, ms, ,, r, -, camp, ##2, ,, 310, cells, ;, 640, ±, 30, ms, ,, jr, ##camp, ##1, ##a, ,, 34, ##7, cells, ;, 500, ±, 45, ms, ,, jr, ##camp, ##1, ##b, ,, 95, cells, ;, activity, of, rca, ##mp, ##1, ##h, expressing, cells, was, to, weak, to, be, re, ##lia, ##bly, characterized, ,, mean, ±, s, ., e, ., m, ., ,, materials, and, methods, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##0, ##fi, ##gur, ##e, 3, ., jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, performance, in, the, mouse, primary, visual, cortex, ., (, a, ), top, ,, sc, ##hema, ##tic, of, the, experiment, ., bottom, ,, image, of, v, ##1, l, ##2, /, 3, cells, expressing, jr, ##ge, ##co, ##1, ##a, (, left, ), ,, and, the, same, field, of, view, color, -, coded, according, to, the, neurons, ’, preferred, orientation, (, hue, ), and, response, amplitude, (, brightness, ), ., (, b, ), example, traces, from, three, l, ##2, /, 3, neurons, expressing, jr, ##ge, ##co, ##1, ##a, (, left, ), and, jr, ##camp, ##1, ##a, (, right, ), ., single, trials, (, gray, ), and, averages, of, 5, trials, (, blue, and, black, for, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, respectively, ), are, over, ##laid, ., eight, gr, ##ating, motion, directions, are, indicated, by, arrows, and, shown, above, traces, ., the, preferred, stimulus, is, the, direction, ev, ##oki, ##ng, the, largest, response, ., jr, ##ge, ##co, ##1, ##a, traces, correspond, to, the, cells, indicated, in, panel, a, (, see, also, video, 1, ), ., (, c, ), average, response, of, neurons, to, their, preferred, stimulus, (, 175, cells, ,, r, -, ge, ##co, ##1, ;, 310, ,, r, -, camp, ##2, ;, 395, ,, jr, ##ge, ##co, ##1, ##a, ;, 34, ##7, ,, jr, ##camp, ##1, ##a, ;, 95, ,, jr, ##camp, ##1, ##b, ., n, =, 4, mice, for, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, ,, n, =, 3, mice, for, all, other, construct, ##s, ., panels, c, -, f, are, based, on, the, same, data, set, ., (, d, ), fourier, spectra, normal, ##ized, to, the, amplitude, at, 0, hz, for, neurons, driven, with, 1, hz, drifting, gr, ##ating, ##s, ,, trans, ##duced, with, rca, ##mp, ##1, ##h, ,, r, -, ge, ##co, ##1, ,, r, -, camp, ##2, ,, jr, ##ge, ##camp, ##1, ##a, ,, jr, ##camp, ##1, ##b, ,, and, jr, ##ge, ##co, ##1, ##a, ., ins, ##et, ,, zoom, ##ed, -, in, view, of, 1, hz, response, amplitude, ##s, ., (, e, ), fraction, of, cells, detected, as, responding, to, visual, stimulus, (, an, ##ova, test, ,, p, <, 0, ., 01, ), when, expressing, different, calcium, indicators, ., this, fraction, was, 8, -, and, 6, -, fold, higher, for, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, compared, to, rca, ##mp, ##1, ##h, ,, respectively, ,, and, 60, %, higher, for, jr, ##ge, ##co, ##1, ##a, compared, to, r, -, ge, ##co, ##1, (, wilcox, ##on, rank, sum, test, ;, *, ,, p, <, 0, ., 05, ;, *, *, ,, p, <, 0, ., 01, ;, *, *, *, ,, p, <, 0, ., 001, ), ., error, bars, correspond, to, s, ., e, ., m, (, 26, fields, -, of, -, view, ,, rca, ##mp, ##1, ##h, ;, 45, ,, jr, ##camp, ##1, ##a, ;, 31, ,, jr, ##camp, ##1, ##b, ;, 30, ,, r, -, ge, ##co, ##1, ;, 40, ,, jr, ##ge, ##co, ##1, ##a, ;, 33, ,, r, -, camp, ##2, ;, 23, ,, g, ##camp, ##6, ##s, ;, 29, ,, g, ##camp, ##6, ##f, ), (, f, ), distribution, of, δ, ##f, /, f, amplitude, for, the, preferred, stimulus, ., a, right, -, shifted, curve, ,, such, as, jr, ##ge, ##co, ##1, ##a, vs, ., r, -, ge, ##co, ##1, or, jr, ##camp, ##1, ##a, /, b, vs, ., jr, ##camp, ##1, ##h, ,, indicates, enhancement, of, response, amplitude, (, 75, percent, ##ile, values, of, 0, ., 36, and, 0, ., 27, vs, ., 0, ., 18, for, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, vs, ., rca, ##mp, ##1, ##h, ,, and, 0, ., 66, vs, ., 0, ., 38, for, jr, ##ge, ##co, ##1, ##a, vs, ., g, ##camp, ##6, ##f, ,, respectively, ), ., (, 121, ##0, cells, ,, r, -, ge, ##co, ##1, ;, 86, ##1, ,, rca, ##mp, ##1, ##h, ;, 1733, ,, r, -, camp, ##2, ;, 1605, ,, jr, ##ge, ##co, ##1, ##a, ;, 1981, ,, jr, ##camp, ##1, ##a, ;, 97, ##1, ,, jr, ##camp, ##1, ##b, ;, 90, ##7, ,, g, ##camp, ##6, ##f, ;, 67, ##2, ,, g, ##camp, ##6, ##s, ), ,, same, colors, as, in, e, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##1, ##fi, ##gur, ##e, 3, —, figure, supplement, 1, ., comparison, of, orientation, tuning, in, v, ##1, neurons, measured, with, different, red, ge, ##cis, ., distribution, of, orientation, select, ##ivity, index, (, os, ##i, ,, 3, upper, rows, ), for, all, cells, detected, as, responsive, ,, measured, using, different, ge, ##cis, ., bottom, panel, ,, mean, ±, s, ., d, for, all, construct, ##s, show, similar, tuning, properties, (, n, =, 238, cells, ,, r, -, ge, ##co, ##1, ;, 308, ,, jr, ##ge, ##co, ##1, ##a, ;, 38, ##6, ,, r, -, camp, ##2, ;, 277, ,, jr, ##camp, ##1, ##a, ;, 141, ,, jr, ##camp, ##1, ##b, ;, 337, ,, g, ##camp, ##6, ##s, ;, 203, ,, g, ##camp, ##6, ##f, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##2, ##fi, ##gur, ##e, 3, —, figure, supplement, 2, ., long, -, term, expression, of, red, ge, ##cis, in, mouse, v, ##1, ., (, a, ), example, images, of, v, ##1, l, ##2, /, 3, neurons, after, long, term, expression, of, red, ge, ##cis, ., (, b, ), comparison, of, the, proportion, of, responsive, cells, ,, orientation, -, tuned, cells, ,, and, the, ratio, between, them, ., each, time, point, corresponds, to, a, different, mouse, ., (, c, ), distributions, of, peak, δ, ##f, /, f, _, 0, for, different, animals, image, ##d, after, different, times, of, expression, of, the, red, ge, ##ci, ., no, strong, effect, of, expression, time, on, peak, response, was, detected, ., (, d, ), half, decay, times, of, the, flu, ##orescence, response, for, different, animals, with, different, expression, time, of, the, red, ge, ##ci, ., no, strong, effect, of, expression, time, on, the, decay, kinetic, ##s, was, seen, ., jr, ##camp, ##1, ##a, data, for, 16, days, of, expression, is, not, shown, because, the, number, of, cells, eligible, for, this, analysis, was, too, small, (, materials, and, methods, ), ., doi, :, video, 1, ., jr, ##ge, ##co, ##1, ##a, l, ##2, /, 3, functional, imaging, in, the, mouse, v, ##1, ., the, mouse, was, an, ##est, ##het, ##ized, and, presented, with, moving, gr, ##ating, ##s, in, eight, directions, to, the, contra, ##lateral, eye, ., gr, ##ating, ##s, were, presented, for, 4, s, (, indicated, by, appearance, of, an, arrow, ##head, in, the, gr, ##ating, propagation, direction, ), followed, by, a, 4, s, of, blank, display, ., field, of, view, size, was, 250, ##x, ##25, ##0, μ, ##m, ^, 2, ,, acquired, at, 15, hz, and, filtered, with, a, 5, frame, moving, average, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##3'},\n", + " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", + " 'section_name': 'PB line expression patterns',\n", + " 'text': \"The rate of obtaining lines with brain expression in the PB screen (78.5% ) was more than twice that obtained with lentiviral transgenesis (Table 1). Lines generated by local hop of PB (within ~100 Kb) had similar expression patterns to that of the original line (Figure 2—figure supplement 1), probably because shared local enhancers regulated expression of the reporter. In most of lines, we did not find clear resemblance between reporter expression patterns and those of genes near insertion sites (see supplemental note). Some lines had dominant expression in a single anatomical structure, such as deep entorhinal cortex (P038, Figure 2A), subiculum (P141, Figure 2B), retrosplenial cortex (P099, Figure 2C), or dorsal hindbrain (P108, Figure 2D). Many lines had expression in multiple regions but with unique cell types in each area. For example, P008 has broad expression in striatum (Figure 2E1) but has restricted expression in the most medial part of the hippocampus (fasciola cinereum, Figure 2E2). P057 had cortical layer 5 expression and restricted expression in anterior-lateral caudate putamen (CP; Figure 2H). Interestingly, the mCitrine-positive CP cells appeared to be part of the direct pathway; the cells projected axons to a limited area in substantia nigra pars reticulata (Figure 2H2 inset) but not to the globus pallidus (Figure 2H1 arrow; compare the GP projection of P008 in Figure 2E1). Lines with broad expression, (Figure 2J), those labeling few cells, and those closely resembling existing lines were terminated (48 lines). Most lines with 'broad expression' had strong mCitrine expression restricted to forebrain and founders carrying multiple PB copies also had strong forebrain expression.10.7554/eLife.13503.011Figure 2.Example PiggyBac lines.(A–D) Examples of lines that appear to label a single cell type. (d) P038 has expression in entorhinal cortex medial part (ENTm) layer 6 neurons (A1: sagittal) that send axons to lateral dorsal nucleus of thalamus (LD in A2: coronal). (B) P141 has expression in a restricted area in subiculum (SUB, B1: sagittal, B2: coronal). (C) Retrosplenial cortex (RSP) expression in P099 (C1: sagittal, C2: coronal). (D) Dorsal hindbrain expression in P108 (D1: sagittal, D2: coronal at hindbrain). (E–H) Examples of lines with regionally distinctive cell type labeling. (E) P008 has expression in striatum (STR) broadly (E1: sagittal) but its hippocampal expression is restricted to the most medial part (fasciola cinereum: FC, E2 inset) (F) P122 has scattered expression in hippocampus and strong expression in cortical amygdalar area. F1: sagittal, F2: coronal sections. (G) P134 has broad expression in cortical interneurons and cerebellar Lugaro cells (G1: sagittal). Its expression in midbrain is restricted to subnuclei (G2, superior olivary complex: SOC and presumably pedunculopontine nucleus: PPN). (H) P057 (H1:coronal, H2, sagittal section) has expression in layer 5 pyramidal cells in the cortex. Expression in caudate putamen (CP) is restricted to lateral-most areas (arrows in H1). H2 inset: coronal section at the level of the dotted line. The striatal neurons project to a small area in the reticular part of the substantia nigra, reticular part (SNr, dotted area in H2 inset) but not to globus pallidus (H2 arrow). (J) Lines with broad expressions. Scale bar: 500 μm.DOI:10.7554/eLife.13503.012Figure 2—source data 1.Viral reporter expression counting data One or two animals per line were injected with TRE3G –myristorylsted mCherry HA.The numbers of cells (mCitirne+, mCherry+, mCitrine+;mCherry+, and mCitrine-:mCherry+) infection rate (mCitrine+;mCherry+/ mCitirne +) were counted from confocal image stacks from sections near injection sites (5 - 9 sections/line). Infection rates (mCherry+;mCitrine+ /mCitrine) and 'off-target' expression rate (mCherry+;mCitirne-/mCherry+) are shown in average ± SEM.DOI:10.7554/eLife.13503.013Figure 2—figure supplement 1.Similar expression patterns in lines with nearby insertions.Insertion sites and expression patterns of a founder PBAS and lines generated from PBAS by local hop are shown. Lines inserted near original PBAS site have scattered expression in Purkinje cells in cerebellum. Many lines have axonal projections in dentate gyrus from entorhinal cortex. P103 and P136 have insertion sites more than 300 kb away from the origin and their expression patterns are quite different from PBAS.DOI:10.7554/eLife.13503.014Figure 2—figure supplement 2.Developmental dynamics in P162 expression patterns.(A and B) sections from P10 (A) and mature (B) animals. Parafascicular nucleus of thalamus had expression at P10 but not in mature animal (arrowheads). (C and D) P10 (C) animal expressed reporter in pontine gray (arrowhead) but matured animal (D) did not. (E and F) Subiculum expression was not seen at P10 (E) but was present in mature (F) animals (arrowheads). (G) Higher magnification of parafascicular nucleus in A. Asterisk: fasciculus retroflexus. (H) Higher magnification of pontine gray. (I) Cerebellum receives axons from pontine gray. (J) High magnification of cerebellum. Mossy terminals were labeled.DOI:10.7554/eLife.13503.015Figure 2—figure supplement 3.Examples of virus injection.AAV–TRE3G- myristoylated mCherry-HA was injected to the brain. Wide field images (1) and confocal images (2, rectangle areas in 1) of injection sites. Note that myristoylated mCherry strongly labels axons and dendrites. (A–C) Injection to retrosplenial cortex. P160 labels layer 2/3 (A), P136 in layer 5 (B), and P160 in layer 6 (C). In P160, virus spread to entire cortex (see infected cells in deep layer (arrows in A2) but viral reporter expression is restricted to mCtirine positive cells. (D) Hippocampal CA1 injection to P160. (E–F) Examples of 'off-target' expression. Primary somatosensory cortex injection in P057 (E) and subiculum injection in P113 (F). Arrowheads: cells with viral reporter without visible mCitrine expression. Blue: DAPI, Green: anti-GFP, Red: anti-HA.DOI:10.7554/eLife.13503.016Figure 2—figure supplement 4.tet reporter expression in cultured cell lines.(A–I) Induction of tet reporter constructs was tested with 293T cells. Cells were transfected without (A–I, first panels) or with (A–I, second panels) CMV-tTA plasmid. Some constructs had strong tTA-independent 'leak' expression (ex. A1, E1, and F1). GBP-split Cre had the strongest expression of Cre reporter in the presence of GFP (I3) but could activate the reporter expression without GFP expression (I2). See Supplemental note for further details.DOI:10.7554/eLife.13503.017Figure 2—figure supplement 5.Specificity of tet reporter expression in vivo.(A) AAV–TREtight-myrmCherry expression in 56L. mCherry expression was restricted to mCitrine positive cells (mCitrine+ cells/ mCherry+ cells: 152/152). (A2) higher magnification of injection site. (B) Co-infection of AAV–TRE3G–Cre and AAV–CAG–Flex-myrmCherry HAnsulator sequence from. There was strong non-specific mCherry expression near injection site (B2). (C) TRE3G–Split Cre had specific expression of reporter without apparent leak. (D) TRE3G–Flpe had non-specific expression in a few cells (D2, arrows) (E) TRE3G split Cre had non-specific expression from Ai14 reporter allele in P113 subiculum. (F) TRE3G-nanobody Split Cre had specific expression (mCitrine+ cells/mCherry + cells: 64/64). (F2) higher magnification of the injection site. (G) Specific expression of AAV Cre repoter by TRE3G-nanobody split Cre in 56L.DOI:\",\n", + " 'paragraph_id': 13,\n", + " 'tokenizer': \"the, rate, of, obtaining, lines, with, brain, expression, in, the, p, ##b, screen, (, 78, ., 5, %, ), was, more, than, twice, that, obtained, with, lent, ##iv, ##ira, ##l, trans, ##genesis, (, table, 1, ), ., lines, generated, by, local, hop, of, p, ##b, (, within, ~, 100, kb, ), had, similar, expression, patterns, to, that, of, the, original, line, (, figure, 2, —, figure, supplement, 1, ), ,, probably, because, shared, local, enhance, ##rs, regulated, expression, of, the, reporter, ., in, most, of, lines, ,, we, did, not, find, clear, resemblance, between, reporter, expression, patterns, and, those, of, genes, near, insertion, sites, (, see, supplemental, note, ), ., some, lines, had, dominant, expression, in, a, single, anatomical, structure, ,, such, as, deep, en, ##tor, ##hin, ##al, cortex, (, p, ##0, ##38, ,, figure, 2a, ), ,, sub, ##ic, ##ulum, (, p, ##14, ##1, ,, figure, 2, ##b, ), ,, retro, ##sp, ##len, ##ial, cortex, (, p, ##0, ##9, ##9, ,, figure, 2, ##c, ), ,, or, dorsal, hind, ##bra, ##in, (, p, ##10, ##8, ,, figure, 2d, ), ., many, lines, had, expression, in, multiple, regions, but, with, unique, cell, types, in, each, area, ., for, example, ,, p, ##00, ##8, has, broad, expression, in, st, ##ria, ##tum, (, figure, 2, ##e, ##1, ), but, has, restricted, expression, in, the, most, medial, part, of, the, hip, ##po, ##camp, ##us, (, fa, ##sc, ##iol, ##a, ci, ##ner, ##eum, ,, figure, 2, ##e, ##2, ), ., p, ##0, ##57, had, co, ##rti, ##cal, layer, 5, expression, and, restricted, expression, in, anterior, -, lateral, ca, ##uda, ##te, put, ##amen, (, cp, ;, figure, 2, ##h, ), ., interesting, ##ly, ,, the, mc, ##it, ##rine, -, positive, cp, cells, appeared, to, be, part, of, the, direct, pathway, ;, the, cells, projected, ax, ##ons, to, a, limited, area, in, sub, ##stan, ##tia, ni, ##gra, par, ##s, re, ##tic, ##ulata, (, figure, 2, ##h, ##2, ins, ##et, ), but, not, to, the, g, ##lo, ##bus, pal, ##lid, ##us, (, figure, 2, ##h, ##1, arrow, ;, compare, the, gp, projection, of, p, ##00, ##8, in, figure, 2, ##e, ##1, ), ., lines, with, broad, expression, ,, (, figure, 2, ##j, ), ,, those, labeling, few, cells, ,, and, those, closely, resembling, existing, lines, were, terminated, (, 48, lines, ), ., most, lines, with, ', broad, expression, ', had, strong, mc, ##it, ##rine, expression, restricted, to, fore, ##bra, ##in, and, founders, carrying, multiple, p, ##b, copies, also, had, strong, fore, ##bra, ##in, expression, ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##1, ##fi, ##gur, ##e, 2, ., example, pig, ##gy, ##ba, ##c, lines, ., (, a, –, d, ), examples, of, lines, that, appear, to, label, a, single, cell, type, ., (, d, ), p, ##0, ##38, has, expression, in, en, ##tor, ##hin, ##al, cortex, medial, part, (, en, ##tm, ), layer, 6, neurons, (, a1, :, sa, ##git, ##tal, ), that, send, ax, ##ons, to, lateral, dorsal, nucleus, of, tha, ##lam, ##us, (, ld, in, a2, :, corona, ##l, ), ., (, b, ), p, ##14, ##1, has, expression, in, a, restricted, area, in, sub, ##ic, ##ulum, (, sub, ,, b1, :, sa, ##git, ##tal, ,, b, ##2, :, corona, ##l, ), ., (, c, ), retro, ##sp, ##len, ##ial, cortex, (, rs, ##p, ), expression, in, p, ##0, ##9, ##9, (, c1, :, sa, ##git, ##tal, ,, c2, :, corona, ##l, ), ., (, d, ), dorsal, hind, ##bra, ##in, expression, in, p, ##10, ##8, (, d, ##1, :, sa, ##git, ##tal, ,, d, ##2, :, corona, ##l, at, hind, ##bra, ##in, ), ., (, e, –, h, ), examples, of, lines, with, regional, ##ly, distinctive, cell, type, labeling, ., (, e, ), p, ##00, ##8, has, expression, in, st, ##ria, ##tum, (, st, ##r, ), broadly, (, e, ##1, :, sa, ##git, ##tal, ), but, its, hip, ##po, ##camp, ##al, expression, is, restricted, to, the, most, medial, part, (, fa, ##sc, ##iol, ##a, ci, ##ner, ##eum, :, fc, ,, e, ##2, ins, ##et, ), (, f, ), p, ##12, ##2, has, scattered, expression, in, hip, ##po, ##camp, ##us, and, strong, expression, in, co, ##rti, ##cal, amy, ##g, ##dal, ##ar, area, ., f1, :, sa, ##git, ##tal, ,, f, ##2, :, corona, ##l, sections, ., (, g, ), p, ##13, ##4, has, broad, expression, in, co, ##rti, ##cal, intern, ##eur, ##ons, and, ce, ##re, ##bella, ##r, lu, ##gar, ##o, cells, (, g, ##1, :, sa, ##git, ##tal, ), ., its, expression, in, mid, ##bra, ##in, is, restricted, to, sub, ##nu, ##cle, ##i, (, g, ##2, ,, superior, ol, ##ivar, ##y, complex, :, soc, and, presumably, pe, ##dun, ##cu, ##lo, ##pon, ##tine, nucleus, :, pp, ##n, ), ., (, h, ), p, ##0, ##57, (, h, ##1, :, corona, ##l, ,, h, ##2, ,, sa, ##git, ##tal, section, ), has, expression, in, layer, 5, pyramid, ##al, cells, in, the, cortex, ., expression, in, ca, ##uda, ##te, put, ##amen, (, cp, ), is, restricted, to, lateral, -, most, areas, (, arrows, in, h, ##1, ), ., h, ##2, ins, ##et, :, corona, ##l, section, at, the, level, of, the, dotted, line, ., the, st, ##ria, ##tal, neurons, project, to, a, small, area, in, the, re, ##tic, ##ular, part, of, the, sub, ##stan, ##tia, ni, ##gra, ,, re, ##tic, ##ular, part, (, s, ##nr, ,, dotted, area, in, h, ##2, ins, ##et, ), but, not, to, g, ##lo, ##bus, pal, ##lid, ##us, (, h, ##2, arrow, ), ., (, j, ), lines, with, broad, expressions, ., scale, bar, :, 500, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##2, ##fi, ##gur, ##e, 2, —, source, data, 1, ., viral, reporter, expression, counting, data, one, or, two, animals, per, line, were, injected, with, tre, ##3, ##g, –, my, ##rist, ##ory, ##ls, ##ted, mc, ##her, ##ry, ha, ., the, numbers, of, cells, (, mc, ##iti, ##rne, +, ,, mc, ##her, ##ry, +, ,, mc, ##it, ##rine, +, ;, mc, ##her, ##ry, +, ,, and, mc, ##it, ##rine, -, :, mc, ##her, ##ry, +, ), infection, rate, (, mc, ##it, ##rine, +, ;, mc, ##her, ##ry, +, /, mc, ##iti, ##rne, +, ), were, counted, from, con, ##fo, ##cal, image, stacks, from, sections, near, injection, sites, (, 5, -, 9, sections, /, line, ), ., infection, rates, (, mc, ##her, ##ry, +, ;, mc, ##it, ##rine, +, /, mc, ##it, ##rine, ), and, ', off, -, target, ', expression, rate, (, mc, ##her, ##ry, +, ;, mc, ##iti, ##rne, -, /, mc, ##her, ##ry, +, ), are, shown, in, average, ±, se, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##3, ##fi, ##gur, ##e, 2, —, figure, supplement, 1, ., similar, expression, patterns, in, lines, with, nearby, insertion, ##s, ., insertion, sites, and, expression, patterns, of, a, founder, pba, ##s, and, lines, generated, from, pba, ##s, by, local, hop, are, shown, ., lines, inserted, near, original, pba, ##s, site, have, scattered, expression, in, pu, ##rkin, ##je, cells, in, ce, ##re, ##bell, ##um, ., many, lines, have, ax, ##onal, projections, in, dent, ##ate, g, ##yr, ##us, from, en, ##tor, ##hin, ##al, cortex, ., p, ##10, ##3, and, p, ##13, ##6, have, insertion, sites, more, than, 300, kb, away, from, the, origin, and, their, expression, patterns, are, quite, different, from, pba, ##s, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##4, ##fi, ##gur, ##e, 2, —, figure, supplement, 2, ., developmental, dynamics, in, p, ##16, ##2, expression, patterns, ., (, a, and, b, ), sections, from, p, ##10, (, a, ), and, mature, (, b, ), animals, ., para, ##fa, ##sc, ##icular, nucleus, of, tha, ##lam, ##us, had, expression, at, p, ##10, but, not, in, mature, animal, (, arrow, ##heads, ), ., (, c, and, d, ), p, ##10, (, c, ), animal, expressed, reporter, in, pont, ##ine, gray, (, arrow, ##head, ), but, mature, ##d, animal, (, d, ), did, not, ., (, e, and, f, ), sub, ##ic, ##ulum, expression, was, not, seen, at, p, ##10, (, e, ), but, was, present, in, mature, (, f, ), animals, (, arrow, ##heads, ), ., (, g, ), higher, mag, ##ni, ##fication, of, para, ##fa, ##sc, ##icular, nucleus, in, a, ., as, ##ter, ##isk, :, fa, ##sc, ##ic, ##ulus, retro, ##fle, ##x, ##us, ., (, h, ), higher, mag, ##ni, ##fication, of, pont, ##ine, gray, ., (, i, ), ce, ##re, ##bell, ##um, receives, ax, ##ons, from, pont, ##ine, gray, ., (, j, ), high, mag, ##ni, ##fication, of, ce, ##re, ##bell, ##um, ., moss, ##y, terminals, were, labeled, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##5, ##fi, ##gur, ##e, 2, —, figure, supplement, 3, ., examples, of, virus, injection, ., aa, ##v, –, tre, ##3, ##g, -, my, ##rist, ##oy, ##lated, mc, ##her, ##ry, -, ha, was, injected, to, the, brain, ., wide, field, images, (, 1, ), and, con, ##fo, ##cal, images, (, 2, ,, rec, ##tangle, areas, in, 1, ), of, injection, sites, ., note, that, my, ##rist, ##oy, ##lated, mc, ##her, ##ry, strongly, labels, ax, ##ons, and, den, ##dr, ##ites, ., (, a, –, c, ), injection, to, retro, ##sp, ##len, ##ial, cortex, ., p, ##16, ##0, labels, layer, 2, /, 3, (, a, ), ,, p, ##13, ##6, in, layer, 5, (, b, ), ,, and, p, ##16, ##0, in, layer, 6, (, c, ), ., in, p, ##16, ##0, ,, virus, spread, to, entire, cortex, (, see, infected, cells, in, deep, layer, (, arrows, in, a2, ), but, viral, reporter, expression, is, restricted, to, mc, ##ti, ##rine, positive, cells, ., (, d, ), hip, ##po, ##camp, ##al, ca, ##1, injection, to, p, ##16, ##0, ., (, e, –, f, ), examples, of, ', off, -, target, ', expression, ., primary, so, ##mat, ##ose, ##nsor, ##y, cortex, injection, in, p, ##0, ##57, (, e, ), and, sub, ##ic, ##ulum, injection, in, p, ##11, ##3, (, f, ), ., arrow, ##heads, :, cells, with, viral, reporter, without, visible, mc, ##it, ##rine, expression, ., blue, :, da, ##pi, ,, green, :, anti, -, g, ##fp, ,, red, :, anti, -, ha, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##6, ##fi, ##gur, ##e, 2, —, figure, supplement, 4, ., te, ##t, reporter, expression, in, culture, ##d, cell, lines, ., (, a, –, i, ), induction, of, te, ##t, reporter, construct, ##s, was, tested, with, 293, ##t, cells, ., cells, were, trans, ##fect, ##ed, without, (, a, –, i, ,, first, panels, ), or, with, (, a, –, i, ,, second, panels, ), cm, ##v, -, tt, ##a, pl, ##as, ##mi, ##d, ., some, construct, ##s, had, strong, tt, ##a, -, independent, ', leak, ', expression, (, ex, ., a1, ,, e, ##1, ,, and, f1, ), ., gb, ##p, -, split, cr, ##e, had, the, strongest, expression, of, cr, ##e, reporter, in, the, presence, of, g, ##fp, (, i, ##3, ), but, could, activate, the, reporter, expression, without, g, ##fp, expression, (, i, ##2, ), ., see, supplemental, note, for, further, details, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##7, ##fi, ##gur, ##e, 2, —, figure, supplement, 5, ., specific, ##ity, of, te, ##t, reporter, expression, in, vivo, ., (, a, ), aa, ##v, –, tre, ##tight, -, my, ##rm, ##cher, ##ry, expression, in, 56, ##l, ., mc, ##her, ##ry, expression, was, restricted, to, mc, ##it, ##rine, positive, cells, (, mc, ##it, ##rine, +, cells, /, mc, ##her, ##ry, +, cells, :, 152, /, 152, ), ., (, a2, ), higher, mag, ##ni, ##fication, of, injection, site, ., (, b, ), co, -, infection, of, aa, ##v, –, tre, ##3, ##g, –, cr, ##e, and, aa, ##v, –, ca, ##g, –, flex, -, my, ##rm, ##cher, ##ry, hans, ##ulator, sequence, from, ., there, was, strong, non, -, specific, mc, ##her, ##ry, expression, near, injection, site, (, b, ##2, ), ., (, c, ), tre, ##3, ##g, –, split, cr, ##e, had, specific, expression, of, reporter, without, apparent, leak, ., (, d, ), tre, ##3, ##g, –, fl, ##pe, had, non, -, specific, expression, in, a, few, cells, (, d, ##2, ,, arrows, ), (, e, ), tre, ##3, ##g, split, cr, ##e, had, non, -, specific, expression, from, ai, ##14, reporter, all, ##ele, in, p, ##11, ##3, sub, ##ic, ##ulum, ., (, f, ), tre, ##3, ##g, -, nano, ##body, split, cr, ##e, had, specific, expression, (, mc, ##it, ##rine, +, cells, /, mc, ##her, ##ry, +, cells, :, 64, /, 64, ), ., (, f, ##2, ), higher, mag, ##ni, ##fication, of, the, injection, site, ., (, g, ), specific, expression, of, aa, ##v, cr, ##e, rep, ##ote, ##r, by, tre, ##3, ##g, -, nano, ##body, split, cr, ##e, in, 56, ##l, ., doi, :\"},\n", + " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", + " 'section_name': 'Hippocampal formation',\n", + " 'text': 'The entorhinal cortex, hippocampus, and subiculum are interconnected by complex loops with reciprocal connections (Ding, 2013; Witter et al., 2014). Many (92) lines have expression in subregions of the hippocampal formation. CA1 is one of major input source of the subiculum, which sends axons to the entorhinal cortex through the presubiculum (PRE) and parasubiculum (PAR). Labeled cells proximal to CA1 in three lines, P162 (Figure 6A), P139 (Figure 6B), and P141 (Figure 6C), do not project to PRE but the distal subiculum population labeled in P157 (Figure 6D) does. P066, which has expression in the whole subiculum, also has PRE projections (Figure 6E). P162, P139, and P141 have expression in adjacent positions (cells in P162 and P139 are in nearly the same positions and P141 cells are located posterior to them, (see distal ends of CA1 marked by arrowheads in Figure 6A–C) but have different axonal projections. P162 has dense mCitrine-positive axons in the reuniens nucleus (RE) and dorsal and ventral submedial nucleus (SMT) but there are few axons in the corresponding areas in P139 and P141 (Figure 6—figure supplement 1A–F). Injection of tet –dependent virus (AAV-Tre3G-myristylated mCherry-HA) into the subiculum in P162 confirmed that axons in RE and SMT were coming from the subiculum (Figure 6—figure supplement 1G–I). P160 has expression in PRE and PAR and dense axonal projections to entorhinal cortex, medial part (ENTm, Figure 6E). P149 has expression in ENTm layer 5 (Figure 6H). P084 also has expression in the same region, but the expression is restricted to the most medial part of ENTm (Figure 6G). 56L had broad expression in deep layer 6 of neocortex, but its expression in ENTm was observed in upper layer 6 (Figure 6J). P038 occupied ENTm deep layer 6 (Figure 6I). We also obtained lines with ENTm layer 2/3 (PBAS, Figure 6K) and entorhinal cortex, lateral part (ENTl) layer 2/3 (P126, Figure 6L).10.7554/eLife.13503.023Figure 6.Lines with expression in the hippocampal formation.Horizontal sections through the hippocampal formation. (A–B) Expression closer to CA1 (P162, A) and to subiculum (P139, B) at the region of their border. CA1: Ammon’s horn, field CA1, SUB: subiculum, PRE: presubiculum, PAR: parasubiculum, ENTm: entorhinal cortex, medial part, ENTl: entorhinal cortex, lateral part. Arrowheads in (A–C) distal end of CA1 pyramidal layer. (C–E) Subiculum expression in P141(C), P157 (D) and P066 (E). (F) Presubiculum expression in P160. (G and H) Expression in medial entorhinal cortex layer 5 in P084 (G) and P149 (H). (I and J) medial entorhinal cortex layer6 expression in P038 (I) and 56L (J). (K and L) medial entorhinal (PBAS, K) and lateral entorhinal (P126, L).layer 2 expression. Scale bar: 500 μm.DOI:10.7554/eLife.13503.024Figure 6—figure supplement 1.P162 subiculum neurons project to thalamus.(A–F) Axonal projection in nucleus of reunions (RE), dorsal (dSMT), and ventral (vSMT) submedial nuclei are prominent in P162 (A–B) but are weak or absent in p139 (C–D) and P141 (E–F). B, D, and F magnified images of areas shown A, C, and E, respectively. (G–I) TRE3G-myrmCherryHA injection to P162. (G) the injection site. (H) axons in RE. (I) axons in RE and vSMT.DOI:',\n", + " 'paragraph_id': 24,\n", + " 'tokenizer': 'the, en, ##tor, ##hin, ##al, cortex, ,, hip, ##po, ##camp, ##us, ,, and, sub, ##ic, ##ulum, are, inter, ##connected, by, complex, loops, with, reciprocal, connections, (, ding, ,, 2013, ;, wit, ##ter, et, al, ., ,, 2014, ), ., many, (, 92, ), lines, have, expression, in, sub, ##region, ##s, of, the, hip, ##po, ##camp, ##al, formation, ., ca, ##1, is, one, of, major, input, source, of, the, sub, ##ic, ##ulum, ,, which, sends, ax, ##ons, to, the, en, ##tor, ##hin, ##al, cortex, through, the, pre, ##su, ##bic, ##ulum, (, pre, ), and, para, ##su, ##bic, ##ulum, (, par, ), ., labeled, cells, pro, ##xi, ##mal, to, ca, ##1, in, three, lines, ,, p, ##16, ##2, (, figure, 6, ##a, ), ,, p, ##13, ##9, (, figure, 6, ##b, ), ,, and, p, ##14, ##1, (, figure, 6, ##c, ), ,, do, not, project, to, pre, but, the, distal, sub, ##ic, ##ulum, population, labeled, in, p, ##15, ##7, (, figure, 6, ##d, ), does, ., p, ##0, ##66, ,, which, has, expression, in, the, whole, sub, ##ic, ##ulum, ,, also, has, pre, projections, (, figure, 6, ##e, ), ., p, ##16, ##2, ,, p, ##13, ##9, ,, and, p, ##14, ##1, have, expression, in, adjacent, positions, (, cells, in, p, ##16, ##2, and, p, ##13, ##9, are, in, nearly, the, same, positions, and, p, ##14, ##1, cells, are, located, posterior, to, them, ,, (, see, distal, ends, of, ca, ##1, marked, by, arrow, ##heads, in, figure, 6, ##a, –, c, ), but, have, different, ax, ##onal, projections, ., p, ##16, ##2, has, dense, mc, ##it, ##rine, -, positive, ax, ##ons, in, the, re, ##uni, ##ens, nucleus, (, re, ), and, dorsal, and, ventral, sub, ##media, ##l, nucleus, (, sm, ##t, ), but, there, are, few, ax, ##ons, in, the, corresponding, areas, in, p, ##13, ##9, and, p, ##14, ##1, (, figure, 6, —, figure, supplement, 1a, –, f, ), ., injection, of, te, ##t, –, dependent, virus, (, aa, ##v, -, tre, ##3, ##g, -, my, ##rist, ##yla, ##ted, mc, ##her, ##ry, -, ha, ), into, the, sub, ##ic, ##ulum, in, p, ##16, ##2, confirmed, that, ax, ##ons, in, re, and, sm, ##t, were, coming, from, the, sub, ##ic, ##ulum, (, figure, 6, —, figure, supplement, 1, ##g, –, i, ), ., p, ##16, ##0, has, expression, in, pre, and, par, and, dense, ax, ##onal, projections, to, en, ##tor, ##hin, ##al, cortex, ,, medial, part, (, en, ##tm, ,, figure, 6, ##e, ), ., p, ##14, ##9, has, expression, in, en, ##tm, layer, 5, (, figure, 6, ##h, ), ., p, ##0, ##8, ##4, also, has, expression, in, the, same, region, ,, but, the, expression, is, restricted, to, the, most, medial, part, of, en, ##tm, (, figure, 6, ##g, ), ., 56, ##l, had, broad, expression, in, deep, layer, 6, of, neo, ##cor, ##te, ##x, ,, but, its, expression, in, en, ##tm, was, observed, in, upper, layer, 6, (, figure, 6, ##j, ), ., p, ##0, ##38, occupied, en, ##tm, deep, layer, 6, (, figure, 6, ##i, ), ., we, also, obtained, lines, with, en, ##tm, layer, 2, /, 3, (, pba, ##s, ,, figure, 6, ##k, ), and, en, ##tor, ##hin, ##al, cortex, ,, lateral, part, (, en, ##tl, ), layer, 2, /, 3, (, p, ##12, ##6, ,, figure, 6, ##l, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##3, ##fi, ##gur, ##e, 6, ., lines, with, expression, in, the, hip, ##po, ##camp, ##al, formation, ., horizontal, sections, through, the, hip, ##po, ##camp, ##al, formation, ., (, a, –, b, ), expression, closer, to, ca, ##1, (, p, ##16, ##2, ,, a, ), and, to, sub, ##ic, ##ulum, (, p, ##13, ##9, ,, b, ), at, the, region, of, their, border, ., ca, ##1, :, am, ##mon, ’, s, horn, ,, field, ca, ##1, ,, sub, :, sub, ##ic, ##ulum, ,, pre, :, pre, ##su, ##bic, ##ulum, ,, par, :, para, ##su, ##bic, ##ulum, ,, en, ##tm, :, en, ##tor, ##hin, ##al, cortex, ,, medial, part, ,, en, ##tl, :, en, ##tor, ##hin, ##al, cortex, ,, lateral, part, ., arrow, ##heads, in, (, a, –, c, ), distal, end, of, ca, ##1, pyramid, ##al, layer, ., (, c, –, e, ), sub, ##ic, ##ulum, expression, in, p, ##14, ##1, (, c, ), ,, p, ##15, ##7, (, d, ), and, p, ##0, ##66, (, e, ), ., (, f, ), pre, ##su, ##bic, ##ulum, expression, in, p, ##16, ##0, ., (, g, and, h, ), expression, in, medial, en, ##tor, ##hin, ##al, cortex, layer, 5, in, p, ##0, ##8, ##4, (, g, ), and, p, ##14, ##9, (, h, ), ., (, i, and, j, ), medial, en, ##tor, ##hin, ##al, cortex, layer, ##6, expression, in, p, ##0, ##38, (, i, ), and, 56, ##l, (, j, ), ., (, k, and, l, ), medial, en, ##tor, ##hin, ##al, (, pba, ##s, ,, k, ), and, lateral, en, ##tor, ##hin, ##al, (, p, ##12, ##6, ,, l, ), ., layer, 2, expression, ., scale, bar, :, 500, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##4, ##fi, ##gur, ##e, 6, —, figure, supplement, 1, ., p, ##16, ##2, sub, ##ic, ##ulum, neurons, project, to, tha, ##lam, ##us, ., (, a, –, f, ), ax, ##onal, projection, in, nucleus, of, reunion, ##s, (, re, ), ,, dorsal, (, ds, ##mt, ), ,, and, ventral, (, vs, ##mt, ), sub, ##media, ##l, nuclei, are, prominent, in, p, ##16, ##2, (, a, –, b, ), but, are, weak, or, absent, in, p, ##13, ##9, (, c, –, d, ), and, p, ##14, ##1, (, e, –, f, ), ., b, ,, d, ,, and, f, mag, ##nified, images, of, areas, shown, a, ,, c, ,, and, e, ,, respectively, ., (, g, –, i, ), tre, ##3, ##g, -, my, ##rm, ##cher, ##ry, ##ha, injection, to, p, ##16, ##2, ., (, g, ), the, injection, site, ., (, h, ), ax, ##ons, in, re, ., (, i, ), ax, ##ons, in, re, and, vs, ##mt, ., doi, :'},\n", + " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", + " 'section_name': 'An altered classification of layer 6 cortico-thalamic pyramidal neurons',\n", + " 'text': 'We obtained three lines with expression in layer 6 cortical pyramidal neurons (Figure 10). P162 has mCitrine-positive cells in primary somatosensory area (SSp), primary visual area (VISp), and retrosplenical cortex and axonal projection in VPm and LGd (Figure 10G–J). P139 has expression in lateral cortex including supplemental somatosensory area (SSs) and gustatory cortex and projection in Po (Figure 10M–P). There are topological projection patterns in RTN; dorsally located P162 cells project to dorsal RTN and laterally located P139 cells project to ventral RTN (Figure 10—figure supplement 1B and C). The third line, 56L, has broad expression across neocortex (Figure 10A–D). 56L neurons have projection to both primary and secondary nuclei but not to RTN (Figure 10—figure supplement 1A).10.7554/eLife.13503.028Figure 10.Projections of layer 6 corticothalamic (CT) neurons.(A–D) Coronal images from 56L. (E and F) confocal images from SSp (E) and VISp (F) from 56L. (G–J) Coronal sections from P162. (K and L) Confocal images from SSp (K) and VISp (L) from P162. (M–P) Coronal images from P139. (Q) Confocal image from P139 SSs. Sections were taken from 0.7 mm (A, G, and M), 1.7 mm (B, D, H, J, N, and P), 2.3 mm (C, I, and O) caudal from bregma. (R–W) tet-reporter virus injection into 56L SSp (R), 56L SSs (T), P162 SSp (V), and P139 SSs (X) and their projection to thalamus (S, U, W, and Y, respectively). (Z) Schematic view of projections in layer 6 lines. ILM: interlaminar nucleus, Po: posterior complex, VPM: ventral posteomedial nucleus. Scale bars: 500 μm.DOI:10.7554/eLife.13503.029Figure 10—figure supplement 1.Projections to the reticular nucleus of the thalamus (RT) (A–C) DAPI (blue), anti-GFP (green), and anti-Parvalbumin (PV, red) staining for thalamus of 56L (A), P162 (B), and P139 (C).Few or no mCitrine-positive axons from 56L (A) project to the PV-positive RT. P162 (B) axons project only to the dorsal (d) part of RT, whereas the ventral (v) part receives axons from P139 (C).DOI:10.7554/eLife.13503.030Figure 10—figure supplement 2.Sublaminar location and intrinsic physiology of layer 6 neurons.(A and B) Positions of mCitrine-positive cell bodies in Layer 5–6 are plotted. (A) P162 (green) and 56L (blue) in SSp. (B) P139 (green) and 56L (blue) in SSs. Dotted lines: averaged borders between layers 5 and 6. (C) Current clamp responses of P162, 56L SSp, P139, 56L SSs to 100 pA current injections. Input resistance (D) whole cell capacitance (E) of layer 6 cells. Asterisks: p<0.05 with Turkey-Kremer’s post hoc test. (F and G) Current clamp responses of labeled (F) and nearby non-labeled (G) neurons in 56L layer 6 during current injection. (H) Firing frequency – current injection plot for labeled and non-labeled neurons in 56L layer 6. n = 16–20.DOI:10.7554/eLife.13503.031Figure 10—figure supplement 3.56L axonal projection from VISp to thalamus.(A) Injection site. (B) High magnification of injection site. (C) Axonal projections to thalamus avoid the dorsal leteral geniculate nuceus (LGd).DOI:10.7554/eLife.13503.032Figure 10—figure supplement 4.Long lateral projections in 56L and P139 AAV–TRE3GmCherryHA was injected to 56L.(A–C) and P139 (D–F). B and C high magnification of designated area in A. E and F high magnification of designated area in D. 56L had callosal projections (arrowhead in A) but these were not seen in P139 (arrowhead in C). Red: anti-HA, Green: anti-GFP, Blue: DAPI. Images in D–F and Figure 10X were taken from the same section.DOI:',\n", + " 'paragraph_id': 33,\n", + " 'tokenizer': 'we, obtained, three, lines, with, expression, in, layer, 6, co, ##rti, ##cal, pyramid, ##al, neurons, (, figure, 10, ), ., p, ##16, ##2, has, mc, ##it, ##rine, -, positive, cells, in, primary, so, ##mat, ##ose, ##nsor, ##y, area, (, ss, ##p, ), ,, primary, visual, area, (, vis, ##p, ), ,, and, retro, ##sp, ##len, ##ical, cortex, and, ax, ##onal, projection, in, vp, ##m, and, l, ##g, ##d, (, figure, 10, ##g, –, j, ), ., p, ##13, ##9, has, expression, in, lateral, cortex, including, supplemental, so, ##mat, ##ose, ##nsor, ##y, area, (, ss, ##s, ), and, gust, ##atory, cortex, and, projection, in, po, (, figure, 10, ##m, –, p, ), ., there, are, topological, projection, patterns, in, rt, ##n, ;, dorsal, ##ly, located, p, ##16, ##2, cells, project, to, dorsal, rt, ##n, and, lateral, ##ly, located, p, ##13, ##9, cells, project, to, ventral, rt, ##n, (, figure, 10, —, figure, supplement, 1b, and, c, ), ., the, third, line, ,, 56, ##l, ,, has, broad, expression, across, neo, ##cor, ##te, ##x, (, figure, 10, ##a, –, d, ), ., 56, ##l, neurons, have, projection, to, both, primary, and, secondary, nuclei, but, not, to, rt, ##n, (, figure, 10, —, figure, supplement, 1a, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##8, ##fi, ##gur, ##e, 10, ., projections, of, layer, 6, co, ##rti, ##cot, ##hala, ##mic, (, ct, ), neurons, ., (, a, –, d, ), corona, ##l, images, from, 56, ##l, ., (, e, and, f, ), con, ##fo, ##cal, images, from, ss, ##p, (, e, ), and, vis, ##p, (, f, ), from, 56, ##l, ., (, g, –, j, ), corona, ##l, sections, from, p, ##16, ##2, ., (, k, and, l, ), con, ##fo, ##cal, images, from, ss, ##p, (, k, ), and, vis, ##p, (, l, ), from, p, ##16, ##2, ., (, m, –, p, ), corona, ##l, images, from, p, ##13, ##9, ., (, q, ), con, ##fo, ##cal, image, from, p, ##13, ##9, ss, ##s, ., sections, were, taken, from, 0, ., 7, mm, (, a, ,, g, ,, and, m, ), ,, 1, ., 7, mm, (, b, ,, d, ,, h, ,, j, ,, n, ,, and, p, ), ,, 2, ., 3, mm, (, c, ,, i, ,, and, o, ), ca, ##uda, ##l, from, br, ##eg, ##ma, ., (, r, –, w, ), te, ##t, -, reporter, virus, injection, into, 56, ##l, ss, ##p, (, r, ), ,, 56, ##l, ss, ##s, (, t, ), ,, p, ##16, ##2, ss, ##p, (, v, ), ,, and, p, ##13, ##9, ss, ##s, (, x, ), and, their, projection, to, tha, ##lam, ##us, (, s, ,, u, ,, w, ,, and, y, ,, respectively, ), ., (, z, ), sc, ##hema, ##tic, view, of, projections, in, layer, 6, lines, ., il, ##m, :, inter, ##lam, ##ina, ##r, nucleus, ,, po, :, posterior, complex, ,, vp, ##m, :, ventral, post, ##eo, ##media, ##l, nucleus, ., scale, bars, :, 500, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##9, ##fi, ##gur, ##e, 10, —, figure, supplement, 1, ., projections, to, the, re, ##tic, ##ular, nucleus, of, the, tha, ##lam, ##us, (, rt, ), (, a, –, c, ), da, ##pi, (, blue, ), ,, anti, -, g, ##fp, (, green, ), ,, and, anti, -, par, ##val, ##bu, ##min, (, pv, ,, red, ), stain, ##ing, for, tha, ##lam, ##us, of, 56, ##l, (, a, ), ,, p, ##16, ##2, (, b, ), ,, and, p, ##13, ##9, (, c, ), ., few, or, no, mc, ##it, ##rine, -, positive, ax, ##ons, from, 56, ##l, (, a, ), project, to, the, pv, -, positive, rt, ., p, ##16, ##2, (, b, ), ax, ##ons, project, only, to, the, dorsal, (, d, ), part, of, rt, ,, whereas, the, ventral, (, v, ), part, receives, ax, ##ons, from, p, ##13, ##9, (, c, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##0, ##fi, ##gur, ##e, 10, —, figure, supplement, 2, ., sub, ##lam, ##ina, ##r, location, and, intrinsic, physiology, of, layer, 6, neurons, ., (, a, and, b, ), positions, of, mc, ##it, ##rine, -, positive, cell, bodies, in, layer, 5, –, 6, are, plotted, ., (, a, ), p, ##16, ##2, (, green, ), and, 56, ##l, (, blue, ), in, ss, ##p, ., (, b, ), p, ##13, ##9, (, green, ), and, 56, ##l, (, blue, ), in, ss, ##s, ., dotted, lines, :, averaged, borders, between, layers, 5, and, 6, ., (, c, ), current, cl, ##amp, responses, of, p, ##16, ##2, ,, 56, ##l, ss, ##p, ,, p, ##13, ##9, ,, 56, ##l, ss, ##s, to, 100, pa, current, injection, ##s, ., input, resistance, (, d, ), whole, cell, cap, ##ac, ##itan, ##ce, (, e, ), of, layer, 6, cells, ., as, ##ter, ##isk, ##s, :, p, <, 0, ., 05, with, turkey, -, k, ##rem, ##er, ’, s, post, hoc, test, ., (, f, and, g, ), current, cl, ##amp, responses, of, labeled, (, f, ), and, nearby, non, -, labeled, (, g, ), neurons, in, 56, ##l, layer, 6, during, current, injection, ., (, h, ), firing, frequency, –, current, injection, plot, for, labeled, and, non, -, labeled, neurons, in, 56, ##l, layer, 6, ., n, =, 16, –, 20, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##1, ##fi, ##gur, ##e, 10, —, figure, supplement, 3, ., 56, ##l, ax, ##onal, projection, from, vis, ##p, to, tha, ##lam, ##us, ., (, a, ), injection, site, ., (, b, ), high, mag, ##ni, ##fication, of, injection, site, ., (, c, ), ax, ##onal, projections, to, tha, ##lam, ##us, avoid, the, dorsal, let, ##eral, gen, ##iculate, nu, ##ce, ##us, (, l, ##g, ##d, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##2, ##fi, ##gur, ##e, 10, —, figure, supplement, 4, ., long, lateral, projections, in, 56, ##l, and, p, ##13, ##9, aa, ##v, –, tre, ##3, ##gm, ##cher, ##ry, ##ha, was, injected, to, 56, ##l, ., (, a, –, c, ), and, p, ##13, ##9, (, d, –, f, ), ., b, and, c, high, mag, ##ni, ##fication, of, designated, area, in, a, ., e, and, f, high, mag, ##ni, ##fication, of, designated, area, in, d, ., 56, ##l, had, call, ##osa, ##l, projections, (, arrow, ##head, in, a, ), but, these, were, not, seen, in, p, ##13, ##9, (, arrow, ##head, in, c, ), ., red, :, anti, -, ha, ,, green, :, anti, -, g, ##fp, ,, blue, :, da, ##pi, ., images, in, d, –, f, and, figure, 10, ##x, were, taken, from, the, same, section, ., doi, :'},\n", + " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", + " 'section_name': 'Lentivirus transgenesis',\n", + " 'text': 'Although only a minority of lentiviral tet lines had reporter expression, the majority of lines with brain expression had highly restricted expression patterns. Some lines had expression only in restricted cell types, including medial prefrontal cortex layer 5 neurons (Figure 1A), retinal ganglion cells projecting axons to superior colliculus (Figure 1B), and Cajal-Retzius cells in cerebral cortex and dentate gyrus (Figure 1C). We had two lines with distinctive expression in cortical layer 4 neurons; TCGS in primary sensory cortices (including primary visual, somatosensory and auditory cortices; Figure 1D) and TCFQ which was devoid of expression in primary sensory cortices but expressed in associative cortices (Figure 1E). We also obtained lines labeling specific cell types, such as thalamocortical projection neurons in the dorsal part of the lateral geniculate complex (LGd; Figure 1F), anatomically clustered subsets of cerebellar granule cells, semilunar cells and a subset of superficial pyramidal neurons in piriform cortex, and a subtype of cortico-thalamic pyramidal neurons in layer 6 of neocortex (see below). Tet reporter expression could be turned off and on by administration of doxycycline (Figure 1—figure supplement 3). For a summary of expression patterns in all lines, see Supplementary file 1.10.7554/eLife.13503.004Figure 1.Example Lentiviral lines.(A) 48L has expression in limbic cortex (A1, coronal section) layer 5 pyramidal cells (A2, magnified image in limbic cortex). (B) Superior colliculus (SC) of TCBV has columnar axons from retina. B1: sagittal section, B2: magnified image of superior colliculus. (C) 52L has expression in piriform cortex (see Figure 9) and Cajal-Retzius cells in dentate gyrus (DG, C2) and cerebral cortex (C3, inset: magnified image of a Cajal-Retzius cell). (D) TCGS has expression in layer 4 neurons of primary sensory cortices (primary somatosensory area: SSp and primary visual area:VISp in D3). (E) TCFQ has nearly complimentary layer 4 expression excluding primary sensory cortices. D1 and E1: sagittal sections, D2 and E2: confocal images of cortex, D3 and E3: dorsal view of whole brains. (F) TCJD has expression in dorsal part of lateral geniculate nucleus (LGd, F1), which projects to primary visual cortex (VISp). F1: sagittal section, F2: higher magnification of LGd, F3: higher magnification of axons in layers 1, 4, and 6 of VISp. Scale bars are 50 μm in A2, B2, C2, F2 and 500 μm in others.DOI:10.7554/eLife.13503.005Figure 1—figure supplement 1.Transgenesis.(A) Lentiviral transgenesis. Lentivirus encoding an enhancer probe is injected into the perivitelline space between the single cell embryo and the zona pellucida. Infected embryos are transferred to foster mothers. Founders are genotyped by PCR and transgene copy number is estimated by southern blot or quantitative PCR and additional rounds of breeding and quantitative genotyping are carried out (not shown) to produce single copy founders. (B) PiggyBac (PB) transgenesis. Plasmid DNA for a PB enhancer probe and PB transposase (PBase) mRNA are injected into the cytosol of single cell embryos. Copy numbers of PB probes are examined as for lentiviral founders. Animals with single copy PB are selected as seed lines for PB transgenesis. Seed lines (P) are crossed with PBase animals, and their children (F1) carrying both PB and PBase are mated with wild-type (WT) animals. PB hops only in F1 PB;PBase mice, and animals with new PB insertion sites are generated in the following generation (F2). Among F2 animals, animals with hopped PB but without PBase are founders of new transgenic lines. PB; prm-PBase females can also be founders since prm-PBase will not be expressed in the female germ line.DOI:10.7554/eLife.13503.006Figure 1—figure supplement 2.Constructs for transgenesis.(A) Lentiviral constructs. Viral sequences were inserted into the lentiviral backbone plasmid. The five variants listed are described in the text. (B) PiggyBac constructs containing tTA or tTA and Cre. Except for hsp-tet3, transcripts from lentiviral constructs use 3’ long terminal repeat (△U3-R–U5 in the backbone plasmid) as poly adenylation signal. In all constructs, tTA and mCitrine share poly adenylation signal sequences. HSPmp: minimal promoter from Hspa1a, tTA: tet transactivator, TRE: tet response element, WPRE: woodchuck hepatitis virus post-transcriptional regulatory element, 2A: FMDV-2A sequence, BGHpA: poly-adenylation signal from bovine growth hormone, HS4ins: insulator sequence from DNase hyper sensitive site in the chicken β-globin gene, PB- 5’ITR and PB-3’ITR: PiggyBac inverted terminal repeat.DOI:10.7554/eLife.13503.007Figure 1—figure supplement 3.Transgene regulation by Doxycycline (Dox).Pregnant 48L females received water with Dox (0.2 mg/ml) or regular water (control) (A–B) P21 (A) and P42 (B) images from 48L animals receiving water lacking Dox. (C–I) Images from 48L animals receiving Dox. Regular water (D–F, second row) and doxycycline water (G–I, third row) were used for 3 weeks from when pups were weaned at P21. Siblings are dissected at P21 (C), P28 (D and G), P35 (E and H) and P42 (F and I).DOI:',\n", + " 'paragraph_id': 6,\n", + " 'tokenizer': 'although, only, a, minority, of, lent, ##iv, ##ira, ##l, te, ##t, lines, had, reporter, expression, ,, the, majority, of, lines, with, brain, expression, had, highly, restricted, expression, patterns, ., some, lines, had, expression, only, in, restricted, cell, types, ,, including, medial, pre, ##front, ##al, cortex, layer, 5, neurons, (, figure, 1a, ), ,, re, ##tina, ##l, gang, ##lion, cells, projecting, ax, ##ons, to, superior, col, ##lic, ##ulus, (, figure, 1b, ), ,, and, ca, ##jal, -, re, ##tz, ##ius, cells, in, cerebral, cortex, and, dent, ##ate, g, ##yr, ##us, (, figure, 1, ##c, ), ., we, had, two, lines, with, distinctive, expression, in, co, ##rti, ##cal, layer, 4, neurons, ;, tc, ##gs, in, primary, sensory, co, ##rti, ##ces, (, including, primary, visual, ,, so, ##mat, ##ose, ##nsor, ##y, and, auditory, co, ##rti, ##ces, ;, figure, 1, ##d, ), and, tc, ##f, ##q, which, was, devoid, of, expression, in, primary, sensory, co, ##rti, ##ces, but, expressed, in, ass, ##oc, ##ia, ##tive, co, ##rti, ##ces, (, figure, 1, ##e, ), ., we, also, obtained, lines, labeling, specific, cell, types, ,, such, as, tha, ##lam, ##oco, ##rti, ##cal, projection, neurons, in, the, dorsal, part, of, the, lateral, gen, ##iculate, complex, (, l, ##g, ##d, ;, figure, 1, ##f, ), ,, anatomical, ##ly, clustered, subset, ##s, of, ce, ##re, ##bella, ##r, gran, ##ule, cells, ,, semi, ##lun, ##ar, cells, and, a, subset, of, superficial, pyramid, ##al, neurons, in, pi, ##ri, ##form, cortex, ,, and, a, sub, ##type, of, co, ##rti, ##co, -, tha, ##lam, ##ic, pyramid, ##al, neurons, in, layer, 6, of, neo, ##cor, ##te, ##x, (, see, below, ), ., te, ##t, reporter, expression, could, be, turned, off, and, on, by, administration, of, do, ##xy, ##cy, ##cl, ##ine, (, figure, 1, —, figure, supplement, 3, ), ., for, a, summary, of, expression, patterns, in, all, lines, ,, see, supplementary, file, 1, ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##4, ##fi, ##gur, ##e, 1, ., example, lent, ##iv, ##ira, ##l, lines, ., (, a, ), 48, ##l, has, expression, in, limb, ##ic, cortex, (, a1, ,, corona, ##l, section, ), layer, 5, pyramid, ##al, cells, (, a2, ,, mag, ##nified, image, in, limb, ##ic, cortex, ), ., (, b, ), superior, col, ##lic, ##ulus, (, sc, ), of, tc, ##b, ##v, has, column, ##ar, ax, ##ons, from, re, ##tina, ., b1, :, sa, ##git, ##tal, section, ,, b, ##2, :, mag, ##nified, image, of, superior, col, ##lic, ##ulus, ., (, c, ), 52, ##l, has, expression, in, pi, ##ri, ##form, cortex, (, see, figure, 9, ), and, ca, ##jal, -, re, ##tz, ##ius, cells, in, dent, ##ate, g, ##yr, ##us, (, d, ##g, ,, c2, ), and, cerebral, cortex, (, c, ##3, ,, ins, ##et, :, mag, ##nified, image, of, a, ca, ##jal, -, re, ##tz, ##ius, cell, ), ., (, d, ), tc, ##gs, has, expression, in, layer, 4, neurons, of, primary, sensory, co, ##rti, ##ces, (, primary, so, ##mat, ##ose, ##nsor, ##y, area, :, ss, ##p, and, primary, visual, area, :, vis, ##p, in, d, ##3, ), ., (, e, ), tc, ##f, ##q, has, nearly, compliment, ##ary, layer, 4, expression, excluding, primary, sensory, co, ##rti, ##ces, ., d, ##1, and, e, ##1, :, sa, ##git, ##tal, sections, ,, d, ##2, and, e, ##2, :, con, ##fo, ##cal, images, of, cortex, ,, d, ##3, and, e, ##3, :, dorsal, view, of, whole, brains, ., (, f, ), tc, ##j, ##d, has, expression, in, dorsal, part, of, lateral, gen, ##iculate, nucleus, (, l, ##g, ##d, ,, f1, ), ,, which, projects, to, primary, visual, cortex, (, vis, ##p, ), ., f1, :, sa, ##git, ##tal, section, ,, f, ##2, :, higher, mag, ##ni, ##fication, of, l, ##g, ##d, ,, f, ##3, :, higher, mag, ##ni, ##fication, of, ax, ##ons, in, layers, 1, ,, 4, ,, and, 6, of, vis, ##p, ., scale, bars, are, 50, μ, ##m, in, a2, ,, b, ##2, ,, c2, ,, f, ##2, and, 500, μ, ##m, in, others, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##5, ##fi, ##gur, ##e, 1, —, figure, supplement, 1, ., trans, ##genesis, ., (, a, ), lent, ##iv, ##ira, ##l, trans, ##genesis, ., lent, ##iv, ##irus, encoding, an, enhance, ##r, probe, is, injected, into, the, per, ##iv, ##ite, ##llin, ##e, space, between, the, single, cell, embryo, and, the, z, ##ona, pe, ##ll, ##uc, ##ida, ., infected, embryo, ##s, are, transferred, to, foster, mothers, ., founders, are, gen, ##otype, ##d, by, pc, ##r, and, trans, ##gen, ##e, copy, number, is, estimated, by, southern, b, ##lot, or, quantitative, pc, ##r, and, additional, rounds, of, breeding, and, quantitative, gen, ##ot, ##yp, ##ing, are, carried, out, (, not, shown, ), to, produce, single, copy, founders, ., (, b, ), pig, ##gy, ##ba, ##c, (, p, ##b, ), trans, ##genesis, ., pl, ##as, ##mi, ##d, dna, for, a, p, ##b, enhance, ##r, probe, and, p, ##b, trans, ##po, ##sas, ##e, (, pba, ##se, ), mrna, are, injected, into, the, cy, ##tos, ##ol, of, single, cell, embryo, ##s, ., copy, numbers, of, p, ##b, probe, ##s, are, examined, as, for, lent, ##iv, ##ira, ##l, founders, ., animals, with, single, copy, p, ##b, are, selected, as, seed, lines, for, p, ##b, trans, ##genesis, ., seed, lines, (, p, ), are, crossed, with, pba, ##se, animals, ,, and, their, children, (, f1, ), carrying, both, p, ##b, and, pba, ##se, are, mated, with, wild, -, type, (, w, ##t, ), animals, ., p, ##b, hop, ##s, only, in, f1, p, ##b, ;, pba, ##se, mice, ,, and, animals, with, new, p, ##b, insertion, sites, are, generated, in, the, following, generation, (, f, ##2, ), ., among, f, ##2, animals, ,, animals, with, hopped, p, ##b, but, without, pba, ##se, are, founders, of, new, trans, ##genic, lines, ., p, ##b, ;, pr, ##m, -, pba, ##se, females, can, also, be, founders, since, pr, ##m, -, pba, ##se, will, not, be, expressed, in, the, female, ge, ##rm, line, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##6, ##fi, ##gur, ##e, 1, —, figure, supplement, 2, ., construct, ##s, for, trans, ##genesis, ., (, a, ), lent, ##iv, ##ira, ##l, construct, ##s, ., viral, sequences, were, inserted, into, the, lent, ##iv, ##ira, ##l, backbone, pl, ##as, ##mi, ##d, ., the, five, variants, listed, are, described, in, the, text, ., (, b, ), pig, ##gy, ##ba, ##c, construct, ##s, containing, tt, ##a, or, tt, ##a, and, cr, ##e, ., except, for, hs, ##p, -, te, ##t, ##3, ,, transcript, ##s, from, lent, ##iv, ##ira, ##l, construct, ##s, use, 3, ’, long, terminal, repeat, (, [UNK], -, r, –, u, ##5, in, the, backbone, pl, ##as, ##mi, ##d, ), as, poly, aden, ##yla, ##tion, signal, ., in, all, construct, ##s, ,, tt, ##a, and, mc, ##it, ##rine, share, poly, aden, ##yla, ##tion, signal, sequences, ., hs, ##pm, ##p, :, minimal, promoter, from, hs, ##pa, ##1, ##a, ,, tt, ##a, :, te, ##t, trans, ##act, ##iva, ##tor, ,, tre, :, te, ##t, response, element, ,, w, ##pre, :, wood, ##chu, ##ck, hepatitis, virus, post, -, transcription, ##al, regulatory, element, ,, 2a, :, fm, ##d, ##v, -, 2a, sequence, ,, b, ##gh, ##pa, :, poly, -, aden, ##yla, ##tion, signal, from, bo, ##vine, growth, hormone, ,, hs, ##4, ##ins, :, ins, ##ulator, sequence, from, dna, ##se, hyper, sensitive, site, in, the, chicken, β, -, g, ##lo, ##bin, gene, ,, p, ##b, -, 5, ’, it, ##r, and, p, ##b, -, 3, ’, it, ##r, :, pig, ##gy, ##ba, ##c, inverted, terminal, repeat, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##7, ##fi, ##gur, ##e, 1, —, figure, supplement, 3, ., trans, ##gen, ##e, regulation, by, do, ##xy, ##cy, ##cl, ##ine, (, do, ##x, ), ., pregnant, 48, ##l, females, received, water, with, do, ##x, (, 0, ., 2, mg, /, ml, ), or, regular, water, (, control, ), (, a, –, b, ), p, ##21, (, a, ), and, p, ##42, (, b, ), images, from, 48, ##l, animals, receiving, water, lacking, do, ##x, ., (, c, –, i, ), images, from, 48, ##l, animals, receiving, do, ##x, ., regular, water, (, d, –, f, ,, second, row, ), and, do, ##xy, ##cy, ##cl, ##ine, water, (, g, –, i, ,, third, row, ), were, used, for, 3, weeks, from, when, pup, ##s, were, we, ##ane, ##d, at, p, ##21, ., siblings, are, di, ##sse, ##cted, at, p, ##21, (, c, ), ,, p, ##28, (, d, and, g, ), ,, p, ##35, (, e, and, h, ), and, p, ##42, (, f, and, i, ), ., doi, :'},\n", + " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", + " 'section_name': 'An altered classification of layer 6 cortico-thalamic pyramidal neurons',\n", + " 'text': 'In order to complement our phenotypic analyses of differences between subtypes of L6 corticothalamic neurons, we also analyzed their RNAseq profiles and compared them to VISp layer 6 pyramidal neurons from the Ntsr1-Cre line, which is also known to have layer 6 specific expression in the cortex (Gong et al., 2007). Ntsr1-Cre labels virtually all primary CT neurons in layer 6 and also has projection to RTN (Bortone et al., 2014; Kim et al., 2014; Olsen et al., 2012). Clustering samples by correlations between gene expression vectors revealed two main clusters: those from 56L and all others (Figure 11A). Samples from P162 and P139 are intermingled in the cluster, implying they have quite similar RNA expression profiles. Analysis of differentially expressed genes also showed clear differences between the two main groups. There were 1869 genes differentially expressed among all sample groups (false discovery rate (FDR) < 0.01), and most differentially expressed genes showed bimodal patterns; high expressions in one group and low expressions in the other (Figure 11B and C). We also examined the expression of previously identified layer 6 marker genes (Molyneaux et al., 2007; Zeisel et al., 2015) and of genes used to generate BAC-Cre lines having layer 6 expression (Harris et al., 2014). Most of these known layer 6 markers are expressed both in the Ntsr1-cre group and in 56L (including the Ntsr1 gene itself) or were present only in the Ntsr1-cre lines. None were reliable markers for the 56L population (see Figure 11—figure supplement 1 and supplemental Note). We also examined expression profile of entorhinal cortical layer 6 cells from P038 in addition to isocortical layer 6 cells. Based on RNAseq expression profiles, P038 cells belonged to the Ntsr1-cre group but expressed unique set of genes (see Figure 11—figure supplement 2).10.7554/eLife.13503.033Figure 11.Two main subtypes of L6 CT neurons distinguished by gene expression .(A) Clustering of L6 CT neuron samples based on correlations (color scale) between expression profiles. (B) Heat map of normalized gene expression (TPM) of 50 genes with lowest ANOVA p-values. Except for Plcxd2 (asterisk), the genes had dominant expression in either Ntsr1/P162/P139 or 56L. (C) Coverage histograms of differentially expressed genes. Examples of genes expressed in P162/P139 (Tle4 and Rgs4), 56L (Nptxr and Cacna1g), P139 (Atp1b2), and P162 (Ifitm2). Scale bars: 100 counts. (D–F) In situ hybridization for Tle4 (red) and Bmp3 (green) in wild type P10 animal SSp. (E) high-magnification image. (F) Proportion of cells expressing Tle4 and Bmp3 in SSp layer 6. (G–O) In situ hybridization for mCitrine and Tle4 (G, J, and M) or Bmp3 (H, K and N) in P162 SSp (G and H), P139 SSs (J and K) and P56 SSp (M and N). (I, L, O) Proportions of mCitrine^+ cells that expressTle4 or Bmp3 and converse proportions of cells expressing the dominant marker (Tle4 for I,L Bmp3 for O) that are mCitrine^+ from P162 (I), P139 (L) and 56L (O). Colors in bar graphs represent in situ signal patterns (Red: cells with marker gene but not mCitrine, Green: cells with mCitrine signal but not marker gene, and Yellow: cells with both marker and mCitrine signals). Scale bar in D: 500 μm, in E: 50 μm.DOI:10.7554/eLife.13503.034Figure 11—figure supplement 1.Expression of known L6 marker genes.(A) Expression levels of known layer 6 marker genes (Molyneaux et al., 2007). (B) Expression levels of genes used to make BAC transgenic lines with layer 6 expression (Harris et al., 2014). (C) Layer 6 marker genes found by single cell RNAseq (Zeisel et al., 2015).DOI:10.7554/eLife.13503.035Figure 11—figure supplement 2.P038 entorhinal cortex layer 6 neurons are a distinct population.(A) Sample clustering (B) Heat map for top 100 genes with lowest ANOVA p-values. Arrows: genes shown in C. (C) Example of genes uniquely expressed in P038 (Nr4a2 and Parm1), Ntsr1 group and 56L markers (Tle4 and Bmp3), and selectively not expressed in P038 (Pcdh7 and Mef2c). y-axes: TPM.DOI:',\n", + " 'paragraph_id': 37,\n", + " 'tokenizer': 'in, order, to, complement, our, ph, ##eno, ##typic, analyses, of, differences, between, sub, ##type, ##s, of, l, ##6, co, ##rti, ##cot, ##hala, ##mic, neurons, ,, we, also, analyzed, their, rna, ##se, ##q, profiles, and, compared, them, to, vis, ##p, layer, 6, pyramid, ##al, neurons, from, the, nt, ##sr, ##1, -, cr, ##e, line, ,, which, is, also, known, to, have, layer, 6, specific, expression, in, the, cortex, (, gong, et, al, ., ,, 2007, ), ., nt, ##sr, ##1, -, cr, ##e, labels, virtually, all, primary, ct, neurons, in, layer, 6, and, also, has, projection, to, rt, ##n, (, bo, ##rton, ##e, et, al, ., ,, 2014, ;, kim, et, al, ., ,, 2014, ;, olsen, et, al, ., ,, 2012, ), ., cluster, ##ing, samples, by, correlation, ##s, between, gene, expression, vectors, revealed, two, main, clusters, :, those, from, 56, ##l, and, all, others, (, figure, 11, ##a, ), ., samples, from, p, ##16, ##2, and, p, ##13, ##9, are, inter, ##ming, ##led, in, the, cluster, ,, implying, they, have, quite, similar, rna, expression, profiles, ., analysis, of, differential, ##ly, expressed, genes, also, showed, clear, differences, between, the, two, main, groups, ., there, were, 1869, genes, differential, ##ly, expressed, among, all, sample, groups, (, false, discovery, rate, (, f, ##dr, ), <, 0, ., 01, ), ,, and, most, differential, ##ly, expressed, genes, showed, bi, ##mo, ##dal, patterns, ;, high, expressions, in, one, group, and, low, expressions, in, the, other, (, figure, 11, ##b, and, c, ), ., we, also, examined, the, expression, of, previously, identified, layer, 6, marker, genes, (, mo, ##lyn, ##eaux, et, al, ., ,, 2007, ;, ze, ##ise, ##l, et, al, ., ,, 2015, ), and, of, genes, used, to, generate, ba, ##c, -, cr, ##e, lines, having, layer, 6, expression, (, harris, et, al, ., ,, 2014, ), ., most, of, these, known, layer, 6, markers, are, expressed, both, in, the, nt, ##sr, ##1, -, cr, ##e, group, and, in, 56, ##l, (, including, the, nt, ##sr, ##1, gene, itself, ), or, were, present, only, in, the, nt, ##sr, ##1, -, cr, ##e, lines, ., none, were, reliable, markers, for, the, 56, ##l, population, (, see, figure, 11, —, figure, supplement, 1, and, supplemental, note, ), ., we, also, examined, expression, profile, of, en, ##tor, ##hin, ##al, co, ##rti, ##cal, layer, 6, cells, from, p, ##0, ##38, in, addition, to, iso, ##cor, ##tical, layer, 6, cells, ., based, on, rna, ##se, ##q, expression, profiles, ,, p, ##0, ##38, cells, belonged, to, the, nt, ##sr, ##1, -, cr, ##e, group, but, expressed, unique, set, of, genes, (, see, figure, 11, —, figure, supplement, 2, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##3, ##fi, ##gur, ##e, 11, ., two, main, sub, ##type, ##s, of, l, ##6, ct, neurons, distinguished, by, gene, expression, ., (, a, ), cluster, ##ing, of, l, ##6, ct, ne, ##uron, samples, based, on, correlation, ##s, (, color, scale, ), between, expression, profiles, ., (, b, ), heat, map, of, normal, ##ized, gene, expression, (, t, ##pm, ), of, 50, genes, with, lowest, an, ##ova, p, -, values, ., except, for, plc, ##x, ##d, ##2, (, as, ##ter, ##isk, ), ,, the, genes, had, dominant, expression, in, either, nt, ##sr, ##1, /, p, ##16, ##2, /, p, ##13, ##9, or, 56, ##l, ., (, c, ), coverage, his, ##to, ##gram, ##s, of, differential, ##ly, expressed, genes, ., examples, of, genes, expressed, in, p, ##16, ##2, /, p, ##13, ##9, (, t, ##le, ##4, and, r, ##gs, ##4, ), ,, 56, ##l, (, np, ##t, ##x, ##r, and, ca, ##c, ##na, ##1, ##g, ), ,, p, ##13, ##9, (, atp, ##1, ##b, ##2, ), ,, and, p, ##16, ##2, (, if, ##it, ##m, ##2, ), ., scale, bars, :, 100, counts, ., (, d, –, f, ), in, situ, hybrid, ##ization, for, t, ##le, ##4, (, red, ), and, b, ##mp, ##3, (, green, ), in, wild, type, p, ##10, animal, ss, ##p, ., (, e, ), high, -, mag, ##ni, ##fication, image, ., (, f, ), proportion, of, cells, expressing, t, ##le, ##4, and, b, ##mp, ##3, in, ss, ##p, layer, 6, ., (, g, –, o, ), in, situ, hybrid, ##ization, for, mc, ##it, ##rine, and, t, ##le, ##4, (, g, ,, j, ,, and, m, ), or, b, ##mp, ##3, (, h, ,, k, and, n, ), in, p, ##16, ##2, ss, ##p, (, g, and, h, ), ,, p, ##13, ##9, ss, ##s, (, j, and, k, ), and, p, ##56, ss, ##p, (, m, and, n, ), ., (, i, ,, l, ,, o, ), proportions, of, mc, ##it, ##rine, ^, +, cells, that, express, ##tle, ##4, or, b, ##mp, ##3, and, converse, proportions, of, cells, expressing, the, dominant, marker, (, t, ##le, ##4, for, i, ,, l, b, ##mp, ##3, for, o, ), that, are, mc, ##it, ##rine, ^, +, from, p, ##16, ##2, (, i, ), ,, p, ##13, ##9, (, l, ), and, 56, ##l, (, o, ), ., colors, in, bar, graphs, represent, in, situ, signal, patterns, (, red, :, cells, with, marker, gene, but, not, mc, ##it, ##rine, ,, green, :, cells, with, mc, ##it, ##rine, signal, but, not, marker, gene, ,, and, yellow, :, cells, with, both, marker, and, mc, ##it, ##rine, signals, ), ., scale, bar, in, d, :, 500, μ, ##m, ,, in, e, :, 50, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##4, ##fi, ##gur, ##e, 11, —, figure, supplement, 1, ., expression, of, known, l, ##6, marker, genes, ., (, a, ), expression, levels, of, known, layer, 6, marker, genes, (, mo, ##lyn, ##eaux, et, al, ., ,, 2007, ), ., (, b, ), expression, levels, of, genes, used, to, make, ba, ##c, trans, ##genic, lines, with, layer, 6, expression, (, harris, et, al, ., ,, 2014, ), ., (, c, ), layer, 6, marker, genes, found, by, single, cell, rna, ##se, ##q, (, ze, ##ise, ##l, et, al, ., ,, 2015, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##5, ##fi, ##gur, ##e, 11, —, figure, supplement, 2, ., p, ##0, ##38, en, ##tor, ##hin, ##al, cortex, layer, 6, neurons, are, a, distinct, population, ., (, a, ), sample, cluster, ##ing, (, b, ), heat, map, for, top, 100, genes, with, lowest, an, ##ova, p, -, values, ., arrows, :, genes, shown, in, c, ., (, c, ), example, of, genes, uniquely, expressed, in, p, ##0, ##38, (, nr, ##4, ##a, ##2, and, par, ##m, ##1, ), ,, nt, ##sr, ##1, group, and, 56, ##l, markers, (, t, ##le, ##4, and, b, ##mp, ##3, ), ,, and, selective, ##ly, not, expressed, in, p, ##0, ##38, (, pc, ##dh, ##7, and, me, ##f, ##2, ##c, ), ., y, -, axes, :, t, ##pm, ., doi, :'},\n", + " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", + " 'section_name': 'Results',\n", + " 'text': \"Research general issues:Abi-Rached JM: The implications of the new brain sciences. 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., 105, ##7, /, bio, ##so, ##c, ., 2012, ., 21, ., wu, kc, :, soul, -, making, in, ne, ##uro, ##ima, ##ging, ?, am, j, bio, ##eth, 2008, ,, 8, (, 9, ), :, 21, -, 22, ., doi, :, 10, ., 108, ##0, /, 152, ##65, ##16, ##0, ##80, ##24, ##12, ##53, ##6, ., za, ##rz, ##ec, ##z, ##ny, a, ,, ca, ##ulf, ##ield, t, :, legal, liability, and, research, ethics, boards, :, the, case, of, ne, ##uro, ##ima, ##ging, and, incident, ##al, findings, ., int, j, law, psychiatry, 2012, ,, 35, (, 2, ), :, si, ##13, ##7, -, si, ##14, ##5, ., doi, :, 10, ., 1016, /, j, ., i, ##j, ##lp, ., 2011, ., 12, ., 00, ##5, .'},\n", + " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", + " 'section_name': 'Results',\n", + " 'text': 'Book Chapters:Arentshorst ME, Broerse JEW, Roelofsen A, de Cock Buning T: Towards responsible neuroimaging applications in health care: guiding visions of scientists and technology developers. In Responsible Innovation 1: Innovative Solutions for Global Issues. Edited by Jeroen van den Hoven. Dordrecht: Springer; 2014: 255-280.Canli T, Amin Z: Neuroimaging of emotion and personality: ethical considerations. In Neuroethics: An Introduction with Readings. Edited by Martha J. Farah. Cambridge, Mass.: MIT Press; 2010:147-154.Canli T: When genes and brains unite: ethical implications of genomic neuroimaging. In Neuroethics: Defining the Issues in Theory, Practice and Policy. Edited by Judith Illes. Oxford: Oxford University Press; 2006: 169-184.Farrah MJ, Gillihan SJ: Neuroimaging in clinical psychiatry. In Neuroethics in Practice. Edited by Anjan Chatterjee, Martha J. Farah. New York: Oxford University Press; 2013: 128-148.Frederico C, Lombera S, Illes J: Intersecting complexities in neuroimaging and neuroethics. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011: 377-387.Hadskis MR, Schmidt MH: Pediatric neuroimaging research. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011:389-404.Illes J et al.: Ethical and practical considerations in managing incidental findings in functional magnetic resonance imaging. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 104-114.Illes J, Racine E: Imaging or imagining? A neuroethics challenge informed by genetics. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 140-162.Illes J: Neuroethics in a new era of neuroimaging. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 99-103.Illes J, Rosen A, Greicius M, Racine E: Prospects for prediction: ethics analysis of neuroimaging in Alzheimer’s disease. In Imaging and the Aging Brain. Edited by Mony J. de Leon, Donald A. Snider, Howard Federoff. Boston: Blackwell; 2007: 278-295.Kahlaoui K et al.: Neurobiological and neuroethical perspectives on the contribution of functional neuroimaging to the study of aging in the brain. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011: 495-512.Karanasion IS, Biniaris CG, Marsh AJ: Ethical issues of brain functional imaging: reading your mind. In Medical and Care Compunetics 5. Edited by Lodewijk Bos. Amsterdam: IOS Press; 2008: 310-320.Koch T: Images of uncertainty: two cases of neuroimages and what they cannot show. In Neurotechnology: Premises, Potential, and Problems. Edited by James Giordano. Boca Raton: CRC Press; 2012: 47-57.Kulynych J: Legal and ethical issues in neuroimaging research: human subjects protection, medical privacy, and the public communication of research results. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 115-133.Mamourian A: Incidental findings on research functional MR images: should we look? In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 134-139.Owen AM: Functional magnetic resonance imaging, covert awareness, and brain injury. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011:135-147.Phelps EA, Thomas LA: Race, behavior, and the brain: the role of neuroimaging in understanding complex social behaviors. In Neuroethics: An Introduction with Readings. Edited by Martha J. Farah. Cambridge, Mass.: MIT Press; 2010: 191-200.Racine E, Bell E, Illes J: Can we read minds? ethical challenges and responsibilities in the use of neuroimaging research. In Scientific and Philosophical Perspectives in Neuroethics. Edited by James J. Giordano, Bert Gordijn. Cambridge: Cambridge University Press; 2010: 244-270.Raschle N et al.: Pediatric neuroimaging in early childhood and infancy: challenges and practical guidelines. In The Neurosciences and Music IV: Learning and Memory. Edited by Katie Overy. Boston, Mass.: Blackwell; 2012: 43-50.Toole C, Zarzeczny A, Caulfield T: Research ethics challenges in neuroimaging research: a Canadian perspective. In International Neurolaw: A Comparative Analysis. Edited by Tade Matthias Spranger. Berlin: Springer; 2012: 89-101.Ulmer S et al.: Incidental findings in neuroimaging research: ethical considerations. In fMRI: Basics and Clinical Applications. Edited by Stephan Ulmer, Olav Jansen. Berlin: Springer; 2013: 311-318.Vanmeter J: Neuroimaging: thinking in pictures. In Scientific and Philosophical Perspectives in Neuroethics. Edited by James J. Giordano, Bert Gordijn. Cambridge: Cambridge University Press; 2010: 230-243.',\n", + " 'paragraph_id': 12,\n", + " 'tokenizer': 'book, chapters, :, aren, ##ts, ##hor, ##st, me, ,, bro, ##ers, ##e, jew, ,, roe, ##lo, ##fs, ##en, a, ,, de, cock, bun, ##ing, t, :, towards, responsible, ne, ##uro, ##ima, ##ging, applications, in, health, care, :, guiding, visions, of, scientists, and, technology, developers, ., in, responsible, innovation, 1, :, innovative, solutions, for, global, issues, ., edited, by, je, ##ro, ##en, van, den, hove, ##n, ., do, ##rd, ##recht, :, springer, ;, 2014, :, 255, -, 280, ., can, ##li, t, ,, amin, z, :, ne, ##uro, ##ima, ##ging, of, emotion, and, personality, :, ethical, considerations, ., in, ne, ##uro, ##eth, ##ics, :, an, introduction, with, readings, ., edited, by, martha, j, ., far, ##ah, ., cambridge, ,, mass, ., :, mit, press, ;, 2010, :, 147, -, 154, ., can, ##li, t, :, when, genes, and, brains, unite, :, ethical, implications, of, gen, ##omic, ne, ##uro, ##ima, ##ging, ., in, 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responsibilities, in, the, use, of, ne, ##uro, ##ima, ##ging, research, ., in, scientific, and, philosophical, perspectives, in, ne, ##uro, ##eth, ##ics, ., edited, by, james, j, ., gi, ##ord, ##ano, ,, bert, go, ##rdi, ##jn, ., cambridge, :, cambridge, university, press, ;, 2010, :, 244, -, 270, ., ras, ##ch, ##le, n, et, al, ., :, pediatric, ne, ##uro, ##ima, ##ging, in, early, childhood, and, infancy, :, challenges, and, practical, guidelines, ., in, the, neuroscience, ##s, and, music, iv, :, learning, and, memory, ., edited, by, katie, over, ##y, ., boston, ,, mass, ., :, blackwell, ;, 2012, :, 43, -, 50, ., tool, ##e, c, ,, za, ##rz, ##ec, ##z, ##ny, a, ,, ca, ##ulf, ##ield, t, :, research, ethics, challenges, in, ne, ##uro, ##ima, ##ging, research, :, a, canadian, perspective, ., in, international, ne, ##uro, ##law, :, a, comparative, analysis, ., edited, by, tad, ##e, matthias, sprang, ##er, ., berlin, :, springer, ;, 2012, :, 89, -, 101, ., ul, ##mer, s, et, al, ., :, incident, 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##2, ., an, ##ido, a, ,, carlson, l, ##m, ,, sherman, sl, :, attitudes, toward, fragile, x, mutation, carrier, testing, from, women, identified, in, a, general, population, survey, ., j, gene, ##t, co, ##un, ##s, 2007, ,, 16, (, 1, ), :, 97, -, 104, ., doi, :, 10, ., 100, ##7, /, s, ##10, ##8, ##9, ##7, -, 00, ##6, -, 90, ##49, -, 0, ., ar, ##nos, ks, :, the, implications, of, genetic, testing, for, deaf, ##ness, ., ear, hear, 2003, ,, 24, (, 4, ), :, 324, -, 331, ., doi, :, 10, ., 109, ##7, /, 01, ., au, ##d, ., 000, ##00, ##7, ##9, ##80, ##0, ., 64, ##7, ##41, ., cf, ., ar, ##nos, ks, :, ethical, and, social, implications, of, genetic, testing, for, communication, disorders, ., j, com, ##mun, di, ##sor, ##d, 2008, ,, 41, (, 5, ), :, 44, ##4, -, 45, ##7, ., doi, :, 10, ., 1016, /, j, ., jc, ##om, ##dis, ., 2008, ., 03, ., 001, ., ass, ##cher, e, ,, ko, ##ops, b, ##j, :, the, right, not, to, know, and, pre, ##im, ##pl, ##anta, ##tion, genetic, diagnosis, for, huntington, \\', s, 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Alcohol Clin Exp Res 2013, 37(9):1451-1455. doi: 10.1111/acer.12115.\",\n", + " 'paragraph_id': 16,\n", + " 'tokenizer': \"ne, ##uro, ##bio, ##mark, ##ers, :, arias, jj, ,, karl, ##aw, ##ish, j, :, confidential, ##ity, in, pre, ##cl, ##ini, ##cal, alzheimer, disease, studies, :, when, research, and, medical, records, meet, ., ne, ##uro, ##logy, 2014, ,, 82, (, 8, ), :, 72, ##5, -, 72, ##9, ., doi, :, 10, ., 121, ##2, /, w, ##nl, ., 000, ##00, ##00, ##00, ##00, ##00, ##15, ##3, ., cho, ##ud, ##hur, ##y, s, ,, gold, i, ,, ki, ##rma, ##yer, l, ##j, :, from, brain, image, to, the, bush, doctrine, :, critical, neuroscience, and, the, political, uses, of, ne, ##uro, ##tech, ##nology, ., aj, ##ob, ne, ##uro, ##sc, ##i, 2010, ,, 1, (, 2, ), :, 17, -, 19, ., doi, :, 10, ., 108, ##0, /, 215, ##0, ##7, ##7, ##41, ##00, ##36, ##9, ##9, ##28, ##0, ., dani, ka, ,, mccormick, mt, ,, muir, kw, :, brain, les, ##ion, volume, and, capacity, for, consent, in, stroke, trials, :, potential, regulatory, 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{'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", + " 'section_name': 'Results',\n", + " 'text': \"Issues Concerning Pediatric Subjects/Patients:Altavilla A et al.: Activity of ethics committees in Europe on issues related to clinical trials in paediatrics: results of a survey. 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##nu, ., 2010, ., 07, ., 01, ##1, .\"},\n", + " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", + " 'section_name': 'Results',\n", + " 'text': 'Mood stabilizers/anti-depressants/antipsychotic and nootropic agents:Adam D, Kasper S, Moller HJ, Singer EA, 3rd European Expert Forum on Ethical Evaluation of Placebo-Controlled Studies in Depression: Placebo-controlled trials in major depression are necessary and ethically justifiable: how to improve the communication between researchers and ethical committees. 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PLoS One 2013, 8(5):e62609. doi:10.1371/journal.pone.0062609.',\n", + " 'paragraph_id': 22,\n", + " 'tokenizer': 'mood, stabilize, ##rs, /, anti, -, de, ##press, ##ants, /, anti, ##psy, ##cho, ##tic, and, no, ##ot, ##rop, ##ic, agents, :, adam, d, ,, ka, ##sper, s, ,, mo, ##ller, h, ##j, ,, singer, ea, ,, 3rd, european, expert, forum, on, ethical, evaluation, of, place, ##bo, -, controlled, studies, in, depression, :, place, ##bo, -, controlled, trials, in, major, depression, are, necessary, and, ethical, ##ly, just, ##if, ##iable, :, how, to, improve, the, communication, between, researchers, and, ethical, committees, ., eu, ##r, arch, psychiatry, cl, ##in, ne, ##uro, ##sc, ##i, 2005, ,, 255, (, 4, ), :, 258, -, 260, ., doi, :, 10, ., 100, ##7, /, s, ##00, ##40, ##6, -, 00, ##4, -, 05, ##55, -, 5, ., ag, ##ius, m, ,, bradley, v, ,, ryan, d, ,, za, ##man, r, :, the, ethics, of, identifying, and, treating, psycho, ##sis, early, ., ps, ##ych, ##ia, ##tr, dan, ##ub, 2008, ,, 20, (, 1, ), 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##8, ##9, ., doi, :, 10, ., 137, ##1, /, journal, ., p, ##bio, ., 100, ##12, ##8, ##9, ., vo, ##ari, ##no, n, :, rec, ##ons, ##ider, ##ing, the, concept, of, ‘, dual, -, use, ’, in, the, context, of, neuroscience, research, ., bio, ##eth, ##ique, ##on, ##line, 2014, ,, 3, /, 16, :, 1, -, 6, ., walsh, c, :, youth, justice, and, neuroscience, :, a, dual, -, use, dilemma, ., br, j, cr, ##imi, ##no, ##l, 2011, ,, 51, (, 1, ), :, 21, -, 29, ., doi, :, 10, ., 109, ##3, /, b, ##j, ##c, /, az, ##q, ##0, ##6, ##1, ., wheel, ##is, m, ,, dan, ##do, m, :, ne, ##uro, ##biology, :, a, case, study, on, the, imminent, mil, ##ita, ##rization, of, biology, ., revue, internationale, de, la, croix, -, rouge, /, international, review, of, the, red, cross, 2005, ,, 87, (, 85, ##9, ), :, 56, ##3, -, 57, ##1, ., doi, :, 10, ., 101, ##7, /, s, ##18, ##16, ##38, ##31, ##00, ##18, ##43, ##8, ##3, ., zimmerman, e, ,, ra, ##cine, e, ., ethical, issues, in, the, translation, of, social, neuroscience, :, a, policy, analysis, of, current, guidelines, for, public, dialogue, in, human, research, ., account, res, 2012, ,, 19, (, 1, ), :, 27, -, 46, ., doi, :, 10, ., 108, ##0, /, 08, ##9, ##8, ##9, ##6, ##21, ., 2012, ., 650, ##9, ##49, ., z, ##ona, ##na, h, :, physicians, must, honor, refusal, of, treatment, to, restore, compete, ##ncy, by, non, -, dangerous, inmates, on, death, row, ., j, law, med, ethics, 2010, ,, 38, (, 4, ), :, 76, ##4, -, 77, ##3, ., doi, :, 10, ., 111, ##1, /, j, ., 1748, -, 720, ##x, ., 2010, ., 00, ##53, ##0, ., x, .'},\n", + " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", + " 'section_name': 'Results',\n", + " 'text': 'Book chapters:Abney K, Lin P, Mehlman M: Military neuroenhancement and risk assessment. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 239-248.Balaban CD: Neurotechnology and operational medicine. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 65-78.Bartolucci V, Dando M: What does neuroethics have to say about the problem of dual use? In On the Dual Uses of Science and Ethics: Principles, Practices, and Prospects. Edited by Brian Rappert, Michael J. Selgelid. Canberra, Australia: ANU Press; 2013: 29-44.Bell C: Why neuroscientists should take the pledge: a collective approach to the misuse of neuroscience. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 227-238.Benanti P: Between neuroskepticism and neurogullibility: the key role of neuroethics in the regulation and mitigation of neurotechnology in national security and defense. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 217-225.Casebeer WD: Postscript: a neuroscience and national security normative framework for the twenty-first century. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 279-283.Dando M: Neuroscience advances and future warfare. In Handbook of Neuroethics. Edited by Jens Clausen, Neil Levy. Dordrecht: Springer; 2014, 2015: 1785-1800.Ganis G: Investigating deception and deception detection with brain stimulation methods. In Detecting Deception: Current Challenges and Cognitive Approaches. Edited by Pär Anders Granhag, Aldert Vrij, Bruno Verschuere. Hoboken, NJ: John Wiley & Sons; 2014, 2015: 253-268.Giordano J: Neurotechnology, global relations, and national security: shifting contexts and neuroethical demands. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 1-10.Farwell JP: Issues of law raised by developments and use of neuroscience and neurotechnology in national security and defense. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 133-165.Marchant GE, Gaudet LM: Neuroscience, national security, and the reverse dual-use dilemma. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 167-178.Marks JH: Neuroskepticism: rethinking the ethics of neuroscience and national security. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 179-198.McCreight R: Brain brinksmanship: devising neuroweapons looking at battlespace, doctrine, and strategy. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 115-132.Murray S, Yanagi MA: Transitioning brain research: from bench to battlefield. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 11-22.Nuffield Council on Bioethics. Non-therapeutic applications. In its Novel Neurotechnologies: Intervening in the Brain. London: Nuffield Council on Bioethics; 2013: 162-190.Oie KS, McDowell K: Neurocognitive engineering for systems’ development. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 33-50.Paulus MP et al.: Neural mechanisms as putative targets for warfighter resilience and optimal performance. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 51-63.Stanney KM et al.: Neural systems in intelligence and training applications. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 23-32.Tabery J: Can (and should) we regulate neurosecurity? lessons from history. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 249-258.Thomsen K: Prison camp or “prison clinic?”: biopolitics, neuroethics, and national security. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 199-216.Tractenberg RE, FitzGerald KT, Giordano J: Engaging neuroethical issues generated by the use of neurotechnology in national security and defense: toward process, methods, and paradigm. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 259-277.Wurzman R, Giordano J: “NEURINT” and neuroweapons: neurotechnologies in national intelligence and defense. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 79-113.',\n", + " 'paragraph_id': 52,\n", + " 'tokenizer': 'book, chapters, :, ab, ##ney, k, ,, lin, p, ,, me, ##hl, ##man, m, :, military, ne, ##uro, ##en, ##han, ##ce, ##ment, and, risk, assessment, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 239, -, 248, ., bala, ##ban, cd, :, ne, ##uro, ##tech, ##nology, and, operational, medicine, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 65, -, 78, ., bart, ##ol, ##ucci, v, ,, dan, ##do, m, :, what, does, ne, ##uro, ##eth, ##ics, have, to, say, about, the, problem, of, dual, use, ?, in, on, the, dual, uses, of, science, and, ethics, :, principles, ,, practices, ,, and, prospects, ., edited, by, brian, rapper, ##t, ,, michael, j, ., se, ##lge, ##lid, ., canberra, ,, australia, :, an, ##u, press, ;, 2013, :, 29, -, 44, ., bell, c, :, why, ne, ##uro, ##sc, ##ient, ##ists, should, take, the, pledge, :, a, collective, approach, to, the, mis, ##use, of, neuroscience, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 227, -, 238, ., ben, ##ant, ##i, p, :, between, ne, ##uro, ##ske, ##ptic, ##ism, and, ne, ##uro, ##gul, ##lib, ##ility, :, the, key, role, of, ne, ##uro, ##eth, ##ics, in, the, regulation, and, mit, ##iga, ##tion, of, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 217, -, 225, ., case, ##bee, ##r, w, ##d, :, posts, ##cript, :, a, neuroscience, and, national, security, norma, ##tive, framework, for, the, twenty, -, first, century, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 279, -, 283, ., dan, ##do, m, :, neuroscience, advances, and, future, warfare, ., in, handbook, of, ne, ##uro, ##eth, ##ics, ., edited, by, jens, clause, ##n, ,, neil, levy, ., do, ##rd, ##recht, :, springer, ;, 2014, ,, 2015, :, 1785, -, 1800, ., gan, ##is, g, :, investigating, deception, and, deception, detection, with, brain, stimulation, methods, ., in, detecting, deception, :, current, challenges, and, cognitive, approaches, ., edited, by, par, anders, gran, ##ha, ##g, ,, al, ##der, ##t, vr, ##ij, ,, bruno, ve, ##rs, ##chu, ##ere, ., ho, ##bo, ##ken, ,, nj, :, john, wiley, &, sons, ;, 2014, ,, 2015, :, 253, -, 268, ., gi, ##ord, ##ano, j, :, ne, ##uro, ##tech, ##nology, ,, global, relations, ,, and, national, security, :, shifting, contexts, and, ne, ##uro, ##eth, ##ical, demands, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 1, -, 10, ., far, ##well, jp, :, issues, of, law, raised, by, developments, and, use, of, neuroscience, and, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 133, -, 165, ., march, ##ant, ge, ,, ga, ##ude, ##t, l, ##m, :, neuroscience, ,, national, security, ,, and, the, reverse, dual, -, use, dilemma, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, j, ., gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 167, -, 178, ., marks, j, ##h, :, ne, ##uro, ##ske, ##ptic, ##ism, :, re, ##thi, ##nk, ##ing, the, ethics, of, neuroscience, and, national, security, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 179, -, 198, ., mcc, ##re, ##ight, r, :, brain, brink, ##sman, ##ship, :, devi, ##sing, ne, ##uro, ##we, ##ap, ##ons, looking, at, battles, ##pace, ,, doctrine, ,, and, strategy, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 115, -, 132, ., murray, s, ,, yan, ##agi, ma, :, transition, ##ing, brain, research, :, from, bench, to, battlefield, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, j, ., gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 11, -, 22, ., nu, ##ffie, ##ld, council, on, bio, ##eth, ##ics, ., 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francis, group, ;, 2014, ,, 2015, :, 51, -, 63, ., stan, ##ney, km, et, al, ., :, neural, systems, in, intelligence, and, training, applications, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, j, ., gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 23, -, 32, ., tab, ##ery, j, :, can, (, and, should, ), we, regulate, ne, ##uro, ##se, ##cu, ##rity, ?, lessons, from, history, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 249, -, 258, ., thom, ##sen, k, :, prison, camp, or, “, prison, clinic, ?, ”, :, bio, ##pol, ##itic, ##s, ,, ne, ##uro, ##eth, ##ics, ,, and, national, security, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 199, -, 216, ., tract, ##enberg, re, ,, fitzgerald, k, ##t, ,, gi, ##ord, ##ano, j, :, engaging, ne, ##uro, ##eth, ##ical, issues, generated, by, the, use, of, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, toward, process, ,, methods, ,, and, paradigm, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 259, -, 277, ., wu, ##rz, ##man, r, ,, gi, ##ord, ##ano, j, :, “, ne, ##uri, ##nt, ”, and, ne, ##uro, ##we, ##ap, ##ons, :, ne, ##uro, ##tech, ##no, ##logies, in, national, intelligence, and, defense, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 79, -, 113, .'},\n", + " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", + " 'section_name': 'Conditional Control on the Rabies Life Cycle',\n", + " 'text': 'We screened the suitability to viral production and TEVp dependence of six viral constructs, in which each viral protein was targeted to the proteasome alone or in combination (Figures 1C–1K; Table S1). To this aim, we generated a stable cell line expressing TEVp and the spike glycoprotein (Figures 1A and 1B). Surprisingly, the destabilization of the viral proteins M, P, N/P, and N/P/L led to a virus unable to efficiently spread even in presence of the protease. In contrast, the virus with proteasome-targeted L protein did amplify both in presence (Figure 1D) and absence (Figure 1J) of the TEV protease, indicating that the partial destabilization of the L protein by the degradation domain is insufficient to impair the viral replication machinery. The virus in which the N protein alone was destabilized showed the desired conditional control: failure to amplify in absence of TEVp and successful amplification in TEVp-expressing cells (at 18 days post transfection +TEVp 80% ± 4%, −TEVp 2% ± 0.2% of infected cells, p = 3 × 10^−3, two-tailed two-sample Student’s t test, Figure 1K). This indicates that N is the sole viral protein whose conditional destabilization, in our design, is sufficient to reversibly suppress the viral transcription-replication cycle. We confirmed that the conditional inactivation of the N-tagged ΔG-rabies is a proteasome-dependent process by amplifying the virus in absence of TEVp but in presence of the proteasome inhibitor MG-132 (Figure S1A). Indeed, the amplification rate of the N-tagged ΔG-rabies virus significantly increases, in a dose-dependent manner, following the administration of the proteasome inhibitor MG-132 (at 12 days post transfection 0 nM MG-132, 0.1% ± 0.1%; 250 nM MG-132, 13% ± 5% of infected cells, p = 0.04, two-tailed two-sample Student’s t test, Figure S1B). After a further round of improvement on the viral cassette design (Figures S2 and S3; STAR Methods), we were able to produce a SiR with the desired TEVp-dependent ON/OFF kinetics constituted by an NPEST-rabies-mCherry cassette containing a TEVp-cleavable linker between N and the PEST sequence.Figure S1Proteasome Inhibition Supports Attenuated Rabies Production, Related to Figure 1(A) Scheme of tested conditions for the production of N-tagged ΔG-Rabies^mCherry in HEK-GG (-TEV_P) cells in presence or absence of proteasome inhibitor (MG-132). (B) Percentage of infected cells at different concentrations of MG-132 administered after 3-12 days post-transfection (mean ± SEM, n = 3).Figure S2Rapamaycin-Induced SPLIT-TEVp Reconstitution and Cleavage of PEST Domain in HEK293T Cells, Related to Figure 1(A) Strategy for the pharmacological stabilization of tagged viral protein by rapamycin-induced dimerization of the SPLIT-TEVp. (B) SPLIT-TEVp rapamycin response in HEK293T cells transfected with a TEVp activity reporter increases at incremental concentration of rapamycin (0-10-50 nM). (C) The SPLIT-TEVp cassette was cloned into the glycoprotein locus in the Rabies genome. Rapamycin dependent TEVp activity in HEK293T 48 hr post transfection with TEVp activity reporter and infection with the SPLIT-TEVp expressing ΔG-Rabies.Figure S3Testing Cytotoxicity of ΔG-N^PESTRabies^SPLIT-TEVp-mCherry In Vitro and In Vivo, Related to Figure 1(A) hESCs derived neurons were infected with ΔG-N^PESTRabies^SPLIT-TEVp-mCherry and imaged longitudinally over 16 days. (B)-B”) ΔG-N^PESTRabies^SPLIT-TEVp-mCherry and B19 ΔG-Rabies control (C)-C”) infected hESCs derived neurons imaged at 4, 10 and 16 days post-infection (p.i.). (D) Percentage of infected cells after administration of control ΔG-Rabies or ΔG-N^PESTRabies^SPLIT-TEVp-mCherry in presence or absence of rapamycin after 4–10 and 16 days normalized to day 4 time-point (mean ± SEM). (E) mCherry signal intensity of ΔG-N^PESTRabies^SPLIT-TEVp-mCherry and ΔG-Rabies infected neurons normalized to day 4 time-point (mean ± SEM., scale as in (D). Scale bar: 50 μm. (F) Hippocampi of Rosa-LoxP-STOP-LoxP-YFP mice were injected bilaterally with ΔG-Rabies^GFP (cyan) and ΔG-N^PESTRabies^SPLIT-TEVp-CRE (magenta). Confocal images of ΔG-Rabies^GFP (G-G’) or ΔG-N^PESTRabies ^SPLIT-TEVp-CRE (H-H’) infected hippocampi at 1, 2 or 3 weeks p.i. Scale bar: 50 μm (I) Percentage of infected neurons at 1, 2 or 3 weeks p.i. of ΔG-Rabies^GFP (black) or ΔG-N^PESTRabies^SPLIT-TEVp-CRE (gray) in hippocampus normalized to 1 week time-point (mean ± SEM, n = 3 animals per time point).',\n", + " 'paragraph_id': 4,\n", + " 'tokenizer': 'we, screened, the, suit, ##ability, to, viral, production, and, te, ##v, ##p, dependence, of, six, viral, construct, ##s, ,, in, which, each, viral, protein, was, targeted, to, the, pro, ##tea, ##some, alone, or, in, combination, (, figures, 1, ##c, –, 1, ##k, ;, table, s, ##1, ), ., to, this, aim, ,, we, generated, a, stable, cell, line, expressing, te, ##v, ##p, and, the, spike, g, ##ly, ##co, ##pro, ##tein, (, figures, 1a, and, 1b, ), ., surprisingly, ,, the, des, ##ta, ##bil, ##ization, of, the, viral, proteins, m, ,, p, ,, n, /, p, ,, and, n, /, p, /, l, led, to, a, virus, unable, to, efficiently, spread, even, in, presence, of, the, pro, ##tea, ##se, ., in, contrast, ,, the, virus, with, pro, ##tea, ##some, -, targeted, l, protein, did, amp, ##li, ##fy, both, in, presence, (, figure, 1, ##d, ), and, absence, (, figure, 1, ##j, ), of, the, te, ##v, pro, ##tea, ##se, ,, indicating, that, the, partial, des, ##ta, ##bil, ##ization, of, the, l, protein, by, the, degradation, domain, is, insufficient, to, imp, ##air, the, viral, replication, machinery, ., the, virus, in, which, the, n, protein, alone, was, des, ##ta, ##bil, ##ized, showed, the, desired, conditional, control, :, failure, to, amp, ##li, ##fy, in, absence, of, te, ##v, ##p, and, successful, amp, ##li, ##fication, in, te, ##v, ##p, -, expressing, cells, (, at, 18, days, post, trans, ##fect, ##ion, +, te, ##v, ##p, 80, %, ±, 4, %, ,, −, ##te, ##v, ##p, 2, %, ±, 0, ., 2, %, of, infected, cells, ,, p, =, 3, ×, 10, ^, −, ##3, ,, two, -, tailed, two, -, sample, student, ’, s, t, test, ,, figure, 1, ##k, ), ., this, indicates, that, n, is, the, sole, viral, protein, whose, conditional, des, ##ta, ##bil, ##ization, ,, in, our, design, ,, is, sufficient, to, rev, ##ers, ##ibly, suppress, the, viral, transcription, -, replication, cycle, ., we, confirmed, that, the, conditional, ina, ##ct, ##ivation, of, the, n, -, tagged, δ, ##g, -, ra, ##bies, is, a, pro, ##tea, ##some, -, dependent, process, by, amp, ##li, ##fying, the, virus, in, absence, of, te, ##v, ##p, but, in, presence, of, the, pro, ##tea, ##some, inhibitor, mg, -, 132, (, figure, s, ##1, ##a, ), ., indeed, ,, the, amp, ##li, ##fication, rate, of, the, n, -, tagged, δ, ##g, -, ra, ##bies, virus, significantly, increases, ,, in, a, dose, -, dependent, manner, ,, following, the, administration, of, the, pro, ##tea, ##some, inhibitor, mg, -, 132, (, at, 12, days, post, trans, ##fect, ##ion, 0, nm, mg, -, 132, ,, 0, ., 1, %, ±, 0, ., 1, %, ;, 250, nm, mg, -, 132, ,, 13, %, ±, 5, %, of, infected, cells, ,, p, =, 0, ., 04, ,, two, -, tailed, two, -, sample, student, ’, s, t, test, ,, figure, s, ##1, ##b, ), ., after, a, further, round, of, improvement, on, the, viral, cassette, design, (, figures, s, ##2, and, s, ##3, ;, star, methods, ), ,, we, were, able, to, produce, a, sir, with, the, desired, te, ##v, ##p, -, dependent, on, /, off, kinetic, ##s, constituted, by, an, np, ##est, -, ra, ##bies, -, mc, ##her, ##ry, cassette, containing, a, te, ##v, ##p, -, cl, ##ea, ##vable, link, ##er, between, n, and, the, pest, sequence, ., figure, s, ##1, ##pro, ##tea, ##some, inhibition, supports, at, ##ten, ##uated, ra, ##bies, production, ,, related, to, figure, 1, (, a, ), scheme, of, tested, conditions, for, the, production, of, n, -, tagged, δ, ##g, -, ra, ##bies, ^, mc, ##her, ##ry, in, he, ##k, -, g, ##g, (, -, te, ##v, _, p, ), cells, in, presence, or, absence, of, pro, ##tea, ##some, inhibitor, (, mg, -, 132, ), ., (, b, ), percentage, of, infected, cells, at, different, concentrations, of, mg, -, 132, administered, after, 3, -, 12, days, post, -, trans, ##fect, ##ion, (, mean, ±, se, ##m, ,, n, =, 3, ), ., figure, s, ##2, ##ra, ##pa, ##may, ##cin, -, induced, split, -, te, ##v, ##p, rec, ##ons, ##ti, ##tu, ##tion, and, cleavage, of, pest, domain, in, he, ##k, ##29, ##3, ##t, cells, ,, related, to, figure, 1, (, a, ), strategy, for, the, ph, ##arm, ##aco, ##logical, stabilization, of, tagged, viral, protein, by, rap, ##amy, ##cin, -, induced, dime, ##rization, of, the, split, -, te, ##v, ##p, ., (, b, ), split, -, te, ##v, ##p, rap, ##amy, ##cin, response, in, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, a, te, ##v, ##p, activity, reporter, increases, at, inc, ##rem, ##ental, concentration, of, rap, ##amy, ##cin, (, 0, -, 10, -, 50, nm, ), ., (, c, ), the, split, -, te, ##v, ##p, cassette, was, clone, ##d, into, the, g, ##ly, ##co, ##pro, ##tein, locus, in, the, ra, ##bies, genome, ., rap, ##amy, ##cin, dependent, te, ##v, ##p, activity, in, he, ##k, ##29, ##3, ##t, 48, hr, post, trans, ##fect, ##ion, with, te, ##v, ##p, activity, reporter, and, infection, with, the, split, -, te, ##v, ##p, expressing, δ, ##g, -, ra, ##bies, ., figure, s, ##3, ##test, ##ing, cy, ##to, ##to, ##xi, ##city, of, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, in, vitro, and, in, vivo, ,, related, to, figure, 1, (, a, ), he, ##sc, ##s, derived, neurons, were, infected, with, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, and, image, ##d, longitudinal, ##ly, over, 16, days, ., (, b, ), -, b, ”, ), δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, and, b1, ##9, δ, ##g, -, ra, ##bies, control, (, c, ), -, c, ”, ), infected, he, ##sc, ##s, derived, neurons, image, ##d, at, 4, ,, 10, and, 16, days, post, -, infection, (, p, ., i, ., ), ., (, d, ), percentage, of, infected, cells, after, administration, of, control, δ, ##g, -, ra, ##bies, or, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, in, presence, or, absence, of, rap, ##amy, ##cin, after, 4, –, 10, and, 16, days, normal, ##ized, to, day, 4, time, -, point, (, mean, ±, se, ##m, ), ., (, e, ), mc, ##her, ##ry, signal, intensity, of, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, and, δ, ##g, -, ra, ##bies, infected, neurons, normal, ##ized, to, day, 4, time, -, point, (, mean, ±, se, ##m, ., ,, scale, as, in, (, d, ), ., scale, bar, :, 50, μ, ##m, ., (, f, ), hip, ##po, ##camp, ##i, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, were, injected, bilateral, ##ly, with, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, cy, ##an, ), and, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, cr, ##e, (, mage, ##nta, ), ., con, ##fo, ##cal, images, of, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, g, -, g, ’, ), or, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, cr, ##e, (, h, -, h, ’, ), infected, hip, ##po, ##camp, ##i, at, 1, ,, 2, or, 3, weeks, p, ., i, ., scale, bar, :, 50, μ, ##m, (, i, ), percentage, of, infected, neurons, at, 1, ,, 2, or, 3, weeks, p, ., i, ., of, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, black, ), or, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, cr, ##e, (, gray, ), in, hip, ##po, ##camp, ##us, normal, ##ized, to, 1, week, time, -, point, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), .'},\n", + " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", + " 'section_name': 'Permanent Genetic Access to Neural Circuits with SiR',\n", + " 'text': 'In order to experimentally assess the in vivo cytotoxicity of the newly generated SiR, we added a CRE recombinase and a destabilized mCherry (SiR^CRE-mCherry, Figure 2B) to the SiR genome. We then tested SiR transcription-replication kinetics and cytotoxicity in vivo by injecting SiR^CRE-mCherry in the CA1 pyramidal layer of Rosa-LoxP-STOP-LoxP-YFP mice (Figure 2B). The transient expression of the CRE recombinase driven by the SiR should be adequate to ensure a permanent recombination of the Rosa locus and consequent YFP expression even after a complete transcriptional shut down of the virus (Figure 2A). At the same time, the destabilized mCherry marks the presence of active virus with high temporal resolution. Indeed, while at 3 days post infection (p.i.) only the virally encoded mCherry can be detected (Figures S4C–S4C′′′ and S4F), by 6 days p.i. the virally encoded CRE has induced recombination of the conditional mouse reporter cassette, triggering the expression of YFP in all infected neurons (Figures S4D–S4D′′′ and S4F′). In order to exclude any SiR-induced cytotoxicity, we monitored the survival of SiR^CRE-mCherry-infected CA1 pyramidal neurons over a 6-month period. By 3 weeks p.i., the SiR had completely shut down (98% ± 2% YFP^ON mCherry^OFF, Figures 2D–2D′′′ and 2G) and, more importantly, no significant neuronal loss was observed during the 6-month period following SiR infection (one-way ANOVA, F = 0.12, p = 0.97, Figures 2F–2F′′′and 2G). This is in striking contrast with what is observed after canonical ΔG-rabies infection, in which the majority of infected neurons in the hippocampus die within 2 weeks from the primary infection (Figures S5A–S5C). We further confirmed the absence of SiR-induced cytotoxic effects in vivo by assessing the level of caspase-3 activation (cCaspase3) at 1 and 2 weeks following SiR infection and comparing it to that elicited in mock-injected controls. The results indicate no significant differences between SiR and mock-injected conditions in the levels of caspase-3 activation (one-way ANOVA, F = 0.11, p = 0.7, Figures S5F–S5G′′′ and S5H). Monitoring the in vivo viral RNA genomic titer during the course of the infection also shows that SiR completely disappears (at a genomic level) from the infected neurons by 2 weeks p.i. (Figure 2H). Overall, these results show that the SiR^CRE-mCherry transcription-replication kinetics provides enough time to generate an early CRE recombination event (Figures S4D–S4D′′′) before the virus disappears (Figures 2D–2D′′′). It thereby ensures permanent genetic (CRE-mediated) access to the infected neurons without affecting their survival (Figures 2G and 2H).Figure 2Absence of Cytotoxicity In Vivo(A) SiR life cycle scheme.(B) SiR expression cassette and experimental procedure.(C–F′′′) Confocal images of hippocampal sections of Rosa-LoxP-STOP-LoxP-YFP mice infected with SiR^CRE-mCherry and imaged at 1 week (C–C′′′), 3 weeks (D–D′′′), 2 months (E–E′′′), and 6 months (F–F′′′) p.i. Scale bar, 25 μm.(G) Number of YFP and mCherry positive neurons at 1–3 weeks, 2 months, and 6 months p.i. normalized to 1 week time point (mean ± SEM, n = 3 animals per time point).(H) Levels of viral RNA (magenta) and endogenous YFP expression (cyan) normalized to 1 week RNA level (mean ± SEM, n = 3 animals per time point).See also Figures S4 and S5.Figure S4Short-Term SiR^CRE-mCherry Kinetics In Vivo, Related to Figure 2(A) SiR^CRE-mCherry cassette design. (B) SiR^CRE-mCherry injection in CA1 of Rosa-LoxP-STOP-LoxP-YFP mice. (C-E”’) Confocal images of CA1 pyramidal neurons infected with SiR^CRE-mCherry at 3, 6 and 9 days p.i. Scale bar: 25 μm. (F-F’’) Percentage of YFP^ON, mCherry^ON and YFP^ONmCherry^ON neurons at 3, 6 and 9 days p.i.Figure S5ΔG-Rabies Induced Mortality in Cortex and Hippocampus, Related to Figure 2(A-A’’) Confocal images of cortical neurons and (B-B’’) CA1 pyramidal neurons infected with ΔG-Rabies^GFP at 1, 2 and 3 weeks p.i. Scale bar: 50 μm. (C) Percentage of ΔG-Rabies infected neurons at 1, 2 or 3 weeks p.i. in cortex (black) or hippocampus (gray) normalized to 1 week time-point (mean ± SEM,) (hippocampus, 92% ± 3% cell death at 2 weeks, n = 3 animals per time-point, one-way ANOVA, F = 101, p = 2.4x10^−5; cortex 85 % ± 2% cell death at 3 weeks, n = 3 animals per time-point, one-way ANOVA, F = 17, p = 3.2x10^−3). Confocal images of ΔG-Rabies^GFP (D-E’’’) or SiR^CRE (F-G’’’) infected hippocampi of Rosa-LoxP-STOP-LoxP-YFP mice at 1 and 2 weeks p.i. stained for cleaved caspase-3 (cCaspase3) (arrowheads point to ΔG-Rab-cCaspase3 double positive neurons). Scale bar: 25 μm (H) Percentage of positive cCaspase3 neurons every 1000 neurons at 1 and 2 weeks p.i. in PBS, ΔG-Rabies or SiR infected hippocampi (mean ± SEM, n = 3 animals per time-point).',\n", + " 'paragraph_id': 5,\n", + " 'tokenizer': 'in, order, to, experimental, ##ly, assess, the, in, vivo, cy, ##to, ##to, ##xi, ##city, of, the, newly, generated, sir, ,, we, added, a, cr, ##e, rec, ##om, ##bina, ##se, and, a, des, ##ta, ##bil, ##ized, mc, ##her, ##ry, (, sir, ^, cr, ##e, -, mc, ##her, ##ry, ,, figure, 2, ##b, ), to, the, sir, genome, ., we, then, tested, sir, transcription, -, replication, kinetic, ##s, and, cy, ##to, ##to, ##xi, ##city, in, vivo, by, in, ##ject, ##ing, sir, ^, cr, ##e, -, mc, ##her, ##ry, in, the, ca, ##1, pyramid, ##al, layer, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, (, figure, 2, ##b, ), ., the, transient, expression, of, the, cr, ##e, rec, ##om, ##bina, ##se, driven, by, the, sir, should, be, adequate, to, ensure, a, permanent, rec, ##om, ##bina, ##tion, of, the, rosa, locus, and, con, ##se, ##quent, y, ##fp, expression, even, after, a, complete, transcription, ##al, shut, down, of, the, virus, (, figure, 2a, ), ., at, the, same, time, ,, the, des, ##ta, ##bil, ##ized, mc, ##her, ##ry, marks, the, presence, of, active, virus, with, high, temporal, resolution, ., indeed, ,, while, at, 3, days, post, infection, (, p, ., i, ., ), only, the, viral, ##ly, encoded, mc, ##her, ##ry, can, be, detected, (, figures, s, ##4, ##c, –, s, ##4, ##c, ′, ′, ′, and, s, ##4, ##f, ), ,, by, 6, days, p, ., i, ., the, viral, ##ly, encoded, cr, ##e, has, induced, rec, ##om, ##bina, ##tion, of, the, conditional, mouse, reporter, cassette, ,, triggering, the, expression, of, y, ##fp, in, all, infected, neurons, (, figures, s, ##4, ##d, –, s, ##4, ##d, ′, ′, ′, and, s, ##4, ##f, ′, ), ., in, order, to, exclude, any, sir, -, induced, cy, ##to, ##to, ##xi, ##city, ,, we, monitored, the, survival, of, sir, ^, cr, ##e, -, mc, ##her, ##ry, -, infected, ca, ##1, pyramid, ##al, neurons, over, a, 6, -, month, period, ., by, 3, weeks, p, ., i, ., ,, the, sir, had, completely, shut, down, (, 98, %, ±, 2, %, y, ##fp, ^, on, mc, ##her, ##ry, ^, off, ,, figures, 2d, –, 2d, ′, ′, ′, and, 2, ##g, ), and, ,, more, importantly, ,, no, significant, ne, ##uron, ##al, loss, was, observed, during, the, 6, -, month, period, following, sir, infection, (, one, -, way, an, ##ova, ,, f, =, 0, ., 12, ,, p, =, 0, ., 97, ,, figures, 2, ##f, –, 2, ##f, ′, ′, ′, and, 2, ##g, ), ., this, is, in, striking, contrast, with, what, is, observed, after, canonical, δ, ##g, -, ra, ##bies, infection, ,, in, which, the, majority, of, infected, neurons, in, the, hip, ##po, ##camp, ##us, die, within, 2, weeks, from, the, primary, infection, (, figures, s, ##5, ##a, –, s, ##5, ##c, ), ., we, further, confirmed, the, absence, of, sir, -, induced, cy, ##to, ##to, ##xi, ##c, effects, in, vivo, by, assessing, the, level, of, cas, ##pas, ##e, -, 3, activation, (, cc, ##as, ##pas, ##e, ##3, ), at, 1, and, 2, weeks, following, sir, infection, and, comparing, it, to, that, eli, ##cite, ##d, in, mock, -, injected, controls, ., the, results, indicate, no, significant, differences, between, sir, and, mock, -, injected, conditions, in, the, levels, of, cas, ##pas, ##e, -, 3, activation, (, one, -, way, an, ##ova, ,, f, =, 0, ., 11, ,, p, =, 0, ., 7, ,, figures, s, ##5, ##f, –, s, ##5, ##g, ′, ′, ′, and, s, ##5, ##h, ), ., monitoring, the, in, vivo, viral, rna, gen, ##omic, ti, ##ter, during, the, course, of, the, infection, also, shows, that, sir, completely, disappears, (, at, a, gen, ##omic, level, ), from, the, infected, neurons, by, 2, weeks, p, ., i, ., (, figure, 2, ##h, ), ., overall, ,, these, results, show, that, the, sir, ^, cr, ##e, -, mc, ##her, ##ry, transcription, -, replication, kinetic, ##s, provides, enough, time, to, generate, an, early, cr, ##e, rec, ##om, ##bina, ##tion, event, (, figures, s, ##4, ##d, –, s, ##4, ##d, ′, ′, ′, ), before, the, virus, disappears, (, figures, 2d, –, 2d, ′, ′, ′, ), ., it, thereby, ensures, permanent, genetic, (, cr, ##e, -, mediated, ), access, to, the, infected, neurons, without, affecting, their, survival, (, figures, 2, ##g, and, 2, ##h, ), ., figure, 2a, ##bs, ##ence, of, cy, ##to, ##to, ##xi, ##city, in, vivo, (, a, ), sir, life, cycle, scheme, ., (, b, ), sir, expression, cassette, and, experimental, procedure, ., (, c, –, f, ′, ′, ′, ), con, ##fo, ##cal, images, of, hip, ##po, ##camp, ##al, sections, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, infected, with, sir, ^, cr, ##e, -, mc, ##her, ##ry, and, image, ##d, at, 1, week, (, c, –, c, ′, ′, ′, ), ,, 3, weeks, (, d, –, d, ′, ′, ′, ), ,, 2, months, (, e, –, e, ′, ′, ′, ), ,, and, 6, months, (, f, –, f, ′, ′, ′, ), p, ., i, ., scale, bar, ,, 25, μ, ##m, ., (, g, ), number, of, y, ##fp, and, mc, ##her, ##ry, positive, neurons, at, 1, –, 3, weeks, ,, 2, months, ,, and, 6, months, p, ., i, ., normal, ##ized, to, 1, week, time, point, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), ., (, h, ), levels, of, viral, rna, (, mage, ##nta, ), and, end, ##ogen, ##ous, y, ##fp, expression, (, cy, ##an, ), normal, ##ized, to, 1, week, rna, level, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), ., see, also, figures, s, ##4, and, s, ##5, ., figure, s, ##4, ##sho, ##rt, -, term, sir, ^, cr, ##e, -, mc, ##her, ##ry, kinetic, ##s, in, vivo, ,, related, to, figure, 2, (, a, ), sir, ^, cr, ##e, -, mc, ##her, ##ry, cassette, design, ., (, b, ), sir, ^, cr, ##e, -, mc, ##her, ##ry, injection, in, ca, ##1, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, ., (, c, -, e, ”, ’, ), con, ##fo, ##cal, images, of, ca, ##1, pyramid, ##al, neurons, infected, with, sir, ^, cr, ##e, -, mc, ##her, ##ry, at, 3, ,, 6, and, 9, days, p, ., i, ., scale, bar, :, 25, μ, ##m, ., (, f, -, f, ’, ’, ), percentage, of, y, ##fp, ^, on, ,, mc, ##her, ##ry, ^, on, and, y, ##fp, ^, on, ##mc, ##her, ##ry, ^, on, neurons, at, 3, ,, 6, and, 9, days, p, ., i, ., figure, s, ##5, ##δ, ##g, -, ra, ##bies, induced, mortality, in, cortex, and, hip, ##po, ##camp, ##us, ,, related, to, figure, 2, (, a, -, a, ’, ’, ), con, ##fo, ##cal, images, of, co, ##rti, ##cal, neurons, and, (, b, -, b, ’, ’, ), ca, ##1, pyramid, ##al, neurons, infected, with, δ, ##g, -, ra, ##bies, ^, g, ##fp, at, 1, ,, 2, and, 3, weeks, p, ., i, ., scale, bar, :, 50, μ, ##m, ., (, c, ), percentage, of, δ, ##g, -, ra, ##bies, infected, neurons, at, 1, ,, 2, or, 3, weeks, p, ., i, ., in, cortex, (, black, ), or, hip, ##po, ##camp, ##us, (, gray, ), normal, ##ized, to, 1, week, time, -, point, (, mean, ±, se, ##m, ,, ), (, hip, ##po, ##camp, ##us, ,, 92, %, ±, 3, %, cell, death, at, 2, weeks, ,, n, =, 3, animals, per, time, -, point, ,, one, -, way, an, ##ova, ,, f, =, 101, ,, p, =, 2, ., 4, ##x, ##10, ^, −, ##5, ;, cortex, 85, %, ±, 2, %, cell, death, at, 3, weeks, ,, n, =, 3, animals, per, time, -, point, ,, one, -, way, an, ##ova, ,, f, =, 17, ,, p, =, 3, ., 2, ##x, ##10, ^, −, ##3, ), ., con, ##fo, ##cal, images, of, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, d, -, e, ’, ’, ’, ), or, sir, ^, cr, ##e, (, f, -, g, ’, ’, ’, ), infected, hip, ##po, ##camp, ##i, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, at, 1, and, 2, weeks, p, ., i, ., stained, for, cl, ##ea, ##ved, cas, ##pas, ##e, -, 3, (, cc, ##as, ##pas, ##e, ##3, ), (, arrow, ##heads, point, to, δ, ##g, -, ra, ##b, -, cc, ##as, ##pas, ##e, ##3, double, positive, neurons, ), ., scale, bar, :, 25, μ, ##m, (, h, ), percentage, of, positive, cc, ##as, ##pas, ##e, ##3, neurons, every, 1000, neurons, at, 1, and, 2, weeks, p, ., i, ., in, pbs, ,, δ, ##g, -, ra, ##bies, or, sir, infected, hip, ##po, ##camp, ##i, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, -, point, ), .'},\n", + " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", + " 'section_name': 'Key Resources 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structures, such as the amygdala and hypothalamus, have been proposed to provide executive control and coordinate goal-driven social behaviors in humans (Insel and Fernald, 2004); however, only a few reports have suggested a link between PFC activity and abnormal social behaviors in rodents (Yizhar, 2012; Wang et al., 2014; Figure 1). Moreover, the computational representations by which the mPFC communicates and facilitates the selective coupling of relevant information in downstream subcortical areas have not been systematically investigated in rodents. On a more detailed level, evidence for a causal link between cell type-specific activity and synchronous brain activity in social behavior is generally lacking. Several transgenic mouse lines carrying mutations in genes associated with social neuropsychiatric diseases have been reported to exhibit altered synaptic transmission (Silverman et al., 2010). Yet, molecular, biochemical, and electrophysiological abnormalities in these transgenic mice are quite divergent and not restricted to the PFC alone (Silverman et al., 2010). Therefore, it remains unclear as to whether local alterations in the excitation/inhibition ratio (E/I) and functional desynchronization between different cell types in the mPFC directly causes abnormal social cognition (see Kim et al., 2016 for an alternative perspective). Nevertheless, a partial correlation between mPFC activity and a subset of social behavior-related neuropsychiatric disorders in humans has led to the hypothesis that E/I balance in mPFC circuits may be critical for normal social behavior (Yizhar, 2012; Bicks et al., 2015). For example, using a three-chamber behavioral paradigm that assesses social cognition in the form of general sociability and preference for social novelty, researchers showed that a subset of mPFC neurons exhibited elevated discharge rates while mice approached an unfamiliar mouse, but not when mice approached an inanimate object or empty chamber (Kaidanovich-Beilin et al., 2011); these observations are consistent with the idea that neural activity in the mPFC correlates with social-approach behavior in mice (Lee et al., 2016). mPFC neurons have also been reported to exhibit functional asymmetry between hemispheres in mice, such that the right mPFC was reported to control the acquisition of stress during hazardous experiences while the left mPFC was found to play a dominant role in translating stress into social behavior (Lee et al., 2016). Additionally, knockdown of phospholipase C-β1 in the mPFC impairs social interactions, whereas chronic deletion of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in the mPFC increases social approach behavior without affecting social novelty preference in mice (Finlay et al., 2015; Kim S. W. et al., 2015). NMDA-NR1 dysfunction in the CA3 region of the hippocampus is also sufficient to impair social approach, suggesting that social interaction can be differentially modulated by distinct alterations in a relevant circuit (Finlay et al., 2015). Yet, the positive correlation between mPFC activity and social behavior is not robust to different manipulations of mPFC activity in rodents. Neuroligin-2 is an inhibitory synapse-specific cell-adhesion molecule that was recently implicated in synaptic inhibition in the mPFC. Conditional deletion of the Nlgn2 gene in mice produced a gradual deterioration in inhibitory synapse structure and transmission, suggesting that neuroligin-2 is essential for the long-term maintenance and reconfiguration of inhibitory synapses in the mPFC (Liang et al., 2015). Moreover, neuroligin-2-knockout (KO) mice exhibit behavioral abnormalities that are partially correlated with electrophysiological phenotypes at 6–7 weeks but not at 2–3 weeks after gene inactivation (Liang et al., 2015). As a possible explanation for this observation, the authors hypothesized that the behavioral phenotype was produced by dysfunction of a peculiarly plastic subpopulation of inhibitory synapses in neuroligin-2-KO mice (Liang et al., 2015). These studies illustrate the idea that various synaptic signaling and adhesion pathways operating in the mPFC contribute to the initiation, maintenance, and/or modulation of social behaviors. A general goal of future studies should be to establish how common social behavioral impairments in various transgenic mice are related on molecular and synaptic levels. In particular, the optogenetic manipulation of mPFC neurons using the recently engineered Stabilized Step-Function Opsins can help to identify the circuit and synaptic mechanisms that underpin mPFC interactions with specific, distant subcortical regions to regulate various social behaviors (Yizhar et al., 2011; Riga et al., 2014; Ferenczi et al., 2016).',\n", + " 'paragraph_id': 6,\n", + " 'tokenizer': 'top, -, down, p, ##fc, projections, to, sub, ##cor, ##tical, structures, ,, such, as, the, amy, ##g, ##dal, ##a, and, h, ##yp, ##oth, ##ala, ##mus, ,, have, been, proposed, to, provide, executive, control, and, coordinate, goal, -, driven, social, behaviors, in, humans, (, ins, ##el, and, fern, ##ald, ,, 2004, ), ;, however, ,, only, a, few, reports, have, suggested, a, link, between, p, ##fc, activity, and, abnormal, social, behaviors, in, rodents, (, yi, ##zh, ##ar, ,, 2012, ;, wang, et, al, ., ,, 2014, ;, figure, 1, ), ., moreover, ,, the, computational, representations, by, which, the, mp, ##fc, communicate, ##s, and, facilitates, the, selective, coupling, of, relevant, information, in, downstream, sub, ##cor, ##tical, areas, have, not, been, systematically, investigated, in, rodents, ., on, a, more, detailed, level, ,, evidence, for, a, causal, link, between, cell, type, -, specific, activity, and, sync, ##hr, ##ono, ##us, brain, activity, in, social, behavior, is, generally, lacking, ., several, trans, ##genic, mouse, lines, carrying, mutations, in, genes, associated, with, social, ne, ##uro, ##psy, ##chia, ##tric, diseases, have, been, reported, to, exhibit, altered, syn, ##ap, ##tic, transmission, (, silver, ##man, et, al, ., ,, 2010, ), ., yet, ,, molecular, ,, bio, ##chemical, ,, and, electro, ##phy, ##sio, ##logical, abnormalities, in, these, trans, ##genic, mice, are, quite, diver, ##gent, and, not, restricted, to, the, p, ##fc, alone, (, silver, ##man, et, al, ., ,, 2010, ), ., therefore, ,, it, remains, unclear, as, to, whether, local, alterations, in, the, ex, ##cit, ##ation, /, inhibition, ratio, (, e, /, i, ), and, functional, des, ##yn, ##ch, ##ron, ##ization, between, different, cell, types, in, the, mp, ##fc, directly, causes, abnormal, social, cognition, (, see, kim, et, al, ., ,, 2016, for, an, alternative, perspective, ), ., nevertheless, ,, a, partial, correlation, between, mp, ##fc, activity, and, a, subset, of, social, behavior, -, related, ne, ##uro, ##psy, ##chia, ##tric, disorders, in, humans, has, led, to, the, hypothesis, that, e, /, i, balance, in, mp, ##fc, circuits, may, be, critical, for, normal, social, behavior, (, yi, ##zh, ##ar, ,, 2012, ;, bi, ##cks, et, al, ., ,, 2015, ), ., for, example, ,, using, a, three, -, chamber, behavioral, paradigm, that, assess, ##es, social, cognition, in, the, form, of, general, soc, ##ia, ##bility, and, preference, for, social, novelty, ,, researchers, showed, that, a, subset, of, mp, ##fc, neurons, exhibited, elevated, discharge, rates, while, mice, approached, an, unfamiliar, mouse, ,, but, not, when, mice, approached, an, ina, ##ni, ##mate, object, or, empty, chamber, (, kai, ##dan, ##ovich, -, bei, ##lin, et, al, ., ,, 2011, ), ;, these, observations, are, consistent, with, the, idea, that, neural, activity, in, the, mp, ##fc, co, ##rre, ##lates, with, social, -, approach, behavior, in, mice, (, lee, et, al, ., ,, 2016, ), ., mp, ##fc, neurons, have, also, been, reported, to, exhibit, functional, as, ##ym, ##metry, between, hemisphere, ##s, in, mice, ,, such, that, the, right, mp, ##fc, was, reported, to, control, the, acquisition, of, stress, during, hazardous, experiences, while, the, left, mp, ##fc, was, found, to, play, a, dominant, role, in, translating, stress, into, social, behavior, (, lee, et, al, ., ,, 2016, ), ., additionally, ,, knock, ##down, of, ph, ##os, ##ph, ##oli, ##pas, ##e, c, -, β, ##1, in, the, mp, ##fc, imp, ##air, ##s, social, interactions, ,, whereas, chronic, del, ##eti, ##on, of, the, nr, ##1, subunit, of, the, n, -, methyl, -, d, -, as, ##par, ##tate, (, nm, ##da, ), receptor, in, the, mp, ##fc, increases, social, approach, behavior, without, affecting, social, novelty, preference, in, mice, (, fin, ##lay, et, al, ., ,, 2015, ;, kim, s, ., w, ., et, al, ., ,, 2015, ), ., nm, ##da, -, nr, ##1, dysfunction, in, the, ca, ##3, region, of, the, hip, ##po, ##camp, ##us, is, also, sufficient, to, imp, ##air, social, approach, ,, suggesting, that, social, interaction, can, be, differential, ##ly, mod, ##ulated, by, distinct, alterations, in, a, relevant, circuit, (, fin, ##lay, et, al, ., ,, 2015, ), ., yet, ,, the, positive, correlation, between, mp, ##fc, activity, and, social, behavior, is, not, robust, to, different, manipulation, ##s, of, mp, ##fc, activity, in, rodents, ., ne, ##uro, ##li, ##gin, -, 2, is, an, inhibitor, ##y, syn, ##ap, ##se, -, specific, cell, -, ad, ##hesion, molecule, that, was, recently, implicated, in, syn, ##ap, ##tic, inhibition, in, the, mp, ##fc, ., conditional, del, ##eti, ##on, of, the, nl, ##gn, ##2, gene, in, mice, produced, a, gradual, deterioration, in, inhibitor, ##y, syn, ##ap, ##se, structure, and, transmission, ,, suggesting, that, ne, ##uro, ##li, ##gin, -, 2, is, essential, for, the, long, -, term, maintenance, and, rec, ##on, ##fi, ##gur, ##ation, of, inhibitor, ##y, syn, ##ap, ##ses, in, the, mp, ##fc, (, liang, et, al, ., ,, 2015, ), ., moreover, ,, ne, ##uro, ##li, ##gin, -, 2, -, knockout, (, ko, ), mice, exhibit, behavioral, abnormalities, that, are, partially, correlated, with, electro, ##phy, ##sio, ##logical, ph, ##eno, ##type, ##s, at, 6, –, 7, weeks, but, not, at, 2, –, 3, weeks, after, gene, ina, ##ct, ##ivation, (, liang, et, al, ., ,, 2015, ), ., as, a, possible, explanation, for, this, observation, ,, the, authors, h, ##yp, ##oth, ##es, ##ized, that, the, behavioral, ph, ##eno, ##type, was, produced, by, dysfunction, of, a, peculiar, ##ly, plastic, sub, ##pop, ##ulation, of, inhibitor, ##y, syn, ##ap, ##ses, in, ne, ##uro, ##li, ##gin, -, 2, -, ko, mice, (, liang, et, al, ., ,, 2015, ), ., these, studies, illustrate, the, idea, that, various, syn, ##ap, ##tic, signaling, and, ad, ##hesion, pathways, operating, in, the, mp, ##fc, contribute, to, the, initiation, ,, maintenance, ,, and, /, or, modulation, of, social, behaviors, ., a, general, goal, of, future, studies, should, be, to, establish, how, common, social, behavioral, impairment, ##s, in, various, trans, ##genic, mice, are, related, on, molecular, and, syn, ##ap, ##tic, levels, ., in, particular, ,, the, opt, ##ogen, ##etic, manipulation, of, mp, ##fc, neurons, using, the, recently, engineered, stabilized, step, -, function, ops, ##ins, can, help, to, identify, the, circuit, and, syn, ##ap, ##tic, mechanisms, that, under, ##pin, mp, ##fc, interactions, with, specific, ,, distant, sub, ##cor, ##tical, regions, to, regulate, various, social, behaviors, (, yi, ##zh, ##ar, et, al, ., ,, 2011, ;, riga, et, al, ., ,, 2014, ;, fe, ##ren, ##cz, ##i, et, al, ., ,, 2016, ), .'},\n", + " {'article_id': '92c9d75c6098986f4d7327dbd4712b4d',\n", + " 'section_name': '4. Impairment of NGF/TrkA Signaling Triggers an Early Activation of “a Dying-Back” Process of Degeneration of Cholinergic Neurons',\n", + " 'text': 'Synaptic dysfunction is an early event in AD pathogenesis and is directly related to progressive cognitive impairment [89,90]. A large body of evidence indicates that neurons affected in AD follow a “dying-back pattern” of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death [91]. In fact, the early cognitive deficits occur during the AD progression in parallel with cortical synaptic loss [92,93,94,95] and are subsequently followed by death and/or atrophy of BFCN. The latter more directly accounts for the full-blown clinical symptoms of the disorder [38,96,97,98,99,100]. In view of the notion that, the synaptic density correlates more closely with memory/learning impairment than any other pathological lesion observable in the AD neuropathology [101] and that dysfunction of NGF/TkA signaling underlies the selective degeneration of cortical cholinergic projecting neurons in AD pathogenesis [29], septal primary cultures have been recently employed by our research group with the intent of analyzing the NGF activity and consequences, at the synaptic level, of its in vitro withdrawal. In order to sensitize primary neurons to the following removal of trophic factor, we have recently developed a novel culturing procedure whereby pretreatment (10 DIV) with NGF in the presence of low 0.2% B27 nutrients, selectively enriches (+36%) NGF-responsive forebrain cholinergic neurons at the expense of all other non-cholinergic resident populations, such as GABAergic (~38%) and glutamatergic (~56%) [102]. This simple, less expensive but valuable method allows a consistent and fully mature cholinergic population to be obtained, as demonstrated by biochemical, morphological, and electrophysiological approaches. In fact, this culturing procedure can actually represent an important achievement in the research of AD neuropathology since the yield in cholinergic neurons following the classical culture protocols is lower [103,104,105,106]. By taking advantage of this newly-established in vitro neuronal paradigm, we revealed that the NGF withdrawal induces a progressive deficit in the presynaptic excitatory neurotransmission which occurs in concomitance with a pronounced and time-dependent reduction in several distinct pre-synaptic markers, such as synapsin I, SNAP-25, and α-synuclein, and in the absence of any sign of neuronal death. This rapid presynaptic dysfunction: (i) is reversible in a time-dependent manner, being suppressed by de novo external administration of NGF within six hours from its initial withdrawal; (ii) is specific, since it is not accompanied by contextual changes in expression levels of non-synaptic proteins from other subcellular compartments including specific markers of endoplasmic reticulum and mitochondria such as calnexin, VDAC, and Tom20; (iii) is not secondary to axonal degeneration, because it precedes the post-translational modifications of tubulin subunits critically controlling the cytoskeleton dynamics and is insensible to pharmacological treatment with known microtubule-stabilizing drug such paclitaxel; (iv) involves TrkA-dependent mechanisms because the effects of NGF re-application are blocked by acute exposure to a specific and cell-permeable inhibitor of TrkA receptor. In addition, in line with previous findings reporting a modulatory effect of NGF signaling on APP expression [39,107], a significant upregulation in expression of three APP isoforms of ~110 kDa, ~120 kDa, and ~130 kDa along with marked increase in the immunoreactivity level of the carboxyl-terminal CTFβ fragment of 14 kDa, are detected in primary septal neurons upon 24–48 h of neurotrophin starvation, indicating that the APP metabolism is also greatly influenced following NGF withdrawal in this novel AD-like neuronal paradigm. These results clearly demonstrate that the combined modulatory actions of NGF on the expression of important pre-synaptic proteins and neurosecretory function(s) of in vitro cholinergic septal primary neurons are directly and causally linked via the stimulation of NGF/TrkA signaling. These findings point out the pathological relevance of the lack of NGF availability in the earliest synaptic deficits occurring at the onset of AD progression [102]. Taken together, these findings: (i) provide a valuable in vitro tool to better investigate the survival/disease changes of basal forebrain septo-hippocampal projecting neurons occurring during the prodromal stages of AD pathology caused by dysfunction in NGF/TrkA signaling; (ii) demonstrate that NGF withdrawal induces neurodegenerative changes initiated by early, selective, and reversible presynaptic dysfunction in cholinergic neurons, just resembling the synapses loss and retrograde “dying-back” axonal degeneration appearing at prodromal stages of AD pathology in correlation with incipient memory dysfunction [46,108,109,110]; (iii) have potential, important clinical implications in the field of therapeutical in vivo NGF delivery in humans, because it not only constitutes a molecular rationale for the existence of its limited therapeutic time window, but also offers a prime useful presynaptic-based target with the intent of extending its neuroprotective action in AD intervention.',\n", + " 'paragraph_id': 13,\n", + " 'tokenizer': 'syn, ##ap, ##tic, dysfunction, is, an, early, event, in, ad, pathogen, ##esis, and, is, directly, related, to, progressive, cognitive, impairment, [, 89, ,, 90, ], ., a, large, body, of, evidence, indicates, that, neurons, affected, in, ad, follow, a, “, dying, -, back, pattern, ”, of, de, ##gen, ##eration, ,, where, abnormalities, in, syn, ##ap, ##tic, function, and, ax, ##onal, connectivity, long, pre, ##cede, so, ##matic, cell, death, [, 91, ], ., in, fact, ,, the, early, cognitive, deficit, ##s, occur, during, the, ad, progression, in, parallel, with, co, ##rti, ##cal, syn, ##ap, ##tic, loss, [, 92, ,, 93, ,, 94, ,, 95, ], and, are, subsequently, followed, by, death, and, /, or, at, ##rop, ##hy, of, bf, ##c, ##n, ., the, latter, more, directly, accounts, for, the, full, -, blown, clinical, symptoms, of, the, disorder, [, 38, ,, 96, ,, 97, ,, 98, ,, 99, ,, 100, ], ., in, view, of, the, notion, that, ,, the, syn, ##ap, ##tic, density, co, ##rre, ##lates, more, closely, with, memory, /, learning, impairment, than, any, other, path, ##ological, les, ##ion, ob, ##ser, ##vable, in, the, ad, ne, ##uro, ##path, ##ology, [, 101, ], and, that, dysfunction, of, ng, ##f, /, t, ##ka, signaling, under, ##lies, the, selective, de, ##gen, ##eration, of, co, ##rti, ##cal, cho, ##liner, ##gic, projecting, neurons, in, ad, pathogen, ##esis, [, 29, ], ,, sept, ##al, primary, cultures, have, been, recently, employed, by, our, research, group, with, the, intent, of, analyzing, the, ng, ##f, activity, and, consequences, ,, at, the, syn, ##ap, ##tic, level, ,, of, its, in, vitro, withdrawal, ., in, order, to, sen, ##sit, ##ize, primary, neurons, to, the, following, removal, of, tr, ##op, ##hic, factor, ,, we, have, recently, developed, a, novel, cult, ##uring, procedure, whereby, pre, ##tre, ##at, ##ment, (, 10, di, ##v, ), with, ng, ##f, in, the, presence, of, low, 0, ., 2, %, b, ##27, nutrients, ,, selective, ##ly, en, ##rich, ##es, (, +, 36, %, ), ng, ##f, -, responsive, fore, ##bra, ##in, cho, ##liner, ##gic, neurons, at, the, expense, of, all, other, non, -, cho, ##liner, ##gic, resident, populations, ,, such, as, ga, ##ba, ##er, ##gic, (, ~, 38, %, ), and, g, ##lu, ##tama, ##ter, ##gic, (, ~, 56, %, ), [, 102, ], ., this, simple, ,, less, expensive, but, valuable, method, allows, a, consistent, and, fully, mature, cho, ##liner, ##gic, population, to, be, obtained, ,, as, demonstrated, by, bio, ##chemical, ,, morphological, ,, and, electro, ##phy, ##sio, ##logical, approaches, ., in, fact, ,, this, cult, ##uring, procedure, can, actually, represent, an, important, achievement, in, the, research, of, ad, ne, ##uro, ##path, ##ology, since, the, yield, in, cho, ##liner, ##gic, neurons, following, the, classical, culture, protocols, is, lower, [, 103, ,, 104, ,, 105, ,, 106, ], ., by, taking, advantage, of, this, newly, -, established, in, vitro, ne, ##uron, ##al, paradigm, ,, we, revealed, that, the, ng, ##f, withdrawal, induce, ##s, a, progressive, deficit, in, the, pre, ##sy, ##na, ##ptic, ex, ##cit, ##atory, ne, ##uro, ##tra, ##ns, ##mission, which, occurs, in, con, ##com, ##itan, ##ce, with, a, pronounced, and, time, -, dependent, reduction, in, several, distinct, pre, -, syn, ##ap, ##tic, markers, ,, such, as, syn, ##ap, ##sin, i, ,, snap, -, 25, ,, and, α, -, syn, ##uc, ##lein, ,, and, in, the, absence, of, any, sign, of, ne, ##uron, ##al, death, ., this, rapid, pre, ##sy, ##na, ##ptic, dysfunction, :, (, i, ), is, rev, ##ers, ##ible, in, a, time, -, dependent, manner, ,, being, suppressed, by, de, novo, external, administration, of, ng, ##f, within, six, hours, from, its, initial, withdrawal, ;, (, ii, ), is, specific, ,, since, it, is, not, accompanied, by, context, ##ual, changes, in, expression, levels, of, non, -, syn, ##ap, ##tic, proteins, from, other, sub, ##cellular, compartments, including, specific, markers, of, end, ##op, ##las, ##mic, re, ##tic, ##ulum, and, mit, ##och, ##ond, ##ria, such, as, cal, ##ne, ##xin, ,, v, ##da, ##c, ,, and, tom, ##20, ;, (, iii, ), is, not, secondary, to, ax, ##onal, de, ##gen, ##eration, ,, because, it, pre, ##cede, ##s, the, post, -, translation, ##al, modifications, of, tub, ##ulin, subunit, ##s, critically, controlling, the, cy, ##tos, ##kel, ##eto, ##n, dynamics, and, is, ins, ##ens, ##ible, to, ph, ##arm, ##aco, ##logical, treatment, with, known, micro, ##tub, ##ule, -, stab, ##ili, ##zing, drug, such, pac, ##lita, ##x, ##el, ;, (, iv, ), involves, tr, ##ka, -, dependent, mechanisms, because, the, effects, of, ng, ##f, re, -, application, are, blocked, by, acute, exposure, to, a, specific, and, cell, -, per, ##me, ##able, inhibitor, of, tr, ##ka, receptor, ., in, addition, ,, in, line, with, previous, findings, reporting, a, mod, ##ulator, ##y, effect, of, ng, ##f, signaling, on, app, expression, [, 39, ,, 107, ], ,, a, significant, up, ##re, ##gul, ##ation, in, expression, of, three, app, iso, ##forms, of, ~, 110, k, ##da, ,, ~, 120, k, ##da, ,, and, ~, 130, k, ##da, along, with, marked, increase, in, the, im, ##mun, ##ore, ##act, ##ivity, level, of, the, car, ##box, ##yl, -, terminal, ct, ##f, ##β, fragment, of, 14, k, ##da, ,, are, detected, in, primary, sept, ##al, neurons, upon, 24, –, 48, h, of, ne, ##uro, ##tro, ##phi, ##n, starvation, ,, indicating, that, the, app, metabolism, is, also, greatly, influenced, following, ng, ##f, withdrawal, in, this, novel, ad, -, like, ne, ##uron, ##al, paradigm, ., these, results, clearly, demonstrate, that, the, combined, mod, ##ulator, ##y, actions, of, ng, ##f, on, the, expression, of, important, pre, -, syn, ##ap, ##tic, proteins, and, ne, ##uro, ##se, ##cre, ##tory, function, (, s, ), of, in, vitro, cho, ##liner, ##gic, sept, ##al, primary, neurons, are, directly, and, causal, ##ly, linked, via, the, stimulation, of, ng, ##f, /, tr, ##ka, signaling, ., these, findings, point, out, the, path, ##ological, relevance, of, the, lack, of, ng, ##f, availability, in, the, earliest, syn, ##ap, ##tic, deficit, ##s, occurring, at, the, onset, of, ad, progression, [, 102, ], ., taken, together, ,, these, findings, :, (, i, ), provide, a, valuable, in, vitro, tool, to, better, investigate, the, survival, /, disease, changes, of, basal, fore, ##bra, ##in, sept, ##o, -, hip, ##po, ##camp, ##al, projecting, neurons, occurring, during, the, pro, ##dro, ##mal, stages, of, ad, pathology, caused, by, dysfunction, in, ng, ##f, /, tr, ##ka, signaling, ;, (, ii, ), demonstrate, that, ng, ##f, withdrawal, induce, ##s, ne, ##uro, ##de, ##gen, ##erative, changes, initiated, by, early, ,, selective, ,, and, rev, ##ers, ##ible, pre, ##sy, ##na, ##ptic, dysfunction, in, cho, ##liner, ##gic, neurons, ,, just, resembling, the, syn, ##ap, ##ses, loss, and, retro, ##grade, “, dying, -, back, ”, ax, ##onal, de, ##gen, ##eration, appearing, at, pro, ##dro, ##mal, stages, of, ad, pathology, in, correlation, with, inc, ##ip, ##ient, memory, dysfunction, [, 46, ,, 108, ,, 109, ,, 110, ], ;, (, iii, ), have, potential, ,, important, clinical, implications, in, the, field, of, therapeutic, ##al, in, vivo, ng, ##f, delivery, in, humans, ,, because, it, not, only, constitutes, a, molecular, rational, ##e, for, the, existence, of, its, limited, therapeutic, time, window, ,, but, also, offers, a, prime, useful, pre, ##sy, ##na, ##ptic, -, based, target, with, the, intent, of, extending, its, ne, ##uro, ##pro, ##tec, ##tive, action, in, ad, intervention, .'},\n", + " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", + " 'section_name': 'SiR Transsynaptic Spreading Capabilities',\n", + " 'text': 'For its use in long-term functional investigations of neural networks, it is key that the SiR retains the ability to spread transsynaptically. Therefore, we assessed the spreading capabilities of SiR and compared it to the canonical B19 ΔG-rabies in both cortical and subcortical circuits. In order to test this, we first injected the nucleus accumbens (NAc) bilaterally with an AAV expressing TVA and the newly developed optimized rabies glycoprotein (oG) (Figure 4A), which has been shown to enhance rabies virus spreading (Kim et al., 2016). The expression of TVA permits selective infection of the starting cells in the NAc by an EnvA pseudotyped SiR, while the expression of oG allows its transsynaptic retrograde spread (Kim et al., 2016, Wickersham et al., 2007b). Then, we re-targeted the NAc in the two hemispheres with either SiR or ΔG-rabies EnvA-pseudotyped viruses. In agreement with the known connectivity of this area (Russo and Nestler, 2013), we identified transsynaptically labeled neurons in various cortical and subcortical regions, including the basolateral amygdala (BLA) and ventral tegmental area (VTA). We focused on these two areas to quantify spreading efficiency. At 1 week p.i., we observed no significant difference in the spreading capabilities between SiR and the canonical B19 ΔG-rabies (Figures 4A, 4B, 4D, 4D′, 4F, 4F′, and 4I; one-way ANOVA, F = 0.03, p = 0.96), indicating that the self-inactivating nature of the SiR does not affect its ability to spread efficiently. Moreover, as expected, by 3 weeks p.i., we observed a decrease in the number of transsynaptically labeled neurons upon B19 ΔG-rabies infection due to neuronal loss, while no changes upon SiR infection were detected (Figures 4C, 4E, 4E′, and 4G–4H; B19 ΔG-rabies, one-way ANOVA, F = 43, p = 6 × 10^−5; SiR, one-way ANOVA, F = 0.03, p = 0.96).Figure 4SiR Transsynaptic and Intraneuronal Retrograde Spread(A) Diagram of the injection procedure for the transsynaptic spread from the nucleus accumbens (NAc).(B and C) Spreading at 1 week (B) and 3 weeks p.i. (C) of B19 ΔG-rabies (cyan) and SiR (magenta). Scale bar, 1,000 μm.(D–E′) Transsynaptically labeled neurons in basolateral amygdala (BLA) at 1 week (D and D′) and 3 weeks p.i. (E and E′) with SiR (D and E, magenta) and ΔG-rabies (D′ and E ′, cyan). Scale bar, 50 μm.(F–G′) Transsynaptically labeled neurons in ventral tegmental area (VTA) at 1 week (F and F′) and 3 weeks p.i. (G and G′) with SiR (D and E, magenta) and ΔG-rabies (D′ and E′, cyan).(H) Number of SiR or ΔG-rabies positive neurons at 1 and 3 weeks p.i. in BLA and VTA normalized to 1 week time points (mean ± SEM, n = 3 animals per time point).(I) Efficiency of spreading at 1 week p.i. as number of inputs normalized to number of starting cells, and of SiR and ΔG-rabies in BLA and VTA (SiR = 1, mean ± SEM, n = 3 animals).(J) Scheme of retrograde intraneuronal spreading from VTA.(K–M′′) Retrogradely labeled neurons with SiR and rAAV2-retro (SiR, magenta; rAAV2-retro, cyan) in medial prefrontal cortex (mPFC) (K–K′′), lateral hypothalamus (LH) (L–L′′), and NAc (M–M′′).(N) Number of SiR- and rAAV2-retro-infected neurons in NAc, LH, and PFC (mean ± SEM, n = 3 animals) Scale bars, 1,000 μm (K–M); 50 μm (K′, K′′, L′, L′′, M′, and M′′).See also Figure S6.',\n", + " 'paragraph_id': 8,\n", + " 'tokenizer': 'for, its, use, in, long, -, term, functional, investigations, of, neural, networks, ,, it, is, key, that, the, sir, retains, the, ability, to, spread, trans, ##sy, ##na, ##ptic, ##ally, ., therefore, ,, we, assessed, the, spreading, capabilities, of, sir, and, compared, it, to, the, canonical, b1, ##9, δ, ##g, -, ra, ##bies, in, both, co, ##rti, ##cal, and, sub, ##cor, ##tical, circuits, ., in, order, to, test, this, ,, we, first, injected, the, nucleus, acc, ##umb, ##ens, (, na, ##c, ), bilateral, ##ly, with, an, aa, ##v, expressing, tv, ##a, and, the, newly, developed, opt, ##imi, ##zed, ra, ##bies, g, ##ly, ##co, ##pro, ##tein, (, og, ), (, figure, 4a, ), ,, which, has, been, shown, to, enhance, ra, ##bies, virus, spreading, (, kim, et, al, ., ,, 2016, ), ., the, expression, of, tv, ##a, permits, selective, infection, of, the, starting, cells, in, the, na, ##c, by, an, en, ##va, pseudo, ##type, ##d, sir, ,, while, the, expression, of, og, allows, its, trans, ##sy, ##na, ##ptic, retro, ##grade, spread, (, kim, et, al, ., ,, 2016, ,, wi, ##cker, ##sham, et, al, ., ,, 2007, ##b, ), ., then, ,, we, re, -, targeted, the, na, ##c, in, the, two, hemisphere, ##s, with, either, sir, or, δ, ##g, -, ra, ##bies, en, ##va, -, pseudo, ##type, ##d, viruses, ., in, agreement, with, the, known, connectivity, of, this, area, (, russo, and, nest, ##ler, ,, 2013, ), ,, we, identified, trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, in, various, co, ##rti, ##cal, and, sub, ##cor, ##tical, regions, ,, including, the, bas, ##olate, ##ral, amy, ##g, ##dal, ##a, (, b, ##la, ), and, ventral, te, ##gm, ##ental, area, (, vt, ##a, ), ., we, focused, on, these, two, areas, to, quan, ##tify, spreading, efficiency, ., at, 1, week, p, ., i, ., ,, we, observed, no, significant, difference, in, the, spreading, capabilities, between, sir, and, the, canonical, b1, ##9, δ, ##g, -, ra, ##bies, (, figures, 4a, ,, 4, ##b, ,, 4, ##d, ,, 4, ##d, ′, ,, 4, ##f, ,, 4, ##f, ′, ,, and, 4, ##i, ;, one, -, way, an, ##ova, ,, f, =, 0, ., 03, ,, p, =, 0, ., 96, ), ,, indicating, that, the, self, -, ina, ##ct, ##ivating, nature, of, the, sir, does, not, affect, its, ability, to, spread, efficiently, ., moreover, ,, as, expected, ,, by, 3, weeks, p, ., i, ., ,, we, observed, a, decrease, in, the, number, of, trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, upon, b1, ##9, δ, ##g, -, ra, ##bies, infection, due, to, ne, ##uron, ##al, loss, ,, while, no, changes, upon, sir, infection, were, detected, (, figures, 4, ##c, ,, 4, ##e, ,, 4, ##e, ′, ,, and, 4, ##g, –, 4, ##h, ;, b1, ##9, δ, ##g, -, ra, ##bies, ,, one, -, way, an, ##ova, ,, f, =, 43, ,, p, =, 6, ×, 10, ^, −, ##5, ;, sir, ,, one, -, way, an, ##ova, ,, f, =, 0, ., 03, ,, p, =, 0, ., 96, ), ., figure, 4, ##sir, trans, ##sy, ##na, ##ptic, and, intra, ##ne, ##uron, ##al, retro, ##grade, spread, (, a, ), diagram, of, the, injection, procedure, for, the, trans, ##sy, ##na, ##ptic, spread, from, the, nucleus, acc, ##umb, ##ens, (, na, ##c, ), ., (, b, and, c, ), spreading, at, 1, week, (, b, ), and, 3, weeks, p, ., i, ., (, c, ), of, b1, ##9, δ, ##g, -, ra, ##bies, (, cy, ##an, ), and, sir, (, mage, ##nta, ), ., scale, bar, ,, 1, ,, 000, μ, ##m, ., (, d, –, e, ′, ), trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, in, bas, ##olate, ##ral, amy, ##g, ##dal, ##a, (, b, ##la, ), at, 1, week, (, d, and, d, ′, ), and, 3, weeks, p, ., i, ., (, e, and, e, ′, ), with, sir, (, d, and, e, ,, mage, ##nta, ), and, δ, ##g, -, ra, ##bies, (, d, ′, and, e, ′, ,, cy, ##an, ), ., scale, bar, ,, 50, μ, ##m, ., (, f, –, g, ′, ), trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, in, ventral, te, ##gm, ##ental, area, (, vt, ##a, ), at, 1, week, (, f, and, f, ′, ), and, 3, weeks, p, ., i, ., (, g, and, g, ′, ), with, sir, (, d, and, e, ,, mage, ##nta, ), and, δ, ##g, -, ra, ##bies, (, d, ′, and, e, ′, ,, cy, ##an, ), ., (, h, ), number, of, sir, or, δ, ##g, -, ra, ##bies, positive, neurons, at, 1, and, 3, weeks, p, ., i, ., in, b, ##la, and, vt, ##a, normal, ##ized, to, 1, week, time, points, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), ., (, i, ), efficiency, of, spreading, at, 1, week, p, ., i, ., as, number, of, inputs, normal, ##ized, to, number, of, starting, cells, ,, and, of, sir, and, δ, ##g, -, ra, ##bies, in, b, ##la, and, vt, ##a, (, sir, =, 1, ,, mean, ±, se, ##m, ,, n, =, 3, animals, ), ., (, j, ), scheme, of, retro, ##grade, intra, ##ne, ##uron, ##al, spreading, from, vt, ##a, ., (, k, –, m, ′, ′, ), retro, ##grade, ##ly, labeled, neurons, with, sir, and, ra, ##av, ##2, -, retro, (, sir, ,, mage, ##nta, ;, ra, ##av, ##2, -, retro, ,, cy, ##an, ), in, medial, pre, ##front, ##al, cortex, (, mp, ##fc, ), (, k, –, k, ′, ′, ), ,, lateral, h, ##yp, ##oth, ##ala, ##mus, (, l, ##h, ), (, l, –, l, ′, ′, ), ,, and, na, ##c, (, m, –, m, ′, ′, ), ., (, n, ), number, of, sir, -, and, ra, ##av, ##2, -, retro, -, infected, neurons, in, na, ##c, ,, l, ##h, ,, and, p, ##fc, (, mean, ±, se, ##m, ,, n, =, 3, animals, ), scale, bars, ,, 1, ,, 000, μ, ##m, (, k, –, m, ), ;, 50, μ, ##m, (, k, ′, ,, k, ′, ′, ,, l, ′, ,, l, ′, ′, ,, m, ′, ,, and, m, ′, ′, ), ., see, also, figure, s, ##6, .'},\n", + " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", + " 'section_name': 'Investigating Network Dynamics with SiR',\n", + " 'text': 'The absence of cytotoxicity and unaltered electrophysiological responses support the use of SiR for long-term circuit manipulations. The presence of functional connectivity between SiR-infected neurons and no adverse effects on synaptic properties also indicate that network function is likely to be preserved following SiR infection. In order to test whether network-dependent computations are also preserved and whether SiR can be used to monitor neural activity in vivo, we looked at a prototypical example of network-dependent computation, orientation tuning in visual cortex. We first targeted V1 neurons projecting to V2 (V1 ^> V2) by injecting oG pseudotyped SiR^CRE in the V2 area of Rosa-LoxP-STOP-LoxP-tdTomato mice. At the same time, we injected an AAV^GCaMP6s in the ipsilateral V1 (Figure 6A). Retrograde spreading of SiR^CRE from V2 induced recombination of the Rosa locus permanently labeling V1 ^> V2 neurons (Figures 6B–6B′′; Movie S1). We then monitored the Ca^2+ dynamics of SiR-infected V1 ^> V2 neurons in vivo 4 weeks p.i., under a two-photon microscope, while anesthetized animals were exposed to moving gratings of different orientations across the visual field (Figure 6C) (Benucci et al., 2009). Infected V1 ^> V2 neurons showed significant increases in fluorescence at particular grating orientations resulting in a cellular tuning curve showing direction or orientation selectivity (Figures 6G and 6H). Notably, recorded Ca^2+ responses, as well as the percentage of active neurons, were similar between SiR-traced neurons (GCaMP6s^ON-tdTomato^ON) and neighboring non-SiR V1 neurons (GCaMP6s^ON-tdTomato^OFF) (Figures 6E and 6F). Furthermore, to exclude the possibility of long-term deleterious effects on circuit function following SiR infection, we repeated functional imaging experiments at 2 and 4 months p.i. (Figure S7). In both cases, we found no significant difference in percentage of active neurons or stimulus-driven responses between GCaMP6s^ON-tdTomato^ON and GCaMP6s^ON-tdTomato^OFF neurons (Figures S7F–S7H′′). These data indicate that SiR-traced networks preserve unaltered computational properties and that SiR can be used in combination with GCaMP6s to monitor the Ca^2+ dynamic with no upper bounds to the temporal window for the optical investigation.Figure 6Unaltered Orientation Tuning Responses of SiR-Traced V1 Neurons(A) Schematic of SiR^CRE and AAV^GCaMP6s injection in Rosa-LoxP-STOP-LoxP-tdTomato mice in V2 and V1, respectively.(B–B′′) Two-photon maximal projection of V1 neurons after SiR^CRE injection. In cyan neurons expressing GCaMP6s (B), in magenta neurons expressing tdTomato (B′), and in the merge neurons expressing both (B′′, merge). Arrows and arrowheads highlight representative GCaMP6s or GCaMP6s-tdTomato expressing neurons, respectively. Scale bar, 50 μm.(C) Schematic of visual stimulation set up.(D) Outline of the active ROIs from the same field of view shown in (B).(E) Representative Ca^2+ traces of GCaMP6s (cyan) and GCaMP6s-tdTomato (magenta) neurons. Scale bars, 200 s, 20% dF/F_0.(F) Mean percentage of active neurons after 4 weeks from SiR injection (n = 163 GCaMP6s neurons [cyan], n = 78 GCaMP6s-tdTomato neurons [magenta]; mean ± SEM).(G) Changes in fluorescence over time reflecting visual responses to drifting gratings at the preferred direction of each neuron.(H) Example of tuning curve of V1-infected neurons (mean ± SEM). Scale bars, 5 s, 10% dF/F_0.See also Figure S7 and Movie S1.Figure S7The Orientation Tuning Responses of SiR traced V1 neurons are preserved up to 4 months from the injection, Related to Figure 6(A) Schematic of SiR^CRE and AAV^GCaMP6s injection in Rosa-LoxP-STOP-LoxP-tdTomato mice in V2 and V1 respectively. (B) Schematic of visual stimulation set up. (C-E’’’) Two-photon maximal projection of V1 neurons 1, 2, or 4 months after SiR^CRE injection. In cyan neurons expressing GCaMP6s (C, D, E), in magenta neurons expressing tdTomato (C’, D’, E’) and in the merge neurons expressing both (C’’, D’’, E’’ merge). Arrows and arrowheads highlight representative GCaMP6s (cyan) or GCaMP6s-tdTomato (magenta) expressing neurons respectively. Scale bar: 20 μm. (C’’’, D’’’, E’’’) Outline of the active ROIs from the same field of view showed in panel C, D and E. (F, G, H) Representative Ca^2+ traces of GCaMP6s (cyan) and GCaMP6s-tdTomato (magenta) neurons. Scale bars: 100 s, 20% dF/F_0. (F’, G’, H’) Mean percentage of active neurons after 1, 2 or 4 months from SiR injection (n = 241, 156, 231 respectively, mean ± SEM). (F’’, G’’, H’’) Example of tuning curve of V1 infected neurons after 1, 2 or 4 months (GCaMP6s neurons (cyan) and GCaMP6s-tdTomato neurons (magenta); dF/F_0 mean ± SEM).',\n", + " 'paragraph_id': 16,\n", + " 'tokenizer': 'the, absence, of, cy, ##to, ##to, ##xi, ##city, and, una, ##lter, ##ed, electro, ##phy, ##sio, ##logical, responses, support, the, use, of, sir, for, long, -, term, circuit, manipulation, ##s, ., the, presence, of, functional, connectivity, between, sir, -, infected, neurons, and, no, adverse, effects, on, syn, ##ap, ##tic, properties, also, indicate, that, network, function, is, likely, to, be, preserved, following, sir, infection, ., in, order, to, test, whether, network, -, dependent, computation, ##s, are, also, preserved, and, whether, sir, can, be, used, to, monitor, neural, activity, in, vivo, ,, we, looked, at, a, proto, ##typical, example, of, network, -, dependent, computation, ,, orientation, tuning, in, visual, cortex, ., we, first, targeted, v, ##1, neurons, projecting, to, v, ##2, (, v, ##1, ^, >, v, ##2, ), by, in, ##ject, ##ing, og, pseudo, ##type, ##d, sir, ^, cr, ##e, in, the, v, ##2, area, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, td, ##tom, ##ato, mice, ., at, the, same, time, ,, we, injected, an, aa, ##v, ^, g, ##camp, ##6, ##s, in, the, ip, ##sil, ##ater, ##al, v, ##1, (, figure, 6, ##a, ), ., retro, ##grade, spreading, of, sir, ^, cr, ##e, from, v, ##2, induced, rec, ##om, ##bina, ##tion, of, the, rosa, locus, permanently, labeling, v, ##1, ^, >, v, ##2, neurons, (, figures, 6, ##b, –, 6, ##b, ′, ′, ;, movie, s, ##1, ), ., we, then, monitored, the, ca, ^, 2, +, dynamics, of, sir, -, infected, v, ##1, ^, >, v, ##2, neurons, in, vivo, 4, weeks, p, ., i, ., ,, under, a, two, -, photon, microscope, ,, while, an, ##est, ##het, ##ized, animals, were, exposed, to, moving, gr, ##ating, ##s, of, different, orientation, ##s, across, the, visual, field, (, figure, 6, ##c, ), (, ben, ##ucci, et, al, ., ,, 2009, ), ., infected, v, ##1, ^, >, v, ##2, neurons, showed, significant, increases, in, flu, ##orescence, at, particular, gr, ##ating, orientation, ##s, resulting, in, a, cellular, tuning, curve, showing, direction, or, orientation, select, ##ivity, (, figures, 6, ##g, and, 6, ##h, ), ., notably, ,, recorded, ca, ^, 2, +, responses, ,, as, well, as, the, percentage, of, active, neurons, ,, were, similar, between, sir, -, traced, neurons, (, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, on, ), and, neighboring, non, -, sir, v, ##1, neurons, (, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, off, ), (, figures, 6, ##e, and, 6, ##f, ), ., furthermore, ,, to, exclude, the, possibility, of, long, -, term, del, ##eter, ##ious, effects, on, circuit, function, following, sir, infection, ,, we, repeated, functional, imaging, experiments, at, 2, and, 4, months, p, ., i, ., (, figure, s, ##7, ), ., in, both, cases, ,, we, found, no, significant, difference, in, percentage, of, active, neurons, or, stimulus, -, driven, responses, between, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, on, and, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, off, neurons, (, figures, s, ##7, ##f, –, s, ##7, ##h, ′, ′, ), ., these, data, indicate, that, sir, -, traced, networks, preserve, una, ##lter, ##ed, computational, properties, and, that, sir, can, be, used, in, combination, with, g, ##camp, ##6, ##s, to, monitor, the, ca, ^, 2, +, dynamic, with, no, upper, bounds, to, the, temporal, window, for, the, optical, investigation, ., figure, 6, ##una, ##lter, ##ed, orientation, tuning, responses, of, sir, -, traced, v, ##1, neurons, (, a, ), sc, ##hema, ##tic, of, sir, ^, cr, ##e, and, aa, ##v, ^, g, ##camp, ##6, ##s, injection, in, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, td, ##tom, ##ato, mice, in, v, ##2, and, v, ##1, ,, respectively, ., (, b, –, b, ′, ′, ), two, -, photon, maximal, projection, of, v, ##1, neurons, after, sir, ^, cr, ##e, injection, ., in, cy, ##an, neurons, expressing, g, ##camp, ##6, ##s, (, b, ), ,, in, mage, ##nta, neurons, expressing, td, ##tom, ##ato, (, b, ′, ), ,, and, in, the, merge, neurons, expressing, both, (, b, ′, ′, ,, merge, ), ., arrows, and, arrow, ##heads, highlight, representative, g, ##camp, ##6, ##s, or, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, expressing, neurons, ,, respectively, ., scale, bar, ,, 50, μ, ##m, ., (, c, ), sc, ##hema, ##tic, of, visual, stimulation, set, up, ., (, d, ), outline, of, the, active, roi, ##s, from, the, same, field, of, view, shown, in, (, b, ), ., (, e, ), representative, ca, ^, 2, +, traces, of, g, ##camp, ##6, ##s, (, cy, ##an, ), and, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, (, mage, ##nta, ), neurons, ., scale, bars, ,, 200, s, ,, 20, %, d, ##f, /, f, _, 0, ., (, f, ), mean, percentage, of, active, neurons, after, 4, weeks, from, sir, injection, (, n, =, 163, g, ##camp, ##6, ##s, neurons, [, cy, ##an, ], ,, n, =, 78, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, neurons, [, mage, ##nta, ], ;, mean, ±, se, ##m, ), ., (, g, ), changes, in, flu, ##orescence, over, time, reflecting, visual, responses, to, drifting, gr, ##ating, ##s, at, the, preferred, direction, of, each, ne, ##uron, ., (, h, ), example, of, tuning, curve, of, v, ##1, -, infected, neurons, (, mean, ±, se, ##m, ), ., scale, bars, ,, 5, s, ,, 10, %, d, ##f, /, f, _, 0, ., see, also, figure, s, ##7, and, movie, s, ##1, ., figure, s, ##7th, ##e, orientation, tuning, responses, of, sir, traced, v, ##1, neurons, are, preserved, up, to, 4, months, from, the, injection, ,, related, to, figure, 6, (, a, ), sc, ##hema, ##tic, of, sir, ^, cr, ##e, and, aa, ##v, ^, g, ##camp, ##6, ##s, injection, in, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, td, ##tom, ##ato, mice, in, v, ##2, and, v, ##1, respectively, ., (, b, ), sc, ##hema, ##tic, of, visual, stimulation, set, up, ., (, c, -, e, ’, ’, ’, ), two, -, photon, maximal, projection, of, v, ##1, neurons, 1, ,, 2, ,, or, 4, months, after, sir, ^, cr, ##e, injection, ., in, cy, ##an, neurons, expressing, g, ##camp, ##6, ##s, (, c, ,, d, ,, e, ), ,, in, mage, ##nta, neurons, expressing, td, ##tom, ##ato, (, c, ’, ,, d, ’, ,, e, ’, ), and, in, the, merge, neurons, expressing, both, (, c, ’, ’, ,, d, ’, ’, ,, e, ’, ’, merge, ), ., arrows, and, arrow, ##heads, highlight, representative, g, ##camp, ##6, ##s, (, cy, ##an, ), or, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, (, mage, ##nta, ), expressing, neurons, respectively, ., scale, bar, :, 20, μ, ##m, ., (, c, ’, ’, ’, ,, d, ’, ’, ’, ,, e, ’, ’, ’, ), outline, of, the, active, roi, ##s, from, the, same, field, of, view, showed, in, panel, c, ,, d, and, e, ., (, f, ,, g, ,, h, ), representative, ca, ^, 2, +, traces, of, g, ##camp, ##6, ##s, (, cy, ##an, ), and, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, (, mage, ##nta, ), neurons, ., scale, bars, :, 100, s, ,, 20, %, d, ##f, /, f, _, 0, ., (, f, ’, ,, g, ’, ,, h, ’, ), mean, percentage, of, active, neurons, after, 1, ,, 2, or, 4, months, from, sir, injection, (, n, =, 241, ,, 156, ,, 231, respectively, ,, mean, ±, se, ##m, ), ., (, f, ’, ’, ,, g, ’, ’, ,, h, ’, ’, ), example, of, tuning, curve, of, v, ##1, infected, neurons, after, 1, ,, 2, or, 4, months, (, g, ##camp, ##6, ##s, neurons, (, cy, ##an, ), and, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, neurons, (, mage, ##nta, ), ;, d, ##f, /, f, _, 0, mean, ±, se, ##m, ), .'},\n", + " {'article_id': '9341682e47b256a3d4291c4898437a36',\n", + " 'section_name': 'Discussion',\n", + " 'text': 'There was a trend to increase one derivative of aspartic acid, N-acetylaspartic (NAA), after death (Simmons et al. 1991). NAA is the second most concentrated molecule in the brain after glutamate, and like glutamate, it may function as a neurotransmitter (Yan et al. 2003). NAA, which is synthesized primarily in neurons, is the second most concentrated molecule in the brain after glutamate, and like glutamate, it may function as a neurotransmitter (Yan et al. 2003). However, its role in these cells remains unclear. One of the main hypotheses is that NAA is involved in cell signaling together with NAAG, controlling the interactions of brain cells and preserving the nervous system (Baslow 2000). NAA is also considered to be an important marker of neuronal viability in many cerebral pathologies, where a decline in its concentration is interpreted as a sign of neuronal or axonal dysfunction or death (Tyson and Sutherland 1998). Nevertheless, an increment in NAA concentration also induces many alterations such as oxidative stress, Canavan disease or genotoxicity and protein interaction due to an increase in nitric oxide produced by the elevated concentration of NAA (Surendran and Bhatnagar 2011). Compared with other organs, the brain has a high content of lipids, some two-thirds of which are phospholipids (Ohkubo and Tanaka 2010). Hippocampal pyramidal neurons represent by far the most abundant type of neuron in the hippocampus, and their dendritic arbor is covered by dendritic spines. Dendritic spines are the main target of excitatory glutamatergic synapses and are considered to be critical for cognition, learning and memory. Thus, many researchers are interested in the study of possible alterations of dendritic spines in brain diseases (DeFelipe 2015). These structures contain a complex mixture of ions, lipids, proteins and other signaling molecules which must be continually restored (Sorra and Harris 2000). In fact, it is well known that cholesterol and sphingolipids (SL) are enriched in dendritic spines. The extraction of cholesterol or inhibition of its synthesis leads to the disappearance of dendritic spines, which proves that cholesterol is a core component of dendritic spines (Dotti et al. 2014). Cholesterol and cholesterol esters were identified by two techniques (GC–MS and LC–MS), but differences over time were not statistically significant after data analysis, indicating that degradation 5 h PT is negligible. This is in line with the study by Williams et al. (1978); they found no appreciable changes in the density and morphology of spines in the dendritic arbors of pyramidal neurons of the mouse with fixation latencies of 5 min to 6 h, but, with latencies of more than 6 h, they observed a reduction in the density of dendritic spines and morphological changes of these structures. SL make up approximately 20% of the hippocampus, including sphingomyelin, cerebrosides, cerebroside sulfates and gangliosides. SL act as important signaling molecules in neuronal tissue, and they have received wide attention due to the relatively high levels of gangliosides found. However, recent studies have shown that simple SL, such as ceramide, sphingosine-1-phosphate and glucosylceramide (GlcCer), also play important roles in neuronal function such as in regulation of neuronal growth rates, differentiation and cell death (Buccoliero and Futerman 2003). Ceramide, a second messenger in neurons, contributes to spine plasticity thanks to its capacity to favor membrane fusogenicity promoting receptor clustering (Kronke 1999). Although ceramide is the best characterized SL, its glucosyl derivative, GlcCer also has important functions since it regulates the rate of axonal and dendritic growth (Boldin and Futerman 1997; Harel and Futerman 1993). However, GlcCer is found in low concentrations since it is a metabolic intermediate in the biosynthetic pathway leading to formation of other GSLs. The proper formation and long-term maintenance of neuronal connectivity are crucial for correct functioning of the brain. The long-lasting stability of dendrite and spine structure in the nervous system is highly dependent on the actin cytoskeleton, which is particularly well developed in these structures (Koleske 2013). Sphingomyelin, one of the most abundant SL in neuronal membranes, has an important role in the spine membrane–cytoskeleton cross talk since it modulates membrane binding and the activity of main regulators of the actin cytoskeleton at synapses (Dotti et al. 2014). Sphingosine 1-phosphate is a bioactive lipid that controls a wide range of the cellular processes described above, and it is also involved in cytoskeletal organization. Moreover, it plays a pivotal role is the formation of memory (Kanno et al. 2010). However, no significant differences in any of these compounds were observed over time.',\n", + " 'paragraph_id': 57,\n", + " 'tokenizer': 'there, was, a, trend, to, increase, one, derivative, of, as, ##par, ##tic, acid, ,, n, -, ace, ##ty, ##las, ##par, ##tic, (, na, ##a, ), ,, after, death, (, simmons, et, al, ., 1991, ), ., na, ##a, is, the, second, most, concentrated, molecule, in, the, brain, after, g, ##lu, ##tama, ##te, ,, and, like, g, ##lu, ##tama, ##te, ,, it, may, function, as, a, ne, ##uro, ##tra, ##ns, ##mit, ##ter, (, yan, et, al, ., 2003, ), ., na, ##a, ,, which, is, synthesized, primarily, in, neurons, ,, is, the, second, most, concentrated, molecule, in, the, brain, after, g, ##lu, ##tama, ##te, ,, and, like, g, ##lu, ##tama, ##te, ,, it, may, function, as, a, ne, ##uro, ##tra, ##ns, ##mit, ##ter, (, yan, et, al, ., 2003, ), ., however, ,, its, role, in, these, cells, remains, unclear, ., one, of, the, main, h, ##yp, ##oth, ##eses, is, that, na, ##a, is, involved, in, cell, signaling, together, with, na, ##ag, ,, controlling, the, interactions, of, brain, cells, and, preserving, the, nervous, system, (, bas, ##low, 2000, ), ., na, ##a, is, also, considered, to, be, an, important, marker, of, ne, ##uron, ##al, via, ##bility, in, many, cerebral, path, ##ologies, ,, where, a, decline, in, its, concentration, is, interpreted, as, a, sign, of, ne, ##uron, ##al, or, ax, ##onal, dysfunction, or, death, (, tyson, and, sutherland, 1998, ), ., nevertheless, ,, an, inc, ##rem, ##ent, in, na, ##a, concentration, also, induce, ##s, many, alterations, such, as, ox, ##ida, ##tive, stress, ,, can, ##ava, ##n, disease, or, gen, ##oto, ##xi, ##city, and, protein, interaction, due, to, an, increase, in, ni, ##tric, oxide, produced, by, the, elevated, concentration, of, na, ##a, (, sure, ##ndra, ##n, and, b, ##hat, ##nagar, 2011, ), ., compared, with, other, organs, ,, the, brain, has, a, high, content, of, lip, ##ids, ,, some, two, -, thirds, of, which, are, ph, ##os, ##ph, ##oli, ##pid, ##s, (, oh, ##ku, ##bo, and, tanaka, 2010, ), ., hip, ##po, ##camp, ##al, pyramid, ##al, neurons, represent, by, far, the, most, abundant, type, of, ne, ##uron, in, the, hip, ##po, ##camp, ##us, ,, and, their, den, ##dr, ##itic, arbor, is, covered, by, den, ##dr, ##itic, spines, ., den, ##dr, ##itic, spines, are, the, main, target, of, ex, ##cit, ##atory, g, ##lu, ##tama, ##ter, ##gic, syn, ##ap, ##ses, and, are, considered, to, be, critical, for, cognition, ,, learning, and, memory, ., thus, ,, many, researchers, are, interested, in, the, study, of, possible, alterations, of, den, ##dr, ##itic, spines, in, brain, diseases, (, def, ##eli, ##pe, 2015, ), ., these, structures, contain, a, complex, mixture, of, ions, ,, lip, ##ids, ,, proteins, and, other, signaling, molecules, which, must, be, continually, restored, (, so, ##rra, and, harris, 2000, ), ., in, fact, ,, it, is, well, known, that, cho, ##les, ##terol, and, sp, ##hing, ##oli, ##pid, ##s, (, sl, ), are, enriched, in, den, ##dr, ##itic, spines, ., the, extraction, of, cho, ##les, ##terol, or, inhibition, of, its, synthesis, leads, to, the, disappearance, of, den, ##dr, ##itic, spines, ,, which, proves, that, cho, ##les, ##terol, is, a, core, component, of, den, ##dr, ##itic, spines, (, dot, ##ti, et, al, ., 2014, ), ., cho, ##les, ##terol, and, cho, ##les, ##terol, este, ##rs, were, identified, by, two, techniques, (, g, ##c, –, ms, and, lc, –, ms, ), ,, but, differences, over, time, were, not, statistical, ##ly, significant, after, data, analysis, ,, indicating, that, degradation, 5, h, pt, is, ne, ##gli, ##gible, ., this, is, in, line, with, the, study, by, williams, et, al, ., (, 1978, ), ;, they, found, no, app, ##re, ##cia, ##ble, changes, in, the, density, and, morphology, of, spines, in, the, den, ##dr, ##itic, arbor, ##s, of, pyramid, ##al, neurons, of, the, mouse, with, fix, ##ation, late, ##ncies, of, 5, min, to, 6, h, ,, but, ,, with, late, ##ncies, of, more, than, 6, h, ,, they, observed, a, reduction, in, the, density, of, den, ##dr, ##itic, spines, and, morphological, changes, of, these, structures, ., sl, make, up, approximately, 20, %, of, the, hip, ##po, ##camp, ##us, ,, including, sp, ##hing, ##omy, ##elin, ,, ce, ##re, ##bro, ##side, ##s, ,, ce, ##re, ##bro, ##side, sulfate, ##s, and, gang, ##lio, ##side, ##s, ., sl, act, as, important, signaling, molecules, in, ne, ##uron, ##al, tissue, ,, and, they, have, received, wide, attention, due, to, the, relatively, high, levels, of, gang, ##lio, ##side, ##s, found, ., however, ,, recent, studies, have, shown, that, simple, sl, ,, such, as, ce, ##ram, ##ide, ,, sp, ##hing, ##osi, ##ne, -, 1, -, phosphate, and, g, ##lu, ##cos, ##yl, ##cera, ##mide, (, g, ##lc, ##cer, ), ,, also, play, important, roles, in, ne, ##uron, ##al, function, such, as, in, regulation, of, ne, ##uron, ##al, growth, rates, ,, differentiation, and, cell, death, (, bu, ##cco, ##lier, ##o, and, fu, ##ter, ##man, 2003, ), ., ce, ##ram, ##ide, ,, a, second, messenger, in, neurons, ,, contributes, to, spine, plastic, ##ity, thanks, to, its, capacity, to, favor, membrane, fu, ##so, ##genic, ##ity, promoting, receptor, cluster, ##ing, (, k, ##ron, ##ke, 1999, ), ., although, ce, ##ram, ##ide, is, the, best, characterized, sl, ,, its, g, ##lu, ##cos, ##yl, derivative, ,, g, ##lc, ##cer, also, has, important, functions, since, it, regulates, the, rate, of, ax, ##onal, and, den, ##dr, ##itic, growth, (, bold, ##in, and, fu, ##ter, ##man, 1997, ;, hare, ##l, and, fu, ##ter, ##man, 1993, ), ., however, ,, g, ##lc, ##cer, is, found, in, low, concentrations, since, it, is, a, metabolic, intermediate, in, the, bio, ##sy, ##nt, ##hetic, pathway, leading, to, formation, of, other, gs, ##ls, ., the, proper, formation, and, long, -, term, maintenance, of, ne, ##uron, ##al, connectivity, are, crucial, for, correct, functioning, of, the, brain, ., the, long, -, lasting, stability, of, den, ##dr, ##ite, and, spine, structure, in, the, nervous, system, is, highly, dependent, on, the, act, ##in, cy, ##tos, ##kel, ##eto, ##n, ,, which, is, particularly, well, developed, in, these, structures, (, ko, ##les, ##ke, 2013, ), ., sp, ##hing, ##omy, ##elin, ,, one, of, the, most, abundant, sl, in, ne, ##uron, ##al, membranes, ,, has, an, important, role, in, the, spine, membrane, –, cy, ##tos, ##kel, ##eto, ##n, cross, talk, since, it, mod, ##ulates, membrane, binding, and, the, activity, of, main, regulators, of, the, act, ##in, cy, ##tos, ##kel, ##eto, ##n, at, syn, ##ap, ##ses, (, dot, ##ti, et, al, ., 2014, ), ., sp, ##hing, ##osi, ##ne, 1, -, phosphate, is, a, bio, ##active, lip, ##id, that, controls, a, wide, range, of, the, cellular, processes, described, above, ,, and, it, is, also, involved, in, cy, ##tos, ##kel, ##eta, ##l, organization, ., moreover, ,, it, plays, a, pivotal, role, is, the, formation, of, memory, (, kan, ##no, et, al, ., 2010, ), ., however, ,, no, significant, differences, in, any, of, these, compounds, were, observed, over, time, .'},\n", + " {'article_id': 'fa6756244b8fbdeb59549a9046a5eecc',\n", + " 'section_name': '4. Assessment of Intermediate-term Recognition Memory by Measuring Novel Object Recognition111213',\n", + " 'text': 'For each phase of this test, thoroughly clean the open field arena with an unscented bleach germicidal wipe, 70% EtOH followed by dH_2O prior to initial use.One day prior to object exposure, habituate the mice to the open field arena.\\nPrior to the start of the habituation session, set up the data acquisition system or video cameras and confirm proper tracking of mice in the maze. Calibrate the distance in the arena using captured video images of a ruler or other object of known length. Mark the corners of the arena in the software to permit scoring of positional biases. NOTE: The behavioral methods in this procedure will work with a variety of data acquisition systems and the authors assume anyone performing this procedure is proficient in the use of their chosen data acquisition system. Power analyses indicate that sample sizes of 15-20 mice per group are required for a β ≤0.2.Remove the cage from the rack and gently place on a table in close proximity to the arena.Remove the mouse from the home cage and gently place the mouse in the center of the arena. Turn on the tracking software and/or video recording system immediately after placing the mouse into the arena.Allow mice to freely explore the arena for 30 min. NOTE: During this period, investigators will not disturb the mice.After the habituation session, place mice back into their home cage and clean the arena thoroughly with an unscented bleach germicidal wipe, 70% EtOH followed by dH_2O.Repeat from step 4.2.2 until all mice have been habituated to the arena.After all mice have been habituated to the arena, analyze the video. NOTE: Endpoints to analyze include total distance traveled in the arena and time spent near each corner. If relevant to the mouse model, stereotyped behaviors are included in these analyses (i.e., myoclonic corner jumping, circling, etc.). Mice exhibiting biases in time spent in particular regions of the arena are excluded from further experimentation as this will influence object exploration. NOTE: The first phase of novel object recognition involves familiarizing mice to an object. Herein this portion of the novel object recognition procedure will be referred to as the Sample phase.Prior to the start of a sample phase session, place objects into the arena and fix them to the floor with a mounting putty so that animals cannot move the objects. Align two identical objects to a particular wall with enough distance between the walls and objects so that the mice can freely explore the objects from all angles.Set up the data acquisition system or video cameras and confirm proper tracking of mice and objects in the maze. Calibrate the distances in the arena using captured video images of a ruler or other object of known length.Mark the corners of the arena in the software to permit scoring of positional biases. Mark objects in software and track their exploratory behavior separately for each object (i.e., \"Object A\" and \"Object B\").Remove the cage from the rack and gently place it on a table in close proximity to the arena.Remove the mouse from the home cage and gently place it into the center of the arena, facing the objects.Allow the mouse to freely explore the objects for 15 min. During this period do not disturb the mice.At the end of the session, gently place the mouse back into its home cage. Clean the arena and objects with 70% EtOH and dH_2O. Place these objects back into the arena.Repeat step 4.2.11 until all mice are familiarized to an object.Once all mice have been familiarized to an object, analyze the videos. NOTE: Object explorations are counted once the following criteria have been met: the mouse is oriented toward the object, the snout is within 2 cm of the object, the midpoint of the animal\\'s body is beyond 2 cm from the object, and the previous criteria have been fulfilled for at least 1 s. Additionally, if an animal has satisfied the exploration criteria but exhibits immobility for > 10 s then the exploratory bout is deemed finished.Calculate an object bias score for each mouse as follows. NOTE: Mice exhibiting an object bias score below 20% or above 80% are excluded from further experimentation.The final phase of novel object recognition involves assessing exploratory behavior directed toward both a novel and familiar object in the environment, referred to here as the Test phase. This phase is performed 2-3 h after completion of sample phase.\\nPrior to the start of a test phase session, place objects into the arena and fix them to the floor so that the animals cannot move the objects. Place the objects in the same position in the arena relative to the sample phase13.Balance the relative position of novel and familiar objects across genotypes and treatment groups.Ensure there is enough distance between the walls and objects so that the mice can freely explore the objects from all angles.Setup the data acquisition system and/or video cameras. Confirm proper tracking of mice and objects in the maze. Calibrate distances in the arena using captured video images of a ruler or other object of known length.Mark corners of the arena in the software to permit scoring of positional biases. Mark objects in software and track exploratory behavior for each object individually (i.e., \"Novel\" and \"Familiar\").Remove the cage from the rack and gently place it on a table in close proximity to the arena.Gently place animals into the center of the arena, facing the objects. Record mice freely exploring objects for 10 min.At the end of the test session, remove mice from the arena and place mice back into their home cage. Thoroughly clean arena and objects with an unscented bleach germicidal wipe, 70% EtOH and dH_2O after each session.Repeat from step 4.4.3 until all animals have been assessed.Once object exploration is measured for all mice, videos are analyzed. NOTE: Object explorations are counted once the following criteria have been met: the mouse is oriented toward the object, the snout is within 2 cm of the object, the midpoint of the animal\\'s body is beyond 2 cm from the object, and the previous criteria have been fulfilled for at least 1 s. Additionally, if an animal has satisfied the exploration criteria but exhibits immobility for > 10 s then the exploratory bout is deemed finished.Assess novel object recognition by comparing time spent exploring the novel to familiar object. Three methods are commonly reported in the literature. Analyze raw time spent exploring both novel and familiar objects using a repeated measure test. This method is best used when genotype and/or treatment do not affect total exploration time.Calculate novelty preference, using the equation: NOTE: This provides the percentage of time spent exploring the novel object relative to the total time exploring objects. Values range from 0% (no exploration of novel object) to 100% (exploration only of the novel object), with a value of 50% indicating equal time spent exploring novel and familiar objects.Calculate discrimination index11, using the equation: NOTE: This yields the difference in time spent exploring the novel and familiar objects relative to the total time spent exploring objects. Values range from -1 (exploration only of the familiar object) to +1 (exploration only of the novel object, with a value of 0 indicating equal time spent exploring novel and familiar objects.Remove animals that do not participate in the test session due to hyperdynamic locomotion or other stereotypies, from consideration11. NOTE: Criteria used for removal must be objective and determined a priori for the mouse model (i.e., <5^th percentile for total exploration time and either >100 average turn angle during test session or >50^th percentile time exhibiting myoclonic corner jumping).',\n", + " 'paragraph_id': 6,\n", + " 'tokenizer': 'for, each, phase, of, this, test, ,, thoroughly, clean, the, open, field, arena, with, an, un, ##scent, ##ed, b, ##lea, ##ch, ge, ##rmi, ##ci, ##dal, wipe, ,, 70, %, et, ##oh, followed, by, dh, _, 2, ##o, prior, to, initial, use, ., one, day, prior, to, object, exposure, ,, habit, ##uate, the, mice, to, the, open, field, arena, ., prior, to, the, start, of, the, habit, ##uation, session, ,, set, up, the, data, acquisition, system, or, video, cameras, and, confirm, proper, tracking, of, mice, in, the, maze, ., cal, ##ib, ##rate, the, distance, in, the, arena, using, captured, video, images, of, a, ruler, or, other, object, of, known, length, ., mark, the, corners, of, the, arena, in, the, software, to, permit, scoring, of, position, ##al, bias, ##es, ., note, :, the, behavioral, methods, in, this, procedure, will, work, with, a, variety, of, data, acquisition, systems, and, the, authors, assume, anyone, performing, this, procedure, is, proficient, in, the, use, of, their, chosen, data, acquisition, system, ., power, analyses, indicate, that, sample, sizes, of, 15, -, 20, mice, per, group, are, required, for, a, β, ≤, ##0, ., 2, ., remove, the, cage, from, the, rack, and, gently, place, on, a, table, in, close, proximity, to, the, arena, ., remove, the, mouse, from, the, home, cage, and, gently, place, the, mouse, in, the, center, of, the, arena, ., turn, on, the, tracking, software, and, /, or, video, recording, system, immediately, after, placing, the, mouse, into, the, arena, ., allow, mice, to, freely, explore, the, arena, for, 30, min, ., note, :, during, this, period, ,, investigators, will, not, disturb, the, mice, ., after, the, habit, ##uation, session, ,, place, mice, back, into, their, home, cage, and, clean, the, arena, thoroughly, with, an, un, ##scent, ##ed, b, ##lea, ##ch, ge, ##rmi, ##ci, ##dal, wipe, ,, 70, %, et, ##oh, followed, by, dh, _, 2, ##o, ., repeat, from, step, 4, ., 2, ., 2, until, all, mice, have, been, habit, ##uated, to, the, arena, ., after, all, mice, have, been, habit, ##uated, to, the, arena, ,, analyze, the, video, ., note, :, end, ##points, to, analyze, include, total, distance, traveled, in, the, arena, and, time, spent, near, each, corner, ., if, relevant, to, the, mouse, model, ,, stereo, ##type, ##d, behaviors, are, included, in, these, analyses, (, i, ., e, ., ,, my, ##oc, ##lon, ##ic, corner, jumping, ,, circling, ,, etc, ., ), ., mice, exhibiting, bias, ##es, in, time, spent, in, particular, regions, of, the, arena, are, excluded, from, further, experimentation, as, this, will, influence, object, exploration, ., note, :, the, first, phase, of, novel, object, recognition, involves, familiar, ##izing, mice, to, an, object, ., here, ##in, this, portion, of, the, novel, object, recognition, procedure, will, be, referred, to, as, the, sample, phase, ., prior, to, the, start, of, a, sample, phase, session, ,, place, objects, into, the, arena, and, fix, them, to, the, floor, with, a, mounting, put, ##ty, so, that, animals, cannot, move, the, objects, ., align, two, identical, objects, to, a, particular, wall, with, enough, distance, between, the, walls, and, objects, so, that, the, mice, can, freely, explore, the, objects, from, all, angles, ., set, up, the, data, acquisition, system, or, video, cameras, and, confirm, proper, tracking, of, mice, and, objects, in, the, maze, ., cal, ##ib, ##rate, the, distances, in, the, arena, using, captured, video, images, of, a, ruler, or, other, object, of, known, length, ., mark, the, corners, of, the, arena, in, the, software, to, permit, scoring, of, position, ##al, bias, ##es, ., mark, objects, in, software, and, track, their, ex, ##pl, ##ora, ##tory, behavior, separately, for, each, object, (, i, ., e, ., ,, \", object, a, \", and, \", object, b, \", ), ., remove, the, cage, from, the, rack, and, gently, place, it, on, a, table, in, close, proximity, to, the, arena, ., remove, the, mouse, from, the, home, cage, and, gently, place, it, into, the, center, of, the, arena, ,, facing, the, objects, ., allow, the, mouse, to, freely, explore, the, objects, for, 15, min, ., during, this, period, do, not, disturb, the, mice, ., at, the, end, of, the, session, ,, gently, place, the, mouse, back, into, its, home, cage, ., clean, the, arena, and, objects, with, 70, %, et, ##oh, and, dh, _, 2, ##o, ., place, these, objects, back, into, the, arena, ., repeat, step, 4, ., 2, ., 11, until, all, mice, are, familiar, ##ized, to, an, object, ., once, all, mice, have, been, familiar, ##ized, to, an, object, ,, analyze, the, videos, ., note, :, object, exploration, ##s, are, counted, once, the, following, criteria, have, been, met, :, the, mouse, is, oriented, toward, the, object, ,, the, snout, is, within, 2, cm, of, the, object, ,, the, mid, ##point, of, the, animal, \\', s, body, is, beyond, 2, cm, from, the, object, ,, and, the, previous, criteria, have, been, fulfilled, for, at, least, 1, s, ., additionally, ,, if, an, animal, has, satisfied, the, exploration, criteria, but, exhibits, im, ##mo, ##bility, for, >, 10, s, then, the, ex, ##pl, ##ora, ##tory, bout, is, deemed, finished, ., calculate, an, object, bias, score, for, each, mouse, as, follows, ., note, :, mice, exhibiting, an, object, bias, score, below, 20, %, or, above, 80, %, are, excluded, from, further, experimentation, ., the, final, phase, of, novel, object, recognition, involves, assessing, ex, ##pl, ##ora, ##tory, behavior, directed, toward, both, a, novel, and, familiar, object, in, the, environment, ,, referred, to, here, as, the, test, phase, ., this, phase, is, performed, 2, -, 3, h, after, completion, of, sample, phase, ., prior, to, the, start, of, a, test, phase, session, ,, place, objects, into, the, arena, and, fix, them, to, the, floor, so, that, the, animals, cannot, move, the, objects, ., place, the, objects, in, the, same, position, in, the, arena, relative, to, the, sample, phase, ##13, ., balance, the, relative, position, of, novel, and, familiar, objects, across, gen, ##otype, ##s, and, treatment, groups, ., ensure, there, is, enough, distance, between, the, walls, and, objects, so, that, the, mice, can, freely, explore, the, objects, from, all, angles, ., setup, the, data, acquisition, system, and, /, or, video, cameras, ., confirm, proper, tracking, of, mice, and, objects, in, the, maze, ., cal, ##ib, ##rate, distances, in, the, arena, using, captured, video, images, of, a, ruler, or, other, object, of, known, length, ., mark, corners, of, the, arena, in, the, software, to, permit, scoring, of, position, ##al, bias, ##es, ., mark, objects, in, software, and, track, ex, ##pl, ##ora, ##tory, behavior, for, each, object, individually, (, i, ., e, ., ,, \", novel, \", and, \", familiar, \", ), ., remove, the, cage, from, the, rack, and, gently, place, it, on, a, table, in, close, proximity, to, the, arena, ., gently, place, animals, into, the, center, of, the, arena, ,, facing, the, objects, ., record, mice, freely, exploring, objects, for, 10, min, ., at, the, end, of, the, test, session, ,, remove, mice, from, the, arena, and, place, mice, back, into, their, home, cage, ., thoroughly, clean, arena, and, objects, with, an, un, ##scent, ##ed, b, ##lea, ##ch, ge, ##rmi, ##ci, ##dal, wipe, ,, 70, %, et, ##oh, and, dh, _, 2, ##o, after, each, session, ., repeat, from, step, 4, ., 4, ., 3, until, all, animals, have, been, assessed, ., once, object, exploration, is, measured, for, all, mice, ,, videos, are, analyzed, ., note, :, object, exploration, ##s, are, counted, once, the, following, criteria, have, been, met, :, the, mouse, is, oriented, toward, the, object, ,, the, snout, is, within, 2, cm, of, the, object, ,, the, mid, ##point, of, the, animal, \\', s, body, is, beyond, 2, cm, from, the, object, ,, and, the, previous, criteria, have, been, fulfilled, for, at, least, 1, s, ., additionally, ,, if, an, animal, has, satisfied, the, exploration, criteria, but, exhibits, im, ##mo, ##bility, for, >, 10, s, then, the, ex, ##pl, ##ora, ##tory, bout, is, deemed, finished, ., assess, novel, object, recognition, by, comparing, time, spent, exploring, the, novel, to, familiar, object, ., three, methods, are, commonly, reported, in, the, literature, ., analyze, raw, time, spent, exploring, both, novel, and, familiar, objects, using, a, repeated, measure, test, ., this, method, is, best, used, when, gen, ##otype, and, /, or, treatment, do, not, affect, total, exploration, time, ., calculate, novelty, preference, ,, using, the, equation, :, note, :, this, provides, the, percentage, of, time, spent, exploring, the, novel, object, relative, to, the, total, time, exploring, objects, ., values, range, from, 0, %, (, no, exploration, of, novel, object, ), to, 100, %, (, exploration, only, of, the, novel, object, ), ,, with, a, value, of, 50, %, indicating, equal, time, spent, exploring, novel, and, familiar, objects, ., calculate, discrimination, index, ##11, ,, using, the, equation, :, note, :, this, yields, the, difference, in, time, spent, exploring, the, novel, and, familiar, objects, relative, to, the, total, time, spent, exploring, objects, ., values, range, from, -, 1, (, exploration, only, of, the, familiar, object, ), to, +, 1, (, exploration, only, of, the, novel, object, ,, with, a, value, of, 0, indicating, equal, time, spent, exploring, novel, and, familiar, objects, ., remove, animals, that, do, not, participate, in, the, test, session, due, to, hyper, ##dy, ##nami, ##c, loco, ##mot, ##ion, or, other, stereo, ##ty, ##pies, ,, from, consideration, ##11, ., note, :, criteria, used, for, removal, must, be, objective, and, determined, a, prior, ##i, for, the, mouse, model, (, i, ., e, ., ,, <, 5, ^, th, percent, ##ile, for, total, exploration, time, and, either, >, 100, average, turn, angle, during, test, session, or, >, 50, ^, th, percent, ##ile, time, exhibiting, my, ##oc, ##lon, ##ic, corner, jumping, ), .'},\n", + " {'article_id': '0f8950051fe4f7639803646d2824d50d',\n", + " 'section_name': 'Neuropathology',\n", + " 'text': 'Post mortem examination restricted to the central nervous system had been performed on five of the affected TIA1 mutation carriers (Tables 1 and 2). In four of the five cases, the entire spinal cord was available for examination; whereas, in case NWU-1, only the upper segments of cervical spinal cord were available. Microscopic evaluation was performed on 5 μm-thick sections of formalin fixed, paraffin-embedded material representing a wide range of anatomical regions (Table 2). Histochemical stains included hematoxylin and eosin (HE), HE combined with Luxol fast blue (HE/LFB), modified Bielschowsky silver stain, Gallyas silver stain, Masson trichrome, Periodic Acid Schiff with and without diastase, Alcian Blue (pH 2.5) and Congo red. Standard immunohistochemistry (IHC) was performed using the Ventana BenchMark XT automated staining system with primary antibodies against alpha-synuclein (Thermo Scientific; 1:10,000 following microwave antigen retrieval), beta amyloid (DAKO; 1:100 with initial incubation for 3 h at room temperature), hyperphosphorylated tau (clone AT-8; Innogenetics, Ghent, Belgium; 1:2000 following microwave antigen retrieval), phosphorylation-independent TDP-43 (ProteinTech; 1:1000 following microwave antigen retrieval), ubiquitin (DAKO; 1:500 following microwave antigen retrieval), FUS (Sigma-Aldrich; 1:1000 following microwave antigen retrieval), p62 (BD Biosciences; 1:500 following microwave antigen retrieval), poly-(A) binding protein (PABP; Santa Cruz; 1:200 following microwave antigen retrieval), hnRNP A1 (Santa Cruz; 1:100 following microwave antigen retrieval), hnRNP A3 (Sigma-Aldrich; 1:100 following microwave antigen retrieval) and hnRNP A2/B1 (Santa Cruz; 1:500 following microwave antigen retrieval). In addition, we tested a number of commercial monoclonal and polyclonal antibodies against different epitopes of human TIA1, raised in different species (Table 3).Table 2Semiquantitative analysis of neurodegeneration and TDP-ir pathology in TIA1 mutation carriersNeurodegenerationTDP-43 ImmunohistochemistryNWU-1TOR-1UBCU2-14UBCU2-1ALS752-1NWU-1TOR-1UBCU2-14UBCU2-1ALS752-1FTD, ALSFTD, prob. ALSFTD, prob. ALSALS, early FTDALSFTD, ALSFTD, prob. ALSFTD, prob. ALSALS, early FTDALSpyramidal motor systemmotor cortex++++++++++++++CN XII++++++++++++++++++++++++CST++++++++++n/an/an/an/an/aant. horn++++++++++++++++++++++++++neocortexprefrontal++++++++–++++++++++++++temporal+++++–++++++++++parietal––+++–++++++++++striatonigral systemcaudate+–+++–++++++++++++putamen–––––++++++++GP–––––+++++SN+++++++++++++++++++++++limbic systemhip. CA–––––+++++hip. dentate+++–––+++++++++++thalamus+––––+–+–+midbrainPAG+–+++–++++++cerebello-pontine systemcb cortex––––––––––cb dentate+–––––––––basis pontis–––––+–+–+The patients are ordered according to their earliest and/or predominant clinical features from predominant FTD (left) to pure ALS (right). ALS amyotrophic lateral sclerosis, ant. anterior, cb cerebellar, CA cornu ammonis, CN XII twelfth cranial nerve (hypoglossal) nucleus, CST corticospinal tract, deg. non-specific changes of chronic degeneration, FTD frontotemporal dementia, GP globus pallidus, hip. hippocampal, n/a not applicable, PAG periaqueductal grey matter, prob. probable, SN substantia nigra. Semiquantitative grading of pathology; −, none; +, mild; ++, moderate; +++, severe\\nTable 3TIA1 antibodies used for immunohistochemistry and double label immunofluorescenceAntibodySpeciesEpitopeDilutionSanta Cruz #sc-1751Goat polyclonal (clone C-20)near C-terminus1:300Santa Cruz #sc-48371Mouse monoclonal (clone D-9)aa 21-140 (near N-terminus)1:200Santa Cruz #sc-28237Rabbit polyclonal (clone H-120)aa 21-140 (near N-terminus)1:300Abcam #ab140595Rabbit monoclonalaa 350 to the C-terminus1:100Abcam #ab40693Rabbit polyclonalaa 350 to the C-terminus1:500ProteinTech #12133-2-APRabbit polyclonalhuman TIA1-GST fusion protein1:100#, catalogue number; GST glutathione S-transferase',\n", + " 'paragraph_id': 5,\n", + " 'tokenizer': 'post, mort, ##em, examination, restricted, to, the, central, nervous, system, had, been, performed, on, five, of, the, affected, tia, ##1, mutation, carriers, (, tables, 1, and, 2, ), ., in, four, of, the, five, cases, ,, the, entire, spinal, cord, was, available, for, examination, ;, whereas, ,, in, case, nw, ##u, -, 1, ,, only, the, upper, segments, of, cervical, spinal, cord, were, available, ., microscopic, evaluation, was, performed, on, 5, μ, ##m, -, thick, sections, of, formal, ##in, fixed, ,, para, ##ffin, -, embedded, material, representing, a, wide, range, of, anatomical, regions, (, table, 2, ), ., his, ##to, ##chemical, stains, included, hem, ##ato, ##xy, ##lin, and, e, ##osi, ##n, (, he, ), ,, he, combined, with, lux, ##ol, fast, blue, (, he, /, l, ##fb, ), ,, modified, bi, ##els, ##cho, ##ws, ##ky, silver, stain, ,, gall, ##yas, silver, stain, ,, mass, ##on, tri, ##chrome, ,, periodic, acid, sc, ##hiff, with, and, without, dia, ##sta, ##se, ,, al, ##cian, blue, (, ph, 2, ., 5, ), and, congo, red, ., standard, im, ##mun, ##oh, ##isto, ##chemist, ##ry, (, i, ##hc, ), was, performed, using, the, vent, ##ana, bench, ##mark, x, ##t, automated, stain, ##ing, system, with, primary, antibodies, against, alpha, -, syn, ##uc, ##lein, (, the, ##rm, ##o, scientific, ;, 1, :, 10, ,, 000, following, microwave, antigen, retrieval, ), ,, beta, amy, ##loid, (, da, ##ko, ;, 1, :, 100, with, initial, inc, ##uba, ##tion, for, 3, h, at, room, temperature, ), ,, hyper, ##ph, ##os, ##ph, ##ory, ##lated, tau, (, clone, at, -, 8, ;, inn, ##ogen, ##etic, ##s, ,, ghent, ,, belgium, ;, 1, :, 2000, following, microwave, antigen, retrieval, ), ,, ph, ##os, ##ph, ##ory, ##lation, -, independent, td, ##p, -, 43, (, protein, ##tech, ;, 1, :, 1000, following, microwave, antigen, retrieval, ), ,, u, ##bi, ##qui, ##tin, (, da, ##ko, ;, 1, :, 500, following, microwave, antigen, retrieval, ), ,, fu, ##s, (, sigma, -, al, ##drich, ;, 1, :, 1000, following, microwave, antigen, retrieval, ), ,, p, ##6, ##2, (, b, ##d, bio, ##sc, ##ience, ##s, ;, 1, :, 500, following, microwave, antigen, retrieval, ), ,, poly, -, (, a, ), binding, protein, (, pa, ##b, ##p, ;, santa, cruz, ;, 1, :, 200, following, microwave, antigen, retrieval, ), ,, h, ##nr, ##np, a1, (, santa, cruz, ;, 1, :, 100, following, microwave, antigen, retrieval, ), ,, h, ##nr, ##np, a, ##3, (, sigma, -, al, ##drich, ;, 1, :, 100, following, microwave, antigen, retrieval, ), and, h, ##nr, ##np, a2, /, b1, (, santa, cruz, ;, 1, :, 500, following, microwave, antigen, retrieval, ), ., in, addition, ,, we, tested, a, number, of, commercial, mono, ##cl, ##onal, and, poly, ##cl, ##onal, antibodies, against, different, ep, ##ito, ##pes, of, human, tia, ##1, ,, raised, in, different, species, (, table, 3, ), ., table, 2, ##se, ##mi, ##qua, ##nti, ##tative, analysis, of, ne, ##uro, ##de, ##gen, ##eration, and, td, ##p, -, ir, pathology, in, tia, ##1, mutation, carriers, ##ne, ##uro, ##de, ##gen, ##eration, ##t, ##dp, -, 43, im, ##mun, ##oh, ##isto, ##chemist, ##ryn, ##wu, -, 1, ##tor, -, 1, ##ub, ##cu, ##2, -, 14, ##ub, ##cu, ##2, -, 1a, ##ls, ##75, ##2, -, 1, ##n, ##wu, -, 1, ##tor, -, 1, ##ub, ##cu, ##2, -, 14, ##ub, ##cu, ##2, -, 1a, ##ls, ##75, ##2, -, 1, ##ft, ##d, ,, als, ##ft, ##d, ,, pro, ##b, ., als, ##ft, ##d, ,, pro, ##b, ., als, ##als, ,, early, ft, ##dal, ##sf, ##t, ##d, ,, als, ##ft, ##d, ,, pro, ##b, ., als, ##ft, ##d, ,, pro, ##b, ., als, ##als, ,, early, ft, ##dal, ##sp, ##yra, ##mi, ##dal, motor, system, ##moto, ##r, cortex, +, +, +, +, +, +, +, +, +, +, +, +, +, +, cn, xii, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, cs, ##t, +, +, +, +, +, +, +, +, +, +, n, /, an, /, an, /, an, /, an, /, aa, ##nt, ., horn, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, neo, ##cor, ##te, ##x, ##pre, ##front, ##al, +, +, +, +, +, +, +, +, –, +, +, +, +, +, +, +, +, +, +, +, +, +, +, temporal, +, +, +, +, +, –, +, +, +, +, +, +, +, +, +, +, par, ##ie, ##tal, –, –, +, +, +, –, +, +, +, +, +, +, +, +, +, +, st, ##ria, ##ton, ##ig, ##ral, system, ##ca, ##uda, ##te, +, –, +, +, +, –, +, +, +, +, +, +, +, +, +, +, +, +, put, ##amen, –, –, –, –, –, +, +, +, +, +, +, +, +, gp, –, –, –, –, –, +, +, +, +, +, s, ##n, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, limb, ##ic, system, ##hip, ., ca, –, –, –, –, –, +, +, +, +, +, hip, ., dent, ##ate, +, +, +, –, –, –, +, +, +, +, +, +, +, +, +, +, +, tha, ##lam, ##us, +, –, –, –, –, +, –, +, –, +, mid, ##bra, ##in, ##pa, ##g, +, –, +, +, +, –, +, +, +, +, +, +, ce, ##re, ##bell, ##o, -, pont, ##ine, system, ##cb, cortex, –, –, –, –, –, –, –, –, –, –, cb, dent, ##ate, +, –, –, –, –, –, –, –, –, –, basis, pont, ##is, –, –, –, –, –, +, –, +, –, +, the, patients, are, ordered, according, to, their, earliest, and, /, or, predominant, clinical, features, from, predominant, ft, ##d, (, left, ), to, pure, als, (, right, ), ., als, amy, ##ot, ##rop, ##hic, lateral, sc, ##ler, ##osis, ,, ant, ., anterior, ,, cb, ce, ##re, ##bella, ##r, ,, ca, corn, ##u, am, ##mon, ##is, ,, cn, xii, twelfth, cr, ##anial, nerve, (, h, ##yp, ##og, ##los, ##sal, ), nucleus, ,, cs, ##t, co, ##rti, ##cos, ##pina, ##l, tract, ,, de, ##g, ., non, -, specific, changes, of, chronic, de, ##gen, ##eration, ,, ft, ##d, front, ##ote, ##mp, ##ora, ##l, dementia, ,, gp, g, ##lo, ##bus, pal, ##lid, ##us, ,, hip, ., hip, ##po, ##camp, ##al, ,, n, /, a, not, applicable, ,, pa, ##g, per, ##ia, ##que, ##du, ##cta, ##l, grey, matter, ,, pro, ##b, ., probable, ,, s, ##n, sub, ##stan, ##tia, ni, ##gra, ., semi, ##qua, ##nti, ##tative, grading, of, pathology, ;, −, ,, none, ;, +, ,, mild, ;, +, +, ,, moderate, ;, +, +, +, ,, severe, table, 3, ##tia, ##1, antibodies, used, for, im, ##mun, ##oh, ##isto, ##chemist, ##ry, and, double, label, im, ##mun, ##of, ##lu, ##orescence, ##ant, ##ib, ##od, ##ys, ##pe, ##cies, ##ep, ##ito, ##ped, ##il, ##ution, ##sant, ##a, cruz, #, sc, -, 1751, ##go, ##at, poly, ##cl, ##onal, (, clone, c, -, 20, ), near, c, -, terminus, ##1, :, 300, ##sant, ##a, cruz, #, sc, -, 48, ##37, ##1, ##mous, ##e, mono, ##cl, ##onal, (, clone, d, -, 9, ), aa, 21, -, 140, (, near, n, -, terminus, ), 1, :, 200, ##sant, ##a, cruz, #, sc, -, 282, ##37, ##ra, ##bb, ##it, poly, ##cl, ##onal, (, clone, h, -, 120, ), aa, 21, -, 140, (, near, n, -, terminus, ), 1, :, 300, ##ab, ##cam, #, ab, ##14, ##0, ##59, ##5, ##ra, ##bb, ##it, mono, ##cl, ##onal, ##aa, 350, to, the, c, -, terminus, ##1, :, 100, ##ab, ##cam, #, ab, ##40, ##6, ##9, ##3, ##ra, ##bb, ##it, poly, ##cl, ##onal, ##aa, 350, to, the, c, -, terminus, ##1, :, 500, ##pro, ##tein, ##tech, #, 121, ##33, -, 2, -, apr, ##ab, ##bit, poly, ##cl, ##onal, ##hum, ##an, tia, ##1, -, gs, ##t, fusion, protein, ##1, :, 100, #, ,, catalogue, number, ;, gs, ##t, g, ##lu, ##tat, ##hi, ##one, s, -, transfer, ##ase'},\n", + " {'article_id': '076b3623a95c1f37b2253931ea58f8bf',\n", + " 'section_name': 'Figure Caption',\n", + " 'text': 'Elevated splenic IFNγ during co‐infection induces splenic CXCL9/CXCL10 and suppresses CXCR3 expression on CD8^+ T cells to limit migration capacity toward the brainALevels of IFNγ protein in the spleen of naïve, PbA, and PbA + CHIKV groups on 2, 4, and 6 dpi (n≥5 per group). Data comparison between PbA and PbA + CHIKV groups was done by Mann–Whitney two‐tailed analysis (6 dpi; *P=0.0317).B, CLevels of CXCL9 and CXCL10 protein in the spleen of WT naïve (n=5), WT + PbA (n=5), WT + PbA + CHIKV (n=5), IFNγ^−/− + PbA (n=4), and IFNγ^−/− + PbA + CHIKV (n=4) on 6 dpi. Data comparison between PbA and PbA + CHIKV groups in the respective WT and IFNγ^−/− background was done by Mann–Whitney two‐tailed analysis (CXCL9–WT + PbA versus WT + PbA + CHIKV; *P=0.0238, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.7429. CXCL10–WT + PbA versus WT + PbA + CHIKV; **P=0.0079, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.3429).DNumber of total CD8^+ T cells and Pb1‐specific CD8^+ T cells in the spleen of WT + PbA (n=5), WT + PbA + CHIKV (n=4), IFNγ^−/− + PbA (n=5), and IFNγ^−/− + PbA + CHIKV (n=6) on 6 dpi. Data comparison between PbA and PbA + CHIKV groups in the respective WT and IFNγ^−/− background was done by Mann–Whitney two‐tailed analysis (total CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0159, IFNγ^−/−+ PbA versus IFNγ^−/−+ PbA + CHIKV; ^ns\\nP=0.0823, Pb1‐specific CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0317, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.4286).E, FCXCR3 surface expression on total CD8^+ T cells and Pb1‐specific CD8^+ T cells in the spleen of WT + PbA (n=5), WT + PbA + CHIKV (n=4), IFNγ^−/− + PbA (n=5), and IFNγ^−/− + PbA + CHIKV (n=6) on 6 dpi. Representative histograms showing CXCR3 expression are shown. Threshold of CXCR3^+ cells is delineated by black dotted line. Data comparison between PbA and PbA + CHIKV groups in the respective WT and IFNγ^−/− background was done by Mann–Whitney two‐tailed analysis (total CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0159, IFNγ^−/−+ PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.0823, Pb1‐specific CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0159, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.9307).GIn vivo migration assay measuring the migratory capacity of LFA‐1^+ and Pb1‐specific CD8^+ T cells from IFNγ^−/− + PbA donors (n=4) and IFNγ^−/− + PbA + CHIKV donors (n=3) toward the brain of WT PbA recipients. 7 × 10^6 isolated donors’ CD8^+ T cells (6 dpi) were transferred into PbA recipient at 5 dpi and harvested 22 h post‐transfer. All data are expressed as ratio of recovered cells to initial numbers of cell transferred into the recipients for each specific cell type. Mann–Whitney two‐tailed analysis (LFA‐1^+CD8^+ T cells: ^ns\\nP=0.9999, Pb1‐specific CD8^+ T cells: ^ns\\nP=0.6286).Data information: For all cytokines or chemokines, quantifications were measured by ELISA using cell lysate from the organ and determined as pg/μg of total protein. Each data point shown in the dot plots was obtained from 1 mouse.',\n", + " 'paragraph_id': 52,\n", + " 'tokenizer': 'elevated, sp, ##len, ##ic, if, ##n, ##γ, during, co, ‐, infection, induce, ##s, sp, ##len, ##ic, c, ##x, ##cl, ##9, /, c, ##x, ##cl, ##10, and, suppress, ##es, c, ##x, ##cr, ##3, expression, on, cd, ##8, ^, +, t, cells, to, limit, migration, capacity, toward, the, brain, ##ale, ##vel, ##s, of, if, ##n, ##γ, protein, in, the, sp, ##leen, of, naive, ,, pba, ,, and, pba, +, chi, ##k, ##v, groups, on, 2, ,, 4, ,, and, 6, d, ##pi, (, n, ##≥, ##5, per, group, ), ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, 6, d, ##pi, ;, *, p, =, 0, ., 03, ##17, ), ., b, ,, cl, ##eve, ##ls, of, c, ##x, ##cl, ##9, and, c, ##x, ##cl, ##10, protein, in, the, sp, ##leen, of, w, ##t, naive, (, n, =, 5, ), ,, w, ##t, +, pba, (, n, =, 5, ), ,, w, ##t, +, pba, +, chi, ##k, ##v, (, n, =, 5, ), ,, if, ##n, ##γ, ^, −, /, −, +, pba, (, n, =, 4, ), ,, and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, (, n, =, 4, ), on, 6, d, ##pi, ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, in, the, respective, w, ##t, and, if, ##n, ##γ, ^, −, /, −, background, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, c, ##x, ##cl, ##9, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 02, ##38, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 74, ##29, ., c, ##x, ##cl, ##10, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, *, p, =, 0, ., 00, ##7, ##9, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 34, ##29, ), ., d, ##num, ##ber, of, total, cd, ##8, ^, +, t, cells, and, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, in, the, sp, ##leen, of, w, ##t, +, pba, (, n, =, 5, ), ,, w, ##t, +, pba, +, chi, ##k, ##v, (, n, =, 4, ), ,, if, ##n, ##γ, ^, −, /, −, +, pba, (, n, =, 5, ), ,, and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, (, n, =, 6, ), on, 6, d, ##pi, ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, in, the, respective, w, ##t, and, if, ##n, ##γ, ^, −, /, −, background, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, total, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 01, ##59, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 08, ##23, ,, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 03, ##17, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 42, ##86, ), ., e, ,, fc, ##x, ##cr, ##3, surface, expression, on, total, cd, ##8, ^, +, t, cells, and, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, in, the, sp, ##leen, of, w, ##t, +, pba, (, n, =, 5, ), ,, w, ##t, +, pba, +, chi, ##k, ##v, (, n, =, 4, ), ,, if, ##n, ##γ, ^, −, /, −, +, pba, (, n, =, 5, ), ,, and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, (, n, =, 6, ), on, 6, d, ##pi, ., representative, his, ##to, ##gram, ##s, showing, c, ##x, ##cr, ##3, expression, are, shown, ., threshold, of, c, ##x, ##cr, ##3, ^, +, cells, is, del, ##ine, ##ated, by, black, dotted, line, ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, in, the, respective, w, ##t, and, if, ##n, ##γ, ^, −, /, −, background, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, total, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 01, ##59, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 08, ##23, ,, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 01, ##59, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 930, ##7, ), ., gin, vivo, migration, ass, ##ay, measuring, the, migratory, capacity, of, l, ##fa, ‐, 1, ^, +, and, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, from, if, ##n, ##γ, ^, −, /, −, +, pba, donors, (, n, =, 4, ), and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, donors, (, n, =, 3, ), toward, the, brain, of, w, ##t, pba, recipients, ., 7, ×, 10, ^, 6, isolated, donors, ’, cd, ##8, ^, +, t, cells, (, 6, d, ##pi, ), were, transferred, into, pba, recipient, at, 5, d, ##pi, and, harvested, 22, h, post, ‐, transfer, ., all, data, are, expressed, as, ratio, of, recovered, cells, to, initial, numbers, of, cell, transferred, into, the, recipients, for, each, specific, cell, type, ., mann, –, whitney, two, ‐, tailed, analysis, (, l, ##fa, ‐, 1, ^, +, cd, ##8, ^, +, t, cells, :, ^, ns, p, =, 0, ., 999, ##9, ,, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, :, ^, ns, p, =, 0, ., 62, ##86, ), ., data, information, :, for, all, cy, ##tok, ##ines, or, che, ##mo, ##kin, ##es, ,, quan, ##ti, ##fication, ##s, were, measured, by, elisa, using, cell, l, ##ys, ##ate, from, the, organ, and, determined, as, pg, /, μ, ##g, of, total, protein, ., each, data, point, shown, in, the, dot, plots, was, obtained, from, 1, mouse, .'},\n", + " {'article_id': '076b3623a95c1f37b2253931ea58f8bf',\n", + " 'section_name': 'Figure Caption',\n", + " 'text': \"Increased IFNγ producing CD4^+ T cells in the spleen drives the enhanced splenic IFNγ on 6 dpi during concurrent co‐infectionRepresentative histogram showing IFNγ production in CD4^+ T cells, CD8^+ T cells, NK cells, NKT cells, and neutrophils in the spleen of naïve (n=5), CHIKV (n=5), PbA (n=6), and PbA + CHIKV (n=8) on 6 dpi. Black dotted line represents threshold setting for IFNγ^+ cells.Numbers of CD4^+ T cells, CD8^+ T cells, NK cells, NKT cells, and neutrophils in the spleen of naïve (n=5), CHIKV (n=5), PbA (n=6), and PbA + CHIKV (n=8) on 6 dpi. CD4^+, CD8^+ T cells, NK cells, NKT cells, and neutrophils were defined as CD3^+CD4^+, CD3^+CD8^+, CD3^−NK1.1^+, CD3^+NK1.1^+, and CD3^−CD11b^+Ly6G^+ cells, respectively. All data analyzed by one‐way ANOVA with Tukey's post‐test. For CD4^+ T cells: naïve versus PbA + CHIKV; *mean diff=−1.49 × 10^7, PbA versus PbA + CHIKV; *mean diff=−1.57 × 10^7. For CD8^+ T cells: naïve versus PbA + CHIKV; *mean diff=−9.61 × 10^6, CHIKV versus PbA + CHIKV; *mean diff=−9.43 × 10^6, PbA versus PbA + CHIKV; *mean diff=−9.75 × 10^6. For NK cells: naïve versus PbA; ***mean diff=5.22 × 10^6, naïve versus PbA + CHIKV; **mean diff=4.03 × 10^6, CHIKV versus PbA; ***mean diff=5.39 × 10^6, CHIKV versus PbA + CHIKV; **mean diff=4.20 × 10^6. For NKT cells: naïve versus PbA; *mean diff=7.95 × 10^5, CHIKV versus PbA; *mean diff=7.34 × 10^5, PbA versus PbA + CHIKV; **mean diff=−8.19 × 10^5. For neutrophils: naïve versus PbA; *mean diff=1.51 × 10^6, CHIKV versus PbA; *mean diff=1.34 × 10^6, CHIKV versus PbA + CHIKV; *mean diff=−1.32 × 10^6, PbA versus PbA + CHIKV; ***mean diff=−2.66 × 10^6.Numbers of IFNγ‐producing CD4^+ T cells, CD8^+ T cells, NK cells, NKT cells, and neutrophils in the spleen of naïve (n=5), CHIKV (n=5), PbA (n=6) and PbA + CHIKV (n=8) on 6 dpi. All data analyzed by one‐way ANOVA with Tukey's post‐test. For IFNγ^+CD4^+ T cells: naïve versus PbA + CHIKV; ***mean diff=−5.99 × 10^6, CHIKV versus PbA + CHIKV; ***mean diff=−5.52 × 10^6, PbA versus PbA + CHIKV; ***mean diff=−3.95 × 10^6. For IFNγ^+CD8^+ T cells: naïve versus PbA + CHIKV; *mean diff=−9.28 × 10^5, CHIKV versus PbA + CHIKV; **mean diff=−1.08 × 10^6. For IFNγ^+ NK cells: naïve versus CHIKV; ***mean diff=1.83 × 10^5, naïve versus PbA; ***mean diff=2.81 × 10^5, naïve versus PbA + CHIKV; ***mean diff=2.83 × 10^5. For IFNγ^+ NKT cells: naïve versus PbA + CHIKV; *mean diff=−68295, CHIKV versus PbA + CHIKV; **mean diff=−93362, PbA versus PbA + CHIKV; **mean diff=−80084. For IFNγ^+ neutrophils: naïve versus PbA; *mean diff=1.58 × 10^6, CHIKV versus PbA; *mean diff=1.40 × 10^6, PbA versus PbA + CHIKV; ***mean diff=−2.50 × 10^6.\",\n", + " 'paragraph_id': 53,\n", + " 'tokenizer': \"increased, if, ##n, ##γ, producing, cd, ##4, ^, +, t, cells, in, the, sp, ##leen, drives, the, enhanced, sp, ##len, ##ic, if, ##n, ##γ, on, 6, d, ##pi, during, concurrent, co, ‐, infection, ##re, ##pres, ##ent, ##ative, his, ##to, ##gram, showing, if, ##n, ##γ, production, in, cd, ##4, ^, +, t, cells, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, in, the, sp, ##leen, of, naive, (, n, =, 5, ), ,, chi, ##k, ##v, (, n, =, 5, ), ,, pba, (, n, =, 6, ), ,, and, pba, +, chi, ##k, ##v, (, n, =, 8, ), on, 6, d, ##pi, ., black, dotted, line, represents, threshold, setting, for, if, ##n, ##γ, ^, +, cells, ., numbers, of, cd, ##4, ^, +, t, cells, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, in, the, sp, ##leen, of, naive, (, n, =, 5, ), ,, chi, ##k, ##v, (, n, =, 5, ), ,, pba, (, n, =, 6, ), ,, and, pba, +, chi, ##k, ##v, (, n, =, 8, ), on, 6, d, ##pi, ., cd, ##4, ^, +, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, were, defined, as, cd, ##3, ^, +, cd, ##4, ^, +, ,, cd, ##3, ^, +, cd, ##8, ^, +, ,, cd, ##3, ^, −, ##nk, ##1, ., 1, ^, +, ,, cd, ##3, ^, +, nk, ##1, ., 1, ^, +, ,, and, cd, ##3, ^, −, ##cd, ##11, ##b, ^, +, l, ##y, ##6, ##g, ^, +, cells, ,, respectively, ., all, data, analyzed, by, one, ‐, way, an, ##ova, with, tu, ##key, ', s, post, ‐, test, ., for, cd, ##4, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##1, ., 49, ×, 10, ^, 7, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##1, ., 57, ×, 10, ^, 7, ., for, cd, ##8, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 61, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 43, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 75, ×, 10, ^, 6, ., for, nk, cells, :, naive, versus, pba, ;, *, *, *, mean, di, ##ff, =, 5, ., 22, ×, 10, ^, 6, ,, naive, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, 4, ., 03, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, ;, *, *, *, mean, di, ##ff, =, 5, ., 39, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, 4, ., 20, ×, 10, ^, 6, ., for, nk, ##t, cells, :, naive, versus, pba, ;, *, mean, di, ##ff, =, 7, ., 95, ×, 10, ^, 5, ,, chi, ##k, ##v, versus, pba, ;, *, mean, di, ##ff, =, 7, ., 34, ×, 10, ^, 5, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##8, ., 19, ×, 10, ^, 5, ., for, ne, ##ut, ##rop, ##hil, ##s, :, naive, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 51, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 34, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##1, ., 32, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##2, ., 66, ×, 10, ^, 6, ., numbers, of, if, ##n, ##γ, ‐, producing, cd, ##4, ^, +, t, cells, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, in, the, sp, ##leen, of, naive, (, n, =, 5, ), ,, chi, ##k, ##v, (, n, =, 5, ), ,, pba, (, n, =, 6, ), and, pba, +, chi, ##k, ##v, (, n, =, 8, ), on, 6, d, ##pi, ., all, data, analyzed, by, one, ‐, way, an, ##ova, with, tu, ##key, ', s, post, ‐, test, ., for, if, ##n, ##γ, ^, +, cd, ##4, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##5, ., 99, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##5, ., 52, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##3, ., 95, ×, 10, ^, 6, ., for, if, ##n, ##γ, ^, +, cd, ##8, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 28, ×, 10, ^, 5, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##1, ., 08, ×, 10, ^, 6, ., for, if, ##n, ##γ, ^, +, nk, cells, :, naive, versus, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, 1, ., 83, ×, 10, ^, 5, ,, naive, versus, pba, ;, *, *, *, mean, di, ##ff, =, 2, ., 81, ×, 10, ^, 5, ,, naive, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, 2, ., 83, ×, 10, ^, 5, ., for, if, ##n, ##γ, ^, +, nk, ##t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##6, ##8, ##29, ##5, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##9, ##33, ##6, ##2, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##80, ##0, ##8, ##4, ., for, if, ##n, ##γ, ^, +, ne, ##ut, ##rop, ##hil, ##s, :, naive, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 58, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 40, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##2, ., 50, ×, 10, ^, 6, .\"},\n", + " {'article_id': 'a3907f2d4d6a3e337073dd74e676efbc',\n", + " 'section_name': 'INTRODUCTION',\n", + " 'text': \"Endogenous circadian clocks enable organisms to predict and adapt to environmental 24h rhythms that are caused by the earth's rotation around its own axis. The hence resulting circadian rhythms in physiology and behavior persist even in the absence of environmental Zeitgebers under constant conditions. Over the past years, the molecular mechanism driving circadian rhythmicity, several interlocked transcriptional and translational feedback loops could be described in large detail for the common model organisms, for example, Synechococcus elongatus, Neurospora crassa, Arabidopsis thaliana, Drosophila melanogaster, and Mus musculus (reviewed by Brown, Kowalska, & Dallmann, 2012). In Drosophila melanogaster ca. 150 clock neurons in the central nervous system, named after their size and location, show oscillations of core clock gene expression (e.g., period, timeless and clock). The neurons are further subdivided according to their neurochemical content and so far described function. Classically, they are divided into four lateral and three dorsal groups. Two of the lateral groups, the small and the large ventrolateral neurons (s‐LN_vs and l‐LNv_s, respectively; Figure 1) express the neuropeptide pigment dispersing factor (PDF), which has been shown to be an important signaling molecule of the circadian clock that modulates the other PDF‐responsive cell groups of the circadian system by slowing down their Ca^2+ oscillations (Liang, Holy, & Taghert, 2016, 2017). Further, it has been shown that the four PDF expressing s‐LN_vs are important to sustain rhythmicity in constant darkness (Helfrich‐Förster, 1998; Renn, Park, Rosbash, Hall, & Taghert, 1999). Since the s‐LN_vs are also important for the generation and proper timing of the morning activity peak, which is part of the characteristic bimodal locomotor activity pattern of Drosophila melanogaster, the small PDF cells are often referred to as M‐cells (Morning oscillators, Main‐pacemakers; Grima, Chélot, Xia, & Rouyer, 2004; Stoleru, Peng, Agosto, & Rosbash, 2004; Rieger, Shafer, Tomioka, & Helfrich‐Förster, 2006). In contrast, the evening activity peak is generated and controlled by the so‐called E‐cells, which comprise the 5th PDF lacking s‐LN_v, three Cryptochrome (CRY) expressing dorsolateral Neurons (LN_ds), three CRY lacking LN_ds, and six to eight dorsal neurons (DN_1). The classification in M‐ and E‐cells in respect to the traditional dual‐oscillator model (Pittendrigh & Daan, 1976), as well as more recent working models (Yao & Shafer, 2014) attribute the lateral clock neurons (LN_s) an essential role for the generation of the bimodal locomotor activity rhythm. The latter study nicely showed the diverse responsiveness of the CRY expressing E‐cells to secreted PDF, suggesting that the E‐oscillator is composed of different functional subunits (E1‐E3; Yao & Shafer, 2014) and that the circadian system is more likely a multi‐oscillator system (Rieger et al., 2006; Shafer, Helfrich‐Förster, Renn, & Taghert, 2006; Yao & Shafer, 2014). The E‐cells cannot only be distinguished by their properties, but also by their neurochemistry. The E1‐oscillator consists of two CRY expressing LN_ds which coexpress the short neuropeptide F (sNPF; Johard et al., 2009; Yao & Shafer, 2014), a peptide that has been shown to have an implication in promoting sleep by an inhibitory effect of the s‐LN_vs (Shang et al., 2013). Further, the two E1‐cells express the receptor for PDF (PDFR) and are strongly coupled to the s‐LN_vs' output (Yao & Shafer, 2014). The E2‐oscillator comprises one CRY expressing LN_d and the PDF lacking 5th s‐LN_v (Yao & Shafer, 2014). The two neurons also express the PDFR, but additionally contain the ion transport peptide (ITP), which gets rhythmically released in the dorsal brain to enhance evening activity and inhibit nocturnal activity (Hermann‐Luibl, Yoshii, Senthilan, Dircksen, & Helfrich‐Förster, 2014). The molecular oscillations of the E2‐cells are less strongly coupled to the M‐cells' output compared to the E1‐cells (Rieger et al., 2006; Yao & Shafer, 2014). The three remaining CRY negative LN_ds lack PDFR expression and form the E3‐unit, which is not directly coupled to the M‐cells' PDF‐signaling (Yao & Shafer, 2014).\",\n", + " 'paragraph_id': 2,\n", + " 'tokenizer': \"end, ##ogen, ##ous, circa, ##dian, clocks, enable, organisms, to, predict, and, adapt, to, environmental, 24, ##h, rhythms, that, are, caused, by, the, earth, ', s, rotation, around, its, own, axis, ., the, hence, resulting, circa, ##dian, rhythms, in, physiology, and, behavior, persist, even, in, the, absence, of, environmental, ze, ##it, ##ge, ##bers, under, constant, conditions, ., over, the, past, years, ,, the, molecular, mechanism, driving, circa, ##dian, rhythmic, ##ity, ,, several, inter, ##lock, ##ed, transcription, ##al, and, translation, ##al, feedback, loops, could, be, described, in, large, detail, for, the, common, model, organisms, ,, for, example, ,, syn, ##ech, ##oco, ##ccus, el, ##onga, ##tus, ,, ne, ##uro, ##sp, ##ora, cr, ##ass, ##a, ,, arab, ##ido, ##psis, tha, ##lian, ##a, ,, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, ,, and, mu, ##s, mu, ##scu, ##lus, (, reviewed, by, brown, ,, ko, ##wal, ##ska, ,, &, dal, ##lman, ##n, ,, 2012, ), ., in, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, ca, ., 150, clock, neurons, in, the, central, nervous, system, ,, named, after, their, size, and, location, ,, show, os, ##ci, ##llation, ##s, of, core, clock, gene, expression, (, e, ., g, ., ,, period, ,, timeless, and, clock, ), ., the, neurons, are, further, subdivided, according, to, their, ne, ##uro, ##chemical, content, and, so, far, described, function, ., classical, ##ly, ,, they, are, divided, into, four, lateral, and, three, dorsal, groups, ., two, of, the, lateral, groups, ,, the, small, and, the, large, vent, ##rol, ##ater, ##al, neurons, (, s, ‐, l, ##n, _, vs, and, l, ‐, l, ##n, ##v, _, s, ,, respectively, ;, figure, 1, ), express, the, ne, ##uro, ##pe, ##pt, ##ide, pigment, di, ##sper, ##sing, factor, (, pdf, ), ,, which, has, been, shown, to, be, an, important, signaling, molecule, of, the, circa, ##dian, clock, that, mod, ##ulates, the, other, pdf, ‐, responsive, cell, groups, of, the, circa, ##dian, system, by, slowing, down, their, ca, ^, 2, +, os, ##ci, ##llation, ##s, (, liang, ,, holy, ,, &, tag, ##her, ##t, ,, 2016, ,, 2017, ), ., further, ,, it, has, been, shown, that, the, four, pdf, expressing, s, ‐, l, ##n, _, vs, are, important, to, sustain, rhythmic, ##ity, in, constant, darkness, (, he, ##lf, ##rich, ‐, forster, ,, 1998, ;, ren, ##n, ,, park, ,, ro, ##sb, ##ash, ,, hall, ,, &, tag, ##her, ##t, ,, 1999, ), ., since, the, s, ‐, l, ##n, _, vs, are, also, important, for, the, generation, and, proper, timing, of, the, morning, activity, peak, ,, which, is, part, of, the, characteristic, bi, ##mo, ##dal, loco, ##moto, ##r, activity, pattern, of, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, ,, the, small, pdf, cells, are, often, referred, to, as, m, ‐, cells, (, morning, os, ##ci, ##lla, ##tors, ,, main, ‐, pace, ##makers, ;, grim, ##a, ,, che, ##lot, ,, xi, ##a, ,, &, ro, ##uy, ##er, ,, 2004, ;, stole, ##ru, ,, peng, ,, ago, ##sto, ,, &, ro, ##sb, ##ash, ,, 2004, ;, ri, ##eger, ,, sha, ##fer, ,, tom, ##io, ##ka, ,, &, he, ##lf, ##rich, ‐, forster, ,, 2006, ), ., in, contrast, ,, the, evening, activity, peak, is, generated, and, controlled, by, the, so, ‐, called, e, ‐, cells, ,, which, comprise, the, 5th, pdf, lacking, s, ‐, l, ##n, _, v, ,, three, crypt, ##och, ##rom, ##e, (, cry, ), expressing, do, ##rso, ##lateral, neurons, (, l, ##n, _, ds, ), ,, three, cry, lacking, l, ##n, _, ds, ,, and, six, to, eight, dorsal, neurons, (, d, ##n, _, 1, ), ., the, classification, in, m, ‐, and, e, ‐, cells, in, respect, to, the, traditional, dual, ‐, os, ##ci, ##lla, ##tor, model, (, pitt, ##end, ##ri, ##gh, &, da, ##an, ,, 1976, ), ,, as, well, as, more, recent, working, models, (, yao, &, sha, ##fer, ,, 2014, ), attribute, the, lateral, clock, neurons, (, l, ##n, _, s, ), an, essential, role, for, the, generation, of, the, bi, ##mo, ##dal, loco, ##moto, ##r, activity, rhythm, ., the, latter, study, nicely, showed, the, diverse, responsive, ##ness, of, the, cry, expressing, e, ‐, cells, to, secret, ##ed, pdf, ,, suggesting, that, the, e, ‐, os, ##ci, ##lla, ##tor, is, composed, of, different, functional, subunit, ##s, (, e, ##1, ‐, e, ##3, ;, yao, &, sha, ##fer, ,, 2014, ), and, that, the, circa, ##dian, system, is, more, likely, a, multi, ‐, os, ##ci, ##lla, ##tor, system, (, ri, ##eger, et, al, ., ,, 2006, ;, sha, ##fer, ,, he, ##lf, ##rich, ‐, forster, ,, ren, ##n, ,, &, tag, ##her, ##t, ,, 2006, ;, yao, &, sha, ##fer, ,, 2014, ), ., the, e, ‐, cells, cannot, only, be, distinguished, by, their, properties, ,, but, also, by, their, ne, ##uro, ##chemist, ##ry, ., the, e, ##1, ‐, os, ##ci, ##lla, ##tor, consists, of, two, cry, expressing, l, ##n, _, ds, which, coe, ##x, ##press, the, short, ne, ##uro, ##pe, ##pt, ##ide, f, (, s, ##np, ##f, ;, jo, ##hard, et, al, ., ,, 2009, ;, yao, &, sha, ##fer, ,, 2014, ), ,, a, peptide, that, has, been, shown, to, have, an, implication, in, promoting, sleep, by, an, inhibitor, ##y, effect, of, the, s, ‐, l, ##n, _, vs, (, shang, et, al, ., ,, 2013, ), ., further, ,, the, two, e, ##1, ‐, cells, express, the, receptor, for, pdf, (, pdf, ##r, ), and, are, strongly, coupled, to, the, s, ‐, l, ##n, _, vs, ', output, (, yao, &, sha, ##fer, ,, 2014, ), ., the, e, ##2, ‐, os, ##ci, ##lla, ##tor, comprises, one, cry, expressing, l, ##n, _, d, and, the, pdf, lacking, 5th, s, ‐, l, ##n, _, v, (, yao, &, sha, ##fer, ,, 2014, ), ., the, two, neurons, also, express, the, pdf, ##r, ,, but, additionally, contain, the, ion, transport, peptide, (, it, ##p, ), ,, which, gets, rhythmic, ##ally, released, in, the, dorsal, brain, to, enhance, evening, activity, and, inhibit, nocturnal, activity, (, hermann, ‐, lu, ##ib, ##l, ,, yo, ##shi, ##i, ,, sent, ##hila, ##n, ,, dir, ##cks, ##en, ,, &, he, ##lf, ##rich, ‐, forster, ,, 2014, ), ., the, molecular, os, ##ci, ##llation, ##s, of, the, e, ##2, ‐, cells, are, less, strongly, coupled, to, the, m, ‐, cells, ', output, compared, to, the, e, ##1, ‐, cells, (, ri, ##eger, et, al, ., ,, 2006, ;, yao, &, sha, ##fer, ,, 2014, ), ., the, three, remaining, cry, negative, l, ##n, _, ds, lack, pdf, ##r, expression, and, form, the, e, ##3, ‐, unit, ,, which, is, not, directly, coupled, to, the, m, ‐, cells, ', pdf, ‐, signaling, (, yao, &, sha, ##fer, ,, 2014, ), .\"},\n", + " {'article_id': 'ae8d1efced67593c317a1f1bc67a68a1',\n", + " 'section_name': 'Studies included in this review',\n", + " 'text': 'Table 1 presents some of the features of the papers included in the present work. Of the 29 studies, the first study [36] was published 50 years ago, in 1966. However, the majority of the studies (n = 15; 52%) were published in 2012–2016, and 24 (83%) of the studies found were published in the last 8 years. Only 4 (14%) were published before 2005. Most studies were conducted in the United States of America (n = 19; 65.52%), followed by the United Kingdom (n = 4; 13.79%) and Australia (n = 2; 6.90%). The remaining four studies were from Canada, India, Poland and Spain.Table 1Main features of the manuscripts included in this review (n = 29)FeaturesNumber (%)StudiesPublication year2012–201615 (51.72)I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV2007–20119 (31.03)XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV2002–20071 (3.45)XXV1966–20014 (13.79)XXVI, XXVII, XXVIII, XXIXPlace of the studyAustralia Canada India Poland Spain UK USA2 (6.90)1 (3.45)1 (3.45)1 (3.45)1 (3.45)4 (13.79)19 (65.52)XI, XIIIIVXVIIIVIIIII, III, XII, XXIIIIV, VI, VII, IX, X, XIV, XV, XVI, XVII, XIX, XX, XXI, XXII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIXType of participantsFaculty members and students1 (3.45)XXIIMaster’s degree health care professional students1 (3.45)XXINon-specified undergraduate students with neuroanatomy experience4 (13.79)VI, VIII, XI, XIIIParticipants without neuroanatomy experience3 (10.34)VII, IX, XVIUndergraduate or graduate biology students3 (10.34)XIV, XVII, XXIVUndergraduate biomedical students1 (3.45)IIUndergraduate medical students11 (37.93)I, III, IV, V, XII, XVIII, XX, XXIII, XXVII, XXVIII, XXIXUndergraduate psychology students4 (13.79)X, XIV, XV, XXVIUndergraduate or graduate physical/ocupational therapy students3 (10.35)XIX, XXIV, XXVNumber of participants+ 2013 (10.35)II, XVIII, XXIII151–2003 (10.35)XIII, XXVII, XXVIII101–1504 (13.79)V, XI, XX, XXIX51–10011 (37.93)IV, VI, VII, VIII, IX, XII, XV, XVI, XIX, XXI, XXII,0–508 (27.59)I, III, X, XIV, XVII, XXIV, XXV, XXVITeaching toolDigital tool14 (50.00)I, II, IV, VII, VIII, IX, XVI, XIX, XX, XXI, XXII, XXIII, XXV, XXVIINon-digital tool14 (50.00)III, V, VI, X, XI, XII, XIII, XIV, XV, XVII, XXIV, XXVI, XXVIII, XXIXType of teaching tool3D computer neuroanatomy tools 3D physical models Apps installed in tablets Case studies Computer-based neuroanatomy tools Equivalence-based instruction, EBI Face-to-face teaching Flipped classroom Inquiry-based laboratory instruction Intensive mode of delivery Interpolation of questions Near-peer teaching Renaissance artists’ depictions Self-instructional stations Truncated lectures, conceptual exercises and manipulatives6 (21.43)1 (3.57)1 (3.57)3 (10.71)6 (21.43)2 (7.14)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)I, IV, VII, VIII, IX, XVI,XXIIXIVXIX, XXI, XXII, XXIII, XXV, XXVIIIII, XVXIIIVVIXIXXIXXIIXXXVIIIXXIV',\n", + " 'paragraph_id': 11,\n", + " 'tokenizer': 'table, 1, presents, some, of, the, features, of, the, papers, included, in, the, present, work, ., of, the, 29, studies, ,, the, first, study, [, 36, ], was, published, 50, years, ago, ,, in, 1966, ., however, ,, the, majority, of, the, studies, (, n, =, 15, ;, 52, %, ), were, published, in, 2012, –, 2016, ,, and, 24, (, 83, %, ), of, the, studies, found, were, published, in, the, last, 8, years, ., only, 4, (, 14, %, ), were, published, before, 2005, ., most, studies, were, conducted, in, the, united, states, of, america, (, n, =, 19, ;, 65, ., 52, %, ), ,, followed, by, the, united, kingdom, (, n, =, 4, ;, 13, ., 79, %, ), and, australia, (, n, =, 2, ;, 6, ., 90, %, ), ., the, remaining, four, studies, were, from, canada, ,, india, ,, poland, and, spain, ., table, 1, ##main, features, of, the, manuscripts, included, in, this, review, (, n, =, 29, ), features, ##num, ##ber, (, %, ), studies, ##pu, ##bl, ##ication, year, ##20, ##12, –, 2016, ##15, (, 51, ., 72, ), i, ,, ii, ,, iii, ,, iv, ,, v, ,, vi, ,, vii, ,, viii, ,, ix, ,, x, ,, xi, ,, xii, ,, xiii, ,, xiv, ,, xv, ##200, ##7, –, 2011, ##9, (, 31, ., 03, ), xvi, ,, xvi, ##i, ,, xvi, ##ii, ,, xi, ##x, ,, xx, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iii, ,, xx, ##iv, ##200, ##2, –, 2007, ##1, (, 3, ., 45, ), xx, ##v, ##19, ##66, –, 2001, ##4, (, 13, ., 79, ), xx, ##vi, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##pl, ##ace, of, the, study, ##aus, ##tral, ##ia, canada, india, poland, spain, uk, usa, ##2, (, 6, ., 90, ), 1, (, 3, ., 45, ), 1, (, 3, ., 45, ), 1, (, 3, ., 45, ), 1, (, 3, ., 45, ), 4, (, 13, ., 79, ), 19, (, 65, ., 52, ), xi, ,, xiii, ##iv, ##x, ##vi, ##ii, ##vi, ##iii, ##i, ,, iii, ,, xii, ,, xx, ##iii, ##iv, ,, vi, ,, vii, ,, ix, ,, x, ,, xiv, ,, xv, ,, xvi, ,, xvi, ##i, ,, xi, ##x, ,, xx, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iv, ,, xx, ##v, ,, xx, ##vi, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##type, of, participants, ##fa, ##cu, ##lty, members, and, students, ##1, (, 3, ., 45, ), xx, ##ii, ##master, ’, s, degree, health, care, professional, students, ##1, (, 3, ., 45, ), xx, ##ino, ##n, -, specified, undergraduate, students, with, ne, ##uro, ##ana, ##tom, ##y, experience, ##4, (, 13, ., 79, ), vi, ,, viii, ,, xi, ,, xiii, ##par, ##tic, ##ip, ##ants, without, ne, ##uro, ##ana, ##tom, ##y, experience, ##3, (, 10, ., 34, ), vii, ,, ix, ,, xvi, ##under, ##grad, ##uate, or, graduate, biology, students, ##3, (, 10, ., 34, ), xiv, ,, xvi, ##i, ,, xx, ##iv, ##under, ##grad, ##uate, biomedical, students, ##1, (, 3, ., 45, ), ii, ##under, ##grad, ##uate, medical, students, ##11, (, 37, ., 93, ), i, ,, iii, ,, iv, ,, v, ,, xii, ,, xvi, ##ii, ,, xx, ,, xx, ##iii, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##under, ##grad, ##uate, psychology, students, ##4, (, 13, ., 79, ), x, ,, xiv, ,, xv, ,, xx, ##vi, ##under, ##grad, ##uate, or, graduate, physical, /, o, ##cup, ##ation, ##al, therapy, students, ##3, (, 10, ., 35, ), xi, ##x, ,, xx, ##iv, ,, xx, ##vn, ##umber, of, participants, +, 2013, (, 10, ., 35, ), ii, ,, xvi, ##ii, ,, xx, ##iii, ##15, ##1, –, 2003, (, 10, ., 35, ), xiii, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ##10, ##1, –, 150, ##4, (, 13, ., 79, ), v, ,, xi, ,, xx, ,, xx, ##ix, ##51, –, 100, ##11, (, 37, ., 93, ), iv, ,, vi, ,, vii, ,, viii, ,, ix, ,, xii, ,, xv, ,, xvi, ,, xi, ##x, ,, xx, ##i, ,, xx, ##ii, ,, 0, –, 50, ##8, (, 27, ., 59, ), i, ,, iii, ,, x, ,, xiv, ,, xvi, ##i, ,, xx, ##iv, ,, xx, ##v, ,, xx, ##vite, ##achi, ##ng, tool, ##di, ##git, ##al, tool, ##14, (, 50, ., 00, ), i, ,, ii, ,, iv, ,, vii, ,, viii, ,, ix, ,, xvi, ,, xi, ##x, ,, xx, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iii, ,, xx, ##v, ,, xx, ##vi, ##ino, ##n, -, digital, tool, ##14, (, 50, ., 00, ), iii, ,, v, ,, vi, ,, x, ,, xi, ,, xii, ,, xiii, ,, xiv, ,, xv, ,, xvi, ##i, ,, xx, ##iv, ,, xx, ##vi, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##type, of, teaching, tool, ##3d, computer, ne, ##uro, ##ana, ##tom, ##y, tools, 3d, physical, models, apps, installed, in, tablets, case, studies, computer, -, based, ne, ##uro, ##ana, ##tom, ##y, tools, equivalence, -, based, instruction, ,, e, ##bi, face, -, to, -, face, teaching, flipped, classroom, inquiry, -, based, laboratory, instruction, intensive, mode, of, delivery, inter, ##pol, ##ation, of, questions, near, -, peer, teaching, renaissance, artists, ’, depictions, self, -, instructional, stations, truncated, lectures, ,, conceptual, exercises, and, mani, ##pu, ##lative, ##s, ##6, (, 21, ., 43, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 3, (, 10, ., 71, ), 6, (, 21, ., 43, ), 2, (, 7, ., 14, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), i, ,, iv, ,, vii, ,, viii, ,, ix, ,, xvi, ,, xx, ##ii, ##xi, ##v, ##xi, ##x, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iii, ,, xx, ##v, ,, xx, ##vi, ##iii, ##i, ,, xv, ##xi, ##ii, ##v, ##vi, ##xi, ##xx, ##ix, ##xi, ##ix, ##xx, ##vi, ##ii, ##xx, ##iv'},\n", + " {'article_id': 'ae8d1efced67593c317a1f1bc67a68a1',\n", + " 'section_name': 'Computer-based neuroanatomy tools',\n", + " 'text': 'Table 2 summarizes each study included in this review, including the teaching tool used, aims, methodology employed, and main results/conclusion. Some researchers [23–28] focused their studies on the impact of using computer-based tools for teaching neuroanatomy. More specifically, McKeough et al. [23, 24] investigated the effect of a computer-based tool on students’ performance and their attitudes. Before and after test questions revealed that scores improved significantly after working with the learning model. In addition, students reported the computer-aided neuroanatomy learning modules as a valuable and enjoyable learning tool, and perceived their clinical-self efficacy as higher as a result of working with them.Table 2Summary description of the 29 studies included in this review (listed by year of publication)TitleAuthors (year)University, countryParticipants (number)Teaching toolAimMethodologyMain results/conclusionEvaluation of an online three-dimensional interactive resource for undergraduate neuroanatomy education^IAllen et al. (2016)Western University, CanadaSecond-year undergraduate medical students (n = 47)3D computer neuroanatomy model (digital tool)To evaluate the impact on learning of a novel, interactive 3D neuroanatomy model.Participants were divided into 2 groups, each accessing 2 learning modalities (3D model and a cadaveric laboratory session). After each modality, students completed a test. (mix between- and within- subject design)Participants were pleased to work with the 3D model. In addition, their learning outcomes significantly improved after accessing this teaching tool.Mobile technology: students perceived benefits of apps for learning neuroanatomy^IIMorris et al. (2016)University of Leeds, UKUndergraduate biomedical students enrolled in a level 2 course (n = 519)5 apps installed in tablet (Apple iPad) devices (digital tool)To examine the students’ use of apps in a neuroanatomy practical class: their perceptions and learning outcomes.There were three cohorts of students (3-year study). The neuroanatomy practical session included the use of tablet devices. After the session the students completed a questionnaire about the use of the apps.Students made extensive use of the apps, considered them easy to use and beneficial for learning. Compared with the year before the trial started, there was an increase in the students’ performance.The student experience of applied equivalence-based instruction for neuroanatomy teaching^IIIGreville et al. (2016)Swansea University, UKFirst- and second-year undergraduate medical students (n = 43)Equivalence-based instruction, EBI (non-digital tool)To develop and assess the effectiveness of EBI learning resources.Initially participants completed a pre-test. Then the learning of the relations occurred, followed by a post-test design to assess students’ learning. (within-subject design)The EBI resources were an effective, efficient and well-received method for teaching neuroanatomy.Development and assessment of a new 3D neuroanatomy teaching tool for MRI training^IVDrapkin et al. (2015)Brown University, USAFirst-year undergraduate medical students (n = 73)3D computer neuroanatomy model (digital tool)To create and evaluate the efficacy of a computerized 3D neuroanatomy teaching toolParticipants were divided into two groups. The first group was taught using the 3D teaching tool, and the second using traditional methods. Scores from an MRI identification quiz and survey were compared. (between-subject design)The 3D teaching tool was an effective way to train students to read an MRI of the brain and particularly effective for teaching C-shaped internal brain structures.Perception of MBBS students to “flipped class room” approach in neuroanatomy module^VVeeramani et al. (2015)Jawaharlal Institute of Postgraduate Medical Education and Research, IndiaFirst-year undergraduate medical students (n = 130)Flipped classroom (non-digital tool)To examine the impact of a flipped classroom approach (i.e., assess students’ perception and the impact on their performance and attitudes)Pre- and post-tests were designed to test the learning aims of the session. The perception of the students was also assessed. (within- subject design)Results showed significant differences between the pre and post-test scores. Student response to the flipped classroom structure was largely positiveA mind of their own: Using inquiry-based teaching to build critical thinking skills and intellectual engagement in an undergraduate neuroanatomy course^VIGreenwald & Quitadamo (2014)A regional university in the Pacific Northwest, USAUndergraduate students enrolled in a human neuroanatomy course (n = 85)Inquiry-based clinical case, IBCC (non-digital tool)To determine which teaching method (conventional and IBCC) produces greater gains in critical thinking and content knowledgeParticipants were divided into two groups: conventional and Experimental group. All students were analyzed for exam and course grade performance. Critical thinking pre- and post- tests were analyzed. (mix between- and within- subject design)Using the California critical thinking skills test, students in the conventional neuroanatomy course gained less than 3 national percentile ranks, whereas IBCC students gained over 7.5 within one academic term.Computer-based learning: graphical integration of whole and sectional neuroanatomy improves long-term retention^VIINaaz et al. (2014)University of Louisville, USAVolunteers between 16 and 34 years, with minimal or no knowledge of neuroanatomy (n = 64)3D computer neuroanatomy models (digital tool)To examine if instruction with graphically integrated representations of whole and sectional neuroanatomy is effectiveParticipants were divided into two groups. After a pretest, participants learned sectional anatomy using one of the two learning programs: sections only or 2-D/3-D. Then tests of generalization were completed. (between- subject design)It showed that the use of graphical representation helps students to achieve a deeper understanding of complex spatial relationsEnhancing neuroanatomy education using computer-based instructional material^VIIIPalomera et al. (2014)University of Salamanca, SpainUndergraduate students enrolled in a medical anatomy course (n = 65)3D computer neuroanatomy models (digital tool)To develop a computer-based tool based on 3D images, and to examine if the for this tool depends on their visuospatial abilityParticipants completed an online rating-scale to measure the educational value that they assigned to the teaching tool. In addition, the student’s visuospatial aptitude was assessed. (between-subject design)Findings showed that students assigned a high educational value to this tool, regardless of their visuospatial skills.Computer-based learning: Interleaving whole and sectional representation of neuroanatomy^IXPani et al. (2013)University of Louisville, USAUndergraduate students with rudimentary knowledge of neuroanatomy (n = 59)3D computer neuroanatomy model (digital tool)To compare a basic transfer method for learning whole and sectional neuroanatomy with a method in which both forms of representation were interleaved.There were 3 experimental conditions: i) section only, ii) whole then sections; and iii) alternation. (between-subject design)Interleaved learning of whole and sectional neuroanatomy was more efficient than the basic transfer method.Da Vinci coding? Using renaissance artists’ depictions of the brain to engage student interest in neuroanatomy^XWatson (2013)Lewis & Clark College, USAUndergraduate psychology students (n = 27)Renaissance artists’ depictions of the central nervous system (non-digital tool)To increase students’ interest in the study of neuroanatomyThere were interactive classroom exercises using well-known Renaissance artists’ depictions of the brain. Then participants completed a feedback questionnaire.These exercises increased the interest of the students in the topic. The authors suggest that these exercises may be a useful addition to courses that introduce or review neuroanatomical concepts.Intensive mode delivery of a neuroanatomy unit: Lower final grades but higher student satisfaction^XIWhillier, & Lystad, (2013)Macquarie University, AustraliaUndergraduate students enrolled in the traditional and intensive neuroanatomy units (n = 125)Intensive mode of delivery (non-digital tool)To compare the intensive and traditional units of neuroanatomy for undergraduate students.The intensive mode neuroanatomy unit showed the students the same quantity and quality of material to the same standard, including the hours. However, the material was delivered in a shorter timeframe. (between-subject design)Students obtained lower final grades in the new intensive mode delivery but reported having similar overall satisfaction with their laboratory practical classes.Near-peer teaching in clinical neuroanatomy^XIIHall et al. (2013)University of Southampton, UKUndergraduate medical students (n = 60)Near-peer teaching (non-digital tool)To develop and deliver a near-peer programme of study.Two medical students organized and delivered the teaching to their colleges in a series of seven sessions. At the end of each session, participants were asked to fill a feedback questionnaire. (within-subject design)Students’ perceived level of knowledge increased after the near-peer teaching sessions, supporting the use of this teaching tool in neuroanatomy courses.The effect of face-to-face teaching on student knowledge and satisfaction in an undergraduate neuroanatomy course^XIIIWhillier & Lystad, (2013)Macquarie University, AustraliaUndergraduate students enrolled in the new and old neuroanatomy units (n = 181)Face-to-face teaching (non-digital tool)To examine if face-to-face teaching has an impact on student performance and overall satisfaction with the course.Two groups of students (old and restructured unit of neuroanatomy) were analyzed. A questionnaire was used to compare them in terms of the rate they gave to the course, satisfaction, and final grades. (between-subject design)The increase in total face-to-face teaching hours in the restructured unit of neuroanatomy does not improve student grades. However, it does increase student satisfaction.Using case studies as a semester-long tool to teach neuroanatomy and structure-function relationships to undergraduates^XIVKennedy (2013)Denison Univer, USAUndergraduate biology and psychology students (n = 50)Case studies (non-digital tool)To investigate the effect of teaching neuroanatomy through presentation and discussion of case studies.Students were expected to collaborate with their colleges in small groups. In each case study, the entire class was asked to participate in some aspect of the case.Students report enjoying learning brain structure using this method, and commented positively on the class activities associated with learning brain anatomy.Using equivalence-based instruction to increase efficiency in teaching neuroanatomy^XVPytte & Fienup (2012)Queens College, USAUndergraduate students, primarily of psychology majors (n = 93)Equivalence-Based Instruction, EBI (non-digital tool)To study if EBI is effective in teaching neuroanatomy in a large classroom settingFourteen brain regions were identified, and conditional relations were explicitly taught during three lectures. Then, students completed test to evaluate some relations that were taught and some not taught.Selection of associations by the teacher can encourage the spontaneous emergence of novel associations within a concept or category. Therefore, it can increase the efficiency of teaching.Computer-based learning of neuroanatomy: a longitudinal study of llearning, transfer, and retention^XVIChariker et al. (2011)University of Louisville, USAUndergraduate students who reported minimal knowledge of neuroanatomy (n = 72)3D computer neuroanatomy model (digital tool)To determine the effectiveness of new methods for teaching neuroanatomy with computer-based instructionUsing a 3D graphical model of the human brain, students learned either sectional anatomy alone (with perceptually continuous or discrete navigation) or whole anatomy followed by sectional anatomy. Participants were tested immediately and after 2–3 weeks. (between-subject design)Results showed efficient learning, good long-term retention, and successful transfer to the interpretation of biomedical images. They suggest that computer-based learning can be a valuable teaching tool.Human brains engaged in rat brains: student-driven neuroanatomy research in an introductory biology lab course^XVIIGardner et al. (2011)Purdue University, USAFirst-year undergraduate students interested in majoring in biology (n = 13)Inquiry-based laboratory instruction (non-digital tool)To increase student interest in biology by exposing them to novel research projectsStudents acquired basic lab skills within the context of a research question of a member of the faculty. Biology students who were not taking the research-based, Bio-CASPiE course, formed the comparison group for pre- and post-semester questionnaires. (mix between-within- subject design)The inquiry-based laboratory instruction increased students’ motivation and excitement, encouraged good scientific practices, and can potentially benefit departmental research.The study techniques of Asian, American, and European medical students during gross anatomy and neuroanatomy courses in Poland^XVIIIZurada et al. (2011)Medical University in Poland, PolandInternational medical students, from the Polish, American, and Taiwanese divisions (n = 705)–To investigate similarities and differences among American, Asian, and European medical students in terms of their study methods.Participants completed a questionnaire in which they reported which methods they used to study, and which of the methods they believed were most efficient for comprehension, memorization, and review. (between-subject design)Results showed some differences in study techniques among students from the different ethnic back- grounds (e.g., Polish and American preferred the use of dissections and prosected specimens)Effectiveness of a computer-aided neuroanatomy program for entry-level physical therapy students: anatomy and clinical examination of the dorsal column-medial lemniscal system^XIXMcKeoughet al. (2010)California State University & University of the Pacific, USAUndergraduate physical therapy students (n = 61)Computer-aided instruction, CAI (digital tool)To determine if a computer- aided instruction learning module improves students’ neuroanatomy knowledgeStudents completed a paper-and-pencil test on the neuroanatomy/physiology and clinical examination of the DCML system, both before and after working with the teaching tool (within-subject design)Findings showed that clinical examination post-test scores improved significantly from the pre-test scoresA Novel Three-Dimensional Tool for Teaching Human Neuroanatomy^XXEstevez et al. (2010)Boston University School of Medicine, USAFirst-year undergraduate medical students (n = 101)3D physical neuroanatomy model (digital tool)To develop and assess a new tool forg teaching 3D neuroanatomy to first-year medical studentsFirst, all students were presented to traditional 2D methods. Then, the experimental group constructed 3D color-coded physical models, while the control group re-examined 2D brain cross-sections. (between-subject design)3D computer model was an effective method for teaching spatial relationships of brain anatomy and seems to better prepare students for visualization of 3D neuroanatomyAttitudes of health care students about computer-aided neuroanatomy instruction^XXIMcKeough& Bagatell (2009)A University in the West Coast, USAMaster’s degree health care professional students (n = 77)Computer-aided instruction, CAI (digital tool)To examine students’ attitudes toward CAI, which factors help their development, and their implications.Three computer-aided neuroanatomy learning modules were used. Students independently reviewed the modules as supplements to lecture and completed a survey to evaluate teaching effectiveness (within-subject design)The CAI modules examined in this study were effective as adjuncts to lecture in helping the students learn and make clinical applications of neuroanatomy informationA usability study of users’ perceptions toward a multimedia computer-assisted learning tool for neuroanatomy^XXIIGould et al. (2008)University of Kentucky & University of Louisville & Nova Southeastern University, USAFaculty and students from some institutions across the country (n = 62)Computer-aided instruction, CAI (digital tool)To assess users’ perceptions of the computer-based tool: “Anatomy of the Central Nervous System: A Multimedia Course”First, participants used the multimedia prototype. Then they completed a usability questionnaire designed to measure two usability properties: program need and program applicabilityThis study showed that the CAI was well-designed for all users, and demonstrates the importance of integrating quality properties of usability with principles of human learning.Attitudes to e-learning, learning style and achievement in learning neuroanatomy by medical students^XXIIISvirko & Mellanby (2008)Oxford University, UKSecond-year pre-clinical undergraduate medical students (n = 205)Computer-aided learning, CAL (digital tool)To investigate the impact of an online course on encouraging students to learn and their academic performance.The students approach to learning towards the CAL course and towards their studies in general was compared. Student attitudes and ratings were also assessed.Findings revealed that students reported using significantly less deep approach to learning for the CAL course.Using truncated lectures, conceptual exercises, and manipulatives to improve learning in the neuroanatomy classroom^XXIVKrontiris-Litowitz (2008)Youngstown State University, USAUndergraduate biology and graduate biology and physical therapy students (n = 19)Truncated lectures, conceptual exercises, and manipulatives (non-digital tool)To use truncated lectures, conceptual exercises, and manipulatives to make learning more effective and increase critical thinkingThe curriculum was revised. More specifically, it became shorter, included practice problems that presented the spinal tracts in an applied context, and included a manipulative. Student’s learning was then assessed and compared with previous classes. (between-subject design).Students’ learning was more effective under the revised curriculum, suggesting that this revised curriculum could potentially be applied to other topics.Design and utility of a web-based computer-assisted instructional tool for neuroanatomy self-study and review for physical and occupational therapy graduate students^XXIVForeman et al. (2005)University of Utah, USAUndergraduate physical therapy and occupational therapy students (n = 43)Computer-assisted instruction, CAI (digital tool)To develop a CAI, and assess their design and utility to teach neuroanatomy.A questionnaire addressed navigation, clarity of the images, benefit of the CAI tool, and students rating. Students were also asked to compare this tool with traditional learning tools.Design and utility of a web-based computer-assisted instructional tool for neuroanatomy self-study and review for physical and occupational therapy graduate students^XXIVA neuroanatomy teaching activity using case studies and collaboration^XXVISheldon (2000)University of Michigan, USAUndergraduatestudents of an introductory psychology course (n = 28)Case studies and collaboration (non-digital tool)To evaluate an easier and less time-consuming method for teaching neuroanatomy.Students collaborated and applied their neuroanatomy knowledge to several case studies during classes.Findings showed that students assessed this method as very enjoyable and helpful for remembering or learning the material.Computer-based neuroanatomy laboratory for medical students^XXVIILamperti & Sodicoff (1997)Temple University, USAFirst-year undergraduate medical students (n = 185)Computer-based neuroanatomy laboratory (digital tool)To develop a computer-based laboratory program to substitute the traditional glass-slide laboratoryThey compared the performances of those classes that previously had the traditional laboratory with two succeeding classes that used computer program (between-subject design).Test scores showed that the students’ performance on laboratory material was similar in both classes.Teaching of neuroanatomy by means of self-instructional laboratory stations^XXVIIIFisher et al. (1980)University of Michigan Medical School, USAFirst-year undergraduate medical students (n = 200)Self-instructional stations (non-digital tool)To teach neuroanatomy using self-instructional laboratory stationsNeuroanatomical laboratory material was presented in a series of six self-instructional stations. Five weeks later, short examinations tests occurred.Results of the tests indicated a mastery of station material as defined by the objectives and an ability to use the material in applied problems.Cognitive processes in learning neuroanatomy^XXIXGeeartsma & Matzke (1966)University of Kansas, USAFirst-year undergraduate medical students (n = 107)Interpolation of questions (non-digital tool)To investigate the effect of interpolation of questions into a lecture presentation.Participants were divided into 2 matched groups. Each group was shown lectures on the visual system which differed only in regard to taxomic level of 10 questions posed lecture. Performance was then measured (between-subject design).Emphasis on recall questions aids performance on subsequent recall questions more than emphasis on problem-solving questions helps in the solution of subsequent problem-solving questions.',\n", + " 'paragraph_id': 14,\n", + " 'tokenizer': 'table, 2, sum, ##mar, ##izes, each, study, included, in, this, review, ,, including, the, teaching, tool, used, ,, aims, ,, methodology, employed, ,, and, main, results, /, conclusion, ., some, researchers, [, 23, –, 28, ], focused, their, studies, on, the, impact, of, using, computer, -, based, tools, for, teaching, ne, ##uro, ##ana, ##tom, ##y, ., more, specifically, ,, mc, ##ke, ##ough, et, al, ., [, 23, ,, 24, ], investigated, the, effect, of, a, computer, -, based, tool, on, students, ’, performance, and, their, attitudes, ., before, and, after, test, questions, revealed, that, scores, improved, significantly, after, working, with, the, learning, model, ., in, addition, ,, students, reported, the, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, learning, modules, as, a, valuable, and, enjoyable, learning, tool, ,, and, perceived, their, clinical, -, self, efficacy, as, higher, as, a, result, of, working, with, them, ., table, 2, ##sum, ##mar, ##y, description, of, the, 29, studies, included, in, this, review, (, listed, by, year, of, publication, ), title, ##au, ##thor, ##s, (, year, ), university, ,, country, ##par, ##tic, ##ip, ##ants, (, number, ), teaching, tool, ##ai, ##mme, ##th, ##od, ##ology, ##main, results, /, conclusion, ##eva, ##lu, ##ation, of, an, online, three, -, dimensional, interactive, resource, for, undergraduate, ne, ##uro, ##ana, ##tom, ##y, education, ^, ia, ##llen, et, al, ., (, 2016, ), western, university, ,, canada, ##se, ##con, ##d, -, year, undergraduate, medical, students, (, n, =, 47, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, evaluate, the, impact, on, learning, of, a, novel, ,, interactive, 3d, ne, ##uro, ##ana, ##tom, ##y, model, ., participants, were, divided, into, 2, groups, ,, each, access, ##ing, 2, learning, mod, ##ali, ##ties, (, 3d, model, and, a, cad, ##aver, ##ic, laboratory, session, ), ., after, each, mod, ##ality, ,, students, completed, a, test, ., (, mix, between, -, and, within, -, subject, design, ), participants, were, pleased, to, work, with, the, 3d, model, ., in, addition, ,, their, learning, outcomes, significantly, improved, after, access, ##ing, this, teaching, tool, ., mobile, technology, :, students, perceived, benefits, of, apps, for, learning, ne, ##uro, ##ana, ##tom, ##y, ^, ii, ##mo, ##rri, ##s, et, al, ., (, 2016, ), university, of, leeds, ,, uk, ##under, ##grad, ##uate, biomedical, students, enrolled, in, a, level, 2, course, (, n, =, 51, ##9, ), 5, apps, installed, in, tablet, (, apple, ipad, ), devices, (, digital, tool, ), to, examine, the, students, ’, use, of, apps, in, a, ne, ##uro, ##ana, ##tom, ##y, practical, class, :, their, perceptions, and, learning, outcomes, ., there, were, three, co, ##hort, ##s, of, students, (, 3, -, year, study, ), ., the, ne, ##uro, ##ana, ##tom, ##y, practical, session, included, the, use, of, tablet, devices, ., after, the, session, the, students, completed, a, question, ##naire, about, the, use, of, the, apps, ., students, made, extensive, use, of, the, apps, ,, considered, them, easy, to, use, and, beneficial, for, learning, ., compared, with, the, year, before, the, trial, started, ,, there, was, an, increase, in, the, students, ’, performance, ., the, student, experience, of, applied, equivalence, -, based, instruction, for, ne, ##uro, ##ana, ##tom, ##y, teaching, ^, iii, ##gre, ##ville, et, al, ., (, 2016, ), swansea, university, ,, uk, ##fi, ##rst, -, and, second, -, year, undergraduate, medical, students, (, n, =, 43, ), equivalence, -, based, instruction, ,, e, ##bi, (, non, -, digital, tool, ), to, develop, and, assess, the, effectiveness, of, e, ##bi, learning, resources, ., initially, participants, completed, a, pre, -, test, ., then, the, learning, of, the, relations, occurred, ,, followed, by, a, post, -, test, design, to, assess, students, ’, learning, ., (, within, -, subject, design, ), the, e, ##bi, resources, were, an, effective, ,, efficient, and, well, -, received, method, for, teaching, ne, ##uro, ##ana, ##tom, ##y, ., development, and, assessment, of, a, new, 3d, ne, ##uro, ##ana, ##tom, ##y, teaching, tool, for, mri, training, ^, iv, ##dra, ##p, ##kin, et, al, ., (, 2015, ), brown, university, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 73, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, create, and, evaluate, the, efficacy, of, a, computer, ##ized, 3d, ne, ##uro, ##ana, ##tom, ##y, teaching, tool, ##par, ##tic, ##ip, ##ants, were, divided, into, two, groups, ., the, first, group, was, taught, using, the, 3d, teaching, tool, ,, and, the, second, using, traditional, methods, ., scores, from, an, mri, identification, quiz, and, survey, were, compared, ., (, between, -, subject, design, ), the, 3d, teaching, tool, was, an, effective, way, to, train, students, to, read, an, mri, of, the, brain, and, particularly, effective, for, teaching, c, -, shaped, internal, brain, structures, ., perception, of, mb, ##bs, students, to, “, flipped, class, room, ”, approach, in, ne, ##uro, ##ana, ##tom, ##y, module, ^, v, ##ve, ##era, ##mani, et, al, ., (, 2015, ), jaw, ##aha, ##rl, ##al, institute, of, postgraduate, medical, education, and, research, ,, india, ##fi, ##rst, -, year, undergraduate, medical, students, (, n, =, 130, ), flipped, classroom, (, non, -, digital, tool, ), to, examine, the, impact, of, a, flipped, classroom, approach, (, i, ., e, ., ,, assess, students, ’, perception, and, the, impact, on, their, performance, and, attitudes, ), pre, -, and, post, -, tests, were, designed, to, test, the, learning, aims, of, the, session, ., the, perception, of, the, students, was, also, assessed, ., (, within, -, subject, design, ), results, showed, significant, differences, between, the, pre, and, post, -, test, scores, ., student, response, to, the, flipped, classroom, structure, was, largely, positive, ##a, mind, of, their, own, :, using, inquiry, -, based, teaching, to, build, critical, thinking, skills, and, intellectual, engagement, in, an, undergraduate, ne, ##uro, ##ana, ##tom, ##y, course, ^, vi, ##gree, ##n, ##wald, &, quit, ##ada, ##mo, (, 2014, ), a, regional, university, in, the, pacific, northwest, ,, usa, ##under, ##grad, ##uate, students, enrolled, in, a, human, ne, ##uro, ##ana, ##tom, ##y, course, (, n, =, 85, ), inquiry, -, based, clinical, case, ,, ib, ##cc, (, non, -, digital, tool, ), to, determine, which, teaching, method, (, conventional, and, ib, ##cc, ), produces, greater, gains, in, critical, thinking, and, content, knowledge, ##par, ##tic, ##ip, ##ants, were, divided, into, two, groups, :, conventional, and, experimental, group, ., all, students, were, analyzed, for, exam, and, course, grade, performance, ., critical, thinking, pre, -, and, post, -, tests, were, analyzed, ., (, mix, between, -, and, within, -, subject, design, ), using, the, california, critical, thinking, skills, test, ,, students, in, the, conventional, ne, ##uro, ##ana, ##tom, ##y, course, gained, less, than, 3, national, percent, ##ile, ranks, ,, whereas, ib, ##cc, students, gained, over, 7, ., 5, within, one, academic, term, ., computer, -, based, learning, :, graphical, integration, of, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, improves, long, -, term, retention, ^, vii, ##na, ##az, et, al, ., (, 2014, ), university, of, louisville, ,, usa, ##vo, ##lun, ##tee, ##rs, between, 16, and, 34, years, ,, with, minimal, or, no, knowledge, of, ne, ##uro, ##ana, ##tom, ##y, (, n, =, 64, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, models, (, digital, tool, ), to, examine, if, instruction, with, graphical, ##ly, integrated, representations, of, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, is, effective, ##par, ##tic, ##ip, ##ants, were, divided, into, two, groups, ., after, a, pre, ##test, ,, participants, learned, sectional, anatomy, using, one, of, the, two, learning, programs, :, sections, only, or, 2, -, d, /, 3, -, d, ., then, tests, of, general, ##ization, were, completed, ., (, between, -, subject, design, ), it, showed, that, the, use, of, graphical, representation, helps, students, to, achieve, a, deeper, understanding, of, complex, spatial, relations, ##en, ##han, ##cing, ne, ##uro, ##ana, ##tom, ##y, education, using, computer, -, based, instructional, material, ^, viii, ##pal, ##ome, ##ra, et, al, ., (, 2014, ), university, of, salamanca, ,, spain, ##under, ##grad, ##uate, students, enrolled, in, a, medical, anatomy, course, (, n, =, 65, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, models, (, digital, tool, ), to, develop, a, computer, -, based, tool, based, on, 3d, images, ,, and, to, examine, if, the, for, this, tool, depends, on, their, vis, ##uo, ##sp, ##ati, ##al, ability, ##par, ##tic, ##ip, ##ants, completed, an, online, rating, -, scale, to, measure, the, educational, value, that, they, assigned, to, the, teaching, tool, ., in, addition, ,, the, student, ’, s, vis, ##uo, ##sp, ##ati, ##al, apt, ##itude, was, assessed, ., (, between, -, subject, design, ), findings, showed, that, students, assigned, a, high, educational, value, to, this, tool, ,, regardless, of, their, vis, ##uo, ##sp, ##ati, ##al, skills, ., computer, -, based, learning, :, inter, ##lea, ##ving, whole, and, sectional, representation, of, ne, ##uro, ##ana, ##tom, ##y, ^, ix, ##pani, et, al, ., (, 2013, ), university, of, louisville, ,, usa, ##under, ##grad, ##uate, students, with, ru, ##diment, ##ary, knowledge, of, ne, ##uro, ##ana, ##tom, ##y, (, n, =, 59, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, compare, a, basic, transfer, method, for, learning, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, with, a, method, in, which, both, forms, of, representation, were, inter, ##lea, ##ved, ., there, were, 3, experimental, conditions, :, i, ), section, only, ,, ii, ), whole, then, sections, ;, and, iii, ), alter, ##nation, ., (, between, -, subject, design, ), inter, ##lea, ##ved, learning, of, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, was, more, efficient, than, the, basic, transfer, method, ., da, vinci, coding, ?, using, renaissance, artists, ’, depictions, of, the, brain, to, engage, student, interest, in, ne, ##uro, ##ana, ##tom, ##y, ^, x, ##wat, ##son, (, 2013, ), lewis, &, clark, college, ,, usa, ##under, ##grad, ##uate, psychology, students, (, n, =, 27, ), renaissance, artists, ’, depictions, of, the, central, nervous, system, (, non, -, digital, tool, ), to, increase, students, ’, interest, in, the, study, of, ne, ##uro, ##ana, ##tom, ##ythe, ##re, were, interactive, classroom, exercises, using, well, -, known, renaissance, artists, ’, depictions, of, the, brain, ., then, participants, completed, a, feedback, question, ##naire, ., these, exercises, increased, the, interest, of, the, students, in, the, topic, ., the, authors, suggest, that, these, exercises, may, be, a, useful, addition, to, courses, that, introduce, or, review, ne, ##uro, ##ana, ##tom, ##ical, concepts, ., intensive, mode, delivery, of, a, ne, ##uro, ##ana, ##tom, ##y, unit, :, lower, final, grades, but, higher, student, satisfaction, ^, xi, ##w, ##hill, ##ier, ,, &, l, ##yst, ##ad, ,, (, 2013, ), macquarie, university, ,, australia, ##under, ##grad, ##uate, students, enrolled, in, the, traditional, and, intensive, ne, ##uro, ##ana, ##tom, ##y, units, (, n, =, 125, ), intensive, mode, of, delivery, (, non, -, digital, tool, ), to, compare, the, intensive, and, traditional, units, of, ne, ##uro, ##ana, ##tom, ##y, for, undergraduate, students, ., the, intensive, mode, ne, ##uro, ##ana, ##tom, ##y, unit, showed, the, students, the, same, quantity, and, quality, of, material, to, the, same, standard, ,, including, the, hours, ., however, ,, the, material, was, delivered, in, a, shorter, time, ##frame, ., (, between, -, subject, design, ), students, obtained, lower, final, grades, in, the, new, intensive, mode, delivery, but, reported, having, similar, overall, satisfaction, with, their, laboratory, practical, classes, ., near, -, peer, teaching, in, clinical, ne, ##uro, ##ana, ##tom, ##y, ^, xii, ##hall, et, al, ., (, 2013, ), university, of, southampton, ,, uk, ##under, ##grad, ##uate, medical, students, (, n, =, 60, ), near, -, peer, teaching, (, non, -, digital, tool, ), to, develop, and, deliver, a, near, -, peer, programme, of, study, ., two, medical, students, organized, and, delivered, the, teaching, to, their, colleges, in, a, series, of, seven, sessions, ., at, the, end, of, each, session, ,, participants, were, asked, to, fill, a, feedback, question, ##naire, ., (, within, -, subject, design, ), students, ’, perceived, level, of, knowledge, increased, after, the, near, -, peer, teaching, sessions, ,, supporting, the, use, of, this, teaching, tool, in, ne, ##uro, ##ana, ##tom, ##y, courses, ., the, effect, of, face, -, to, -, face, teaching, on, student, knowledge, and, satisfaction, in, an, undergraduate, ne, ##uro, ##ana, ##tom, ##y, course, ^, xiii, ##w, ##hill, ##ier, &, l, ##yst, ##ad, ,, (, 2013, ), macquarie, university, ,, australia, ##under, ##grad, ##uate, students, enrolled, in, the, new, and, old, ne, ##uro, ##ana, ##tom, ##y, units, (, n, =, 181, ), face, -, to, -, face, teaching, (, non, -, digital, tool, ), to, examine, if, face, -, to, -, face, teaching, has, an, impact, on, student, performance, and, overall, satisfaction, with, the, course, ., two, groups, of, students, (, old, and, rest, ##ructured, unit, of, ne, ##uro, ##ana, ##tom, ##y, ), were, analyzed, ., a, question, ##naire, was, used, to, compare, them, in, terms, of, the, rate, they, gave, to, the, course, ,, satisfaction, ,, and, final, grades, ., (, between, -, subject, design, ), the, increase, in, total, face, -, to, -, face, teaching, hours, in, the, rest, ##ructured, unit, of, ne, ##uro, ##ana, ##tom, ##y, does, not, improve, student, grades, ., however, ,, it, does, increase, student, satisfaction, ., using, case, studies, as, a, semester, -, long, tool, to, teach, ne, ##uro, ##ana, ##tom, ##y, and, structure, -, function, relationships, to, undergraduate, ##s, ^, xiv, ##ken, ##ned, ##y, (, 2013, ), denis, ##on, un, ##iver, ,, usa, ##under, ##grad, ##uate, biology, and, psychology, students, (, n, =, 50, ), case, studies, (, non, -, digital, tool, ), to, investigate, the, effect, of, teaching, ne, ##uro, ##ana, ##tom, ##y, through, presentation, and, discussion, of, case, studies, ., students, were, expected, to, collaborate, with, their, colleges, in, small, groups, ., in, each, case, study, ,, the, entire, class, was, asked, to, participate, in, some, aspect, of, the, case, ., students, report, enjoying, learning, brain, structure, using, this, method, ,, and, commented, positively, on, the, class, activities, associated, with, learning, brain, anatomy, ., using, equivalence, -, based, instruction, to, increase, efficiency, in, teaching, ne, ##uro, ##ana, ##tom, ##y, ^, xv, ##py, ##tte, &, fi, ##en, ##up, (, 2012, ), queens, college, ,, usa, ##under, ##grad, ##uate, students, ,, primarily, of, psychology, majors, (, n, =, 93, ), equivalence, -, based, instruction, ,, e, ##bi, (, non, -, digital, tool, ), to, study, if, e, ##bi, is, effective, in, teaching, ne, ##uro, ##ana, ##tom, ##y, in, a, large, classroom, setting, ##fo, ##urt, ##een, brain, regions, were, identified, ,, and, conditional, relations, were, explicitly, taught, during, three, lectures, ., then, ,, students, completed, test, to, evaluate, some, relations, that, were, taught, and, some, not, taught, ., selection, of, associations, by, the, teacher, can, encourage, the, spontaneous, emergence, of, novel, associations, within, a, concept, or, category, ., therefore, ,, it, can, increase, the, efficiency, of, teaching, ., computer, -, based, learning, of, ne, ##uro, ##ana, ##tom, ##y, :, a, longitudinal, study, of, ll, ##ear, ##ning, ,, transfer, ,, and, retention, ^, xvi, ##cha, ##rik, ##er, et, al, ., (, 2011, ), university, of, louisville, ,, usa, ##under, ##grad, ##uate, students, who, reported, minimal, knowledge, of, ne, ##uro, ##ana, ##tom, ##y, (, n, =, 72, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, determine, the, effectiveness, of, new, methods, for, teaching, ne, ##uro, ##ana, ##tom, ##y, with, computer, -, based, instruction, ##using, a, 3d, graphical, model, of, the, human, brain, ,, students, learned, either, sectional, anatomy, alone, (, with, per, ##ce, ##pt, ##ually, continuous, or, discrete, navigation, ), or, whole, anatomy, followed, by, sectional, anatomy, ., participants, were, tested, immediately, and, after, 2, –, 3, weeks, ., (, between, -, subject, design, ), results, showed, efficient, learning, ,, good, long, -, term, retention, ,, and, successful, transfer, to, the, interpretation, of, biomedical, images, ., they, suggest, that, computer, -, based, learning, can, be, a, valuable, teaching, tool, ., human, brains, engaged, in, rat, brains, :, student, -, driven, ne, ##uro, ##ana, ##tom, ##y, research, in, an, introductory, biology, lab, course, ^, xvi, ##iga, ##rd, ##ner, et, al, ., (, 2011, ), purdue, university, ,, usaf, ##irs, ##t, -, year, undergraduate, students, interested, in, major, ##ing, in, biology, (, n, =, 13, ), inquiry, -, based, laboratory, instruction, (, non, -, digital, tool, ), to, increase, student, interest, in, biology, by, exposing, them, to, novel, research, projects, ##st, ##ude, ##nts, acquired, basic, lab, skills, within, the, context, of, a, research, question, of, a, member, of, the, faculty, ., biology, students, who, were, not, taking, the, research, -, based, ,, bio, -, cas, ##pie, course, ,, formed, the, comparison, group, for, pre, -, and, post, -, semester, question, ##naire, ##s, ., (, mix, between, -, within, -, subject, design, ), the, inquiry, -, based, laboratory, instruction, increased, students, ’, motivation, and, excitement, ,, encouraged, good, scientific, practices, ,, and, can, potentially, benefit, departmental, research, ., the, study, techniques, of, asian, ,, american, ,, and, european, medical, students, during, gross, anatomy, and, ne, ##uro, ##ana, ##tom, ##y, courses, in, poland, ^, xvi, ##ii, ##zu, ##rada, et, al, ., (, 2011, ), medical, university, in, poland, ,, poland, ##int, ##ern, ##ation, ##al, medical, students, ,, from, the, polish, ,, american, ,, and, taiwanese, divisions, (, n, =, 70, ##5, ), –, to, investigate, similarities, and, differences, among, american, ,, asian, ,, and, european, medical, students, in, terms, of, their, study, methods, ., participants, completed, a, question, ##naire, in, which, they, reported, which, methods, they, used, to, study, ,, and, which, of, the, methods, they, believed, were, most, efficient, for, comprehension, ,, memo, ##rization, ,, and, review, ., (, between, -, subject, design, ), results, showed, some, differences, in, study, techniques, among, students, from, the, different, ethnic, back, -, grounds, (, e, ., g, ., ,, polish, and, american, preferred, the, use, of, di, ##sse, ##ctions, and, prose, ##cted, specimens, ), effectiveness, of, a, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, program, for, entry, -, level, physical, therapy, students, :, anatomy, and, clinical, examination, of, the, dorsal, column, -, medial, le, ##m, ##nis, ##cal, system, ^, xi, ##x, ##mc, ##ke, ##ough, ##et, al, ., (, 2010, ), california, state, university, &, university, of, the, pacific, ,, usa, ##under, ##grad, ##uate, physical, therapy, students, (, n, =, 61, ), computer, -, aided, instruction, ,, cai, (, digital, tool, ), to, determine, if, a, computer, -, aided, instruction, learning, module, improves, students, ’, ne, ##uro, ##ana, ##tom, ##y, knowledge, ##st, ##ude, ##nts, completed, a, paper, -, and, -, pencil, test, on, the, ne, ##uro, ##ana, ##tom, ##y, /, physiology, and, clinical, examination, of, the, dc, ##ml, system, ,, both, before, and, after, working, with, the, teaching, tool, (, within, -, subject, design, ), findings, showed, that, clinical, examination, post, -, test, scores, improved, significantly, from, the, pre, -, test, scores, ##a, novel, three, -, dimensional, tool, for, teaching, human, ne, ##uro, ##ana, ##tom, ##y, ^, xx, ##est, ##eve, ##z, et, al, ., (, 2010, ), boston, university, school, of, medicine, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 101, ), 3d, physical, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, develop, and, assess, a, new, tool, for, ##g, teaching, 3d, ne, ##uro, ##ana, ##tom, ##y, to, first, -, year, medical, students, ##fi, ##rst, ,, all, students, were, presented, to, traditional, 2d, methods, ., then, ,, the, experimental, group, constructed, 3d, color, -, coded, physical, models, ,, while, the, control, group, re, -, examined, 2d, brain, cross, -, sections, ., (, between, -, subject, design, ), 3d, computer, model, was, an, effective, method, for, teaching, spatial, relationships, of, brain, anatomy, and, seems, to, better, prepare, students, for, visual, ##ization, of, 3d, ne, ##uro, ##ana, ##tom, ##yat, ##ti, ##tu, ##des, of, health, care, students, about, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, instruction, ^, xx, ##im, ##cke, ##ough, &, bag, ##ate, ##ll, (, 2009, ), a, university, in, the, west, coast, ,, usa, ##master, ’, s, degree, health, care, professional, students, (, n, =, 77, ), computer, -, aided, instruction, ,, cai, (, digital, tool, ), to, examine, students, ’, attitudes, toward, cai, ,, which, factors, help, their, development, ,, and, their, implications, ., three, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, learning, modules, were, used, ., students, independently, reviewed, the, modules, as, supplements, to, lecture, and, completed, a, survey, to, evaluate, teaching, effectiveness, (, within, -, subject, design, ), the, cai, modules, examined, in, this, study, were, effective, as, adjunct, ##s, to, lecture, in, helping, the, students, learn, and, make, clinical, applications, of, ne, ##uro, ##ana, ##tom, ##y, information, ##a, usa, ##bility, study, of, users, ’, perceptions, toward, a, multimedia, computer, -, assisted, learning, tool, for, ne, ##uro, ##ana, ##tom, ##y, ^, xx, ##ii, ##go, ##uld, et, al, ., (, 2008, ), university, of, kentucky, &, university, of, louisville, &, nova, southeastern, university, ,, usaf, ##ac, ##ult, ##y, and, students, from, some, institutions, across, the, country, (, n, =, 62, ), computer, -, aided, instruction, ,, cai, (, digital, tool, ), to, assess, users, ’, perceptions, of, the, computer, -, based, tool, :, “, anatomy, of, the, central, nervous, system, :, a, multimedia, course, ”, first, ,, participants, used, the, multimedia, prototype, ., then, they, completed, a, usa, ##bility, question, ##naire, designed, to, measure, two, usa, ##bility, properties, :, program, need, and, program, app, ##lica, ##bility, ##thi, ##s, study, showed, that, the, cai, was, well, -, designed, for, all, users, ,, and, demonstrates, the, importance, of, integrating, quality, properties, of, usa, ##bility, with, principles, of, human, learning, ., attitudes, to, e, -, learning, ,, learning, style, and, achievement, in, learning, ne, ##uro, ##ana, ##tom, ##y, by, medical, students, ^, xx, ##iii, ##s, ##vir, ##ko, &, mel, ##lan, ##by, (, 2008, ), oxford, university, ,, uk, ##se, ##con, ##d, -, year, pre, -, clinical, undergraduate, medical, students, (, n, =, 205, ), computer, -, aided, learning, ,, cal, (, digital, tool, ), to, investigate, the, impact, of, an, online, course, on, encouraging, students, to, learn, and, their, academic, performance, ., the, students, approach, to, learning, towards, the, cal, course, and, towards, their, studies, in, general, was, compared, ., student, attitudes, and, ratings, were, also, assessed, ., findings, revealed, that, students, reported, using, significantly, less, deep, approach, to, learning, for, the, cal, course, ., using, truncated, lectures, ,, conceptual, exercises, ,, and, mani, ##pu, ##lative, ##s, to, improve, learning, in, the, ne, ##uro, ##ana, ##tom, ##y, classroom, ^, xx, ##iv, ##kr, ##ont, ##iri, ##s, -, lit, ##ow, ##itz, (, 2008, ), young, ##stown, state, university, ,, usa, ##under, ##grad, ##uate, biology, and, graduate, biology, and, physical, therapy, students, (, n, =, 19, ), truncated, lectures, ,, conceptual, exercises, ,, and, mani, ##pu, ##lative, ##s, (, non, -, digital, tool, ), to, use, truncated, lectures, ,, conceptual, exercises, ,, and, mani, ##pu, ##lative, ##s, to, make, learning, more, effective, and, increase, critical, thinking, ##the, curriculum, was, revised, ., more, specifically, ,, it, became, shorter, ,, included, practice, problems, that, presented, the, spinal, tracts, in, an, applied, context, ,, and, included, a, mani, ##pu, ##lative, ., student, ’, s, learning, was, then, assessed, and, compared, with, previous, classes, ., (, between, -, subject, design, ), ., students, ’, learning, was, more, effective, under, the, revised, curriculum, ,, suggesting, that, this, revised, curriculum, could, potentially, be, applied, to, other, topics, ., design, and, utility, of, a, web, -, based, computer, -, assisted, instructional, tool, for, ne, ##uro, ##ana, ##tom, ##y, self, -, study, and, review, for, physical, and, occupational, therapy, graduate, students, ^, xx, ##iv, ##for, ##eman, et, al, ., (, 2005, ), university, of, utah, ,, usa, ##under, ##grad, ##uate, physical, therapy, and, occupational, therapy, students, (, n, =, 43, ), computer, -, assisted, instruction, ,, cai, (, digital, tool, ), to, develop, a, cai, ,, and, assess, their, design, and, utility, to, teach, ne, ##uro, ##ana, ##tom, ##y, ., a, question, ##naire, addressed, navigation, ,, clarity, of, the, images, ,, benefit, of, the, cai, tool, ,, and, students, rating, ., students, were, also, asked, to, compare, this, tool, with, traditional, learning, tools, ., design, and, utility, of, a, web, -, based, computer, -, assisted, instructional, tool, for, ne, ##uro, ##ana, ##tom, ##y, self, -, study, and, review, for, physical, and, occupational, therapy, graduate, students, ^, xx, ##iva, ne, ##uro, ##ana, ##tom, ##y, teaching, activity, using, case, studies, and, collaboration, ^, xx, ##vish, ##eld, ##on, (, 2000, ), university, of, michigan, ,, usa, ##under, ##grad, ##uate, ##st, ##ude, ##nts, of, an, introductory, psychology, course, (, n, =, 28, ), case, studies, and, collaboration, (, non, -, digital, tool, ), to, evaluate, an, easier, and, less, time, -, consuming, method, for, teaching, ne, ##uro, ##ana, ##tom, ##y, ., students, collaborated, and, applied, their, ne, ##uro, ##ana, ##tom, ##y, knowledge, to, several, case, studies, during, classes, ., findings, showed, that, students, assessed, this, method, as, very, enjoyable, and, helpful, for, remembering, or, learning, the, material, ., computer, -, based, ne, ##uro, ##ana, ##tom, ##y, laboratory, for, medical, students, ^, xx, ##vi, ##ila, ##mp, ##ert, ##i, &, so, ##dic, ##off, (, 1997, ), temple, university, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 185, ), computer, -, based, ne, ##uro, ##ana, ##tom, ##y, laboratory, (, digital, tool, ), to, develop, a, computer, -, based, laboratory, program, to, substitute, the, traditional, glass, -, slide, laboratory, ##the, ##y, compared, the, performances, of, those, classes, that, previously, had, the, traditional, laboratory, with, two, succeeding, classes, that, used, computer, program, (, between, -, subject, design, ), ., test, scores, showed, that, the, students, ’, performance, on, laboratory, material, was, similar, in, both, classes, ., teaching, of, ne, ##uro, ##ana, ##tom, ##y, by, means, of, self, -, instructional, laboratory, stations, ^, xx, ##vi, ##ii, ##fish, ##er, et, al, ., (, 1980, ), university, of, michigan, medical, school, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 200, ), self, -, instructional, stations, (, non, -, digital, tool, ), to, teach, ne, ##uro, ##ana, ##tom, ##y, using, self, -, instructional, laboratory, stations, ##ne, ##uro, ##ana, ##tom, ##ical, laboratory, material, was, presented, in, a, series, of, six, self, -, instructional, stations, ., five, weeks, later, ,, short, examinations, tests, occurred, ., results, of, the, tests, indicated, a, mastery, of, station, material, as, defined, by, the, objectives, and, an, ability, to, use, the, material, in, applied, problems, ., cognitive, processes, in, learning, ne, ##uro, ##ana, ##tom, ##y, ^, xx, ##ix, ##gee, ##arts, ##ma, &, mat, ##z, ##ke, (, 1966, ), university, of, kansas, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 107, ), inter, ##pol, ##ation, of, questions, (, non, -, digital, tool, ), to, investigate, the, effect, of, inter, ##pol, ##ation, of, questions, into, a, lecture, presentation, ., participants, were, divided, into, 2, matched, groups, ., each, group, was, shown, lectures, on, the, visual, system, which, differed, only, in, regard, to, tax, ##omic, level, of, 10, questions, posed, lecture, ., performance, was, then, measured, (, between, -, subject, design, ), ., emphasis, on, recall, questions, aids, performance, on, subsequent, recall, questions, more, than, emphasis, on, problem, -, solving, questions, helps, in, the, solution, of, subsequent, problem, -, solving, questions, .'},\n", + " {'article_id': '300a4d420106d0d9ca46d886abf7ae4a',\n", + " 'section_name': 'MEMRI can detect canonical and novel sexual dimorphisms',\n", + " 'text': 'To compare structure volumes between sexes, an atlas that segments 182 structures in the adult mouse brain^25 was overlaid onto the p65 consensus average brain. Figure 3a (i, ii) shows segmentations of the MeA, BNST, and MPON, which are canonical sexually dimorphic areas. Extensive literature has shown that these areas are larger in the male brain. MEMRI captures these sexual dimorphisms (top-panels, Fig. 3b–d) and shows that these dimorphisms emerge between p10 and p17. Males tend to have bigger brains than females^18; as MEMRI allows for whole-brain imaging, we were also able to identify dimorphisms in brain structure relative volumes—that is, subjects’ structure volumes divided by their whole-brain volume. Similar to absolute volumes, males had larger relative volumes of BNST, MeA, and MPON. However, relative volumetric sex differences emerged earlier than the absolute volume differences, around p5. Moreover, several structures, such as the periaqueductal gray (PAG) (Fig. 3e), exhibited no sex-dependent growth differences in absolute volumes, but did exhibit significant differences in relative volumes. Compared with male-enlarged structures, the PAG became relatively larger in females at a later developmental time, around p29 (summary structure data in Table 1 and Supplementary table 1). Correction for whole-brain size using relative volume measurements from MEMRI data reveal time courses of well-established and novel sexual dimorphisms, highlighting the strength of whole-brain MRI.Fig. 3MEMRI captures sex differences in brain structure sizes. a Sagittal and coronal slices of the average p65 brain showing segmentations of mouse brain structures: bed nucleus of the stria terminalis (BNST), medial preoptic nucleus (MPON), medial nucleus of the amygdala (MeA), and periaqueductal gray (PAG). b–e the absolute and relative volumes of these structures over time. Points in these plots represent measurement at a time point for individual mice and lines connect the measurements for the same mouse over time. Shaded regions represent standard error estimated using linear mixed-effects models. Relative volume corrects for whole-brain size differences between subjects and is expressed as a percent difference from the average volume of the brain structure. Using linear mixed-effects models, we recapitulate known canonical sex differences in absolute volumes of the MeA (, P<10^−10), BNST (, P<10^−12), and MPON (, P<10^−3). Sex differences in these structures emerge pre-puberty, at around p10. Using relative volumes to correct for whole brain size, we see that sex differences in these structures are preserved but differences emerge earlier in development around p5. PAG relative volume also shows a significant effect of interaction between sex and age (, P<10^−2), which is not found in the absolute volumes (, P = 0.2). Taken together, these results indicate that relative volumes obtained by MEMRI are a sensitive marker for detecting canonical and novel sexual dimorphisms in neuroanatomyTable 1Mean volume of sexually dimorphic structures in males and femalesBed nucleus of the stria terminalisMedial preoptic nucleusMedial amygdalaPeriaqueductal grayAgeMFMFMFMFAbsolute volume (mm^3)30.5890.5830.08560.08440.5060.4902.6302.58050.7190.7240.1030.1020.5730.5782.9502.98070.8570.8500.1170.1150.6600.6533.3103.310101.0601.0100.1520.1470.8000.7643.9603.860171.1601.1100.1840.1780.9730.9334.0703.990231.1101.0600.1490.1460.9760.9383.8203.770291.1001.0500.1500.1460.9660.9173.7403.670361.1301.0600.1580.1521.0000.9303.7603.690651.2001.1200.1680.1581.0600.9834.0103.970Relative volume (% Brain)30.28100.28500.03940.04000.24200.24100.97400.984050.28000.27500.03970.03820.24400.24000.98300.970070.28100.27400.04000.03890.24500.23800.97500.9580100.27800.27100.03960.03900.24400.23600.95900.9510170.27600.26500.03990.03880.24400.23500.97000.9580230.27400.26300.03930.03860.24500.23500.96200.9490290.27000.26200.03830.03780.24300.23500.95800.9560360.26900.26300.03800.03800.24300.23400.94000.9590650.27700.26400.03860.03730.24300.23100.92400.9340',\n", + " 'paragraph_id': 11,\n", + " 'tokenizer': 'to, compare, structure, volumes, between, sexes, ,, an, atlas, that, segments, 182, structures, in, the, adult, mouse, brain, ^, 25, was, over, ##laid, onto, the, p, ##65, consensus, average, brain, ., figure, 3a, (, i, ,, ii, ), shows, segment, ##ations, of, the, me, ##a, ,, bn, ##st, ,, and, mp, ##on, ,, which, are, canonical, sexually, dim, ##or, ##phic, areas, ., extensive, literature, has, shown, that, these, areas, are, larger, in, the, male, brain, ., me, ##m, ##ri, captures, these, sexual, dim, ##or, ##phi, ##sms, (, top, -, panels, ,, fig, ., 3, ##b, –, d, ), and, shows, that, these, dim, ##or, ##phi, ##sms, emerge, between, p, ##10, and, p, ##17, ., males, tend, to, have, bigger, brains, than, females, ^, 18, ;, as, me, ##m, ##ri, allows, for, whole, -, brain, imaging, ,, we, were, also, able, to, identify, dim, ##or, ##phi, ##sms, in, brain, structure, relative, volumes, —, that, is, ,, subjects, ’, structure, volumes, divided, by, their, whole, -, brain, volume, ., similar, to, absolute, volumes, ,, males, had, larger, relative, volumes, of, bn, ##st, ,, me, ##a, ,, and, mp, ##on, ., however, ,, relative, volume, ##tric, sex, differences, emerged, earlier, than, the, absolute, volume, differences, ,, around, p, ##5, ., moreover, ,, several, structures, ,, such, as, the, per, ##ia, ##que, ##du, ##cta, ##l, gray, (, pa, ##g, ), (, fig, ., 3, ##e, ), ,, exhibited, no, sex, -, dependent, growth, differences, in, absolute, volumes, ,, but, did, exhibit, significant, differences, in, relative, volumes, ., compared, with, male, -, enlarged, structures, ,, the, pa, ##g, became, relatively, larger, in, females, at, a, later, developmental, time, ,, around, p, ##29, (, summary, structure, data, in, table, 1, and, supplementary, table, 1, ), ., correction, for, whole, -, brain, size, using, relative, volume, measurements, from, me, ##m, ##ri, data, reveal, time, courses, of, well, -, established, and, novel, sexual, dim, ##or, ##phi, ##sms, ,, highlighting, the, strength, of, whole, -, brain, mri, ., fig, ., 3, ##me, ##m, ##ri, captures, sex, differences, in, brain, structure, sizes, ., a, sa, ##git, ##tal, and, corona, ##l, slices, of, the, average, p, ##65, brain, showing, segment, ##ations, of, mouse, brain, structures, :, bed, nucleus, of, the, st, ##ria, terminal, ##is, (, bn, ##st, ), ,, medial, pre, ##op, ##tic, nucleus, (, mp, ##on, ), ,, medial, nucleus, of, the, amy, ##g, ##dal, ##a, (, me, ##a, ), ,, and, per, ##ia, ##que, ##du, ##cta, ##l, gray, (, pa, ##g, ), ., b, –, e, the, absolute, and, relative, volumes, of, these, structures, over, time, ., points, in, these, plots, represent, measurement, at, a, time, point, for, individual, mice, and, lines, connect, the, measurements, for, the, same, mouse, over, time, ., shaded, regions, represent, standard, error, estimated, using, linear, mixed, -, effects, models, ., relative, volume, correct, ##s, for, whole, -, brain, size, differences, between, subjects, and, is, expressed, as, a, percent, difference, from, the, average, volume, of, the, brain, structure, ., using, linear, mixed, -, effects, models, ,, we, rec, ##ap, ##it, ##ulate, known, canonical, sex, differences, in, absolute, volumes, of, the, me, ##a, (, ,, p, <, 10, ^, −, ##10, ), ,, bn, ##st, (, ,, p, <, 10, ^, −, ##12, ), ,, and, mp, ##on, (, ,, p, <, 10, ^, −, ##3, ), ., sex, differences, in, these, structures, emerge, pre, -, pub, ##erty, ,, at, around, p, ##10, ., using, relative, volumes, to, correct, for, whole, brain, size, ,, we, see, that, sex, differences, in, these, structures, are, preserved, but, differences, emerge, earlier, in, development, around, p, ##5, ., pa, ##g, relative, volume, also, shows, a, significant, effect, of, interaction, between, sex, and, age, (, ,, p, <, 10, ^, −, ##2, ), ,, which, is, not, found, in, the, absolute, volumes, (, ,, p, =, 0, ., 2, ), ., taken, together, ,, these, results, indicate, that, relative, volumes, obtained, by, me, ##m, ##ri, are, a, sensitive, marker, for, detecting, canonical, and, novel, sexual, dim, ##or, ##phi, ##sms, in, ne, ##uro, ##ana, ##tom, ##yt, ##able, 1, ##me, ##an, volume, of, sexually, dim, ##or, ##phic, structures, in, males, and, females, ##bed, nucleus, of, the, st, ##ria, terminal, ##ism, ##ed, ##ial, pre, ##op, ##tic, nucleus, ##media, ##l, amy, ##g, ##dal, ##ape, ##ria, ##que, ##du, ##cta, ##l, gray, ##age, ##m, ##fm, ##fm, ##fm, ##fa, ##bs, ##ol, ##ute, volume, (, mm, ^, 3, ), 30, ., 58, ##90, ., 58, ##30, ., 08, ##56, ##0, ., 08, ##44, ##0, ., 50, ##60, ., 490, ##2, ., 630, ##2, ., 580, ##50, ., 71, ##90, ., 72, ##40, ., 103, ##0, ., 102, ##0, ., 57, ##30, ., 57, ##8, ##2, ., 950, ##2, ., 980, ##70, ., 85, ##70, ., 850, ##0, ., 117, ##0, ., 115, ##0, ., 660, ##0, ., 65, ##33, ., 310, ##3, ., 310, ##10, ##1, ., 06, ##01, ., 01, ##00, ., 152, ##0, ., 147, ##0, ., 800, ##0, ., 76, ##43, ., 960, ##3, ., 86, ##01, ##7, ##1, ., 160, ##1, ., 1100, ., 1840, ., 1780, ., 97, ##30, ., 93, ##34, ., 07, ##0, ##3, ., 99, ##0, ##23, ##1, ., 110, ##1, ., 06, ##00, ., 149, ##0, ., 146, ##0, ., 97, ##60, ., 93, ##8, ##3, ., 820, ##3, ., 770, ##29, ##1, ., 100, ##1, ., 050, ##0, ., 1500, ., 146, ##0, ., 96, ##60, ., 91, ##7, ##3, ., 740, ##3, ., 670, ##36, ##1, ., 130, ##1, ., 06, ##00, ., 1580, ., 152, ##1, ., 000, ##0, ., 930, ##3, ., 760, ##3, ., 690, ##65, ##1, ., 2001, ., 1200, ., 1680, ., 158, ##1, ., 06, ##00, ., 98, ##34, ., 01, ##0, ##3, ., 97, ##0, ##rel, ##ative, volume, (, %, brain, ), 30, ., 281, ##00, ., 285, ##00, ., 03, ##9, ##40, ., 04, ##00, ##0, ., 242, ##00, ., 241, ##00, ., 97, ##400, ., 98, ##40, ##50, ., 280, ##00, ., 275, ##00, ., 03, ##9, ##70, ., 03, ##8, ##20, ., 244, ##00, ., 240, ##00, ., 98, ##30, ##0, ., 97, ##00, ##70, ., 281, ##00, ., 274, ##00, ., 04, ##00, ##0, ., 03, ##8, ##90, ., 245, ##00, ., 238, ##00, ., 97, ##500, ., 95, ##80, ##100, ., 278, ##00, ., 271, ##00, ., 03, ##9, ##60, ., 03, ##90, ##0, ., 244, ##00, ., 236, ##00, ., 95, ##90, ##0, ., 95, ##10, ##17, ##0, ., 276, ##00, ., 265, ##00, ., 03, ##9, ##90, ., 03, ##8, ##80, ., 244, ##00, ., 235, ##00, ., 97, ##00, ##0, ., 95, ##80, ##23, ##0, ., 274, ##00, ., 263, ##00, ., 03, ##9, ##30, ., 03, ##86, ##0, ., 245, ##00, ., 235, ##00, ., 96, ##200, ., 94, ##90, ##29, ##0, ., 270, ##00, ., 262, ##00, ., 03, ##8, ##30, ., 03, ##7, ##80, ., 243, ##00, ., 235, ##00, ., 95, ##80, ##0, ., 95, ##60, ##36, ##0, ., 269, ##00, ., 263, ##00, ., 03, ##80, ##0, ., 03, ##80, ##0, ., 243, ##00, ., 234, ##00, ., 94, ##00, ##0, ., 95, ##90, ##65, ##0, ., 277, ##00, ., 264, ##00, ., 03, ##86, ##0, ., 03, ##7, ##30, ., 243, ##00, ., 231, ##00, ., 92, ##400, ., 93, ##40'},\n", + " {'article_id': 'b083da95424dc116271fbbff7680bc97',\n", + " 'section_name': 'Case report of 103 year old female',\n", + " 'text': 'Case 100069 was a female centenarian with a fit physique included in the 100-plus Study at the age of 102. She finished the first stage of tertiary education, and had enjoyed a total of 18 years of education (ISCED level 5). At baseline she scored 27 points on the MMSE and 3/5 points on the CDT. She volunteered to undergo an MRI and PIB-PET scan 1 month after inclusion into the study. The MRI scan revealed moderate hippocampal atrophy (MTA score 2), white matter abnormalities (Fazekas score II), and few microbleeds. The PET scan using [^11C]PiB as an amyloid tracer was positive throughout the brain, with the highest signal in the frontal area (Fig. 4). The centenarian died 10 months after inclusion of cachexia. Proxies reported maintained cognitive health until the terminal phase. Brain autopsy was performed with a post mortem delay of 8.5 h. Overall, no major abnormalities were observed at the macroscopic level. Mild atrophy of the temporal lobe was observed and arteries were mildly atherosclerotic. Two small meningeomas were observed in the left part of the scull, as well as a small (0.6 cm) old cortical infarct in the medial frontal gyrus. The substantia nigra appeared relatively pale. Neuropathological evaluation revealed intermediate AD neuropathologic changes (A3B2C1). Consistent with the positive amyloid PET scan in vivo, we observed Aβ pathology in the form of classical and diffuse plaques (Thal stage Aβ 4), as well as capillary CAA-type 1 (capCAA) (Thal stage CAA 2) (Fig. 5 panel d-f) during the post-mortem neuropathological analysis. Diffuse Aβ deposits were detected in the frontal, frontobasal, occipital, temporal and parietal cortex, the molecular layer, CA1 and subiculum of the hippocampus, as well as the caudate nucleus, putamen and nucleus accumbens. A relatively low number of classic senile plaques with a dense core was observed throughout the neocortex. Prominent presence of CAA was observed in the parietal cortex and the leptomeninges. Capillary CAA (type 1) was observed in moderate levels in the frontal cortex (Fig. 5, panel f), the cerebellum, sporadically in the occipital cortex, and was absent in the temporal cortex. Together, the relatively high levels of CAA might explain the high signal of the [^11C]PiB-PET, as CAA is also known to be detected by this tracer (Farid et al., 2017 [15]), as well as the abnormalities observed on the MRI.Fig. 4Dynamic [^11C]PiB-PET and MRI scan of case 100069. The scan was performed by the ECAT EXACT HR1 scanner (Siemens/CTI) 1 month after study inclusion. PET scan for amyloid is positive in the frontal area, MRI shows moderate hippocampal atrophy (MTA score 2) as well as vascular lesions in the white matter (Fazekas score II), suggesting amyloid angiopathyFig. 5Representative neuropathological lesions found in the hippocampus (a, d, g, j), middle temporal lobe cortex (b, e, h, i, k), amygdala (c) and frontal lobe cortex (f) of case 100069. Shown are exemplary pTDP-43 accumulations (a-c) in the hippocampal subregion CA1 (a1) and dentate gyrus (DG) (a2), temporal pole cortex (T) (b) and Amygdala (Amy) (c), Aβ positivity (d-f) in the form of diffuse and classical plaques in the hippocampal CA1 region (d) and temporal pole cortex (e), as well as CAA of large vessels and capillaries in the frontal lobe (F2) (f). pTau immuno-staining (g-i) is shown as (pre)tangles and neuritic plaque like structures in the hippocampal CA1 region (g) and temporal pole cortex (h1 and h2), as well as astroglial pTau in ARTAG in the temporal pole cortex (i1 and i2). GVD (CK1δ granules) (j-k) is shown in the hippocampus (j) and temporal pole cortex (k). Scale bar 25 μm',\n", + " 'paragraph_id': 24,\n", + " 'tokenizer': 'case, 1000, ##6, ##9, was, a, female, cent, ##ena, ##rian, with, a, fit, ph, ##ys, ##ique, included, in, the, 100, -, plus, study, at, the, age, of, 102, ., she, finished, the, first, stage, of, tertiary, education, ,, and, had, enjoyed, a, total, of, 18, years, of, education, (, is, ##ced, level, 5, ), ., at, baseline, she, scored, 27, points, on, the, mm, ##se, and, 3, /, 5, points, on, the, cd, ##t, ., she, volunteered, to, undergo, an, mri, and, pi, ##b, -, pet, scan, 1, month, after, inclusion, into, the, study, ., the, mri, scan, revealed, moderate, hip, ##po, ##camp, ##al, at, ##rop, ##hy, (, mt, ##a, score, 2, ), ,, white, matter, abnormalities, (, fa, ##zek, ##as, score, ii, ), ,, and, few, micro, ##ble, ##ed, ##s, ., the, pet, scan, using, [, ^, 11, ##c, ], pi, ##b, as, an, amy, ##loid, trace, ##r, was, positive, throughout, the, brain, ,, with, the, highest, signal, in, the, frontal, area, (, fig, ., 4, ), ., the, cent, ##ena, ##rian, died, 10, months, after, inclusion, of, cache, ##xia, ., pro, ##xie, ##s, reported, maintained, cognitive, health, until, the, terminal, phase, ., brain, autopsy, was, performed, with, a, post, mort, ##em, delay, of, 8, ., 5, h, ., overall, ,, no, major, abnormalities, were, observed, at, the, macro, ##scopic, level, ., mild, at, ##rop, ##hy, of, the, temporal, lobe, was, observed, and, arteries, were, mildly, at, ##her, ##os, ##cle, ##rot, ##ic, ., two, small, men, ##inge, ##oma, ##s, were, observed, in, the, left, part, of, the, sc, ##ull, ,, as, well, as, a, small, (, 0, ., 6, cm, ), old, co, ##rti, ##cal, in, ##far, ##ct, in, the, medial, frontal, g, ##yr, ##us, ., the, sub, ##stan, ##tia, ni, ##gra, appeared, relatively, pale, ., ne, ##uro, ##path, ##ological, evaluation, revealed, intermediate, ad, ne, ##uro, ##path, ##olo, ##gic, changes, (, a, ##3, ##b, ##2, ##c, ##1, ), ., consistent, with, the, positive, amy, ##loid, pet, scan, in, vivo, ,, we, observed, a, ##β, pathology, in, the, form, of, classical, and, diffuse, plaques, (, tha, ##l, stage, a, ##β, 4, ), ,, as, well, as, cap, ##illa, ##ry, ca, ##a, -, type, 1, (, cap, ##ca, ##a, ), (, tha, ##l, stage, ca, ##a, 2, ), (, fig, ., 5, panel, d, -, f, ), during, the, post, -, mort, ##em, ne, ##uro, ##path, ##ological, analysis, ., diffuse, a, ##β, deposits, were, detected, in, the, frontal, ,, front, ##ob, ##asa, ##l, ,, o, ##cci, ##pit, ##al, ,, temporal, and, par, ##ie, ##tal, cortex, ,, the, molecular, layer, ,, ca, ##1, and, sub, ##ic, ##ulum, of, the, hip, ##po, ##camp, ##us, ,, as, well, as, the, ca, ##uda, ##te, nucleus, ,, put, ##amen, and, nucleus, acc, ##umb, ##ens, ., a, relatively, low, number, of, classic, sen, ##ile, plaques, with, a, dense, core, was, observed, throughout, the, neo, ##cor, ##te, ##x, ., prominent, presence, of, ca, ##a, was, observed, in, the, par, ##ie, ##tal, cortex, and, the, le, ##pt, ##ome, ##ning, ##es, ., cap, ##illa, ##ry, ca, ##a, (, type, 1, ), was, observed, in, moderate, levels, in, the, frontal, cortex, (, fig, ., 5, ,, panel, f, ), ,, the, ce, ##re, ##bell, ##um, ,, sporadic, ##ally, in, the, o, ##cci, ##pit, ##al, cortex, ,, and, was, absent, in, the, temporal, cortex, ., together, ,, the, relatively, high, levels, of, ca, ##a, might, explain, the, high, signal, of, the, [, ^, 11, ##c, ], pi, ##b, -, pet, ,, as, ca, ##a, is, also, known, to, be, detected, by, this, trace, ##r, (, far, ##id, et, al, ., ,, 2017, [, 15, ], ), ,, as, well, as, the, abnormalities, observed, on, the, mri, ., fig, ., 4, ##dy, ##nami, ##c, [, ^, 11, ##c, ], pi, ##b, -, pet, and, mri, scan, of, case, 1000, ##6, ##9, ., the, scan, was, performed, by, the, ec, ##at, exact, hr, ##1, scanner, (, siemens, /, ct, ##i, ), 1, month, after, study, inclusion, ., pet, scan, for, amy, ##loid, is, positive, in, the, frontal, area, ,, mri, shows, moderate, hip, ##po, ##camp, ##al, at, ##rop, ##hy, (, mt, ##a, score, 2, ), as, well, as, vascular, lesions, in, the, white, matter, (, fa, ##zek, ##as, score, ii, ), ,, suggesting, amy, ##loid, ang, ##io, ##pathy, ##fi, ##g, ., 5, ##re, ##pres, ##ent, ##ative, ne, ##uro, ##path, ##ological, lesions, found, in, the, hip, ##po, ##camp, ##us, (, a, ,, d, ,, g, ,, j, ), ,, middle, temporal, lobe, cortex, (, b, ,, e, ,, h, ,, i, ,, k, ), ,, amy, ##g, ##dal, ##a, (, c, ), and, frontal, lobe, cortex, (, f, ), of, case, 1000, ##6, ##9, ., shown, are, exemplary, pt, ##dp, -, 43, accumulation, ##s, (, a, -, c, ), in, the, hip, ##po, ##camp, ##al, sub, ##region, ca, ##1, (, a1, ), and, dent, ##ate, g, ##yr, ##us, (, d, ##g, ), (, a2, ), ,, temporal, pole, cortex, (, t, ), (, b, ), and, amy, ##g, ##dal, ##a, (, amy, ), (, c, ), ,, a, ##β, po, ##sit, ##ivity, (, d, -, f, ), in, the, form, of, diffuse, and, classical, plaques, in, the, hip, ##po, ##camp, ##al, ca, ##1, region, (, d, ), and, temporal, pole, cortex, (, e, ), ,, as, well, as, ca, ##a, of, large, vessels, and, cap, ##illa, ##ries, in, the, frontal, lobe, (, f, ##2, ), (, f, ), ., pt, ##au, im, ##mun, ##o, -, stain, ##ing, (, g, -, i, ), is, shown, as, (, pre, ), tangle, ##s, and, ne, ##uri, ##tic, plaque, like, structures, in, the, hip, ##po, ##camp, ##al, ca, ##1, region, (, g, ), and, temporal, pole, cortex, (, h, ##1, and, h, ##2, ), ,, as, well, as, astro, ##glia, ##l, pt, ##au, in, art, ##ag, in, the, temporal, pole, cortex, (, i, ##1, and, i, ##2, ), ., g, ##vd, (, ck, ##1, ##δ, gran, ##ules, ), (, j, -, k, ), is, shown, in, the, hip, ##po, ##camp, ##us, (, j, ), and, temporal, pole, cortex, (, k, ), ., scale, bar, 25, μ, ##m'},\n", + " {'article_id': '88fab0c4347e89402bfac9036ffbcc7e',\n", + " 'section_name': 'DUSP1/MKP-1 in innate and adaptive immunity',\n", + " 'text': 'Given the wide range of roles that MAPKs perform in the development and function of cells of the immune system [[22], [23], [24]] it was perhaps no surprise that amongst the first phenotypes detected in DUSP1^−/− mice was a failure to regulate stress-activated JNK and p38 signalling in macrophages and dendritic cells (Fig. 2: Table 2). These cells are key mediators of the innate immune response in which the p38 and JNK MAPKs lie downstream of the toll-like receptors (TLRs), which are activated by a wide variety of pathogen-derived stimuli and act to regulate the expression of both pro and anti-inflammatory cytokines and chemokines [22]. Several groups demonstrated that loss of DUSP1/MKP-1 led to elevated JNK and p38 activities in macrophages exposed to the bacterial endotoxin lipopolysaccharide (LPS) [[25], [26], [27], [28]]. This led to an initial increase in the expression of pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFα), interleukin-6 (IL-6), interleukin-12 (IL-12) and interferon-gamma (IFN-γ) while, at later times, levels of the anti-inflammatory mediator interleukin-10 (IL-10) were increased [25]. These cellular effects were accompanied by pathological changes such as inflammatory tissue infiltration, hypotension and multiple organ failure, all of which are markers of the severe septic shock and increased mortality observed in LPS-injected DUSP1^−/− mice when compared to wild type controls.Fig. 2DUSP1/MKP-1 in innate immunity. Schematic showing the regulation of MAP kinase activities in cells of the innate immune system by DUSP1/MKP-1 and the consequences of genetic deletion of this MKP on the physiological responses of these cell populations. For details see text.Fig. 2Table 2Immunological phenotypes of MKP KO mice.Table 2GroupGene/MKPImmunological phenotypes of MKP KO miceReferencesNuclear, inducible MKPsDUSP1/MKP-1Increased pro-inflammatory cytokine production & innate immune response LPS challenge.[25]Impaired resolution of inflammation.[30]Decreased adaptive immune response & viral clearance.[33]Protection from autoimmune encephalitis (EAE).[33]Increased sensitivity to bacterial infections.[35]Exacerbates inflammatory phenotypes including: colitis, anaphylaxis and psoriasis.[[40], [41], [42]]DUSP2Protection from experimentally-induced arthritis.[86]Decreased macrophage cytokine expression & mast cell survival.[86]Increased susceptibility to DSS-induced model of intestinal inflammation.[87]Altered T-cell balance, via the promotion of Th17 differentiation and inhibition of Treg generation.[87]DUSP4/MKP-2Increased susceptibility to Leishmania mexicana, Leishmania donovani & Toxoplasma gondii infection.[[97], [98], [99]]Resistant to LPS-induced endotoxic shock.[100]Increased CD4+ T-cell proliferation.[101]Protection from autoimmune encephalitis (EAE).[102]DUSP5Negatively regulates Il-33 mediated eosinophil survival.[119]Resistant to helminth infection, due to enhanced eosinophil activity.[119]Regulates CD8+ populations in response to LCMV infection.[120]Cytoplasmic ERK-selective MKPsDUSP6/MKP-3Exacerbates intestinal colitis.[150]Decreased CD4+ T-cell proliferation, altered T-cell polarisation & impaired Treg function.[150]DUSP7/MKP-XN/ADUSP9/MKP-4N/AJNK/p38-selective MKPsDUSP8N/ADUSP10/MKP-5Impaired T cell expansion, but enhanced priming of T-cells by APCs.[185]Protection from autoimmune encephalitis (EAE).[185]Increased cytokine and ROS production in macrophages, neutrophils and T cells.[187]Protection from DSS-induced intestinal inflammation.[191]DUSP16/MKP-7Impaired GM-CSF-driven proliferation of bone marrow progenitors.[195]Increased CD4+ T-cell proliferation & a reduced Th17 cell population.[196]Protection from autoimmune encephalitis (EAE).[196]LCMV, lymphocytic choriomeningitis virus. DSS, dextran sodium sulfate.',\n", + " 'paragraph_id': 7,\n", + " 'tokenizer': 'given, the, wide, range, of, roles, that, map, ##ks, perform, in, the, development, and, function, of, cells, of, the, immune, system, [, [, 22, ], ,, [, 23, ], ,, [, 24, ], ], it, was, perhaps, no, surprise, that, amongst, the, first, ph, ##eno, ##type, ##s, detected, in, du, ##sp, ##1, ^, −, /, −, mice, was, a, failure, to, regulate, stress, -, activated, j, ##nk, and, p, ##38, signalling, in, macro, ##pha, ##ges, and, den, ##dr, ##itic, cells, (, fig, ., 2, :, table, 2, ), ., these, cells, are, key, media, ##tors, of, the, innate, immune, response, in, which, the, p, ##38, and, j, ##nk, map, ##ks, lie, downstream, of, the, toll, -, like, receptors, (, t, ##lr, ##s, ), ,, which, are, activated, by, a, wide, variety, of, pathogen, -, derived, stimuli, and, act, to, regulate, the, expression, of, both, pro, and, anti, -, inflammatory, cy, ##tok, ##ines, and, che, ##mo, ##kin, ##es, [, 22, ], ., several, groups, demonstrated, that, loss, of, du, ##sp, ##1, /, mk, ##p, -, 1, led, to, elevated, j, ##nk, and, p, ##38, activities, in, macro, ##pha, ##ges, exposed, to, the, bacterial, end, ##oto, ##xin, lip, ##op, ##ol, ##ys, ##ac, ##cha, ##ride, (, lp, ##s, ), [, [, 25, ], ,, [, 26, ], ,, [, 27, ], ,, [, 28, ], ], ., this, led, to, an, initial, increase, in, the, expression, of, pro, -, inflammatory, cy, ##tok, ##ines, such, as, tu, ##mour, nec, ##rosis, factor, alpha, (, tn, ##f, ##α, ), ,, inter, ##le, ##uki, ##n, -, 6, (, il, -, 6, ), ,, inter, ##le, ##uki, ##n, -, 12, (, il, -, 12, ), and, inter, ##fer, ##on, -, gamma, (, if, ##n, -, γ, ), while, ,, at, later, times, ,, levels, of, the, anti, -, inflammatory, media, ##tor, inter, ##le, ##uki, ##n, -, 10, (, il, -, 10, ), were, increased, [, 25, ], ., these, cellular, effects, were, accompanied, by, path, ##ological, changes, such, as, inflammatory, tissue, in, ##filtration, ,, h, ##yp, ##ote, ##ns, ##ion, and, multiple, organ, failure, ,, all, of, which, are, markers, of, the, severe, sept, ##ic, shock, and, increased, mortality, observed, in, lp, ##s, -, injected, du, ##sp, ##1, ^, −, /, −, mice, when, compared, to, wild, type, controls, ., fig, ., 2d, ##us, ##p, ##1, /, mk, ##p, -, 1, in, innate, immunity, ., sc, ##hema, ##tic, showing, the, regulation, of, map, kinase, activities, in, cells, of, the, innate, immune, system, by, du, ##sp, ##1, /, mk, ##p, -, 1, and, the, consequences, of, genetic, del, ##eti, ##on, of, this, mk, ##p, on, the, physiological, responses, of, these, cell, populations, ., for, details, see, text, ., fig, ., 2, ##table, 2, ##im, ##mun, ##ological, ph, ##eno, ##type, ##s, of, mk, ##p, ko, mice, ., table, 2, ##group, ##gen, ##e, /, mk, ##pi, ##mm, ##uno, ##logical, ph, ##eno, ##type, ##s, of, mk, ##p, ko, mice, ##re, ##ference, ##s, ##nu, ##cle, ##ar, ,, ind, ##ucible, mk, ##ps, ##dus, ##p, ##1, /, mk, ##p, -, 1, ##in, ##cre, ##ase, ##d, pro, -, inflammatory, cy, ##tok, ##ine, production, &, innate, immune, response, lp, ##s, challenge, ., [, 25, ], impaired, resolution, of, inflammation, ., [, 30, ], decreased, adaptive, immune, response, &, viral, clearance, ., [, 33, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 33, ], increased, sensitivity, to, bacterial, infections, ., [, 35, ], ex, ##ace, ##rba, ##tes, inflammatory, ph, ##eno, ##type, ##s, including, :, coli, ##tis, ,, ana, ##phy, ##la, ##xi, ##s, and, ps, ##oria, ##sis, ., [, [, 40, ], ,, [, 41, ], ,, [, 42, ], ], du, ##sp, ##2, ##pro, ##tec, ##tion, from, experimental, ##ly, -, induced, arthritis, ., [, 86, ], decreased, macro, ##pha, ##ge, cy, ##tok, ##ine, expression, &, mast, cell, survival, ., [, 86, ], increased, su, ##sc, ##ept, ##ibility, to, ds, ##s, -, induced, model, of, int, ##estinal, inflammation, ., [, 87, ], altered, t, -, cell, balance, ,, via, the, promotion, of, th, ##17, differentiation, and, inhibition, of, tre, ##g, generation, ., [, 87, ], du, ##sp, ##4, /, mk, ##p, -, 2, ##in, ##cre, ##ase, ##d, su, ##sc, ##ept, ##ibility, to, lei, ##sh, ##mania, mexican, ##a, ,, lei, ##sh, ##mania, donovan, ##i, &, to, ##x, ##op, ##las, ##ma, go, ##ndi, ##i, infection, ., [, [, 97, ], ,, [, 98, ], ,, [, 99, ], ], resistant, to, lp, ##s, -, induced, end, ##oto, ##xi, ##c, shock, ., [, 100, ], increased, cd, ##4, +, t, -, cell, proliferation, ., [, 101, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 102, ], du, ##sp, ##5, ##ne, ##gative, ##ly, regulates, il, -, 33, mediated, e, ##osi, ##no, ##phi, ##l, survival, ., [, 119, ], resistant, to, helm, ##int, ##h, infection, ,, due, to, enhanced, e, ##osi, ##no, ##phi, ##l, activity, ., [, 119, ], regulates, cd, ##8, +, populations, in, response, to, lc, ##m, ##v, infection, ., [, 120, ], cy, ##top, ##las, ##mic, er, ##k, -, selective, mk, ##ps, ##dus, ##p, ##6, /, mk, ##p, -, 3, ##ex, ##ace, ##rba, ##tes, int, ##estinal, coli, ##tis, ., [, 150, ], decreased, cd, ##4, +, t, -, cell, proliferation, ,, altered, t, -, cell, polar, ##isation, &, impaired, tre, ##g, function, ., [, 150, ], du, ##sp, ##7, /, mk, ##p, -, x, ##n, /, ad, ##us, ##p, ##9, /, mk, ##p, -, 4, ##n, /, aj, ##nk, /, p, ##38, -, selective, mk, ##ps, ##dus, ##p, ##8, ##n, /, ad, ##us, ##p, ##10, /, mk, ##p, -, 5, ##im, ##pa, ##ired, t, cell, expansion, ,, but, enhanced, pri, ##ming, of, t, -, cells, by, ap, ##cs, ., [, 185, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 185, ], increased, cy, ##tok, ##ine, and, ro, ##s, production, in, macro, ##pha, ##ges, ,, ne, ##ut, ##rop, ##hil, ##s, and, t, cells, ., [, 187, ], protection, from, ds, ##s, -, induced, int, ##estinal, inflammation, ., [, 191, ], du, ##sp, ##16, /, mk, ##p, -, 7, ##im, ##pa, ##ired, gm, -, cs, ##f, -, driven, proliferation, of, bone, marrow, pro, ##gen, ##itors, ., [, 195, ], increased, cd, ##4, +, t, -, cell, proliferation, &, a, reduced, th, ##17, cell, population, ., [, 196, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 196, ], lc, ##m, ##v, ,, l, ##ym, ##ph, ##oc, ##ytic, cho, ##rio, ##men, ##ing, ##itis, virus, ., ds, ##s, ,, dex, ##tra, ##n, sodium, sulfate, .'},\n", + " {'article_id': '8b10c2efdaec5aa6769f1e69e0d78bea',\n", + " 'section_name': 'Brain neurochemistry',\n", + " 'text': 'To further explore the interrelationship between parous-induced neuroinflammation and neurotransmitters, we systematically analyzed the neurochemistry both in the prefrontal cortex and in the hippocampus of rats. As shown in Tables 2 and 3, DA level were significantly decreased both in the prefrontal cortex (p < 0.01) and in the hippocampus (p < 0.05) of parous groups, while its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remain stable. Parous rats that exposed to control diet also exhibited decreased norepinephrine (NE, p < 0.01 for prefrontal cortex), without altering the metabolites vanilmandelic acid (VMA) and 4-Hydroxy-3-methoxyphenylglycol (MHPG). However, virgin rats that with daily supply of Ω-3 fatty acids exhibited decreased NE (p < 0.01 for prefrontal cortex) and increased VMA (p < 0.05 for prefrontal cortex). It was worth to mention that both parous and Ω-3 fatty acids supplementation did not affect the serotonin (5-HT) level, but parous rats that exposed to daily supplementary of Ω-3 fatty acids exhibited decreased 5-hydroxy indole acetic acid (5-HIAA, p < 0.01) and the 5-HT turnover (the ratio of 5-HIAA to 5-HT, p < 0.05). Unexpectedly, parous resulted in significant increase of γ-aminobutyric acid (GABA) status (Table 2, p < 0.01) and glutamine (GLN, Table 2, p < 0.01) in the prefrontal cortex. Conversely, we find opposite trend in the hippocampus which exhibit decrease of GABA (p < 0.01) and GLN (p < 0.01) in parous.Table 2The content of major neurotransmitters and their metabolites in the prefrontal cortexCompoundVirginParousControlSupplementaryControlSupplementaryDA (ng/g)5.3 ± 0.65.4 ± 1.22.2 ± 0.3^##3.4 ± 0.3^#DOPAC (ng/g)6.8 ± 0.910.1 ± 1.910.1 ± 1.07.7 ± 0.5HVA (ng/g)1.1 ± 0.21.3 ± 0.31.3 ± 0.11.8 ± 0.2NE (ng/g)8.2 ± 1.83.8 ± 0.9**3.3 ± 0.6^##5.9 ± 0.7MHPG (ng/g)0.7 ± 0.10.9 ± 0.10.9 ± 0.11.1 ± 0.1VMA(ng/g)1.2 ± 0.12.0 ± 0.4*0.6 ± 0.10.5 ± 0.1^##TRY (ug/g)9.2 ± 1.66.7 ± 1.48.2 ± 0.712.0 ± 1.0^##,*5-HT (ng/g)153.7 ± 14.0127.7 ± 31.3116.0 ± 14.6178.6 ± 26.15-HIAA (ng/g)373.9 ± 45.6355.6 ± 27.0304.0 ± 25.8215.3 ± 11.02^##,*5-HIAA/5-HT3.0 ± 0.43.2 ± 0.82.8 ± 0.41.2 ± 0.2^#,*KYN (ng/g)540.7 ± 99.0429.0 ± 101.2526.1 ± 51.4622.2 ± 58.8GABA (ug/g)292.6 ± 41.5200.3 ± 49.8602.7 ± 82.8^##730.1 ± 99.2^##GLU (ug/g)0.4 ± 0.060.3 ± 0.050.5 ± 0.060.7 ± 0.07GLN (ug/g)178.2 ± 25.2132.0 ± 35.8356.7 ± 41.5^#501.0 ± 64.2^##Data are means ± SEM (n = 6–7). ^#p < 0.05, ^##p < 0.01 compared to virgin group; *p < 0.05, **p < 0.01compared to control groupTable 3The content of major neurotransmitters and their metabolites in the hippocampusCompoundVirginParousControlSupplementaryControlSupplementaryDA (ng/g)6.3 ± 0.85.0 ± 0.74.2 ± 0.4^#3.6 ± 0.5^#DOPAC (ng/g)3.1 ± 0.52.0 ± 0.23.1 ± 0.73.5 ± 0.7HVA (ng/g)0.5 ± 0.10.4 ± 0.10.3 ± 0.00.4 ± 0.1NE (ng/g)3.8 ± 0.43.5 ± 0.52.7 ± 0.33.0 ± 0.3MHPG (ng/g)0.4 ± 0.00.3 ± 0.00.3 ± 0.00.3 ± 0.0VMA(ng/g)4.0 ± 0.33.5 ± 0.74.5 ± 0.43.5 ± 0.4TRY (ug/g)4.8 ± 0.34.0 ± 0.13.7 ± 0.14.6 ± 0.45-HT (ng/g)129.6 ± 17.9105.5 ± 14.0108.1 ± 9.1121.1 ± 12.35-HIAA (ng/g)194.5 ± 30.3166.8 ± 29.6123.4 ± 9.571.8 ± 14.1^##5-HIAA/5-HT1.8 ± 0.52.3 ± 0.60.7 ± 0.10.7 ± 0.2^#KYN (ng/g)282.6 ± 24.5242.4 ± 6.9222.8 ± 8.8239.3 ± 14.4GABA (ug/g)63.3 ± 5.049.5 ± 3.131.6 ± 1.5^##34.4 ± 1.5GLU (ug/g)0.1 ± 0.00.1 ± 0.00.1 ± 0.00.1 ± 0.0GLN (ug/g)48.3 ± 3.738.0 ± 3.729.2 ± 1.3^##32.5 ± 1.1Data are means ± SEM (n = 6–7). ^#p < 0.05, ^##p < 0.01 compared to virgin group; *p < 0.05, **p < 0.01compared to control group',\n", + " 'paragraph_id': 18,\n", + " 'tokenizer': 'to, further, explore, the, inter, ##rel, ##ations, ##hip, between, par, ##ous, -, induced, ne, ##uro, ##in, ##fl, ##am, ##mation, and, ne, ##uro, ##tra, ##ns, ##mit, ##ters, ,, we, systematically, analyzed, the, ne, ##uro, ##chemist, ##ry, both, in, the, pre, ##front, ##al, cortex, and, in, the, hip, ##po, ##camp, ##us, of, rats, ., as, shown, in, tables, 2, and, 3, ,, da, level, were, significantly, decreased, both, in, the, pre, ##front, ##al, cortex, (, p, <, 0, ., 01, ), and, in, the, hip, ##po, ##camp, ##us, (, p, <, 0, ., 05, ), of, par, ##ous, groups, ,, while, its, meta, ##bol, ##ites, 3, ,, 4, -, di, ##hy, ##dro, ##xy, ##ph, ##en, ##yla, ##ce, ##tic, acid, (, do, ##pac, ), and, homo, ##vani, ##lli, ##c, acid, (, h, ##va, ), remain, stable, ., par, ##ous, rats, that, exposed, to, control, diet, also, exhibited, decreased, nor, ##ep, ##ine, ##ph, ##rine, (, ne, ,, p, <, 0, ., 01, for, pre, ##front, ##al, cortex, ), ,, without, altering, the, meta, ##bol, ##ites, van, ##il, ##man, ##del, ##ic, acid, (, v, ##ma, ), and, 4, -, hydro, ##xy, -, 3, -, met, ##ho, ##xy, ##ph, ##en, ##yl, ##gly, ##col, (, m, ##hp, ##g, ), ., however, ,, virgin, rats, that, with, daily, supply, of, ω, -, 3, fatty, acids, exhibited, decreased, ne, (, p, <, 0, ., 01, for, pre, ##front, ##al, cortex, ), and, increased, v, ##ma, (, p, <, 0, ., 05, for, pre, ##front, ##al, cortex, ), ., it, was, worth, to, mention, that, both, par, ##ous, and, ω, -, 3, fatty, acids, supplement, ##ation, did, not, affect, the, ser, ##oton, ##in, (, 5, -, h, ##t, ), level, ,, but, par, ##ous, rats, that, exposed, to, daily, supplementary, of, ω, -, 3, fatty, acids, exhibited, decreased, 5, -, hydro, ##xy, indo, ##le, ace, ##tic, acid, (, 5, -, hi, ##aa, ,, p, <, 0, ., 01, ), and, the, 5, -, h, ##t, turnover, (, the, ratio, of, 5, -, hi, ##aa, to, 5, -, h, ##t, ,, p, <, 0, ., 05, ), ., unexpectedly, ,, par, ##ous, resulted, in, significant, increase, of, γ, -, amino, ##bu, ##ty, ##ric, acid, (, ga, ##ba, ), status, (, table, 2, ,, p, <, 0, ., 01, ), and, g, ##lu, ##tam, ##ine, (, g, ##ln, ,, table, 2, ,, p, <, 0, ., 01, ), in, the, pre, ##front, ##al, cortex, ., conversely, ,, we, find, opposite, trend, in, the, hip, ##po, ##camp, ##us, which, exhibit, decrease, of, ga, ##ba, (, p, <, 0, ., 01, ), and, g, ##ln, (, p, <, 0, ., 01, ), in, par, ##ous, ., table, 2, ##the, content, of, major, ne, ##uro, ##tra, ##ns, ##mit, ##ters, and, their, meta, ##bol, ##ites, in, the, pre, ##front, ##al, cortex, ##com, ##po, ##und, ##vir, ##gin, ##par, ##ous, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##da, (, ng, /, g, ), 5, ., 3, ±, 0, ., 65, ., 4, ±, 1, ., 22, ., 2, ±, 0, ., 3, ^, #, #, 3, ., 4, ±, 0, ., 3, ^, #, do, ##pac, (, ng, /, g, ), 6, ., 8, ±, 0, ., 910, ., 1, ±, 1, ., 910, ., 1, ±, 1, ., 07, ., 7, ±, 0, ., 5, ##h, ##va, (, ng, /, g, ), 1, ., 1, ±, 0, ., 21, ., 3, ±, 0, ., 31, ., 3, ±, 0, ., 11, ., 8, ±, 0, ., 2, ##ne, (, ng, /, g, ), 8, ., 2, ±, 1, ., 83, ., 8, ±, 0, ., 9, *, *, 3, ., 3, ±, 0, ., 6, ^, #, #, 5, ., 9, ±, 0, ., 7, ##m, ##hp, ##g, (, ng, /, g, ), 0, ., 7, ±, 0, ., 10, ., 9, ±, 0, ., 10, ., 9, ±, 0, ., 11, ., 1, ±, 0, ., 1, ##v, ##ma, (, ng, /, g, ), 1, ., 2, ±, 0, ., 12, ., 0, ±, 0, ., 4, *, 0, ., 6, ±, 0, ., 10, ., 5, ±, 0, ., 1, ^, #, #, try, (, u, ##g, /, g, ), 9, ., 2, ±, 1, ., 66, ., 7, ±, 1, ., 48, ., 2, ±, 0, ., 71, ##2, ., 0, ±, 1, ., 0, ^, #, #, ,, *, 5, -, h, ##t, (, ng, /, g, ), 153, ., 7, ±, 14, ., 01, ##27, ., 7, ±, 31, ., 311, ##6, ., 0, ±, 14, ., 61, ##7, ##8, ., 6, ±, 26, ., 15, -, hi, ##aa, (, ng, /, g, ), 37, ##3, ., 9, ±, 45, ., 63, ##55, ., 6, ±, 27, ., 03, ##0, ##4, ., 0, ±, 25, ., 82, ##15, ., 3, ±, 11, ., 02, ^, #, #, ,, *, 5, -, hi, ##aa, /, 5, -, h, ##t, ##3, ., 0, ±, 0, ., 43, ., 2, ±, 0, ., 82, ., 8, ±, 0, ., 41, ., 2, ±, 0, ., 2, ^, #, ,, *, ky, ##n, (, ng, /, g, ), 540, ., 7, ±, 99, ., 04, ##29, ., 0, ±, 101, ., 252, ##6, ., 1, ±, 51, ., 46, ##22, ., 2, ±, 58, ., 8, ##ga, ##ba, (, u, ##g, /, g, ), 292, ., 6, ±, 41, ., 520, ##0, ., 3, ±, 49, ., 86, ##0, ##2, ., 7, ±, 82, ., 8, ^, #, #, 730, ., 1, ±, 99, ., 2, ^, #, #, g, ##lu, (, u, ##g, /, g, ), 0, ., 4, ±, 0, ., 06, ##0, ., 3, ±, 0, ., 050, ., 5, ±, 0, ., 06, ##0, ., 7, ±, 0, ., 07, ##gl, ##n, (, u, ##g, /, g, ), 178, ., 2, ±, 25, ., 213, ##2, ., 0, ±, 35, ., 83, ##56, ., 7, ±, 41, ., 5, ^, #, 501, ., 0, ±, 64, ., 2, ^, #, #, data, are, means, ±, se, ##m, (, n, =, 6, –, 7, ), ., ^, #, p, <, 0, ., 05, ,, ^, #, #, p, <, 0, ., 01, compared, to, virgin, group, ;, *, p, <, 0, ., 05, ,, *, *, p, <, 0, ., 01, ##com, ##par, ##ed, to, control, group, ##table, 3, ##the, content, of, major, ne, ##uro, ##tra, ##ns, ##mit, ##ters, and, their, meta, ##bol, ##ites, in, the, hip, ##po, ##camp, ##us, ##com, ##po, ##und, ##vir, ##gin, ##par, ##ous, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##da, (, ng, /, g, ), 6, ., 3, ±, 0, ., 85, ., 0, ±, 0, ., 74, ., 2, ±, 0, ., 4, ^, #, 3, ., 6, ±, 0, ., 5, ^, #, do, ##pac, (, ng, /, g, ), 3, ., 1, ±, 0, ., 52, ., 0, ±, 0, ., 23, ., 1, ±, 0, ., 73, ., 5, ±, 0, ., 7, ##h, ##va, (, ng, /, g, ), 0, ., 5, ±, 0, ., 10, ., 4, ±, 0, ., 10, ., 3, ±, 0, ., 00, ., 4, ±, 0, ., 1, ##ne, (, ng, /, g, ), 3, ., 8, ±, 0, ., 43, ., 5, ±, 0, ., 52, ., 7, ±, 0, ., 33, ., 0, ±, 0, ., 3, ##m, ##hp, ##g, (, ng, /, g, ), 0, ., 4, ±, 0, ., 00, ., 3, ±, 0, ., 00, ., 3, ±, 0, ., 00, ., 3, ±, 0, ., 0, ##v, ##ma, (, ng, /, g, ), 4, ., 0, ±, 0, ., 33, ., 5, ±, 0, ., 74, ., 5, ±, 0, ., 43, ., 5, ±, 0, ., 4, ##try, (, u, ##g, /, g, ), 4, ., 8, ±, 0, ., 34, ., 0, ±, 0, ., 13, ., 7, ±, 0, ., 14, ., 6, ±, 0, ., 45, -, h, ##t, (, ng, /, g, ), 129, ., 6, ±, 17, ., 910, ##5, ., 5, ±, 14, ., 01, ##0, ##8, ., 1, ±, 9, ., 112, ##1, ., 1, ±, 12, ., 35, -, hi, ##aa, (, ng, /, g, ), 194, ., 5, ±, 30, ., 316, ##6, ., 8, ±, 29, ., 61, ##23, ., 4, ±, 9, ., 57, ##1, ., 8, ±, 14, ., 1, ^, #, #, 5, -, hi, ##aa, /, 5, -, h, ##t, ##1, ., 8, ±, 0, ., 52, ., 3, ±, 0, ., 60, ., 7, ±, 0, ., 10, ., 7, ±, 0, ., 2, ^, #, ky, ##n, (, ng, /, g, ), 282, ., 6, ±, 24, ., 52, ##42, ., 4, ±, 6, ., 92, ##22, ., 8, ±, 8, ., 82, ##39, ., 3, ±, 14, ., 4, ##ga, ##ba, (, u, ##g, /, g, ), 63, ., 3, ±, 5, ., 04, ##9, ., 5, ±, 3, ., 131, ., 6, ±, 1, ., 5, ^, #, #, 34, ., 4, ±, 1, ., 5, ##gl, ##u, (, u, ##g, /, g, ), 0, ., 1, ±, 0, ., 00, ., 1, ±, 0, ., 00, ., 1, ±, 0, ., 00, ., 1, ±, 0, ., 0, ##gl, ##n, (, u, ##g, /, g, ), 48, ., 3, ±, 3, ., 73, ##8, ., 0, ±, 3, ., 72, ##9, ., 2, ±, 1, ., 3, ^, #, #, 32, ., 5, ±, 1, ., 1, ##da, ##ta, are, means, ±, se, ##m, (, n, =, 6, –, 7, ), ., ^, #, p, <, 0, ., 05, ,, ^, #, #, p, <, 0, ., 01, compared, to, virgin, group, ;, *, p, <, 0, ., 05, ,, *, *, p, <, 0, ., 01, ##com, ##par, ##ed, to, control, group'},\n", + " {'article_id': '1003e6984412debd4e0706f54060e4b5',\n", + " 'section_name': '',\n", + " 'text': 'Discovering diversity: identify and provide experimental access to the different brain cell types to determine their roles in health and disease. Characterization of all the cell types in the nervous system is within reach, and a cell “census” of neuronal and glial cell types will aid in the development of tools that can precisely target and manipulate them.The (BICCN), launched in 2017 based on extraordinary early progress, is the single largest BRAIN Initiative project to date and plans to invest US$250 million over the next five years to construct a comprehensive reference of diverse cell types in human, monkey, and mouse brains. This team science program will provide essential characterization for the diversity of cell types, an open-access 3D digital mouse brain cell reference atlas, and a comprehensive neural circuit diagram, as well as genomic access to specific cell types to monitor, map, or modulate their activity. These tools will serve as unprecedented resources for the scientific community to develop a deep understanding of neural circuit function across species. To achieve its goals, the BICCN requires its scientists to work together with agreed upon standards, methods, and a common framework for assembling the large variety of data coming from multiple laboratories, a social neuroscience experiment in itself.Maps at multiple scales: generate circuit diagrams that vary in resolution, from synapses to the whole brain. As our ability to map neuronal connections within local circuits; micro-, meso-, and macroconnectomes; and between distributed brain systems improves, scalable circuit maps will relate structure to function.Successful efforts have been made in serial section electron microscopy and their analytic pipelines to enable whole brain connectomics in Drosophila and zebrafish as well as in regions of the mouse cortex. Improved track-tracing tools that leverage multiphoton imaging, expansion microscopy, and advanced techniques like viral circuit tracing have been devised and applied to identify synaptic inputs to specific neurons. Innovative whole brain–clearing techniques like clear lipid-exchanged acrylamide-hybridized rigid imaging/immunostaining/in situ hyrbridization-compatible tissue-hydrogel (CLARITY) enable morphological assessment in 3D and should be adaptable to postmortem human tissue.The brain in action: produce a dynamic picture of the functioning brain by developing and applying improved methods for large‐scale monitoring of neural activity. Various neuronal-recording methods continue to emerge and offer innovative ways to record neuronal activity at a single-cell level from ever more cells over larger brain regions in awake behaving animals. Successful efforts have visualized network brain activity over wide areas of the mouse cortex while preserving the ability to focus at single-cell resolution. Investigator teams are recording longer and from more brain regions in patients undergoing deep brain stimulation to understand human circuit activity underlying speech, movement, intention, and emotion.Demonstrating causality: link brain activity to behavior with precise interventional tools that change neural circuit dynamics. Tools that enable circuit manipulation open the door to probe how neural activity gives rise to behavior. Teams of scientists are monitoring and modulating neural activity linked to behavior both in awake behaving animals and in patients undergoing deep brain stimulation for disorders such as epilepsy, Parkinsons disease, chronic pain, obsessive compulsive disorders, and depression.Identifying fundamental principles: produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data-analysis tools. The ability to capture neural activity in thousands to millions of neurons poses analytic challenges but offers a new opportunity to understand the language of the brain and the rules that underly its information processing. Progress relies on engaging statisticians, mathematicians, and computer scientists to join the effort. Teams of scientists are capturing neural activity in specific circuits and developing models that explain and predict key circuit characteristics as well as theories of fundamental brain processes.Advancing human neuroscience: develop innovative technologies to understand the human brain and treat its disorders; create and support integrated human brain research networks. The burden of illness due to neurologic, psychiatric, and substance-abuse disorders is due largely to disordered brain circuits. The ability to measure and characterize activity in these circuits will change diagnostics and provide targets to precisely modulate them, ultimately changing the landscape of therapeutics. Early examples are the tuning of closed-loop deep brain stimulation devices based on measures of brain activity in patients with essential tremor and Parkinsons disease. Ultimately, the tools and technologies that emerge from BRAIN are expected to open the door to new FDA-approved drug therapies and devices for neurological and psychiatric disorders over the next decade.From BRAIN Initiative to the brain: integrate new technological and conceptual approaches produced in Goals 1–6 to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease. Taken together, the goals outlined above lay the foundation for a comprehensive, integrated, and mechanistic understanding of brain function across species to understand the basis of our human capabilities. Since the NIH BRAIN Initiative began, more than 500 awards have gone out to investigators around the world, reflecting an investment of nearly US$1 billion.',\n", + " 'paragraph_id': 4,\n", + " 'tokenizer': 'discovering, diversity, :, identify, and, provide, experimental, access, to, the, different, brain, cell, types, to, determine, their, roles, in, health, and, disease, ., characterization, of, all, the, cell, types, in, the, nervous, system, is, within, reach, ,, and, a, cell, “, census, ”, of, ne, ##uron, ##al, and, g, ##lia, ##l, cell, types, will, aid, in, the, development, of, tools, that, can, precisely, target, and, manipulate, them, ., the, (, bi, ##cc, ##n, ), ,, launched, in, 2017, based, on, extraordinary, early, progress, ,, is, the, single, largest, brain, initiative, project, to, date, and, plans, to, invest, us, $, 250, million, over, the, next, five, years, to, construct, a, comprehensive, reference, of, diverse, cell, types, in, human, ,, monkey, ,, and, mouse, brains, ., this, team, science, program, will, provide, essential, characterization, for, the, diversity, of, cell, types, ,, an, open, -, access, 3d, digital, mouse, brain, cell, reference, atlas, ,, and, a, comprehensive, neural, circuit, diagram, ,, as, well, as, gen, ##omic, access, to, specific, cell, types, to, monitor, ,, map, ,, or, mod, ##ulate, their, activity, ., these, tools, will, serve, as, unprecedented, resources, for, the, scientific, community, to, develop, a, deep, understanding, of, neural, circuit, function, across, species, ., to, achieve, its, goals, ,, the, bi, ##cc, ##n, requires, its, scientists, to, work, together, with, agreed, upon, standards, ,, methods, ,, and, a, common, framework, for, ass, ##em, ##bling, the, large, variety, of, data, coming, from, multiple, laboratories, ,, a, social, neuroscience, experiment, in, itself, ., maps, at, multiple, scales, :, generate, circuit, diagrams, that, vary, in, resolution, ,, from, syn, ##ap, ##ses, to, the, whole, brain, ., as, our, ability, to, map, ne, ##uron, ##al, connections, within, local, circuits, ;, micro, -, ,, me, ##so, -, ,, and, macro, ##con, ##ne, ##ct, ##ome, ##s, ;, and, between, distributed, brain, systems, improves, ,, scala, ##ble, circuit, maps, will, relate, structure, to, function, ., successful, efforts, have, been, made, in, serial, section, electron, microscopy, and, their, analytic, pipeline, ##s, to, enable, whole, brain, connect, ##omics, in, dr, ##oso, ##phila, and, zebra, ##fish, as, well, as, in, regions, of, the, mouse, cortex, ., improved, track, -, tracing, tools, that, leverage, multi, ##ph, ##oton, imaging, ,, expansion, microscopy, ,, and, advanced, techniques, like, viral, circuit, tracing, have, been, devised, and, applied, to, identify, syn, ##ap, ##tic, inputs, to, specific, neurons, ., innovative, whole, brain, –, clearing, techniques, like, clear, lip, ##id, -, exchanged, ac, ##ryl, ##ami, ##de, -, hybrid, ##ized, rigid, imaging, /, im, ##mun, ##osta, ##ining, /, in, situ, h, ##yr, ##bri, ##di, ##zation, -, compatible, tissue, -, hydro, ##gel, (, clarity, ), enable, morphological, assessment, in, 3d, and, should, be, adapt, ##able, to, post, ##mo, ##rte, ##m, human, tissue, ., the, brain, in, action, :, produce, a, dynamic, picture, of, the, functioning, brain, by, developing, and, applying, improved, methods, for, large, ‐, scale, monitoring, of, neural, activity, ., various, ne, ##uron, ##al, -, recording, methods, continue, to, emerge, and, offer, innovative, ways, to, record, ne, ##uron, ##al, activity, at, a, single, -, cell, level, from, ever, more, cells, over, larger, brain, regions, in, awake, be, ##ha, ##ving, animals, ., successful, efforts, have, visual, ##ized, network, brain, activity, over, wide, areas, of, the, mouse, cortex, while, preserving, the, ability, to, focus, at, single, -, cell, resolution, ., investigator, teams, are, recording, longer, and, from, more, brain, regions, in, patients, undergoing, deep, brain, stimulation, to, understand, human, circuit, activity, underlying, speech, ,, movement, ,, intention, ,, and, emotion, ., demonstrating, causal, ##ity, :, link, brain, activity, to, behavior, with, precise, intervention, ##al, tools, that, change, neural, circuit, dynamics, ., tools, that, enable, circuit, manipulation, open, the, door, to, probe, how, neural, activity, gives, rise, to, behavior, ., teams, of, scientists, are, monitoring, and, mod, ##ulating, neural, activity, linked, to, behavior, both, in, awake, be, ##ha, ##ving, animals, and, in, patients, undergoing, deep, brain, stimulation, for, disorders, such, as, ep, ##ile, ##psy, ,, parkinson, ##s, disease, ,, chronic, pain, ,, ob, ##ses, ##sive, com, ##pu, ##ls, ##ive, disorders, ,, and, depression, ., identifying, fundamental, principles, :, produce, conceptual, foundations, for, understanding, the, biological, basis, of, mental, processes, through, development, of, new, theoretical, and, data, -, analysis, tools, ., the, ability, to, capture, neural, activity, in, thousands, to, millions, of, neurons, poses, analytic, challenges, but, offers, a, new, opportunity, to, understand, the, language, of, the, brain, and, the, rules, that, under, ##ly, its, information, processing, ., progress, relies, on, engaging, stat, ##istic, ##ians, ,, mathematicians, ,, and, computer, scientists, to, join, the, effort, ., teams, of, scientists, are, capturing, neural, activity, in, specific, circuits, and, developing, models, that, explain, and, predict, key, circuit, characteristics, as, well, as, theories, of, fundamental, brain, processes, ., advancing, human, neuroscience, :, develop, innovative, technologies, to, understand, the, human, brain, and, treat, its, disorders, ;, create, and, support, integrated, human, brain, research, networks, ., the, burden, of, illness, due, to, ne, ##uro, ##logic, ,, psychiatric, ,, and, substance, -, abuse, disorders, is, due, largely, to, disorder, ##ed, brain, circuits, ., the, ability, to, measure, and, character, ##ize, activity, in, these, circuits, will, change, diagnostic, ##s, and, provide, targets, to, precisely, mod, ##ulate, them, ,, ultimately, changing, the, landscape, of, therapeutic, ##s, ., early, examples, are, the, tuning, of, closed, -, loop, deep, brain, stimulation, devices, based, on, measures, of, brain, activity, in, patients, with, essential, tremor, and, parkinson, ##s, disease, ., ultimately, ,, the, tools, and, technologies, that, emerge, from, brain, are, expected, to, open, the, door, to, new, fda, -, approved, drug, the, ##ra, ##pies, and, devices, for, neurological, and, psychiatric, disorders, over, the, next, decade, ., from, brain, initiative, to, the, brain, :, integrate, new, technological, and, conceptual, approaches, produced, in, goals, 1, –, 6, to, discover, how, dynamic, patterns, of, neural, activity, are, transformed, into, cognition, ,, emotion, ,, perception, ,, and, action, in, health, and, disease, ., taken, together, ,, the, goals, outlined, above, lay, the, foundation, for, a, comprehensive, ,, integrated, ,, and, me, ##chan, ##istic, understanding, of, brain, function, across, species, to, understand, the, basis, of, our, human, capabilities, ., since, the, ni, ##h, brain, initiative, began, ,, more, than, 500, awards, have, gone, out, to, investigators, around, the, world, ,, reflecting, an, investment, of, nearly, us, $, 1, billion, .'},\n", + " {'article_id': 'c1bebb31c874aa2fad9ac008fc3fbe24',\n", + " 'section_name': 'Cav-1 and neuroinflammation (Fig. 3)',\n", + " 'text': 'In the endothelium, after exposure to LPS, cav-1 was phosphorylated at Tyr(14) which resulted in interaction between cav-1 and toll-like receptor 4 (TLR4), and then TLR4 promoted activation of MyD88, leading to NF-κB activation and the generation of proinflammatory cytokines [130]. Cav-1 OE dose-dependently increased monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) mRNA levels in human umbilical vein ECs. Pigment epithelium-derived factor binding to cav-1 could inhibit the pro-inflammatory effects of cav-1 in endothelial cells [131]. Cav-1 can affect NF-κB to influence the inflammatory response. Signaling by the proinflammatory cytokine interleukin-1β (IL-1β) is dependent on ROS, because after IL-1β binding to its receptor (IL-1R1), ROS generated by Nox2 is responsible for the downstream recruitment of IL-1R1 effectors (IRAK, TRAF6, IkappaB kinase kinases) and ultimately for activation of NF-κB. Lipid rafts and cav-1 coordinate IL-1β-dependent activation of NF-κB. Inhibiting cav-1-mediated endocytosis can prevent NF-κB activation [132]. Cav-1 gene KO lungs displayed suppression of NF-κB activity and reduced transcription of iNOS and intercellular adhesion molecule 1 (ICAM-1) [133]. Secondary to the loss of cav-1, eNOS is activated, which inhibits the innate immune response to LPS through interleukin-1 receptor-associated kinase 4 (IRAK4) nitration. IRAK4 is a signaling factor required for NF-κB activation and innate immunity. Cav-1 KO can impair the activity of NF-κB and reduce LPS-induced lung injury [134]. Cav-1 appears to have different roles in different cells. In macrophages, the interaction of cav-1 with TLR4 has an opposite outcome compared with that in endothelium, whereby overexpression of cav-1 decreased LPS-induced TNF-α and IL-6 proinflammatory cytokine production and augmented anti-inflammatory cytokine IL-10 production. Cav-1 regulates LPS-induced inflammatory cytokine production through the MKK3/p38 MAPK pathway [135]. It is valuable to mention that TLR4 activation by LPS also stimulates heme oxygenase-1 (HO-1) transporting to the caveolae by a p38 MAPK-dependent mechanism and producing carbon oxide (CO). CO has anti-inflammatory effects and augments the cav-1/TLR4 interaction in murine macrophages [136]. In PMN leukocytes, cav-1 appears to promote activation, adhesion, and transendothelial migration and shows a positive role in PMN activation-induced lung and vascular injury [137]. Cav-1 also plays a key role in antigen-presenting cells, leading to the activation of T lymphocytes [138]. Furthermore, apoptosis of thymocytes in cav-1-deficient mice was higher than that in wild type mice, indicating that cav-1 is a key regulator of thymocyte apoptosis during inflammation [139]. In addition, cav-1 has a possible role in microglial activation. Cav-1 was remarkably reduced and localized in the plasmalemma and cytoplasmic vesicles of inactive microglia, whereas active (amoeboid-shaped) microglia exhibited increased cav-1 expression [46]. Recently, Portugal et al. found that cav-1 in microglia induced the internalization of plasma membrane sodium-vitamin C cotransporter 2 (SVCT2), triggering a proinflammatory phenotype in microglia and inducing microglia activation [140]. Besides, cav-1 transfection into Fatty acid-binding proteins-KO astrocytes remarkably enhanced TLR4 recruitment into lipid raft and tumor necrosis factor-ɑ production after LPS stimulation [141]. Together, in non-pathological states or after LPS stimulation, cav-1 in endothelial cells increases proinflammatory cytokines, while cav-1 inhibits LPS-induced inflammatory effects in murine macrophages. Cav-1 is involved in activation of microglia, PMN, and T lymphocytes.',\n", + " 'paragraph_id': 22,\n", + " 'tokenizer': 'in, the, end, ##oth, ##eli, ##um, ,, after, exposure, to, lp, ##s, ,, ca, ##v, -, 1, was, ph, ##os, ##ph, ##ory, ##lated, at, ty, ##r, (, 14, ), which, resulted, in, interaction, between, ca, ##v, -, 1, and, toll, -, like, receptor, 4, (, t, ##lr, ##4, ), ,, and, then, t, ##lr, ##4, promoted, activation, of, my, ##d, ##8, ##8, ,, leading, to, n, ##f, -, κ, ##b, activation, and, the, generation, of, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ines, [, 130, ], ., ca, ##v, -, 1, o, ##e, dose, -, dependent, ##ly, increased, mono, ##cy, ##te, che, ##mo, ##att, ##rac, ##tan, ##t, protein, -, 1, (, mc, ##p, -, 1, ), ,, vascular, cell, ad, ##hesion, molecule, -, 1, (, vc, ##am, -, 1, ), ,, and, pl, ##as, ##min, ##ogen, act, ##iva, ##tor, inhibitor, -, 1, (, pa, ##i, -, 1, ), mrna, levels, in, human, um, ##bil, ##ical, vein, ec, ##s, ., pigment, ep, ##ith, ##eli, ##um, -, derived, factor, binding, to, ca, ##v, -, 1, could, inhibit, the, pro, -, inflammatory, effects, of, ca, ##v, -, 1, in, end, ##oth, ##elial, cells, [, 131, ], ., ca, ##v, -, 1, can, affect, n, ##f, -, κ, ##b, to, influence, the, inflammatory, response, ., signaling, by, the, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ine, inter, ##le, ##uki, ##n, -, 1, ##β, (, il, -, 1, ##β, ), is, dependent, on, ro, ##s, ,, because, after, il, -, 1, ##β, binding, to, its, receptor, (, il, -, 1, ##r, ##1, ), ,, ro, ##s, generated, by, no, ##x, ##2, is, responsible, for, the, downstream, recruitment, of, il, -, 1, ##r, ##1, effect, ##ors, (, ira, ##k, ,, tr, ##af, ##6, ,, ik, ##app, ##ab, kinase, kinase, ##s, ), and, ultimately, for, activation, of, n, ##f, -, κ, ##b, ., lip, ##id, raft, ##s, and, ca, ##v, -, 1, coordinate, il, -, 1, ##β, -, dependent, activation, of, n, ##f, -, κ, ##b, ., inhibit, ##ing, ca, ##v, -, 1, -, mediated, end, ##oc, ##yt, ##osis, can, prevent, n, ##f, -, κ, ##b, activation, [, 132, ], ., ca, ##v, -, 1, gene, ko, lungs, displayed, suppression, of, n, ##f, -, κ, ##b, activity, and, reduced, transcription, of, in, ##os, and, inter, ##cellular, ad, ##hesion, molecule, 1, (, ic, ##am, -, 1, ), [, 133, ], ., secondary, to, the, loss, of, ca, ##v, -, 1, ,, en, ##os, is, activated, ,, which, inhibit, ##s, the, innate, immune, response, to, lp, ##s, through, inter, ##le, ##uki, ##n, -, 1, receptor, -, associated, kinase, 4, (, ira, ##k, ##4, ), ni, ##tra, ##tion, ., ira, ##k, ##4, is, a, signaling, factor, required, for, n, ##f, -, κ, ##b, activation, and, innate, immunity, ., ca, ##v, -, 1, ko, can, imp, ##air, the, activity, of, n, ##f, -, κ, ##b, and, reduce, lp, ##s, -, induced, lung, injury, [, 134, ], ., ca, ##v, -, 1, appears, to, have, different, roles, in, different, cells, ., in, macro, ##pha, ##ges, ,, the, interaction, of, ca, ##v, -, 1, with, t, ##lr, ##4, has, an, opposite, outcome, compared, with, that, in, end, ##oth, ##eli, ##um, ,, whereby, over, ##ex, ##press, ##ion, of, ca, ##v, -, 1, decreased, lp, ##s, -, induced, tn, ##f, -, α, and, il, -, 6, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ine, production, and, augmented, anti, -, inflammatory, cy, ##tok, ##ine, il, -, 10, production, ., ca, ##v, -, 1, regulates, lp, ##s, -, induced, inflammatory, cy, ##tok, ##ine, production, through, the, mk, ##k, ##3, /, p, ##38, map, ##k, pathway, [, 135, ], ., it, is, valuable, to, mention, that, t, ##lr, ##4, activation, by, lp, ##s, also, stimulate, ##s, hem, ##e, oxygen, ##ase, -, 1, (, ho, -, 1, ), transporting, to, the, cave, ##ola, ##e, by, a, p, ##38, map, ##k, -, dependent, mechanism, and, producing, carbon, oxide, (, co, ), ., co, has, anti, -, inflammatory, effects, and, aug, ##ments, the, ca, ##v, -, 1, /, t, ##lr, ##4, interaction, in, mu, ##rine, macro, ##pha, ##ges, [, 136, ], ., in, pm, ##n, le, ##uk, ##ocytes, ,, ca, ##v, -, 1, appears, to, promote, activation, ,, ad, ##hesion, ,, and, trans, ##end, ##oth, ##elial, migration, and, shows, a, positive, role, in, pm, ##n, activation, -, induced, lung, and, vascular, injury, [, 137, ], ., ca, ##v, -, 1, also, plays, a, key, role, in, antigen, -, presenting, cells, ,, leading, to, the, activation, of, t, l, ##ym, ##ph, ##ocytes, [, 138, ], ., furthermore, ,, ap, ##op, ##tosis, of, thy, ##mo, ##cytes, in, ca, ##v, -, 1, -, def, ##icient, mice, was, higher, than, that, in, wild, type, mice, ,, indicating, that, ca, ##v, -, 1, is, a, key, regulator, of, thy, ##mo, ##cy, ##te, ap, ##op, ##tosis, during, inflammation, [, 139, ], ., in, addition, ,, ca, ##v, -, 1, has, a, possible, role, in, micro, ##glia, ##l, activation, ., ca, ##v, -, 1, was, remarkably, reduced, and, localized, in, the, plasma, ##lem, ##ma, and, cy, ##top, ##las, ##mic, ve, ##sic, ##les, of, inactive, micro, ##glia, ,, whereas, active, (, am, ##oe, ##bo, ##id, -, shaped, ), micro, ##glia, exhibited, increased, ca, ##v, -, 1, expression, [, 46, ], ., recently, ,, portugal, et, al, ., found, that, ca, ##v, -, 1, in, micro, ##glia, induced, the, internal, ##ization, of, plasma, membrane, sodium, -, vitamin, c, cot, ##ran, ##sport, ##er, 2, (, sv, ##ct, ##2, ), ,, triggering, a, pro, ##in, ##fl, ##am, ##mat, ##ory, ph, ##eno, ##type, in, micro, ##glia, and, inducing, micro, ##glia, activation, [, 140, ], ., besides, ,, ca, ##v, -, 1, trans, ##fect, ##ion, into, fatty, acid, -, binding, proteins, -, ko, astro, ##cytes, remarkably, enhanced, t, ##lr, ##4, recruitment, into, lip, ##id, raft, and, tumor, nec, ##rosis, factor, -, ɑ, production, after, lp, ##s, stimulation, [, 141, ], ., together, ,, in, non, -, path, ##ological, states, or, after, lp, ##s, stimulation, ,, ca, ##v, -, 1, in, end, ##oth, ##elial, cells, increases, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ines, ,, while, ca, ##v, -, 1, inhibit, ##s, lp, ##s, -, induced, inflammatory, effects, in, mu, ##rine, macro, ##pha, ##ges, ., ca, ##v, -, 1, is, involved, in, activation, of, micro, ##glia, ,, pm, ##n, ,, and, t, l, ##ym, ##ph, ##ocytes, .'},\n", + " {'article_id': 'd1cbb8890196b1d896c3ca4b9ecf0978',\n", + " 'section_name': 'High-throughput brain activity mapping (HT-BAMing) technology',\n", + " 'text': 'Advances in microscopy techniques^17 and the development of novel calcium-sensitive fluorescent reporters^11 have enabled recording of brain-wide activity in larval zebrafish with single-cell resolution^12. Here, changes in the fluorescence of calcium-sensitive fluorophores provides an established proxy for imaging of neuronal activity^11,12,18. However, the challenges posed by handling of zebrafish larvae prohibit the wide application to large-scale analysis, and as a result the throughput for these experiments is quite limited and can be greatly improved by robotic automation and microfluidic systems^19,20. With the goal of investigating whole-brain CNS physiology on a large scale, we developed an autonomous system capable of orienting and immobilizing multiple awake, nonanesthetized animals for high-throughput recording of brain-wide neuronal activity. This system was based on our recent development of a microfluidic chip that utilizes hydrodynamic force to trap, position, and orient zebrafish larvae^13,14 (Fig. 1a−c). The processing throughput was further enhanced by a system for larvae loading and transportation that employs digitally controlled syringe pumps, electromagnetic valves and video detection to enable automatic feeding of larvae into the microfluidic chip (Supplementary Fig. 1). In this study, all larvae were loaded with a dorsal-up orientation to facilitate brain imaging from above. The use of transgenic zebrafish (elavl3:GCaMP5G) with a genetically encoded calcium indicator (Fig. 1d) allowed for real-time whole-brain imaging, and subsequent analysis of drug-induced changes in neuronal activity (Supplementary Fig. 1d). To generate the functional BAM of a larva in response to a 15-min period of chemical perfusion, or treatment, each larva was imaged over a 10-min period before and after treatment (Fig. 1e). Readings from multiple focal planes along the Z-axis (ventral direction) were acquired, and the accumulated number of calcium transients were derived from the fluorescence fluctuations of each Z-plane with a lateral resolution of 15.21 μm^2. The difference in calcium transient counts between the post- and pretreatment periods was calculated and projected (by summing up along the Z-axis) to a two-dimensional surface to construct a BAM that reflects changes in brain activity and physiology of an individual larva in response to treatment (Fig. 1a, e). For each compound, BAMs from five individual larvae were acquired following treatment with a 10 μM dose. To avoid false-positive or false-negative errors potentially introduced by variation among different individuals, the five BAMs for each compound were statistically compared by T-score test at every 15.21 μm^2 unit across the whole projection surface to extract the brain regions significantly regulated by compound treatment. In addition, a significance score was assigned to each unit to form a T-score brain activity map (T-score BAM) unique to each compound (Supplementary Fig. 2). In the control larvae, (dimethyl sulfoxide) DMSO treatment resulted in white-noise-like T-score BAMs (n = 50) (Supplementary Fig. 3).Fig. 1High-throughput brain activity mapping (HT-BAMing) in zebrafish larvae. a Illustration of the HT-BAMing technology. b Image sequences showing the autonomous larva loading and immobilization in the microfluidic chip. Red arrows indicate the direction of the bulk flow. Scale bar, 2 mm. c Immobilization of multiple awake larvae in a microfluidic chip with a dorsal-up orientation. Scale bar, 5 mm. d Representative brain image of a larva (from elavl3:GCaMP5G transgenic line) trapped in the system. Inset shows the merged image of the larva trapped in the chip. The white dotted line indicates the trapping channel. Scale bar, 100 μm. e Representative curves showing the change of calcium fluorescence fluctuation in selected neuronal cells from a zebrafish brain. The sample showing inhibition was treated with the typical antipsychotic loxapine, while the sample data showing excitation follows treatment with pyrithioxine. f−h T-score BAMs showing the regulation of brain physiology induced by different CNS drugs including f loxapine, a dibenzoxazepine-class typical antipsychotic; g pyrithioxine, a synthetic, dimeric, disulfide bridged, derivative of vitamin B6 (pyridoxine) with reported psychostimulant/nootropic activity; and h ethopropazine, a phenothiazine derivative with anticholinergic, antihistamine, and antiadenergic activities used as an antiparkinsonian medication',\n", + " 'paragraph_id': 3,\n", + " 'tokenizer': 'advances, in, microscopy, techniques, ^, 17, and, the, development, of, novel, calcium, -, sensitive, fluorescent, reporters, ^, 11, have, enabled, recording, of, brain, -, wide, activity, in, la, ##rval, zebra, ##fish, with, single, -, cell, resolution, ^, 12, ., here, ,, changes, in, the, flu, ##orescence, of, calcium, -, sensitive, flu, ##oro, ##ph, ##ores, provides, an, established, proxy, for, imaging, of, ne, ##uron, ##al, activity, ^, 11, ,, 12, ,, 18, ., however, ,, the, challenges, posed, by, handling, of, zebra, ##fish, larvae, prohibit, the, wide, application, to, large, -, scale, analysis, ,, and, as, a, result, the, through, ##put, for, these, experiments, is, quite, limited, and, can, be, greatly, improved, by, robotic, automation, and, micro, ##fl, ##uid, ##ic, systems, ^, 19, ,, 20, ., with, the, goal, of, investigating, whole, -, brain, cn, ##s, physiology, on, a, large, scale, ,, we, developed, an, autonomous, system, capable, of, orient, ##ing, and, im, ##mo, ##bil, ##izing, multiple, awake, ,, non, ##ane, ##st, ##het, ##ized, animals, for, high, -, through, ##put, recording, of, brain, -, wide, ne, ##uron, ##al, activity, ., this, system, was, based, on, our, recent, development, of, a, micro, ##fl, ##uid, ##ic, chip, that, utilizes, hydro, ##dy, ##nami, ##c, force, to, trap, ,, position, ,, and, orient, zebra, ##fish, larvae, ^, 13, ,, 14, (, fig, ., 1a, ##−, ##c, ), ., the, processing, through, ##put, was, further, enhanced, by, a, system, for, larvae, loading, and, transportation, that, employs, digitally, controlled, sy, ##ring, ##e, pumps, ,, electromagnetic, valves, and, video, detection, to, enable, automatic, feeding, of, larvae, into, the, micro, ##fl, ##uid, ##ic, chip, (, supplementary, fig, ., 1, ), ., in, this, study, ,, all, larvae, were, loaded, with, a, dorsal, -, up, orientation, to, facilitate, brain, imaging, from, above, ., the, use, of, trans, ##genic, zebra, ##fish, (, el, ##av, ##l, ##3, :, g, ##camp, ##5, ##g, ), with, a, genetically, encoded, calcium, indicator, (, fig, ., 1, ##d, ), allowed, for, real, -, time, whole, -, brain, imaging, ,, and, subsequent, analysis, of, drug, -, induced, changes, in, ne, ##uron, ##al, activity, (, supplementary, fig, ., 1, ##d, ), ., to, generate, the, functional, bam, of, a, la, ##rva, in, response, to, a, 15, -, min, period, of, chemical, per, ##fusion, ,, or, treatment, ,, each, la, ##rva, was, image, ##d, over, a, 10, -, min, period, before, and, after, treatment, (, fig, ., 1, ##e, ), ., readings, from, multiple, focal, planes, along, the, z, -, axis, (, ventral, direction, ), were, acquired, ,, and, the, accumulated, number, of, calcium, transient, ##s, were, derived, from, the, flu, ##orescence, fluctuations, of, each, z, -, plane, with, a, lateral, resolution, of, 15, ., 21, μ, ##m, ^, 2, ., the, difference, in, calcium, transient, counts, between, the, post, -, and, pre, ##tre, ##at, ##ment, periods, was, calculated, and, projected, (, by, sum, ##ming, up, along, the, z, -, axis, ), to, a, two, -, dimensional, surface, to, construct, a, bam, that, reflects, changes, in, brain, activity, and, physiology, of, an, individual, la, ##rva, in, response, to, treatment, (, fig, ., 1a, ,, e, ), ., for, each, compound, ,, bam, ##s, from, five, individual, larvae, were, acquired, following, treatment, with, a, 10, μ, ##m, dose, ., to, avoid, false, -, positive, or, false, -, negative, errors, potentially, introduced, by, variation, among, different, individuals, ,, the, five, bam, ##s, for, each, compound, were, statistical, ##ly, compared, by, t, -, score, test, at, every, 15, ., 21, μ, ##m, ^, 2, unit, across, the, whole, projection, surface, to, extract, the, brain, regions, significantly, regulated, by, compound, treatment, ., in, addition, ,, a, significance, score, was, assigned, to, each, unit, to, form, a, t, -, score, brain, activity, map, (, t, -, score, bam, ), unique, to, each, compound, (, supplementary, fig, ., 2, ), ., in, the, control, larvae, ,, (, dime, ##thy, ##l, sul, ##fo, ##xide, ), d, ##ms, ##o, treatment, resulted, in, white, -, noise, -, like, t, -, score, bam, ##s, (, n, =, 50, ), (, supplementary, fig, ., 3, ), ., fig, ., 1, ##hi, ##gh, -, through, ##put, brain, activity, mapping, (, h, ##t, -, bam, ##ing, ), in, zebra, ##fish, larvae, ., a, illustration, of, the, h, ##t, -, bam, ##ing, technology, ., b, image, sequences, showing, the, autonomous, la, ##rva, loading, and, im, ##mo, ##bil, ##ization, in, the, micro, ##fl, ##uid, ##ic, chip, ., red, arrows, indicate, the, direction, of, the, bulk, flow, ., scale, bar, ,, 2, mm, ., c, im, ##mo, ##bil, ##ization, of, multiple, awake, larvae, in, a, micro, ##fl, ##uid, ##ic, chip, with, a, dorsal, -, up, orientation, ., scale, bar, ,, 5, mm, ., d, representative, brain, image, of, a, la, ##rva, (, from, el, ##av, ##l, ##3, :, g, ##camp, ##5, ##g, trans, ##genic, line, ), trapped, in, the, system, ., ins, ##et, shows, the, merged, image, of, the, la, ##rva, trapped, in, the, chip, ., the, white, dotted, line, indicates, the, trapping, channel, ., scale, bar, ,, 100, μ, ##m, ., e, representative, curves, showing, the, change, of, calcium, flu, ##orescence, flu, ##ct, ##uation, in, selected, ne, ##uron, ##al, cells, from, a, zebra, ##fish, brain, ., the, sample, showing, inhibition, was, treated, with, the, typical, anti, ##psy, ##cho, ##tic, lo, ##xa, ##pine, ,, while, the, sample, data, showing, ex, ##cit, ##ation, follows, treatment, with, p, ##yr, ##ith, ##io, ##xin, ##e, ., f, ##−, ##h, t, -, score, bam, ##s, showing, the, regulation, of, brain, physiology, induced, by, different, cn, ##s, drugs, including, f, lo, ##xa, ##pine, ,, a, di, ##ben, ##zo, ##xa, ##ze, ##pine, -, class, typical, anti, ##psy, ##cho, ##tic, ;, g, p, ##yr, ##ith, ##io, ##xin, ##e, ,, a, synthetic, ,, dime, ##ric, ,, di, ##sul, ##fide, bridge, ##d, ,, derivative, of, vitamin, b, ##6, (, p, ##yr, ##ido, ##xin, ##e, ), with, reported, psycho, ##sti, ##mu, ##lan, ##t, /, no, ##ot, ##rop, ##ic, activity, ;, and, h, et, ##hop, ##rop, ##azi, ##ne, ,, a, ph, ##eno, ##thi, ##azi, ##ne, derivative, with, anti, ##cho, ##liner, ##gic, ,, anti, ##his, ##tam, ##ine, ,, and, anti, ##ade, ##ner, ##gic, activities, used, as, an, anti, ##park, ##ins, ##onia, ##n, medication'},\n", + " {'article_id': '616dd196a48d6d0e8ede1867f5502755',\n", + " 'section_name': 'Genetic architecture of microglial activation',\n", + " 'text': 'Given the imperfect correlation between MF and IT PAM measures (Spearman ρ = 0.66), we performed two separate genome-wide association studies (GWAS). All significant and suggestive GWAS results are listed in Table 2 (details in Supplementary Datas 4 and 5). For IT PAM, a single locus on chromosome 1 reached genome-wide significance (rs183093970; linear regression β = 0.154, SE = 0.024, p = 5.47 × 10^−10) (Fig. 4a, b). However, while the 191 kb region encompassed by this lead SNP contains three independent signals, all three have low minor allele frequency (MAF) (0.02 > MAF > 0.015). Notably, this association was driven by only seven individuals in our sample carrying minor alleles tagging this haplotype and should therefore be considered cautiously. Beyond this genome-wide significant locus, 27 additional independent regions were associated at p < 1 × 10^−5, and mapping based on position and combined eQTL evidence identified a total of 52 candidate genes as possible functional targets of these variants (Fig. 4c).Table 2Independent loci identified by cortical PAM GWASPAM regionChLead SNPSNP positionA1A2Freq (A1)Beta (A1)P-valueGenes mapped to locus (combined positional and/or eQTL mapping)MF1rs299732583641424AT0.629−0.03891.88E−08RP11-170N11.11rs157864165383761TC0.14150.04438.60E−06RXRG1rs651691193958320TC0.55310.03176.45E−062rs12623587232160554AC0.29−0.03216.00E−06C2orf72, PSMD1, HTR2B, ARMC93rs78461316104858434TC0.05870.07492.54E−077rs14121965270367062CT0.02260.10838.72E−0610rs61860520134826645TC0.0543−0.07194.02E−06TTC40, LINC0116611rs13866235792058950CA0.05550.0743.49E−07NDUFB11P1, FAT3, PGAM1P913rs9514523106927120TC0.1871−0.03869.20E−0613rs9521336110023731CT0.21460.03781.96E−06MYO16-AS1, LINC0039914rs2105997107209226TA0.22760.03888.46E−06IGHV4-39, HOMER2P1, IGHV4-61, IGHV3-64, IGHV3-66, IGHV1-69, IGHV3-72, IGHV3-73, IGHV3-7415rs14470530167855035CT0.02630.111.74E−07AAGAB, RPS24P16, MAP2K5, SKOR1IT1rs5626755821005316TG0.12870.04316.40E−06MUL1, CDA, PINK1, PINK1-AS, DDOST, KIF171rs11328527570896319AG0.2344−0.03283.10E−06HHLA3, CTH1rs18309397088454261GA0.01470.15355.47E−101rs147836155113501607TC0.01290.13462.46E−06SLC16A1, SLC16A1-AS12rs14825939328713654GC0.02040.10383.30E−06PLB12rs14141897040576095TG0.01020.15934.82E−07SLC8A12rs1701813880154236GC0.050.05887.53E−06CTNNA22rs79341575129133292CG0.05510.0632.75E−06GPR172rs60200364160708050AG0.06230.05552.14E−06BAZ2B, LY75, LY75-CD302, PLA2R1, ITGB62rs2348117201598521TG0.8893−0.04149.76E−06AOX3P, AOX2P, AC007163.3, PPIL3, RNU6-312P3rs9289581139405842TG0.370.02718.32E−06NMNAT34rs765679522398514TC0.8175−0.0371.22E−06GPR1254rs11410589923027094GA0.01580.11978.10E−07RP11-412P11.14rs1001171786136864AG0.3774−0.02826.09E−064rs77601419148249054TC0.0150.11682.22E−067rs77033896115513816AG0.01690.12626.84E−07TFEC, CAV18rs1749432220673550GA0.0750.05354.18E−0611rs13962992576144667GA0.01210.13475.91E−06RP11-111M22.2, C11orf30, LRRC3211rs2084308111051351TA0.0280.09674.29E−0713rs732823541998022TC0.9439−0.06076.72E−06MTRF1, OR7E36P13rs956798248605441GA0.13750.03943.08E−06LINC00444, LINC00562, SUCLA2, SUCLA2-AS1, NUDT15, MED4, MED4-AS1, POLR2KP213rs11737272061819169TC0.01490.10928.97E−0613rs149383020112585032AG0.03410.07875.09E−0714rs14443456391361842GA0.01350.12656.79E−06RPS6KA514rs13789921691830706TC0.02770.09113.06E−06GPR68, CCDC88C, SMEK117rs11264535866248531TC0.03840.0699.94E−06KPNA2, LRRC37A16P, AMZ2, ARSG18rs14822222265675614TC0.01690.11331.47E−06RP11-638L3.120rs713369985467150GA0.0180.12661.17E−07LINC00654Ch chromosome, A1 allele 1 (effect allele), A2 allele 2, eQTL expression quantitative trait loci, Freq allele frequency, IT inferior temporal cortex, MF midfrontal cortexFig. 4Genome-wide association studies (GWAS) of PAM with TSPO PET imaging follow-up. a Manhattan plot, (b) Q–Q plot, and (c) locus summary chart for inferior temporal cortex (IT) PAM, and corresponding, (d) Manhattan plot, (e) Q–Q plot, and (f) locus summary chart for midfrontal cortex (MF) PAM GWAS. Both analyses co-varied for genotype platform, age at death, sex, postmortem interval, APOE ε4 status, and top three EIGENSTRAT principal components. g Regional association plot highlighting the MF PAM genome-wide significant locus surrounding rs2997325 (p = 1.88 × 10^−8, n = 225). The color of each dot represents degree of linkage disequilibrium at that SNP based on 1000 Genomes Phase 3 reference data. The combined annotation-dependent depletion (CADD) score is plotted below the regional association plot on a scale from 0 to 20, where 20 indicates a variant with highest predicted deleteriousness. The RegulomeDB score is plotted below the CADD score, and summarizes evidence for effects on regulatory elements of each plotted SNP (5 = transcription factor-binding site or DNAase peak, 6 = other motif altered, 7 = no evidence). Below the RegulomeDB plot is an eQTL plot showing –log_10(p-values) for association of each plotted SNP with the expression of the mapped gene RP11-170N11.1 (LINC01361). h Strip chart showing the significant relationship between MF PAM (on y-axis as GWAS covariate-only model residuals) and rs2997325 genotype. i Whisker plot showing the means and standard deviations of [^11C]-PBR28 standard uptake value ratio (SUVR) for the left entorhinal cortex in the PET imaging sample from the Indiana Memory and Aging Study (p = 0.02, r^2 = 17.1, n = 27), stratified by rs2997325 genotype. Model co-varied for TSPO rs6971 genotype, APOE ε4 status, age at study entry, and sex. Tissue enrichment analyses for (j) IT and (k) MF PAM gene sets in 30 general tissue types from GTEx v7 show Bonferroni significant enrichment (two-sided) of only the MF gene set with colon, salivary gland, breast, small intestine, stomach, lung, and blood vessel tissues. Heat maps showing enrichment for all 53 tissue types in GTEx v7, including uni-directional analyses for up-regulation and down-regulation specifically can be found in Supplementary Figure 5',\n", + " 'paragraph_id': 9,\n", + " 'tokenizer': 'given, the, imperfect, correlation, between, m, ##f, and, it, pam, measures, (, spear, ##man, ρ, =, 0, ., 66, ), ,, we, performed, two, separate, genome, -, wide, association, studies, (, g, ##was, ), ., all, significant, and, suggest, ##ive, g, ##was, results, are, listed, in, table, 2, (, details, in, supplementary, data, ##s, 4, and, 5, ), ., for, it, pam, ,, a, single, locus, on, chromosome, 1, reached, genome, -, wide, significance, (, rs, ##18, ##30, ##9, ##39, ##70, ;, linear, regression, β, =, 0, ., 154, ,, se, =, 0, ., 02, ##4, ,, p, =, 5, ., 47, ×, 10, ^, −, ##10, ), (, fig, ., 4a, ,, b, ), ., however, ,, while, the, 191, kb, region, encompassed, by, this, lead, s, ##np, contains, three, independent, signals, ,, all, three, have, low, minor, all, ##ele, frequency, (, ma, ##f, ), (, 0, ., 02, >, ma, ##f, >, 0, ., 01, ##5, ), ., notably, ,, this, association, was, driven, by, only, seven, individuals, in, our, sample, carrying, minor, all, ##eles, tag, ##ging, this, ha, ##pl, ##otype, and, should, therefore, be, considered, cautiously, ., beyond, this, genome, -, wide, significant, locus, ,, 27, additional, independent, regions, were, associated, at, p, <, 1, ×, 10, ^, −, ##5, ,, and, mapping, based, on, position, and, combined, e, ##q, ##tl, evidence, identified, a, total, of, 52, candidate, genes, as, possible, functional, targets, of, these, variants, (, fig, ., 4, ##c, ), ., table, 2, ##ind, ##ep, ##end, ##ent, lo, ##ci, identified, by, co, ##rti, ##cal, pam, g, ##was, ##pa, ##m, region, ##ch, ##lea, ##d, s, ##np, ##s, ##np, position, ##a1, ##a, ##2, ##fr, ##e, ##q, (, a1, ), beta, (, a1, ), p, -, value, ##gen, ##es, mapped, to, locus, (, combined, position, ##al, and, /, or, e, ##q, ##tl, mapping, ), m, ##f, ##1, ##rs, ##29, ##9, ##7, ##32, ##58, ##36, ##41, ##42, ##4, ##at, ##0, ., 62, ##9, ##−, ##0, ., 03, ##8, ##9, ##1, ., 88, ##e, ##−, ##0, ##8, ##rp, ##11, -, 170, ##n, ##11, ., 11, ##rs, ##15, ##7, ##86, ##41, ##65, ##38, ##37, ##6, ##1, ##tc, ##0, ., 141, ##50, ., 04, ##43, ##8, ., 60, ##e, ##−, ##0, ##6, ##r, ##x, ##rg, ##1, ##rs, ##65, ##16, ##9, ##11, ##9, ##39, ##58, ##32, ##0, ##tc, ##0, ., 55, ##31, ##0, ., 03, ##17, ##6, ., 45, ##e, ##−, ##0, ##6, ##2, ##rs, ##12, ##6, ##23, ##58, ##7, ##23, ##21, ##60, ##55, ##4, ##ac, ##0, ., 29, ##−, ##0, ., 03, ##21, ##6, ., 00, ##e, ##−, ##0, ##6, ##c, ##2, ##orf, ##7, ##2, ,, ps, ##md, ##1, ,, h, ##tr, ##2, ##b, ,, arm, ##c, ##9, ##3, ##rs, ##7, ##8, ##46, ##13, ##16, ##10, ##48, ##58, ##43, ##4, ##tc, ##0, ., 05, ##8, ##70, ., 07, ##49, ##2, ., 54, ##e, ##−, ##0, ##7, ##7, ##rs, ##14, ##12, ##19, ##65, ##27, ##0, ##36, ##70, ##6, ##2, ##ct, ##0, ., 02, ##26, ##0, ., 108, ##38, ., 72, ##e, ##−, ##0, ##6, ##10, ##rs, ##6, ##18, ##60, ##52, ##01, ##34, ##8, ##26, ##64, ##5, ##tc, ##0, ., 05, ##43, ##−, ##0, ., 07, ##19, ##4, ., 02, ##e, ##−, ##0, ##6, ##tt, ##c, ##40, ,, lin, ##c, ##01, ##16, ##6, ##11, ##rs, ##13, ##86, ##6, ##23, ##57, ##9, ##20, ##58, ##9, ##50, ##ca, ##0, ., 05, ##55, ##0, ., 07, ##43, ., 49, ##e, ##−, ##0, ##7, ##nd, ##uf, ##b, ##11, ##p, ##1, ,, fat, ##3, ,, pga, ##m, ##1, ##p, ##9, ##13, ##rs, ##9, ##51, ##45, ##23, ##10, ##6, ##9, ##27, ##12, ##0, ##tc, ##0, ., 1871, ##−, ##0, ., 03, ##86, ##9, ., 20, ##e, ##−, ##0, ##6, ##13, ##rs, ##9, ##52, ##13, ##36, ##11, ##00, ##23, ##7, ##31, ##ct, ##0, ., 214, ##60, ., 03, ##7, ##8, ##1, ., 96, ##e, ##−, ##0, ##6, ##my, ##o, ##16, -, as, ##1, ,, lin, ##c, ##00, ##39, ##9, ##14, ##rs, ##21, ##0, ##59, ##9, ##7, ##10, ##7, ##20, ##9, ##22, ##6, ##ta, ##0, ., 227, ##60, ., 03, ##8, ##8, ##8, ., 46, ##e, ##−, ##0, ##6, ##igh, ##v, ##4, -, 39, ,, homer, ##2, ##p, ##1, ,, i, ##gh, ##v, ##4, -, 61, ,, i, ##gh, ##v, ##3, -, 64, ,, i, ##gh, ##v, ##3, -, 66, ,, i, ##gh, ##v, ##1, -, 69, ,, i, ##gh, ##v, ##3, -, 72, ,, i, ##gh, ##v, ##3, -, 73, ,, i, ##gh, ##v, ##3, -, 74, ##15, ##rs, ##14, ##47, ##0, ##53, ##01, ##6, ##7, ##85, ##50, ##35, ##ct, ##0, ., 02, ##6, ##30, ., 111, ., 74, ##e, ##−, ##0, ##7, ##aa, ##ga, ##b, ,, r, ##ps, ##24, ##p, ##16, ,, map, ##2, ##k, ##5, ,, sk, ##or, ##1, ##it, ##1, ##rs, ##56, ##26, ##75, ##58, ##21, ##00, ##53, ##16, ##t, ##g, ##0, ., 128, ##70, ., 04, ##31, ##6, ., 40, ##e, ##−, ##0, ##6, ##mu, ##l, ##1, ,, cd, ##a, ,, pink, ##1, ,, pink, ##1, -, as, ,, dd, ##ost, ,, ki, ##f, ##17, ##1, ##rs, ##11, ##32, ##85, ##27, ##57, ##0, ##8, ##9, ##6, ##31, ##9, ##ag, ##0, ., 234, ##4, ##−, ##0, ., 03, ##28, ##3, ., 10, ##e, ##−, ##0, ##6, ##hh, ##la, ##3, ,, ct, ##h, ##1, ##rs, ##18, ##30, ##9, ##39, ##70, ##8, ##8, ##45, ##42, ##6, ##1, ##ga, ##0, ., 01, ##47, ##0, ., 153, ##55, ., 47, ##e, ##−1, ##01, ##rs, ##14, ##7, ##8, ##36, ##15, ##51, ##13, ##50, ##16, ##0, ##7, ##tc, ##0, ., 01, ##29, ##0, ., 134, ##6, ##2, ., 46, ##e, ##−, ##0, ##6, ##sl, ##c, ##16, ##a1, ,, sl, ##c, ##16, ##a1, -, as, ##12, ##rs, ##14, ##8, ##25, ##9, ##39, ##32, ##8, ##7, ##13, ##65, ##4, ##gc, ##0, ., 02, ##0, ##40, ., 103, ##8, ##3, ., 30, ##e, ##−, ##0, ##6, ##pl, ##b, ##12, ##rs, ##14, ##14, ##18, ##9, ##70, ##40, ##57, ##60, ##9, ##5, ##t, ##g, ##0, ., 01, ##0, ##20, ., 159, ##34, ., 82, ##e, ##−, ##0, ##7, ##sl, ##c, ##8, ##a1, ##2, ##rs, ##17, ##01, ##8, ##13, ##8, ##80, ##15, ##42, ##36, ##gc, ##0, ., 050, ., 05, ##8, ##8, ##7, ., 53, ##e, ##−, ##0, ##6, ##ct, ##nna, ##22, ##rs, ##7, ##9, ##34, ##15, ##75, ##12, ##9, ##13, ##32, ##9, ##2, ##c, ##g, ##0, ., 05, ##51, ##0, ., 06, ##32, ., 75, ##e, ##−, ##0, ##6, ##gp, ##r, ##17, ##2, ##rs, ##60, ##200, ##36, ##41, ##60, ##70, ##80, ##50, ##ag, ##0, ., 06, ##23, ##0, ., 05, ##55, ##2, ., 14, ##e, ##−, ##0, ##6, ##ba, ##z, ##2, ##b, ,, l, ##y, ##75, ,, l, ##y, ##75, -, cd, ##30, ##2, ,, pl, ##a, ##2, ##r, ##1, ,, it, ##gb, ##6, ##2, ##rs, ##23, ##48, ##11, ##7, ##20, ##15, ##9, ##85, ##21, ##t, ##g, ##0, ., 88, ##9, ##3, ##−, ##0, ., 04, ##14, ##9, ., 76, ##e, ##−, ##0, ##6, ##ao, ##x, ##3, ##p, ,, ao, ##x, ##2, ##p, ,, ac, ##00, ##7, ##16, ##3, ., 3, ,, pp, ##il, ##3, ,, rn, ##u, ##6, -, 312, ##p, ##3, ##rs, ##9, ##28, ##9, ##58, ##11, ##39, ##40, ##58, ##42, ##t, ##g, ##0, ., 370, ., 02, ##7, ##18, ., 32, ##e, ##−, ##0, ##6, ##n, ##m, ##nat, ##34, ##rs, ##7, ##65, ##6, ##7, ##9, ##52, ##23, ##9, ##85, ##14, ##tc, ##0, ., 81, ##75, ##−, ##0, ., 03, ##7, ##1, ., 22, ##e, ##−, ##0, ##6, ##gp, ##r, ##12, ##54, ##rs, ##11, ##41, ##0, ##58, ##9, ##9, ##23, ##0, ##27, ##0, ##9, ##4, ##ga, ##0, ., 01, ##58, ##0, ., 119, ##7, ##8, ., 10, ##e, ##−, ##0, ##7, ##rp, ##11, -, 412, ##p, ##11, ., 14, ##rs, ##100, ##11, ##7, ##17, ##86, ##13, ##6, ##86, ##4, ##ag, ##0, ., 37, ##7, ##4, ##−, ##0, ., 02, ##8, ##26, ., 09, ##e, ##−, ##0, ##64, ##rs, ##7, ##7, ##60, ##14, ##19, ##14, ##8, ##24, ##90, ##54, ##tc, ##0, ., 01, ##50, ., 116, ##8, ##2, ., 22, ##e, ##−, ##0, ##6, ##7, ##rs, ##7, ##70, ##33, ##8, ##9, ##6, ##11, ##55, ##13, ##8, ##16, ##ag, ##0, ., 01, ##6, ##90, ., 126, ##26, ., 84, ##e, ##−, ##0, ##7, ##tf, ##ec, ,, ca, ##v, ##18, ##rs, ##17, ##49, ##43, ##22, ##20, ##6, ##7, ##35, ##50, ##ga, ##0, ., 07, ##50, ., 05, ##35, ##4, ., 18, ##e, ##−, ##0, ##6, ##11, ##rs, ##13, ##9, ##6, ##29, ##9, ##25, ##7, ##6, ##14, ##46, ##6, ##7, ##ga, ##0, ., 01, ##21, ##0, ., 134, ##75, ., 91, ##e, ##−, ##0, ##6, ##rp, ##11, -, 111, ##m, ##22, ., 2, ,, c1, ##1, ##orf, ##30, ,, l, ##rr, ##c, ##32, ##11, ##rs, ##20, ##8, ##43, ##0, ##8, ##11, ##10, ##51, ##35, ##1, ##ta, ##0, ., 02, ##80, ., 09, ##6, ##7, ##4, ., 29, ##e, ##−, ##0, ##7, ##13, ##rs, ##7, ##32, ##8, ##23, ##54, ##19, ##9, ##80, ##22, ##tc, ##0, ., 94, ##39, ##−, ##0, ., 06, ##0, ##7, ##6, ., 72, ##e, ##−, ##0, ##6, ##mt, ##rf, ##1, ,, or, ##7, ##e, ##36, ##p, ##13, ##rs, ##9, ##56, ##7, ##9, ##8, ##24, ##86, ##0, ##54, ##41, ##ga, ##0, ., 137, ##50, ., 03, ##9, ##43, ., 08, ##e, ##−, ##0, ##6, ##lin, ##c, ##00, ##44, ##4, ,, lin, ##c, ##00, ##56, ##2, ,, su, ##cl, ##a, ##2, ,, su, ##cl, ##a, ##2, -, as, ##1, ,, nu, ##dt, ##15, ,, med, ##4, ,, med, ##4, -, as, ##1, ,, pol, ##r, ##2, ##k, ##p, ##21, ##3, ##rs, ##11, ##7, ##37, ##27, ##20, ##6, ##18, ##19, ##16, ##9, ##tc, ##0, ., 01, ##49, ##0, ., 109, ##28, ., 97, ##e, ##−, ##0, ##6, ##13, ##rs, ##14, ##9, ##38, ##30, ##20, ##11, ##25, ##85, ##0, ##32, ##ag, ##0, ., 03, ##41, ##0, ., 07, ##8, ##75, ., 09, ##e, ##−, ##0, ##7, ##14, ##rs, ##14, ##44, ##34, ##56, ##39, ##13, ##6, ##18, ##42, ##ga, ##0, ., 01, ##35, ##0, ., 126, ##56, ., 79, ##e, ##−, ##0, ##6, ##rp, ##s, ##6, ##ka, ##51, ##4, ##rs, ##13, ##7, ##8, ##9, ##9, ##21, ##6, ##9, ##18, ##30, ##70, ##6, ##tc, ##0, ., 02, ##7, ##70, ., 09, ##11, ##3, ., 06, ##e, ##−, ##0, ##6, ##gp, ##r, ##6, ##8, ,, cc, ##dc, ##8, ##8, ##c, ,, sm, ##ek, ##11, ##7, ##rs, ##11, ##26, ##45, ##35, ##86, ##6, ##24, ##85, ##31, ##tc, ##0, ., 03, ##8, ##40, ., 06, ##9, ##9, ., 94, ##e, ##−, ##0, ##6, ##k, ##p, ##na, ##2, ,, l, ##rr, ##c, ##37, ##a1, ##6, ##p, ,, am, ##z, ##2, ,, ars, ##g, ##18, ##rs, ##14, ##8, ##22, ##22, ##22, ##65, ##6, ##75, ##6, ##14, ##tc, ##0, ., 01, ##6, ##90, ., 113, ##31, ., 47, ##e, ##−, ##0, ##6, ##rp, ##11, -, 63, ##8, ##l, ##3, ., 120, ##rs, ##7, ##13, ##36, ##9, ##9, ##85, ##46, ##7, ##15, ##0, ##ga, ##0, ., 01, ##80, ., 126, ##6, ##1, ., 17, ##e, ##−, ##0, ##7, ##lin, ##c, ##00, ##65, ##4, ##ch, chromosome, ,, a1, all, ##ele, 1, (, effect, all, ##ele, ), ,, a2, all, ##ele, 2, ,, e, ##q, ##tl, expression, quantitative, trait, lo, ##ci, ,, fr, ##e, ##q, all, ##ele, frequency, ,, it, inferior, temporal, cortex, ,, m, ##f, mid, ##front, ##al, cortex, ##fi, ##g, ., 4, ##gen, ##ome, -, wide, association, studies, (, g, ##was, ), of, pam, with, ts, ##po, pet, imaging, follow, -, up, ., a, manhattan, plot, ,, (, b, ), q, –, q, plot, ,, and, (, c, ), locus, summary, chart, for, inferior, temporal, cortex, (, it, ), pam, ,, and, corresponding, ,, (, d, ), manhattan, plot, ,, (, e, ), q, –, q, plot, ,, and, (, f, ), locus, summary, chart, for, mid, ##front, ##al, cortex, (, m, ##f, ), pam, g, ##was, ., both, analyses, co, -, varied, for, gen, ##otype, platform, ,, age, at, death, ,, sex, ,, post, ##mo, ##rte, ##m, interval, ,, ap, ##oe, ε, ##4, status, ,, and, top, three, e, ##igen, ##stra, ##t, principal, components, ., g, regional, association, plot, highlighting, the, m, ##f, pam, genome, -, wide, significant, locus, surrounding, rs, ##29, ##9, ##7, ##32, ##5, (, p, =, 1, ., 88, ×, 10, ^, −, ##8, ,, n, =, 225, ), ., the, color, of, each, dot, represents, degree, of, link, ##age, di, ##se, ##quil, ##ib, ##rium, at, that, s, ##np, based, on, 1000, genome, ##s, phase, 3, reference, data, ., the, combined, ann, ##ota, ##tion, -, dependent, de, ##ple, ##tion, (, cad, ##d, ), score, is, plotted, below, the, regional, association, plot, on, a, scale, from, 0, to, 20, ,, where, 20, indicates, a, variant, with, highest, predicted, del, ##eter, ##ious, ##ness, ., the, reg, ##ulo, ##med, ##b, score, is, plotted, below, the, cad, ##d, score, ,, and, sum, ##mar, ##izes, evidence, for, effects, on, regulatory, elements, of, each, plotted, s, ##np, (, 5, =, transcription, factor, -, binding, site, or, dna, ##ase, peak, ,, 6, =, other, motif, altered, ,, 7, =, no, evidence, ), ., below, the, reg, ##ulo, ##med, ##b, plot, is, an, e, ##q, ##tl, plot, showing, –, log, _, 10, (, p, -, values, ), for, association, of, each, plotted, s, ##np, with, the, expression, of, the, mapped, gene, r, ##p, ##11, -, 170, ##n, ##11, ., 1, (, lin, ##c, ##01, ##36, ##1, ), ., h, strip, chart, showing, the, significant, relationship, between, m, ##f, pam, (, on, y, -, axis, as, g, ##was, co, ##var, ##iate, -, only, model, residual, ##s, ), and, rs, ##29, ##9, ##7, ##32, ##5, gen, ##otype, ., i, w, ##his, ##ker, plot, showing, the, means, and, standard, deviation, ##s, of, [, ^, 11, ##c, ], -, p, ##br, ##28, standard, up, ##take, value, ratio, (, suv, ##r, ), for, the, left, en, ##tor, ##hin, ##al, cortex, in, the, pet, imaging, sample, from, the, indiana, memory, and, aging, study, (, p, =, 0, ., 02, ,, r, ^, 2, =, 17, ., 1, ,, n, =, 27, ), ,, st, ##rat, ##ified, by, rs, ##29, ##9, ##7, ##32, ##5, gen, ##otype, ., model, co, -, varied, for, ts, ##po, rs, ##6, ##9, ##7, ##1, gen, ##otype, ,, ap, ##oe, ε, ##4, status, ,, age, at, study, entry, ,, and, sex, ., tissue, enrichment, analyses, for, (, j, ), it, and, (, k, ), m, ##f, pam, gene, sets, in, 30, general, tissue, types, from, gt, ##ex, v, ##7, show, bon, ##fer, ##ron, ##i, significant, enrichment, (, two, -, sided, ), of, only, the, m, ##f, gene, set, with, colon, ,, saliva, ##ry, gland, ,, breast, ,, small, int, ##est, ##ine, ,, stomach, ,, lung, ,, and, blood, vessel, tissues, ., heat, maps, showing, enrichment, for, all, 53, tissue, types, in, gt, ##ex, v, ##7, ,, including, un, ##i, -, directional, analyses, for, up, -, regulation, and, down, -, regulation, specifically, can, be, found, in, supplementary, figure, 5'},\n", + " {'article_id': '342d06e10bcae551eb609061dc71a20c',\n", + " 'section_name': 'Multiplex brain immunofluorescent labeling with subclass switched R-mAbs',\n", + " 'text': 'One benefit of subclass switching R-mAbs is the ability to perform multiplex immunolabeling not previously possible due to IgG subclass conflicts. Examples of such enrichment in cellular protein localization are shown in Figure 4. Figure 4A shows labeling with the subclass switched IgG2a R-mAb derived from the widely used pan-voltage-gated sodium channel or ‘pan-Nav channel’ IgG1 mAb K58/35 (Rasband et al., 1999). Like the corresponding mAb, K58/35 R-mAb gives robust labeling of Nav channels concentrated on the axon initial segment (AIS, arrows in Figure 4A main panel), and at nodes of Ranvier (arrows in Figure 4A insets). Importantly, subclass switching allowed Nav channel labeling at nodes to be verified by co-labeling with K65/35 an IgG1 subclass antibody directed against CASPR, a protein concentrated at paranodes (Menegoz et al., 1997; Peles et al., 1997). Similarly, simultaneous labeling for the highly-related GABA-A receptor β1 and β3 subunits (Zhang et al., 1991) with their widely used respective mAbs N96/55 and N87/25 could not be performed as both are IgG1 subclass. Switching the N96/55 mAb to the IgG2a N96/55R R-mAb allowed simultaneous detection of these two highly-related but distinct GABA-A receptor subunits. In Figure 4B localization of GABA-A receptor β1 and β3 subunits appeared completely non-overlapping in separate layers of cerebellum. Figure 4C illustrates localization of protein Kv2.1 and AnkyrinG in separate subcellular neuronal compartments. Labeling for the K89/34R R-mAb (IgG2a, red), specific for the Kv2.1 channel, highly expressed in the plasma membrane of the cell body and proximal dendrites (arrows in panel C1) is shown together with labeling for N106/65 (green), an IgG1 mAb specific for AnkyrinG, a scaffolding protein highly expressed in the AIS (arrows in panel C2) and at nodes of Ranvier. Subclass switching N229A/32 (IgG1, GABA-AR α6) to IgG2a, allows comparison with Kv4.2 potassium channel (K57/1, IgG1) in the cerebellum where both are highly expressed in the granule cell layer (Figure 4D). While both are prominently found in the glomerular synapses present on the dendrites of these cells, simultaneous labeling reveals that some cells express both (Figure 4D, magenta) while others appear to predominantly express Kv4.2 (Figure 4D, blue). Labeling for both proteins is in contrast to that for mAb N147/6 (IgG2b) which recognizes all isoforms of the QKI transcription factor and labels oligodendrocytes within the granule cell layer and throughout the Purkinje cell layer (PCL, green). In Figure 4E, localization of pan-QKI (N147/6, IgG2b, blue) is compared with GFAP (N206A/8, IgG1, green) predominantly thought to be in astrocytes. Surprisingly many (but not all) cells co-label both proteins. We also labeled cortical neurons with these two mAbs (pan-QKI in blue, GFAP in green). Multiplex labeling for the neuron-specific Kv2.1 channel, using subclass-switched K89/34R (IgG2a, red) confirms non-neuronal localization of both proteins. Lastly, we labeled for the postsynaptic scaffold protein PSD-93 using R-mAb N18/30R (IgG2a, red), which in the cerebellum is prominently localized to Purkinje cell somata and dendrites (Brenman et al., 1998). As shown in Figure 4F, the R-mAb labeling is consistent with the established localization of PSD-93. Because of subclass switching the N18/30R R-mAb, this labeling can now be contrasted with labeling for the excitatory presynaptic terminal marker VGluT1, labeled with mAb N28/9 (IgG1, blue), which exhibits robust labeling of parallel fiber synapses in the molecular layer, and glomerular synapses in the granule cell layer. Together these results demonstrate the utility of employing subclass-switched R-mAbs to obtain labeling combinations not possible with native mAbs.',\n", + " 'paragraph_id': 15,\n", + " 'tokenizer': 'one, benefit, of, sub, ##class, switching, r, -, mab, ##s, is, the, ability, to, perform, multiple, ##x, im, ##mun, ##ola, ##bel, ##ing, not, previously, possible, due, to, i, ##gg, sub, ##class, conflicts, ., examples, of, such, enrichment, in, cellular, protein, local, ##ization, are, shown, in, figure, 4, ., figure, 4a, shows, labeling, with, the, sub, ##class, switched, i, ##gg, ##2, ##a, r, -, mab, derived, from, the, widely, used, pan, -, voltage, -, gate, ##d, sodium, channel, or, ‘, pan, -, na, ##v, channel, ’, i, ##gg, ##1, mab, k, ##58, /, 35, (, ras, ##band, et, al, ., ,, 1999, ), ., like, the, corresponding, mab, ,, k, ##58, /, 35, r, -, mab, gives, robust, labeling, of, na, ##v, channels, concentrated, on, the, ax, ##on, initial, segment, (, ai, ##s, ,, arrows, in, figure, 4a, main, panel, ), ,, and, at, nodes, of, ran, ##vier, (, arrows, in, figure, 4a, ins, ##ets, ), ., importantly, ,, sub, ##class, switching, allowed, na, ##v, channel, labeling, at, nodes, to, be, verified, by, co, -, labeling, with, k, ##65, /, 35, an, i, ##gg, ##1, sub, ##class, antibody, directed, against, cas, ##pr, ,, a, protein, concentrated, at, para, ##no, ##des, (, men, ##ego, ##z, et, al, ., ,, 1997, ;, pe, ##les, et, al, ., ,, 1997, ), ., similarly, ,, simultaneous, labeling, for, the, highly, -, related, ga, ##ba, -, a, receptor, β, ##1, and, β, ##3, subunit, ##s, (, zhang, et, al, ., ,, 1991, ), with, their, widely, used, respective, mab, ##s, n, ##9, ##6, /, 55, and, n, ##8, ##7, /, 25, could, not, be, performed, as, both, are, i, ##gg, ##1, sub, ##class, ., switching, the, n, ##9, ##6, /, 55, mab, to, the, i, ##gg, ##2, ##a, n, ##9, ##6, /, 55, ##r, r, -, mab, allowed, simultaneous, detection, of, these, two, highly, -, related, but, distinct, ga, ##ba, -, a, receptor, subunit, ##s, ., in, figure, 4, ##b, local, ##ization, of, ga, ##ba, -, a, receptor, β, ##1, and, β, ##3, subunit, ##s, appeared, completely, non, -, overlapping, in, separate, layers, of, ce, ##re, ##bell, ##um, ., figure, 4, ##c, illustrates, local, ##ization, of, protein, kv, ##2, ., 1, and, an, ##ky, ##ring, in, separate, sub, ##cellular, ne, ##uron, ##al, compartments, ., labeling, for, the, k, ##8, ##9, /, 34, ##r, r, -, mab, (, i, ##gg, ##2, ##a, ,, red, ), ,, specific, for, the, kv, ##2, ., 1, channel, ,, highly, expressed, in, the, plasma, membrane, of, the, cell, body, and, pro, ##xi, ##mal, den, ##dr, ##ites, (, arrows, in, panel, c1, ), is, shown, together, with, labeling, for, n, ##10, ##6, /, 65, (, green, ), ,, an, i, ##gg, ##1, mab, specific, for, an, ##ky, ##ring, ,, a, sc, ##af, ##folding, protein, highly, expressed, in, the, ai, ##s, (, arrows, in, panel, c2, ), and, at, nodes, of, ran, ##vier, ., sub, ##class, switching, n, ##22, ##9, ##a, /, 32, (, i, ##gg, ##1, ,, ga, ##ba, -, ar, α, ##6, ), to, i, ##gg, ##2, ##a, ,, allows, comparison, with, kv, ##4, ., 2, potassium, channel, (, k, ##57, /, 1, ,, i, ##gg, ##1, ), in, the, ce, ##re, ##bell, ##um, where, both, are, highly, expressed, in, the, gran, ##ule, cell, layer, (, figure, 4, ##d, ), ., while, both, are, prominently, found, in, the, g, ##lom, ##er, ##ular, syn, ##ap, ##ses, present, on, the, den, ##dr, ##ites, of, these, cells, ,, simultaneous, labeling, reveals, that, some, cells, express, both, (, figure, 4, ##d, ,, mage, ##nta, ), while, others, appear, to, predominantly, express, kv, ##4, ., 2, (, figure, 4, ##d, ,, blue, ), ., labeling, for, both, proteins, is, in, contrast, to, that, for, mab, n, ##14, ##7, /, 6, (, i, ##gg, ##2, ##b, ), which, recognizes, all, iso, ##forms, of, the, q, ##ki, transcription, factor, and, labels, ol, ##igo, ##den, ##dro, ##cytes, within, the, gran, ##ule, cell, layer, and, throughout, the, pu, ##rkin, ##je, cell, layer, (, pc, ##l, ,, green, ), ., in, figure, 4, ##e, ,, local, ##ization, of, pan, -, q, ##ki, (, n, ##14, ##7, /, 6, ,, i, ##gg, ##2, ##b, ,, blue, ), is, compared, with, g, ##fa, ##p, (, n, ##20, ##6, ##a, /, 8, ,, i, ##gg, ##1, ,, green, ), predominantly, thought, to, be, in, astro, ##cytes, ., surprisingly, many, (, but, not, all, ), cells, co, -, label, both, proteins, ., we, also, labeled, co, ##rti, ##cal, neurons, with, these, two, mab, ##s, (, pan, -, q, ##ki, in, blue, ,, g, ##fa, ##p, in, green, ), ., multiple, ##x, labeling, for, the, ne, ##uron, -, specific, kv, ##2, ., 1, channel, ,, using, sub, ##class, -, switched, k, ##8, ##9, /, 34, ##r, (, i, ##gg, ##2, ##a, ,, red, ), confirms, non, -, ne, ##uron, ##al, local, ##ization, of, both, proteins, ., lastly, ,, we, labeled, for, the, posts, ##yna, ##ptic, sc, ##af, ##fold, protein, ps, ##d, -, 93, using, r, -, mab, n, ##18, /, 30, ##r, (, i, ##gg, ##2, ##a, ,, red, ), ,, which, in, the, ce, ##re, ##bell, ##um, is, prominently, localized, to, pu, ##rkin, ##je, cell, so, ##mata, and, den, ##dr, ##ites, (, br, ##en, ##man, et, al, ., ,, 1998, ), ., as, shown, in, figure, 4, ##f, ,, the, r, -, mab, labeling, is, consistent, with, the, established, local, ##ization, of, ps, ##d, -, 93, ., because, of, sub, ##class, switching, the, n, ##18, /, 30, ##r, r, -, mab, ,, this, labeling, can, now, be, contrasted, with, labeling, for, the, ex, ##cit, ##atory, pre, ##sy, ##na, ##ptic, terminal, marker, v, ##gl, ##ut, ##1, ,, labeled, with, mab, n, ##28, /, 9, (, i, ##gg, ##1, ,, blue, ), ,, which, exhibits, robust, labeling, of, parallel, fiber, syn, ##ap, ##ses, in, the, molecular, layer, ,, and, g, ##lom, ##er, ##ular, syn, ##ap, ##ses, in, the, gran, ##ule, cell, layer, ., together, these, results, demonstrate, the, utility, of, employing, sub, ##class, -, switched, r, -, mab, ##s, to, obtain, labeling, combinations, not, possible, with, native, mab, ##s, .'},\n", + " {'article_id': '9526704a47665f9cf9741e7fd30ad68d',\n", + " 'section_name': 'INTRODUCTION',\n", + " 'text': 'The autonomic space model provides a conceptual framework in which to understand reciprocal, independent, and coactive patterns of sympathetic and parasympathetic cardiac control, both in the context of within‐individual and between‐individual study designs (Berntson, Cacioppo, Binkley et al., 1994; Berntson, Cacioppo, & Quigley, 1994; Berntson, Norman, Hawkley, & Cacioppo, 2008). However, to be useful in empirical studies, the model requires separate measures of cardiac sympathetic and cardiac vagal activity. Although these measures could be obtained by pharmaceutical blockage of sympathetic and vagal activation, to do so is labor intensive, not without risk, hard to justify in children, and of limited practicality in larger‐scaled studies. Noninvasive metrics that predominantly capture either sympathetic or vagal activity are better suited for such studies. This has been a major driver for the development and use of HRV metrics in psychophysiology.BOX 1 What are the neurophysiological drivers of HRV?Both the parasympathetic and sympathetic arms of the ANS act on the cardiac pacemaker cells of the SA node. SA cells exhibit a special capacity for self‐excitation, which is characterized by spontaneous membrane depolarization and the consequent generation of rhythmic action potentials by the voltage clock and Ca^++ mechanisms (Bartos, Grandi, & Ripplinger, 2015) that establish the intrinsic HR (HR in the absence of autonomic or hormonal influences). Several ion channels play a critical role in setting the rhythmic excitation of SA cells. Subsets of these ion channels are influenced by the release of acetylcholine (ACh) by the parasympathetic vagi onto muscarinic M2 receptors and by the release of norepinephrine (NE) by sympathetic motor neurons onto beta‐1 adrenergic receptors. ACh release strongly slows the spontaneous diastolic depolarization and may also increase the depth of repolarization of the SA cells (see Figure 1). This basic autonomic influence on SA activity leads to the well‐known observation that increases in the mean activity of the vagal nerve lead to increases in the heart period.In parallel, increases in mean activity in the vagal nerve are accompanied by an increase in HRV through the principle of vagal gating (Eckberg, 1983, 2003). Vagal gating is based on two fundamental processes. First, tonic efferent vagal activity arising in the structures of the so‐called central autonomic network (Saper, 2002) is subject to phasic (frequency) modulation by other neurophysiological processes at the brain stem level, including cardiorespiratory coupling and the baroreflex (Berntson, Cacioppo, & Quigley, 1993). To elaborate, cardiorespiratory coupling exerts inhibitory influences during inspiration on vagal motor neurons in the nucleus ambiguus (NA), the predominant brainstem source of cardio‐inhibition by the vagal nerve in mammals (Chapleau & Abboud, 2001). This causes a periodic waxing and waning of the tonic vagal influence on SA node cells in phase with the respiratory cycle. This vagal influence translates into a decrease in heart period during inspiration relative to expiration, which is a chief source of high‐frequency HRV within normative rates of breathing. Figure 2a provides a schematic representation of this process.We hasten to note that RSA neither implies a complete absence of vagal inhibition during expiration nor a complete vagal inhibition during inspiration,1 but rather relative changes in responsiveness of vagal motor neurons across the respiratory cycle, with less responsiveness during inspiration and more responsiveness during expiration. The ensuing modulation of central vagal activity by cardiorespiratory coupling and other neurophysiological sources of influence on RSA alter only a small fraction of the total influence of the vagus nerve on the SA node (Craft & Schwartz, 1995; Eckberg, 2003). For example, Craft and Schwartz performed full vagal blockade studies in 20 young (mean age 30) and 19 older (mean age 69) participants. In this study, the heart period shortened from 1,090 ms to 506 ms (Δ584 ms) in young participants, and from 1,053 ms to 718 ms (Δ335 ms) in older participants. These changes dwarf the typical modulation of heart period by phasic (respiratory‐related) inhibition that amounts to an average pvRSA of ~50 ms, with an approximate range of 0–200 ms.It is critical to note here that respiratory influences also entrain sympathetic nervous system (SNS) outflow to SA node cells. The SNS outflow‐induced increase in NE release depolarizes and enhances the excitability of SA cells via metabotropic, cAMP‐mediated, second‐messenger processes. The latter processes not only accelerate the spontaneous depolarization of the SA cells, but also accelerate the speed of neural conduction in cardiac tissue. Compared to the fast (~400 ms) vagal influences, these sympathetic influences on HRV are strongly attenuated by the low‐pass filtering characteristics of slow (i.e., 2–3 s) G‐protein coupled metabotropic cascades that are initiated by NE binding at beta‐1 adrenergic receptors (Berntson et al., 1993; Mark & Herlitze, 2000). Thus, although both steady state and phasic increases in sympathetic SA node activity can shorten basal heart period, high frequency sympathetic fluctuations (e.g., in the respiratory frequency range) do not translate into phasic heart period fluctuations. Accordingly, most HRV metrics that are usually employed in psychophysiology and behavioral medicine (i.e., RMSSD, HF, pvRSA) can be largely ascribed to modulation of the vagal nerve outflow to SA cells.A second fundamental principle in vagal gating is that the amplitude of the phasic modulation of activity in the autonomic motor neurons at the brainstem level (e.g., the NA) is a function of the absolute tonic level of firing of these autonomic motor neurons (Eckberg, 2003). The amplitude of the final modulated vagal signal traveling to the SA node therefore scales with the frequency of the tonic vagal pulse train presumptively arising in brain systems and cell groups comprising the so‐called central autonomic network. This means that the modulation of a pulse train of 12 Hz to vagal motor neurons will yield a larger peak‐to‐trough difference in the vagal signal to the SA node than the modulation of a 6 Hz pulse train. This is illustrated in Figure 2b. Here, we depict a person with lower centrally generated tonic vagal activity than in Figure 2a, which leads to a smaller difference between the shortest and longest beats in inspiration and expiration (50 ms compared to 100 ms). This principle is attributable to the fact that, at high levels of neural activity, there is a larger “carrier signal” to be subjected to phasic (respiratory‐related) inhibition.',\n", + " 'paragraph_id': 3,\n", + " 'tokenizer': 'the, auto, ##no, ##mic, space, model, provides, a, conceptual, framework, in, which, to, understand, reciprocal, ,, independent, ,, and, coa, ##ctive, patterns, of, sympathetic, and, para, ##sy, ##mp, ##ath, ##etic, cardiac, control, ,, both, in, the, context, of, within, ‐, individual, and, between, ‐, individual, study, designs, (, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, bin, ##kley, et, al, ., ,, 1994, ;, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, &, qui, ##gley, ,, 1994, ;, bern, ##tson, ,, norman, ,, hawk, ##ley, ,, &, ca, ##cio, ##pp, ##o, ,, 2008, ), ., however, ,, to, be, useful, in, empirical, studies, ,, the, model, requires, separate, measures, of, cardiac, sympathetic, and, cardiac, va, ##gal, activity, ., although, these, measures, could, be, obtained, by, pharmaceutical, block, ##age, of, sympathetic, and, va, ##gal, activation, ,, to, do, so, is, labor, intensive, ,, not, without, risk, ,, hard, to, justify, in, children, ,, and, of, limited, practical, ##ity, in, larger, ‐, scaled, studies, ., non, ##in, ##vas, ##ive, metric, ##s, that, predominantly, capture, either, sympathetic, or, va, ##gal, activity, are, better, suited, for, such, studies, ., this, has, been, a, major, driver, for, the, development, and, use, of, hr, ##v, metric, ##s, in, psycho, ##phy, ##sio, ##logy, ., box, 1, what, are, the, ne, ##uro, ##phy, ##sio, ##logical, drivers, of, hr, ##v, ?, both, the, para, ##sy, ##mp, ##ath, ##etic, and, sympathetic, arms, of, the, an, ##s, act, on, the, cardiac, pace, ##maker, cells, of, the, sa, node, ., sa, cells, exhibit, a, special, capacity, for, self, ‐, ex, ##cit, ##ation, ,, which, is, characterized, by, spontaneous, membrane, de, ##pol, ##ari, ##zation, and, the, con, ##se, ##quent, generation, of, rhythmic, action, potential, ##s, by, the, voltage, clock, and, ca, ^, +, +, mechanisms, (, bart, ##os, ,, grand, ##i, ,, &, rip, ##pling, ##er, ,, 2015, ), that, establish, the, intrinsic, hr, (, hr, in, the, absence, of, auto, ##no, ##mic, or, ho, ##rm, ##onal, influences, ), ., several, ion, channels, play, a, critical, role, in, setting, the, rhythmic, ex, ##cit, ##ation, of, sa, cells, ., subset, ##s, of, these, ion, channels, are, influenced, by, the, release, of, ace, ##ty, ##lch, ##olin, ##e, (, ac, ##h, ), by, the, para, ##sy, ##mp, ##ath, ##etic, va, ##gi, onto, mu, ##sca, ##rini, ##c, m2, receptors, and, by, the, release, of, nor, ##ep, ##ine, ##ph, ##rine, (, ne, ), by, sympathetic, motor, neurons, onto, beta, ‐, 1, ad, ##ren, ##er, ##gic, receptors, ., ac, ##h, release, strongly, slow, ##s, the, spontaneous, dia, ##sto, ##lic, de, ##pol, ##ari, ##zation, and, may, also, increase, the, depth, of, rep, ##olar, ##ization, of, the, sa, cells, (, see, figure, 1, ), ., this, basic, auto, ##no, ##mic, influence, on, sa, activity, leads, to, the, well, ‐, known, observation, that, increases, in, the, mean, activity, of, the, va, ##gal, nerve, lead, to, increases, in, the, heart, period, ., in, parallel, ,, increases, in, mean, activity, in, the, va, ##gal, nerve, are, accompanied, by, an, increase, in, hr, ##v, through, the, principle, of, va, ##gal, ga, ##ting, (, ec, ##k, ##berg, ,, 1983, ,, 2003, ), ., va, ##gal, ga, ##ting, is, based, on, two, fundamental, processes, ., first, ,, tonic, e, ##ffer, ##ent, va, ##gal, activity, arising, in, the, structures, of, the, so, ‐, called, central, auto, ##no, ##mic, network, (, sap, ##er, ,, 2002, ), is, subject, to, ph, ##asi, ##c, (, frequency, ), modulation, by, other, ne, ##uro, ##phy, ##sio, ##logical, processes, at, the, brain, stem, level, ,, including, card, ##ior, ##es, ##pi, ##rator, ##y, coupling, and, the, bar, ##ore, ##fle, ##x, (, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, &, qui, ##gley, ,, 1993, ), ., to, elaborate, ,, card, ##ior, ##es, ##pi, ##rator, ##y, coupling, ex, ##ert, ##s, inhibitor, ##y, influences, during, inspiration, on, va, ##gal, motor, neurons, in, the, nucleus, am, ##bi, ##gu, ##us, (, na, ), ,, the, predominant, brains, ##tem, source, of, card, ##io, ‐, inhibition, by, the, va, ##gal, nerve, in, mammals, (, cha, ##ple, ##au, &, ab, ##bo, ##ud, ,, 2001, ), ., this, causes, a, periodic, wax, ##ing, and, wan, ##ing, of, the, tonic, va, ##gal, influence, on, sa, node, cells, in, phase, with, the, respiratory, cycle, ., this, va, ##gal, influence, translates, into, a, decrease, in, heart, period, during, inspiration, relative, to, ex, ##piration, ,, which, is, a, chief, source, of, high, ‐, frequency, hr, ##v, within, norma, ##tive, rates, of, breathing, ., figure, 2a, provides, a, sc, ##hema, ##tic, representation, of, this, process, ., we, haste, ##n, to, note, that, rs, ##a, neither, implies, a, complete, absence, of, va, ##gal, inhibition, during, ex, ##piration, nor, a, complete, va, ##gal, inhibition, during, inspiration, ,, 1, but, rather, relative, changes, in, responsive, ##ness, of, va, ##gal, motor, neurons, across, the, respiratory, cycle, ,, with, less, responsive, ##ness, during, inspiration, and, more, responsive, ##ness, during, ex, ##piration, ., the, ensuing, modulation, of, central, va, ##gal, activity, by, card, ##ior, ##es, ##pi, ##rator, ##y, coupling, and, other, ne, ##uro, ##phy, ##sio, ##logical, sources, of, influence, on, rs, ##a, alter, only, a, small, fraction, of, the, total, influence, of, the, va, ##gus, nerve, on, the, sa, node, (, craft, &, schwartz, ,, 1995, ;, ec, ##k, ##berg, ,, 2003, ), ., for, example, ,, craft, and, schwartz, performed, full, va, ##gal, blockade, studies, in, 20, young, (, mean, age, 30, ), and, 19, older, (, mean, age, 69, ), participants, ., in, this, study, ,, the, heart, period, shortened, from, 1, ,, 09, ##0, ms, to, 50, ##6, ms, (, δ, ##58, ##4, ms, ), in, young, participants, ,, and, from, 1, ,, 05, ##3, ms, to, 71, ##8, ms, (, δ, ##33, ##5, ms, ), in, older, participants, ., these, changes, dwarf, the, typical, modulation, of, heart, period, by, ph, ##asi, ##c, (, respiratory, ‐, related, ), inhibition, that, amounts, to, an, average, pv, ##rsa, of, ~, 50, ms, ,, with, an, approximate, range, of, 0, –, 200, ms, ., it, is, critical, to, note, here, that, respiratory, influences, also, en, ##train, sympathetic, nervous, system, (, s, ##ns, ), out, ##flow, to, sa, node, cells, ., the, s, ##ns, out, ##flow, ‐, induced, increase, in, ne, release, de, ##pol, ##ari, ##zes, and, enhance, ##s, the, ex, ##cit, ##ability, of, sa, cells, via, meta, ##bot, ##rop, ##ic, ,, camp, ‐, mediated, ,, second, ‐, messenger, processes, ., the, latter, processes, not, only, accelerate, the, spontaneous, de, ##pol, ##ari, ##zation, of, the, sa, cells, ,, but, also, accelerate, the, speed, of, neural, conduct, ##ion, in, cardiac, tissue, ., compared, to, the, fast, (, ~, 400, ms, ), va, ##gal, influences, ,, these, sympathetic, influences, on, hr, ##v, are, strongly, at, ##ten, ##uated, by, the, low, ‐, pass, filtering, characteristics, of, slow, (, i, ., e, ., ,, 2, –, 3, s, ), g, ‐, protein, coupled, meta, ##bot, ##rop, ##ic, cascade, ##s, that, are, initiated, by, ne, binding, at, beta, ‐, 1, ad, ##ren, ##er, ##gic, receptors, (, bern, ##tson, et, al, ., ,, 1993, ;, mark, &, her, ##litz, ##e, ,, 2000, ), ., thus, ,, although, both, steady, state, and, ph, ##asi, ##c, increases, in, sympathetic, sa, node, activity, can, short, ##en, basal, heart, period, ,, high, frequency, sympathetic, fluctuations, (, e, ., g, ., ,, in, the, respiratory, frequency, range, ), do, not, translate, into, ph, ##asi, ##c, heart, period, fluctuations, ., accordingly, ,, most, hr, ##v, metric, ##s, that, are, usually, employed, in, psycho, ##phy, ##sio, ##logy, and, behavioral, medicine, (, i, ., e, ., ,, rms, ##sd, ,, h, ##f, ,, pv, ##rsa, ), can, be, largely, ascribed, to, modulation, of, the, va, ##gal, nerve, out, ##flow, to, sa, cells, ., a, second, fundamental, principle, in, va, ##gal, ga, ##ting, is, that, the, amplitude, of, the, ph, ##asi, ##c, modulation, of, activity, in, the, auto, ##no, ##mic, motor, neurons, at, the, brains, ##tem, level, (, e, ., g, ., ,, the, na, ), is, a, function, of, the, absolute, tonic, level, of, firing, of, these, auto, ##no, ##mic, motor, neurons, (, ec, ##k, ##berg, ,, 2003, ), ., the, amplitude, of, the, final, mod, ##ulated, va, ##gal, signal, traveling, to, the, sa, node, therefore, scales, with, the, frequency, of, the, tonic, va, ##gal, pulse, train, pre, ##sum, ##ptive, ##ly, arising, in, brain, systems, and, cell, groups, comprising, the, so, ‐, called, central, auto, ##no, ##mic, network, ., this, means, that, the, modulation, of, a, pulse, train, of, 12, hz, to, va, ##gal, motor, neurons, will, yield, a, larger, peak, ‐, to, ‐, trough, difference, in, the, va, ##gal, signal, to, the, sa, node, than, the, modulation, of, a, 6, hz, pulse, train, ., this, is, illustrated, in, figure, 2, ##b, ., here, ,, we, depict, a, person, with, lower, centrally, generated, tonic, va, ##gal, activity, than, in, figure, 2a, ,, which, leads, to, a, smaller, difference, between, the, shortest, and, longest, beats, in, inspiration, and, ex, ##piration, (, 50, ms, compared, to, 100, ms, ), ., this, principle, is, at, ##tri, ##bu, ##table, to, the, fact, that, ,, at, high, levels, of, neural, activity, ,, there, is, a, larger, “, carrier, signal, ”, to, be, subjected, to, ph, ##asi, ##c, (, respiratory, ‐, related, ), inhibition, .'},\n", + " {'article_id': '9526704a47665f9cf9741e7fd30ad68d',\n", + " 'section_name': 'INTRODUCTION',\n", + " 'text': 'As explained in detail in Box 1, specific measures of HRV, such as peak‐to‐valley respiratory sinus arrhythmia (pvRSA) and related metrics of heart period oscillations within common breathing frequencies, capture the inspiratory shortening and expiratory lengthening of heart periods across the respiratory cycle that is predominantly due to variations in cardiac vagal activity. In combination with measures that predominantly capture cardiac sympathetic activity, such as the pre‐ejection period (PEP), metrics of RSA may be interpreted and treated to meaningfully understand autonomic cardiac regulation within a two‐dimensional autonomic space model beyond ambiguous end‐organ activity provided by cardiac chronotropic metrics like heart period (Berntson, Cacioppo, Binkley et al., 1994; Bosch, de Geus, Veerman, Hoogstraten, & Nieuw Amerongen, 2003; Cacioppo et al., 1994). A 2007 special issue of Biological Psychology on cardiac vagal control illustrated its widespread use and highlighted issues pertaining to the use and abuse of various HRV metrics (Allen & Chambers, 2007). A recurrent concern has been the sometimes uncritical use of RSA as an index of vagal tone (see Box 2). In the decade since the publication of that special issue, interest in RSA and other HRV metrics has only expanded and deepened. This interest, however, has partly revived debate over a key and still open question addressed in this paper: Should HRV be “corrected” for heart rate (HR)? Based on a seminal paper by Monfredi and colleagues in 2014 (Monfredi et al., 2014), a rather strong viewpoint has been advocated that HRV is “just a nonlinear surrogate for HR” (Boyett, 2017; Boyett et al., 2017). Clearly, if HRV is confounded by a direct effect of the cardiac chronotropic state itself, this would fundamentally complicate its use to specifically capture one branch of the ANS.BOX 2 RSA and cardiac vagal activityThe observation that RSA scales with levels of tonic vagal activity is the source of the widespread use of RSA as an index of vagal tone, a vague concept variably used to denote parasympathetic activity generated by the central autonomic network, the baroreflex circuitry, or simply the net effect of ACh on the SA node. However, inferring absolute levels of vagal activity at cortical, limbic, brainstem, or even SA node levels from any particular quantitative value of RSA is neither simple nor straightforward for many reasons. First, depth and rate of breathing strongly impact HRV metrics, especially those that index RSA (Eckberg, 2003; Grossman & Kollai, 1993; Grossman & Taylor, 2007; Grossman, Karemaker, & Wieling, 1991; Kollai & Mizsei, 1990; Taylor, Myers, Halliwill, Seidel, & Eckberg, 2001). Within individuals, RSA is inversely related to respiration rate and directly related to tidal volume. Hence, rapid and shallow breathing yields low RSA. The important observation here, which has been demonstrated many times over, is that an increase in RSA by slowing respiratory rate and increasing volume may be seen in the absence of any change in tonic vagal activity, as reflected in unchanged or even slightly decreasing mean heart period (Chapleau & Abboud, 2001). The impact of differences in breathing behavior on between‐individual comparisons of RSA is somewhat harder to gauge, but cannot be ignored. Given the importance of respiratory rate and tidal volume as critical determinants of RSA values independent of cardiac vagal activity, RSA measures are often obtained under controlled breathing conditions or they are statistically corrected for spontaneous variation within and between individuals, albeit with varying degrees of rigor (Ritz & Dahme, 2006).A second reason not to equate RSA with tonic vagal activity is that the translation of fluctuations in vagal activity at the SA node into the actual slowing/speeding of the pacemaker potential is dependent on a complex interplay of postsynaptic signal transducers in the SA cells. Between‐individual differences and within‐individual changes in the efficiency of these transducers will distort any simple one‐to‐one mapping of vagal activity on HRV metrics. A classic example is the paradoxical reduction in HRV metrics at high levels of cardiac vagal activity induced in within‐individual designs by infusing pressor agents (Goldberger, Ahmed, Parker, & Kadish, 1994; Goldberger, Challapalli, Tung, Parker, & Kadish, 2001; Goldberger, Kim, Ahmed, & Kadish, 1996). Here, a saturation of a core element of postsynaptic ACh signal transduction, the SA muscarinic M2 receptors, causes low HRV in the presence of high vagal activity. A similar ceiling effect in the M2‐receptor signaling cascade may occur in regular vigorous exercisers with strong bradycardia. During nighttime, when their heart periods are much longer compared to daytime, these individuals exhibit a paradoxical lowering of RSA (van Lien et al., 2011).Notwithstanding the many pitfalls highlighted thus far, RSA offers our best opportunity for estimating cardiac vagal activity noninvasively, most notably in larger‐scaled research in humans. We lack means for directly recording efferent vagal nerve activity to the heart, and pharmacological blockade suffers from its own disadvantages apart from being only feasible in small sample size studies. Various findings suggest that, in general, we can expect higher RSA with higher average levels of cardiac vagal activity. Within individuals, this is illustrated by gradual pharmacological blockade of ACh effects on the SA cells, which exerts no effects on respiratory behavior but is loyally tracked by parallel changes in RSA (Grossman & Taylor, 2007). Various studies have addressed this issue by administering a parasympathetic antagonist during a resting baseline condition and inferring vagal activity from the resultant decrease in heart period (Fouad, Tarazi, Ferrario, Fighaly, & Alicandri, 1984; Grossman & Kollai, 1993; Hayano et al., 1991; Kollai & Mizsei, 1990). RSA was estimated in parallel (e.g., with the peak‐to‐valley method). If pvRSA was completely proportional to cardiac vagal activity, then a perfect between‐individual correlation of the increases in heart period and pvRSA would have been observed. The actual correlations were quite appreciable but not perfect, even under controlled breathing conditions and incompletely saturated M2 receptors, varying between 0.5 and 0.9.BOX 3 A more in‐depth look at vagal stimulation studiesMost of the vagal stimulation studies presented in Table 1 use a design in which the heart period attained during a steady state phase of vagal stimulation at a fixed frequency is compared to the heart period at prestimulation baseline. This procedure is repeated across a number of different vagal stimulation frequencies. The change in the heart period over the baseline heart period is computed for each frequency and, when plotted against stimulation frequency, typically yields a near‐perfect linear relation. The essence is that each stimulation event starts at the same baseline heart period, typically in the denervated heart (i.e., in the presence of bilateral vagal sectioning with sympathetic ganglia sectioning and/or sympathetic blockade). One could argue that this only indirectly answers the core question of dependency of vagal effects on the ongoing mean heart period. This potential limitation can be addressed by experimental manipulation of the baseline heart period before vagal stimulation commences, by changing cardiac sympathetic activity, or by changing nonautonomic effects on the diastolic depolarization rate, for example, by ivabradine or other blockers of the funny channel (decreasing If). Testing the effects of vagal stimulation under different levels of concurrent cardiac sympathetic nerve stimulation (and hence baseline heart period) has been repeatedly done in the context of testing for accentuated antagonism (Quigley & Berntson, 1996). In mongrel dogs, the relative angle scenario in Figure 3b seemed to best fit the observed relationship between changes in vagal firing and chronotropic effects across different baseline values of heart period (Levy & Zieske, 1969a; Randall et al., 2003; Urthaler, Neely, Hageman, & Smith, 1986). When mean heart period levels were shortened by 30% to 35% through sympathetic stimulation at 4 Hz (S‐stim), a linear relation between vagal stimulation and heart period was again found in all studies, with comparable slopes between the S‐stim and no S‐stim conditions in two of the three studies (Table 1, lower). Combined manipulation of sympathetic and vagal tone by exercise in a conscious animal was used to manipulate basal mean heart period in another study (Stramba‐Badiale et al., 1991). When dogs (with a vagal stimulator) walked on a treadmill, their heart period changed from a resting value of 500 to 299 ms. In spite of this strong decrease in mean heart period, the slope obtained with vagal stimulation was comparable at rest (33.2 ms/Hz) and during exercise (28.8 ms/Hz).We can conclude from these studies that, within a species, there is a relatively linear translation of phasic changes in vagal activity into changes in heart period across a wide range of baseline heart period levels with a reasonably stable slope. This is, again, what would have been predicted by the relative angle scenario in Figure 5b. However, in a dog model where central autonomic outflow was blocked, vagal pacing at 12 Hz produced lower increases in RSA when parallel sympathetic stimulation was applied (Hedman, Tahvanainen, Hartikainen, & Hakumaki, 1995). Pharmacological blockade in humans confirms that RSA is sensitive to moderate‐to‐large changes in cardiac sympathetic activity. As reviewed by Grossman and Taylor (2007), beta‐blockade in parallel increases heart period and RSA, even when vagal activity is not changed. This might be taken to suggest that there is indeed some direct effect of the mean heart period on RSA as would have been predicted by the fixed angle scenario in Figure 5a. Similarly, sympathetic agonists raising blood pressure like dobutamine cause a shortening of the mean heart period with a parallel decrease in HRV, when a baroreflex‐induced increase in vagal activity would be expected (Monfredi et al., 2014). Unfortunately, such effects on HRV could also occur independently of mediation by heart period, because sympathetic antagonists and agonists can interact directly with vagal activity at the brainstem level, and pre‐ and postjunctionally in the SA node (e.g., by the inhibitory action of the NE coreleased and the neuromodulator neuropeptide Y on ACh release (Quigley & Berntson, 1996).A final class of relevant studies are those that used funny channel blockade to increase mean heart period (e.g., zetabradine or ivabradine). Funny channel blockade prolongs heart period, and many studies show that this bradycardia is coupled to a parallel increase in HRV (Borer & Le Heuzey, 2008; Kurtoglu et al., 2014). Vagal activity is still widely regarded to be the primary driver of HRV under ivabradine because atropine completely prevents the increase in HRV (Kozasa et al., 2018; Mangin et al., 1998). Nonetheless, the increase in HRV is counterintuitive, as ivabradine‐evoked bradycardia causes a parallel decrease in blood pressure. The latter causes a reflex increase in sympathetic nerve activity (Dias da Silva et al., 2015) and, one assumes, a reflex decrease in vagal activity in accord with baroreflex action. The observed increase in HRV was therefore explained as reflecting an “intrinsic dependency of HRV on pacemaker cycle length” (Dias da Silva at al., 2015, p. 32). This appears at first sight to be most compatible with the fixed angle scenario of Figure 5b.However, using a murine genetic knockdown of HCN4, Kozasa et al. (2018) reported findings that were at odds with a fixed angle scenario. HCN4 is a main component of the funny channel, and this knockdown model mimics the bradycardic effects of ivabradine, as well as its positive, increasing effects on HRV. In the context of this model, they showed that funny channel action can directly impact the strength of vagal effects in the SA node. By counteracting K+ GIRK channels (reducing K+ efflux), the funny channel protects the SA cells against complete sinus pause under high vagal stimulation. Because the funny channel has a “limiter function” for the bradycardic effects induced by vagal activity, blocking it by ivabradine would act to amplify the effectiveness of phasic—for example, baroreflex or respiration‐induced—increases in vagal activity to induce phasic changes in heart period. The latter changes would serve to boost HRV. In keeping with this notion, amplifying funny channel action by HCN4 overexpression strongly reduced HRV, whereas mean heart period was unchanged. These results can all be explained by the funny channel counteracting the effectiveness of vagal activity without invoking an intrinsic dependency of HRV on heart period. Kozasa et al. (2018) also provide direct support for the relative angle scenario of Figure 5b. In isolated pacemaker cells, the basal diastolic depolarization rate in HCN4 knockdown mice was much slower than in the wild type animals (Kozasa et al., 2018, their figure D, p. 821). When exposed to increasing concentrations of ACh [0 to 30 nmol], the additional decrease in the depolarization rate induced by the same dose of ACh was much lower in the HCN4 knockdown (~35 mV/s) than in the wild type mice (~80 mV/s).',\n", + " 'paragraph_id': 4,\n", + " 'tokenizer': 'as, explained, in, detail, in, box, 1, ,, specific, measures, of, hr, ##v, ,, such, as, peak, ‐, to, ‐, valley, respiratory, sin, ##us, ar, ##rh, ##yt, ##hmi, ##a, (, pv, ##rsa, ), and, related, metric, ##s, of, heart, period, os, ##ci, ##llation, ##s, within, common, breathing, frequencies, ,, capture, the, ins, ##pi, ##rator, ##y, short, ##ening, and, ex, ##pi, ##rator, ##y, length, ##ening, of, heart, periods, across, the, respiratory, cycle, that, is, predominantly, due, to, variations, in, cardiac, va, ##gal, activity, ., in, combination, with, measures, that, predominantly, capture, cardiac, sympathetic, activity, ,, such, as, the, pre, ‐, e, ##ject, ##ion, period, (, pep, ), ,, metric, ##s, of, rs, ##a, may, be, interpreted, and, treated, to, meaningful, ##ly, understand, auto, ##no, ##mic, cardiac, regulation, within, a, two, ‐, dimensional, auto, ##no, ##mic, space, model, beyond, ambiguous, end, ‐, organ, activity, provided, by, cardiac, ch, ##ron, ##ot, ##rop, ##ic, metric, ##s, like, heart, period, (, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, bin, ##kley, et, al, ., ,, 1994, ;, bosch, ,, de, ge, ##us, ,, ve, ##erman, ,, ho, ##og, ##stra, ##ten, ,, &, ni, ##eu, ##w, am, ##eron, ##gen, ,, 2003, ;, ca, ##cio, ##pp, ##o, et, al, ., ,, 1994, ), ., a, 2007, special, issue, of, biological, psychology, on, cardiac, va, ##gal, control, illustrated, its, widespread, use, and, highlighted, issues, pertaining, to, the, use, and, abuse, of, various, hr, ##v, metric, ##s, (, allen, &, chambers, ,, 2007, ), ., a, rec, ##urrent, concern, has, been, the, sometimes, un, ##cr, ##itical, use, of, rs, ##a, as, an, index, of, va, ##gal, tone, (, see, box, 2, ), ., in, the, decade, since, the, publication, of, that, special, issue, ,, interest, in, rs, ##a, and, other, hr, ##v, metric, ##s, has, only, expanded, and, deepened, ., this, interest, ,, however, ,, has, partly, revived, debate, over, a, key, and, still, open, question, addressed, in, this, paper, :, should, hr, ##v, be, “, corrected, ”, for, heart, rate, (, hr, ), ?, based, on, a, seminal, paper, by, mon, ##fr, ##ed, ##i, and, colleagues, in, 2014, (, mon, ##fr, ##ed, ##i, et, al, ., ,, 2014, ), ,, a, rather, strong, viewpoint, has, been, advocated, that, hr, ##v, is, “, just, a, nonlinear, sur, ##rogate, for, hr, ”, (, boy, ##ett, ,, 2017, ;, boy, ##ett, et, al, ., ,, 2017, ), ., clearly, ,, if, hr, ##v, is, con, ##founded, by, a, direct, effect, of, the, cardiac, ch, ##ron, ##ot, ##rop, ##ic, state, itself, ,, this, would, fundamentally, com, ##pl, ##icate, its, use, to, specifically, capture, one, branch, of, the, an, ##s, ., box, 2, rs, ##a, and, cardiac, va, ##gal, activity, ##the, observation, that, rs, ##a, scales, with, levels, of, tonic, va, ##gal, activity, is, the, source, of, the, widespread, use, of, rs, ##a, as, an, index, of, va, ##gal, tone, ,, a, vague, concept, var, ##ia, ##bly, used, to, denote, para, ##sy, ##mp, ##ath, ##etic, activity, generated, by, the, central, auto, ##no, ##mic, network, ,, the, bar, ##ore, ##fle, ##x, circuit, ##ry, ,, or, simply, the, net, effect, of, ac, ##h, on, the, sa, node, ., however, ,, in, ##fer, ##ring, absolute, levels, of, va, ##gal, activity, at, co, ##rti, ##cal, ,, limb, ##ic, ,, brains, ##tem, ,, or, even, sa, node, levels, from, any, particular, quantitative, value, of, rs, ##a, is, neither, simple, nor, straightforward, for, many, reasons, ., first, ,, depth, and, rate, of, breathing, strongly, impact, hr, ##v, metric, ##s, ,, especially, those, that, index, rs, ##a, (, ec, ##k, ##berg, ,, 2003, ;, gross, ##man, &, ko, ##lla, ##i, ,, 1993, ;, gross, ##man, &, taylor, ,, 2007, ;, gross, ##man, ,, ka, ##rem, ##aker, ,, &, wi, ##elin, ##g, ,, 1991, ;, ko, ##lla, ##i, &, mi, ##z, ##sei, ,, 1990, ;, taylor, ,, myers, ,, hall, ##i, ##wil, ##l, ,, se, ##ide, ##l, ,, &, ec, ##k, ##berg, ,, 2001, ), ., within, individuals, ,, rs, ##a, is, inverse, ##ly, related, to, res, ##piration, rate, and, directly, related, to, tidal, volume, ., hence, ,, rapid, and, shallow, breathing, yields, low, rs, ##a, ., the, important, observation, here, ,, which, has, been, demonstrated, many, times, over, ,, is, that, an, increase, in, rs, ##a, by, slowing, respiratory, rate, and, increasing, volume, may, be, seen, in, the, absence, of, any, change, in, tonic, va, ##gal, activity, ,, as, reflected, in, unchanged, or, even, slightly, decreasing, mean, heart, period, (, cha, ##ple, ##au, &, ab, ##bo, ##ud, ,, 2001, ), ., the, impact, of, differences, in, breathing, behavior, on, between, ‐, individual, comparisons, of, rs, ##a, is, somewhat, harder, to, gauge, ,, but, cannot, be, ignored, ., given, the, importance, of, respiratory, rate, and, tidal, volume, as, critical, deter, ##mina, ##nts, of, rs, ##a, values, independent, of, cardiac, va, ##gal, activity, ,, rs, ##a, measures, are, often, obtained, under, controlled, breathing, conditions, or, they, are, statistical, ##ly, corrected, for, spontaneous, variation, within, and, between, individuals, ,, albeit, with, varying, degrees, of, rig, ##or, (, ri, ##tz, &, da, ##hm, ##e, ,, 2006, ), ., a, second, reason, not, to, e, ##qua, ##te, rs, ##a, with, tonic, va, ##gal, activity, is, that, the, translation, of, fluctuations, in, va, ##gal, activity, at, the, sa, node, into, the, actual, slowing, /, speeding, of, the, pace, ##maker, potential, is, dependent, on, a, complex, inter, ##play, of, posts, ##yna, ##ptic, signal, trans, ##du, ##cer, ##s, in, the, sa, cells, ., between, ‐, individual, differences, and, within, ‐, individual, changes, in, the, efficiency, of, these, trans, ##du, ##cer, ##s, will, di, ##stor, ##t, any, simple, one, ‐, to, ‐, one, mapping, of, va, ##gal, activity, on, hr, ##v, metric, ##s, ., a, classic, example, is, the, paradox, ##ical, reduction, in, hr, ##v, metric, ##s, at, high, levels, of, cardiac, va, ##gal, activity, induced, in, within, ‐, individual, designs, by, in, ##fus, ##ing, press, ##or, agents, (, goldberg, ##er, ,, ahmed, ,, parker, ,, &, ka, ##dis, ##h, ,, 1994, ;, goldberg, ##er, ,, cha, ##lla, ##pal, ##li, ,, tung, ,, parker, ,, &, ka, ##dis, ##h, ,, 2001, ;, goldberg, ##er, ,, kim, ,, ahmed, ,, &, ka, ##dis, ##h, ,, 1996, ), ., here, ,, a, sat, ##uration, of, a, core, element, of, posts, ##yna, ##ptic, ac, ##h, signal, trans, ##duction, ,, the, sa, mu, ##sca, ##rini, ##c, m2, receptors, ,, causes, low, hr, ##v, in, the, presence, of, high, va, ##gal, activity, ., a, similar, ceiling, effect, in, the, m2, ‐, receptor, signaling, cascade, may, occur, in, regular, vigorous, exercise, ##rs, with, strong, brady, ##card, ##ia, ., during, nighttime, ,, when, their, heart, periods, are, much, longer, compared, to, daytime, ,, these, individuals, exhibit, a, paradox, ##ical, lowering, of, rs, ##a, (, van, lie, ##n, et, al, ., ,, 2011, ), ., notwithstanding, the, many, pit, ##falls, highlighted, thus, far, ,, rs, ##a, offers, our, best, opportunity, for, est, ##imating, cardiac, va, ##gal, activity, non, ##in, ##vas, ##ively, ,, most, notably, in, larger, ‐, scaled, research, in, humans, ., we, lack, means, for, directly, recording, e, ##ffer, ##ent, va, ##gal, nerve, activity, to, the, heart, ,, and, ph, ##arm, ##aco, ##logical, blockade, suffers, from, its, own, disadvantage, ##s, apart, from, being, only, feasible, in, small, sample, size, studies, ., various, findings, suggest, that, ,, in, general, ,, we, can, expect, higher, rs, ##a, with, higher, average, levels, of, cardiac, va, ##gal, activity, ., within, individuals, ,, this, is, illustrated, by, gradual, ph, ##arm, ##aco, ##logical, blockade, of, ac, ##h, effects, on, the, sa, cells, ,, which, ex, ##ert, ##s, no, effects, on, respiratory, behavior, but, is, loyal, ##ly, tracked, by, parallel, changes, in, rs, ##a, (, gross, ##man, &, taylor, ,, 2007, ), ., various, studies, have, addressed, this, issue, by, administering, a, para, ##sy, ##mp, ##ath, ##etic, antagonist, during, a, resting, baseline, condition, and, in, ##fer, ##ring, va, ##gal, activity, from, the, resultant, decrease, in, heart, period, (, f, ##ou, ##ad, ,, tara, ##zi, ,, ferrari, ##o, ,, fig, ##hal, ##y, ,, &, ali, ##can, ##dr, ##i, ,, 1984, ;, gross, ##man, &, ko, ##lla, ##i, ,, 1993, ;, hay, ##ano, et, al, ., ,, 1991, ;, ko, ##lla, ##i, &, mi, ##z, ##sei, ,, 1990, ), ., rs, ##a, was, estimated, in, parallel, (, e, ., g, ., ,, with, the, peak, ‐, to, ‐, valley, method, ), ., if, pv, ##rsa, was, completely, proportional, to, cardiac, va, ##gal, activity, ,, then, a, perfect, between, ‐, individual, correlation, of, the, increases, in, heart, period, and, pv, ##rsa, would, have, been, observed, ., the, actual, correlation, ##s, were, quite, app, ##re, ##cia, ##ble, but, not, perfect, ,, even, under, controlled, breathing, conditions, and, incomplete, ##ly, saturated, m2, receptors, ,, varying, between, 0, ., 5, and, 0, ., 9, ., box, 3, a, more, in, ‐, depth, look, at, va, ##gal, stimulation, studies, ##most, of, the, va, ##gal, stimulation, studies, presented, in, table, 1, use, a, design, in, which, the, heart, period, attained, during, a, steady, state, phase, of, va, ##gal, stimulation, at, a, fixed, frequency, is, compared, to, the, heart, period, at, pre, ##sti, ##mu, ##lation, baseline, ., this, procedure, is, repeated, across, a, number, of, different, va, ##gal, stimulation, frequencies, ., the, change, in, the, heart, period, over, the, baseline, heart, period, is, computed, for, each, frequency, and, ,, when, plotted, against, stimulation, frequency, ,, typically, yields, a, near, ‐, perfect, linear, relation, ., the, essence, is, that, each, stimulation, event, starts, at, the, same, baseline, heart, period, ,, typically, in, the, den, ##er, ##vate, ##d, heart, (, i, ., e, ., ,, in, the, presence, of, bilateral, va, ##gal, section, ##ing, with, sympathetic, gang, ##lia, section, ##ing, and, /, or, sympathetic, blockade, ), ., one, could, argue, that, this, only, indirectly, answers, the, core, question, of, dependency, of, va, ##gal, effects, on, the, ongoing, mean, heart, period, ., this, potential, limitation, can, be, addressed, by, experimental, manipulation, of, the, baseline, heart, period, before, va, ##gal, stimulation, commence, ##s, ,, by, changing, cardiac, sympathetic, activity, ,, or, by, changing, non, ##au, ##ton, ##omic, effects, on, the, dia, ##sto, ##lic, de, ##pol, ##ari, ##zation, rate, ,, for, example, ,, by, iv, ##ab, ##rad, ##ine, or, other, block, ##ers, of, the, funny, channel, (, decreasing, if, ), ., testing, the, effects, of, va, ##gal, stimulation, under, different, levels, of, concurrent, cardiac, sympathetic, nerve, stimulation, (, and, hence, baseline, heart, period, ), has, been, repeatedly, done, in, the, context, of, testing, for, accent, ##uated, ant, ##ago, ##nism, (, qui, ##gley, &, bern, ##tson, ,, 1996, ), ., in, mon, ##gre, ##l, dogs, ,, the, relative, angle, scenario, in, figure, 3, ##b, seemed, to, best, fit, the, observed, relationship, between, changes, in, va, ##gal, firing, and, ch, ##ron, ##ot, ##rop, ##ic, effects, across, different, baseline, values, of, heart, period, (, levy, &, z, ##ies, ##ke, ,, 1969, ##a, ;, randall, et, al, ., ,, 2003, ;, ur, ##thal, ##er, ,, nee, ##ly, ,, ha, ##ge, ##man, ,, &, smith, ,, 1986, ), ., when, mean, heart, period, levels, were, shortened, by, 30, %, to, 35, %, through, sympathetic, stimulation, at, 4, hz, (, s, ‐, st, ##im, ), ,, a, linear, relation, between, va, ##gal, stimulation, and, heart, period, was, again, found, in, all, studies, ,, with, comparable, slopes, between, the, s, ‐, st, ##im, and, no, s, ‐, st, ##im, conditions, in, two, of, the, three, studies, (, table, 1, ,, lower, ), ., combined, manipulation, of, sympathetic, and, va, ##gal, tone, by, exercise, in, a, conscious, animal, was, used, to, manipulate, basal, mean, heart, period, in, another, study, (, st, ##ram, ##ba, ‐, bad, ##ial, ##e, et, al, ., ,, 1991, ), ., when, dogs, (, with, a, va, ##gal, st, ##im, ##ulator, ), walked, on, a, tread, ##mill, ,, their, heart, period, changed, from, a, resting, value, of, 500, to, 299, ms, ., in, spite, of, this, strong, decrease, in, mean, heart, period, ,, the, slope, obtained, with, va, ##gal, stimulation, was, comparable, at, rest, (, 33, ., 2, ms, /, hz, ), and, during, exercise, (, 28, ., 8, ms, /, hz, ), ., we, can, conclude, from, these, studies, that, ,, within, a, species, ,, there, is, a, relatively, linear, translation, of, ph, ##asi, ##c, changes, in, va, ##gal, activity, into, changes, in, heart, period, across, a, wide, range, of, baseline, heart, period, levels, with, a, reasonably, stable, slope, ., this, is, ,, again, ,, what, would, have, been, predicted, by, the, relative, angle, scenario, in, figure, 5, ##b, ., however, ,, in, a, dog, model, where, central, auto, ##no, ##mic, out, ##flow, was, blocked, ,, va, ##gal, pacing, at, 12, hz, produced, lower, increases, in, rs, ##a, when, parallel, sympathetic, stimulation, was, applied, (, he, ##dman, ,, ta, ##h, ##vana, ##inen, ,, hart, ##ika, ##inen, ,, &, ha, ##ku, ##ma, ##ki, ,, 1995, ), ., ph, ##arm, ##aco, ##logical, blockade, in, humans, confirms, that, rs, ##a, is, sensitive, to, moderate, ‐, to, ‐, large, changes, in, cardiac, sympathetic, activity, ., as, reviewed, by, gross, ##man, and, taylor, (, 2007, ), ,, beta, ‐, blockade, in, parallel, increases, heart, period, and, rs, ##a, ,, even, when, va, ##gal, activity, is, not, changed, ., this, might, be, taken, to, suggest, that, there, is, indeed, some, direct, effect, of, the, mean, heart, period, on, rs, ##a, as, would, have, been, predicted, by, the, fixed, angle, scenario, in, figure, 5, ##a, ., similarly, ,, sympathetic, ago, ##nist, ##s, raising, blood, pressure, like, do, ##bu, ##tam, ##ine, cause, a, short, ##ening, of, the, mean, heart, period, with, a, parallel, decrease, in, hr, ##v, ,, when, a, bar, ##ore, ##fle, ##x, ‐, induced, increase, in, va, ##gal, activity, would, be, expected, (, mon, ##fr, ##ed, ##i, et, al, ., ,, 2014, ), ., unfortunately, ,, such, effects, on, hr, ##v, could, also, occur, independently, of, mediation, by, heart, period, ,, because, sympathetic, antagonist, ##s, and, ago, ##nist, ##s, can, interact, directly, with, va, ##gal, activity, at, the, brains, ##tem, level, ,, and, pre, ‐, and, post, ##jun, ##ction, ##ally, in, the, sa, node, (, e, ., g, ., ,, by, the, inhibitor, ##y, action, of, the, ne, core, ##lea, ##sed, and, the, ne, ##uro, ##mo, ##du, ##lat, ##or, ne, ##uro, ##pe, ##pt, ##ide, y, on, ac, ##h, release, (, qui, ##gley, &, bern, ##tson, ,, 1996, ), ., a, final, class, of, relevant, studies, are, those, that, used, funny, channel, blockade, to, increase, mean, heart, period, (, e, ., g, ., ,, zeta, ##bra, ##dine, or, iv, ##ab, ##rad, ##ine, ), ., funny, channel, blockade, pro, ##long, ##s, heart, period, ,, and, many, studies, show, that, this, brady, ##card, ##ia, is, coupled, to, a, parallel, increase, in, hr, ##v, (, bore, ##r, &, le, he, ##uze, ##y, ,, 2008, ;, kurt, ##og, ##lu, et, al, ., ,, 2014, ), ., va, ##gal, activity, is, still, widely, regarded, to, be, the, primary, driver, of, hr, ##v, under, iv, ##ab, ##rad, ##ine, because, at, ##rop, ##ine, completely, prevents, the, increase, in, hr, ##v, (, ko, ##za, ##sa, et, al, ., ,, 2018, ;, man, ##gin, et, al, ., ,, 1998, ), ., nonetheless, ,, the, increase, in, hr, ##v, is, counter, ##int, ##uit, ##ive, ,, as, iv, ##ab, ##rad, ##ine, ‐, ev, ##oked, brady, ##card, ##ia, causes, a, parallel, decrease, in, blood, pressure, ., the, latter, causes, a, reflex, increase, in, sympathetic, nerve, activity, (, dia, ##s, da, silva, et, al, ., ,, 2015, ), and, ,, one, assumes, ,, a, reflex, decrease, in, va, ##gal, activity, in, accord, with, bar, ##ore, ##fle, ##x, action, ., the, observed, increase, in, hr, ##v, was, therefore, explained, as, reflecting, an, “, intrinsic, dependency, of, hr, ##v, on, pace, ##maker, cycle, length, ”, (, dia, ##s, da, silva, at, al, ., ,, 2015, ,, p, ., 32, ), ., this, appears, at, first, sight, to, be, most, compatible, with, the, fixed, angle, scenario, of, figure, 5, ##b, ., however, ,, using, a, mu, ##rine, genetic, knock, ##down, of, hc, ##n, ##4, ,, ko, ##za, ##sa, et, al, ., (, 2018, ), reported, findings, that, were, at, odds, with, a, fixed, angle, scenario, ., hc, ##n, ##4, is, a, main, component, of, the, funny, channel, ,, and, this, knock, ##down, model, mimic, ##s, the, brady, ##card, ##ic, effects, of, iv, ##ab, ##rad, ##ine, ,, as, well, as, its, positive, ,, increasing, effects, on, hr, ##v, ., in, the, context, of, this, model, ,, they, showed, that, funny, channel, action, can, directly, impact, the, strength, of, va, ##gal, effects, in, the, sa, node, ., by, counter, ##act, ##ing, k, +, gi, ##rk, channels, (, reducing, k, +, e, ##ff, ##lux, ), ,, the, funny, channel, protects, the, sa, cells, against, complete, sin, ##us, pause, under, high, va, ##gal, stimulation, ., because, the, funny, channel, has, a, “, limit, ##er, function, ”, for, the, brady, ##card, ##ic, effects, induced, by, va, ##gal, activity, ,, blocking, it, by, iv, ##ab, ##rad, ##ine, would, act, to, amp, ##li, ##fy, the, effectiveness, of, ph, ##asi, ##c, —, for, example, ,, bar, ##ore, ##fle, ##x, or, res, ##piration, ‐, induced, —, increases, in, va, ##gal, activity, to, induce, ph, ##asi, ##c, changes, in, heart, period, ., the, latter, changes, would, serve, to, boost, hr, ##v, ., in, keeping, with, this, notion, ,, amp, ##li, ##fying, funny, channel, action, by, hc, ##n, ##4, over, ##ex, ##press, ##ion, strongly, reduced, hr, ##v, ,, whereas, mean, heart, period, was, unchanged, ., these, results, can, all, be, explained, by, the, funny, channel, counter, ##act, ##ing, the, effectiveness, of, va, ##gal, activity, without, in, ##voking, an, intrinsic, dependency, of, hr, ##v, on, heart, period, ., ko, ##za, ##sa, et, al, ., (, 2018, ), also, provide, direct, support, for, the, relative, angle, scenario, of, figure, 5, ##b, ., in, isolated, pace, ##maker, cells, ,, the, basal, dia, ##sto, ##lic, de, ##pol, ##ari, ##zation, rate, in, hc, ##n, ##4, knock, ##down, mice, was, much, slower, than, in, the, wild, type, animals, (, ko, ##za, ##sa, et, al, ., ,, 2018, ,, their, figure, d, ,, p, ., 82, ##1, ), ., when, exposed, to, increasing, concentrations, of, ac, ##h, [, 0, to, 30, nm, ##ol, ], ,, the, additional, decrease, in, the, de, ##pol, ##ari, ##zation, rate, induced, by, the, same, dose, of, ac, ##h, was, much, lower, in, the, hc, ##n, ##4, knock, ##down, (, ~, 35, mv, /, s, ), than, in, the, wild, type, mice, (, ~, 80, mv, /, s, ), .'},\n", + " {'article_id': '992bfa0b2a3e7bd521e302775dfc0ea8',\n", + " 'section_name': 'Tubulinergic nervous system',\n", + " 'text': 'The tubulinergic nervous system in Echinoderes reveals a circumpharyngeal brain with several longitudinal neurite bundles originating from the neuropil (np) and extending along the introvert and trunk (Fig. 3). The neuropil includes a condensed set of parallel neurites forming a ring measuring 15–20 μm in diameter (Figs. 2b-c, 3a-c, 5b-c, e-e’, 6a and 7a; Additional file 1), which is constricted on the ventral side (Figs. 2b, 3b and 5b-c). From the anterior end of the neuropil, ten radially arranged longitudinal neurite bundles (lnb) extend anteriorly along the introvert, bend toward the body wall and then extend posteriorly along the trunk (Figs. 2b, 3a-c and 7a). At the level of the first trunk segment, eight of those neurite bundles fuse in pairs to form two subdorsal (sdn) and two ventrolateral nerves (vln) (Figs. 2c-d, 3 and 4a). The ventrolateral nerves extend to segment 9 (Figs. 2a and 3a-b). The subdorsal nerves also extend to segment 9 where they converge into a putative ganglion on the dorsal midline (Figs. 2h, 3a and 6a). From there, two neurites extend from that junction to innervate segments 10–11 (Figs. 2f-h, 3a-b and g). Two additional subdorsal neurites, most likely associated with the gonads (gn) extend posteriorly from within segment 6 and converge with the longitudinal dorsal nerves in segment 9 (Figs. 2h, 3a and 7a).Fig. 3Schematic representation of acetylated α-tubulin-LIR in Echinoderes. Only conserved traits across species are represented. For clarity, innervation and external arrangements of species-specific cuticular characters and head scalids have been omitted. Anterior is up in (a-b), dorsal is up in (c-g). a-b Overview of tubulinergic elements of the nervous system in (a) dorsal and (b) ventral views. Arrowheads in (b) mark the anterior-posterior axial positions of cross-section schematics in (c-g). c Introvert. Note the outer ring has 10 radially arranged longitudinal neurite bundles (× 10), the middle ring corresponds with the neuropil, and the inner ring shows 9 oral styles neurites (× 9), without the middorsal neurite (see legend). d Neck. e Segment 1 (arrows mark convergent longitudinal bundles). The two ventral bundles with black dots in (c-e) mark the unfused condition of the ventral nerve cord. f Segments 3–7. g Segment 8. Abbreviations: gn, gonad neurite; gon, gonopore neurite; lnb, longitudinal neurite bundle; ltasn, lateral terminal accessory spine neurite; mcnr, mouth cone nerve ring; ncn, neck circular neurite; nen, nephridial neurite; np, neuropil; osn, oral styles neurite; sdn, subdorsal longitudinal nerve; s1–11, trunk segment number; tn, transverse neurite; tsn, terminal spine neurite; vln, ventrolateral nerve; vnc, ventral nerve cord; vncn, ventral nerve cord neuriteFig. 4Predicted correlations between internal acetylated α-tubulin-LIR and external cuticular structures in Echinoderes. Anterior is up in all panels. Specimen silhouettes with dashed squares indicate the axial region of each z-stack. Color legend applies to all panels. Confocal z-stack projections and SEM micrographs were obtained from different specimens. a-j\\nEchinoderes ohtsukai. k-p\\nEchinoderes horni. a Confocal z-stack of segments 1–3 in lateral view co-labeled for acTub-LIR (acTub) and DNA. b SEM micrograph showing a pair of sensory spots in segment 1 that correspond to the upper boxed area in (d). The upper pair of dashed arrows in (a) correspond to innervation of the sensory spots in (b). c SEM micrograph showing a pair of sensory spots in segment 2 corresponding to the lower boxed area in (d). Lower pair of dashed arrows in (a) correspond to innervation of the sensory spots in (c). g confocal z-stack of segments 6–11 in ventral view co-labeled for acTub-LIR and DNA. e SEM micrograph of a midventral sensory spot corresponding to innervation (dashed arrow) in (g). f SEM of a lateroventral fringed tube from segment 7 corresponding to innervation in (g). h SEM of a lateroventral acicular spine and its innervation in (g). i SEM of a sieve plate on segment 9 and innervation in (g). j SEM of segments 8–11 in ventral view showing the position of the sieve plate (boxed area) magnified in (i). k Confocal z-stack of acTub-LIR within segment 7 in ventral view. l SEM of a ventromedial sensory spot and its corresponding innervation in (k). m SEM of the ventral side of segment 7 showing the relative position (boxed area) of the sensory spot in (l). n Confocal z-stack of acTub-LIR within segments 9–11 in ventral view. o SEM of sensory spots from segment 11 and their correlation with innervation in (n). p SEM of segments 9–11 in ventral view showing the sensory spots (boxed areas) magnified in (o). Scale bars: 20 μm in (a, d, n), 10 μm in (b, c, g, k, j, m, p), 2 μm in (e, f, h, i, o). Abbreviations: lnb, longitudinal neurite bundle; lvs, lateroventral spine; ncn, neck circular neurite; nen, nephridial neurite; s, segment; sdn, subdorsal longitudinal nerve; sn, spine neurite; sp., sieve plate; spn, ss, sensory spot; ssn, sensory spot neurite; tbn, tube neurite; tn, transverse neurite; tsn, terminal spine neurite; vnc, ventral nerve cord. Numbers after abbreviations refer to segment number',\n", + " 'paragraph_id': 7,\n", + " 'tokenizer': 'the, tub, ##ulin, ##er, ##gic, nervous, system, in, ec, ##hin, ##oder, ##es, reveals, a, ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, brain, with, several, longitudinal, ne, ##uri, ##te, bundles, originating, from, the, ne, ##uro, ##pi, ##l, (, np, ), and, extending, along, the, intro, ##vert, and, trunk, (, fig, ., 3, ), ., the, ne, ##uro, ##pi, ##l, includes, a, condensed, set, of, parallel, ne, ##uri, ##tes, forming, a, ring, measuring, 15, –, 20, μ, ##m, in, diameter, (, fig, ##s, ., 2, ##b, -, c, ,, 3a, -, c, ,, 5, ##b, -, c, ,, e, -, e, ’, ,, 6, ##a, and, 7, ##a, ;, additional, file, 1, ), ,, which, is, con, ##st, ##ricted, on, the, ventral, side, (, fig, ##s, ., 2, ##b, ,, 3, ##b, and, 5, ##b, -, c, ), ., from, the, anterior, end, of, the, ne, ##uro, ##pi, ##l, ,, ten, radial, ##ly, arranged, longitudinal, ne, ##uri, ##te, bundles, (, l, ##nb, ), extend, anterior, ##ly, along, the, intro, ##vert, ,, bend, toward, the, body, wall, and, then, extend, posterior, ##ly, along, the, trunk, (, fig, ##s, ., 2, ##b, ,, 3a, -, c, and, 7, ##a, ), ., at, the, level, of, the, first, trunk, segment, ,, eight, of, those, ne, ##uri, ##te, bundles, fuse, in, pairs, to, form, two, sub, ##dor, ##sal, (, sd, ##n, ), and, two, vent, ##rol, ##ater, ##al, nerves, (, v, ##ln, ), (, fig, ##s, ., 2, ##c, -, d, ,, 3, and, 4a, ), ., the, vent, ##rol, ##ater, ##al, nerves, extend, to, segment, 9, (, fig, ##s, ., 2a, and, 3a, -, b, ), ., the, sub, ##dor, ##sal, nerves, also, extend, to, segment, 9, where, they, converge, into, a, put, ##ative, gang, ##lion, on, the, dorsal, mid, ##line, (, fig, ##s, ., 2, ##h, ,, 3a, and, 6, ##a, ), ., from, there, ,, two, ne, ##uri, ##tes, extend, from, that, junction, to, inner, ##vate, segments, 10, –, 11, (, fig, ##s, ., 2, ##f, -, h, ,, 3a, -, b, and, g, ), ., two, additional, sub, ##dor, ##sal, ne, ##uri, ##tes, ,, most, likely, associated, with, the, go, ##nad, ##s, (, g, ##n, ), extend, posterior, ##ly, from, within, segment, 6, and, converge, with, the, longitudinal, dorsal, nerves, in, segment, 9, (, fig, ##s, ., 2, ##h, ,, 3a, and, 7, ##a, ), ., fig, ., 3, ##sche, ##matic, representation, of, ace, ##ty, ##lated, α, -, tub, ##ulin, -, li, ##r, in, ec, ##hin, ##oder, ##es, ., only, conserved, traits, across, species, are, represented, ., for, clarity, ,, inner, ##vation, and, external, arrangements, of, species, -, specific, cut, ##icular, characters, and, head, sc, ##ali, ##ds, have, been, omitted, ., anterior, is, up, in, (, a, -, b, ), ,, dorsal, is, up, in, (, c, -, g, ), ., a, -, b, overview, of, tub, ##ulin, ##er, ##gic, elements, of, the, nervous, system, in, (, a, ), dorsal, and, (, b, ), ventral, views, ., arrow, ##heads, in, (, b, ), mark, the, anterior, -, posterior, axial, positions, of, cross, -, section, sc, ##hema, ##tics, in, (, c, -, g, ), ., c, intro, ##vert, ., note, the, outer, ring, has, 10, radial, ##ly, arranged, longitudinal, ne, ##uri, ##te, bundles, (, ×, 10, ), ,, the, middle, ring, corresponds, with, the, ne, ##uro, ##pi, ##l, ,, and, the, inner, ring, shows, 9, oral, styles, ne, ##uri, ##tes, (, ×, 9, ), ,, without, the, mid, ##dor, ##sal, ne, ##uri, ##te, (, see, legend, ), ., d, neck, ., e, segment, 1, (, arrows, mark, converge, ##nt, longitudinal, bundles, ), ., the, two, ventral, bundles, with, black, dots, in, (, c, -, e, ), mark, the, un, ##fus, ##ed, condition, of, the, ventral, nerve, cord, ., f, segments, 3, –, 7, ., g, segment, 8, ., abbreviation, ##s, :, g, ##n, ,, go, ##nad, ne, ##uri, ##te, ;, go, ##n, ,, go, ##no, ##pore, ne, ##uri, ##te, ;, l, ##nb, ,, longitudinal, ne, ##uri, ##te, bundle, ;, lt, ##as, ##n, ,, lateral, terminal, accessory, spine, ne, ##uri, ##te, ;, mc, ##nr, ,, mouth, cone, nerve, ring, ;, nc, ##n, ,, neck, circular, ne, ##uri, ##te, ;, ne, ##n, ,, ne, ##ph, ##rid, ##ial, ne, ##uri, ##te, ;, np, ,, ne, ##uro, ##pi, ##l, ;, os, ##n, ,, oral, styles, ne, ##uri, ##te, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, s, ##1, –, 11, ,, trunk, segment, number, ;, tn, ,, transverse, ne, ##uri, ##te, ;, ts, ##n, ,, terminal, spine, ne, ##uri, ##te, ;, v, ##ln, ,, vent, ##rol, ##ater, ##al, nerve, ;, v, ##nc, ,, ventral, nerve, cord, ;, v, ##nc, ##n, ,, ventral, nerve, cord, ne, ##uri, ##te, ##fi, ##g, ., 4, ##pre, ##dict, ##ed, correlation, ##s, between, internal, ace, ##ty, ##lated, α, -, tub, ##ulin, -, li, ##r, and, external, cut, ##icular, structures, in, ec, ##hin, ##oder, ##es, ., anterior, is, up, in, all, panels, ., specimen, silhouette, ##s, with, dashed, squares, indicate, the, axial, region, of, each, z, -, stack, ., color, legend, applies, to, all, panels, ., con, ##fo, ##cal, z, -, stack, projections, and, se, ##m, micro, ##graphs, were, obtained, from, different, specimens, ., a, -, j, ec, ##hin, ##oder, ##es, oh, ##tsu, ##kai, ., k, -, p, ec, ##hin, ##oder, ##es, horn, ##i, ., a, con, ##fo, ##cal, z, -, stack, of, segments, 1, –, 3, in, lateral, view, co, -, labeled, for, act, ##ub, -, li, ##r, (, act, ##ub, ), and, dna, ., b, se, ##m, micro, ##graph, showing, a, pair, of, sensory, spots, in, segment, 1, that, correspond, to, the, upper, boxed, area, in, (, d, ), ., the, upper, pair, of, dashed, arrows, in, (, a, ), correspond, to, inner, ##vation, of, the, sensory, spots, in, (, b, ), ., c, se, ##m, micro, ##graph, showing, a, pair, of, sensory, spots, in, segment, 2, corresponding, to, the, lower, boxed, area, in, (, d, ), ., lower, pair, of, dashed, arrows, in, (, a, ), correspond, to, inner, ##vation, of, the, sensory, spots, in, (, c, ), ., g, con, ##fo, ##cal, z, -, stack, of, segments, 6, –, 11, in, ventral, view, co, -, labeled, for, act, ##ub, -, li, ##r, and, dna, ., e, se, ##m, micro, ##graph, of, a, mid, ##vent, ##ral, sensory, spot, corresponding, to, inner, ##vation, (, dashed, arrow, ), in, (, g, ), ., f, se, ##m, of, a, later, ##oven, ##tral, fringe, ##d, tube, from, segment, 7, corresponding, to, inner, ##vation, in, (, g, ), ., h, se, ##m, of, a, later, ##oven, ##tral, ac, ##icular, spine, and, its, inner, ##vation, in, (, g, ), ., i, se, ##m, of, a, si, ##eve, plate, on, segment, 9, and, inner, ##vation, in, (, g, ), ., j, se, ##m, of, segments, 8, –, 11, in, ventral, view, showing, the, position, of, the, si, ##eve, plate, (, boxed, area, ), mag, ##nified, in, (, i, ), ., k, con, ##fo, ##cal, z, -, stack, of, act, ##ub, -, li, ##r, within, segment, 7, in, ventral, view, ., l, se, ##m, of, a, vent, ##rom, ##ed, ##ial, sensory, spot, and, its, corresponding, inner, ##vation, in, (, k, ), ., m, se, ##m, of, the, ventral, side, of, segment, 7, showing, the, relative, position, (, boxed, area, ), of, the, sensory, spot, in, (, l, ), ., n, con, ##fo, ##cal, z, -, stack, of, act, ##ub, -, li, ##r, within, segments, 9, –, 11, in, ventral, view, ., o, se, ##m, of, sensory, spots, from, segment, 11, and, their, correlation, with, inner, ##vation, in, (, n, ), ., p, se, ##m, of, segments, 9, –, 11, in, ventral, view, showing, the, sensory, spots, (, boxed, areas, ), mag, ##nified, in, (, o, ), ., scale, bars, :, 20, μ, ##m, in, (, a, ,, d, ,, n, ), ,, 10, μ, ##m, in, (, b, ,, c, ,, g, ,, k, ,, j, ,, m, ,, p, ), ,, 2, μ, ##m, in, (, e, ,, f, ,, h, ,, i, ,, o, ), ., abbreviation, ##s, :, l, ##nb, ,, longitudinal, ne, ##uri, ##te, bundle, ;, l, ##vs, ,, later, ##oven, ##tral, spine, ;, nc, ##n, ,, neck, circular, ne, ##uri, ##te, ;, ne, ##n, ,, ne, ##ph, ##rid, ##ial, ne, ##uri, ##te, ;, s, ,, segment, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, s, ##n, ,, spine, ne, ##uri, ##te, ;, sp, ., ,, si, ##eve, plate, ;, sp, ##n, ,, ss, ,, sensory, spot, ;, ss, ##n, ,, sensory, spot, ne, ##uri, ##te, ;, tb, ##n, ,, tube, ne, ##uri, ##te, ;, tn, ,, transverse, ne, ##uri, ##te, ;, ts, ##n, ,, terminal, spine, ne, ##uri, ##te, ;, v, ##nc, ,, ventral, nerve, cord, ., numbers, after, abbreviation, ##s, refer, to, segment, number'},\n", + " {'article_id': '992bfa0b2a3e7bd521e302775dfc0ea8',\n", + " 'section_name': 'Comparative neuroanatomy in Kinorhyncha',\n", + " 'text': 'Prior to our investigation, only two studies of kinorhynch nervous systems using immunohistochemistry and confocal microscopy have been performed, and only with a small number of species: Echinoderes spinifurca, Antygomonas paulae Sørensen, 2007, Zelinkaderes brightae Sørensen, 2007 and Setaphyes kielensis (Zelinka, 1928) (summarized in Table 1) [28, 29]. The serotoninergic nervous system was investigated in all these species and tubulin-like immunoreactivity (Tub-LIR) was also characterized in S. kielensis (Pycnophyes kielensis in Altenburger 2016 [28]). The pattern of Tub-LIR in S. kielensis is similar to what we observed in Echinoderes, which included a ring-like neuropil, a ganglionated ventral nerve cord composed of two anterior longitudinal neurite bundles that bifurcate in the posterior end, and transverse peripheral neurites emerging from the ventral nerve cord within at least four trunk segments [28]. Our study represents the first successful experiments with FMRF-LIR in Kinorhyncha; therefore, additional studies using this neural marker on other species are needed for a broader comparative framework. Serotonin- \\\\LIR has revealed a similar architecture in the brain and ventral nerve cord in all species studied so far [28, 29]. The observed variation among genera consisted of the number of neuropil rings (2 in Setaphyes; 4 in Antygomonas, Echinoderes and Zelinkaderes) and the number of neurons associated with the neuropil [28, 29]. Additionally, the posterior end of the serotonergic ventral nerve cord forms either a ring-like structure in species with a midterminal spine (Antygomonas and Zelinkaderes) or an inverted Y-like bifurcation in species without a midterminal spine (Echinoderes and Setaphyes) [29]. As suggested above, there appears to be important correlations between neural organization and species-specific cuticular structures (e.g. terminal spines) situated at the posterior end of kinorhynchs. In the case of 5HT-LIR, we find evidence for potential links between terminal anatomy of the ventral nerve cord and functional morphology of appendage-like characters in mud dragons.Table 1Comparison of nervous system architecture within Kinorhyncha. Abbreviations: np, neuropil; ios, inner oral styles; oos, outer oral styles; so, somata; ss, sensory spots; vnc, ventral nerve cord. Question marks represent absence of dataSpeciesData sourceBrainNumber of longitudinal nervesTransverse neurites (commissures)VncInnervation of introvert scalidsInnervation mouth coneInnervation of neckInnervation of trunk cuticular structuresReferencesA. paulaeCLSMCircumpharyngeal with 3 regions(So-Np-So)??Paired origin of vnc?Serotonin positive nerve ring??[29]E. capitatusTEMCircumpharyngeal with 3 regions(So-Np-So)Ten lobbed anterior somata10 fusing into 5(2 subdorsal, 2 ventrolateral and 1 vnc)2 per trunk segmentPaired origin of vncSingle ganglion per segmentNeurites from the 10 longitudinal nerves9 nerves innervating the oos from the “hindbrain” fusing into 5 nerves innervating iosProximal and terminal nerve ring10 longitudinal nervesSpines, tubes (named “setae”) and ss innervated from the 5 longitudinal nerves of the trunk[24, 25, 38]E. aquiloniusTEMCircumpharyngeal with 3 regions(So-Np-So)8“Circular nerve fibers” in each segmentPaired origin of vncDouble ganglia per segmentNeurites from the anterior perikarya of the brain10 nerves innervating the oos from the \"forebrain\"Proximal and terminal nerve ringNeurites from the longitudinal nervesSpines, ss, tubes innervated from the middorsal, laterodorsal and ventrolateral cords[26]E. horni\\n\\nE. spinifurca\\n\\nE. ohtsukaiCLSMCircumpharyngeal with 3 regions(So-Np-So)Ten lobbed anterior somata10 fusing into 5 (2 subdorsal, 2 ventrolateral and 1 vnc)2 per trunk segment (except for segments 1, 10-11)Paired origin of vncSingle ganglion per segmentRadially arranged neurites arising from the neuropil9 nerves innervating the oos arising from the neuropilAnterior nerve ring10 longitudinal nerves + 2 circularneuritesSpines, ss, tubes, and nephridia innervated from transverse neuritesTerminal spines innervated from longitudinal neurites from the vncPresent study, [29]P. greenlandicusTEMCircumpharyngeal with 3 regions(So-Np-So)8“Circular nerve fibers” in each segmentPaired origin of vncDouble ganglia per segmentNeurites from the anterior perikarya of the brain10 nerves innervating the oos from the \"forebrain\"Proximal and terminal nerve ringNeurites from the longitudinal nervesSpines, ss, tubes innervated from the longitudinal cords[26, 48]P. dentatusTEMCircumpharyngeal with 3 regions(So-Np-So)7?Paired origin of vnc (only illustrated)?9 nerves innervating the oos from the posterior brain region??[34, 49]S. kielensisTEM, CLSMCircumpharyngeal with 3 regions(So-Np-So)8 (TEM)At least one “nerve” per segment (CLSM)Paired origin of vnc (only illustrated) (TEM)1 ganglion per segment (TEM)/ 1 ganglion in vnc segment 6 (CLSM)?9 nerves innervating the oos (TEM)??[28, 48]Z. brightaeCLSMCircumpharyngeal with 3 regions(So-Np-So)??Paired origin of vnc?Serotonin positive nerve ring??[29]Z. floridensisTEMCircumpharyngeal with 3 regions(So-Np-So)12???9 nerves innervating the oos??[49]',\n", + " 'paragraph_id': 30,\n", + " 'tokenizer': 'prior, to, our, investigation, ,, only, two, studies, of, kin, ##or, ##hy, ##nch, nervous, systems, using, im, ##mun, ##oh, ##isto, ##chemist, ##ry, and, con, ##fo, ##cal, microscopy, have, been, performed, ,, and, only, with, a, small, number, of, species, :, ec, ##hin, ##oder, ##es, spin, ##if, ##ur, ##ca, ,, ant, ##y, ##go, ##mona, ##s, paula, ##e, s, ##ø, ##ren, ##sen, ,, 2007, ,, ze, ##link, ##ade, ##res, bright, ##ae, s, ##ø, ##ren, ##sen, ,, 2007, and, set, ##ap, ##hy, ##es, kiel, ##ensis, (, ze, ##link, ##a, ,, 1928, ), (, summarized, in, table, 1, ), [, 28, ,, 29, ], ., the, ser, ##oton, ##iner, ##gic, nervous, system, was, investigated, in, all, these, species, and, tub, ##ulin, -, like, im, ##mun, ##ore, ##act, ##ivity, (, tub, -, li, ##r, ), was, also, characterized, in, s, ., kiel, ##ensis, (, p, ##y, ##c, ##no, ##phy, ##es, kiel, ##ensis, in, alt, ##enburg, ##er, 2016, [, 28, ], ), ., the, pattern, of, tub, -, li, ##r, in, s, ., kiel, ##ensis, is, similar, to, what, we, observed, in, ec, ##hin, ##oder, ##es, ,, which, included, a, ring, -, like, ne, ##uro, ##pi, ##l, ,, a, gang, ##lion, ##ated, ventral, nerve, cord, composed, of, two, anterior, longitudinal, ne, ##uri, ##te, bundles, that, bi, ##fur, ##cate, in, the, posterior, end, ,, and, transverse, peripheral, ne, ##uri, ##tes, emerging, from, the, ventral, nerve, cord, within, at, least, four, trunk, segments, [, 28, ], ., our, study, represents, the, first, successful, experiments, with, fm, ##rf, -, li, ##r, in, kin, ##or, ##hy, ##nch, ##a, ;, therefore, ,, additional, studies, using, this, neural, marker, on, other, species, are, needed, for, a, broader, comparative, framework, ., ser, ##oton, ##in, -, \\\\, li, ##r, has, revealed, a, similar, architecture, in, the, brain, and, ventral, nerve, cord, in, all, species, studied, so, far, [, 28, ,, 29, ], ., the, observed, variation, among, genera, consisted, of, the, number, of, ne, ##uro, ##pi, ##l, rings, (, 2, in, set, ##ap, ##hy, ##es, ;, 4, in, ant, ##y, ##go, ##mona, ##s, ,, ec, ##hin, ##oder, ##es, and, ze, ##link, ##ade, ##res, ), and, the, number, of, neurons, associated, with, the, ne, ##uro, ##pi, ##l, [, 28, ,, 29, ], ., additionally, ,, the, posterior, end, of, the, ser, ##oton, ##er, ##gic, ventral, nerve, cord, forms, either, a, ring, -, like, structure, in, species, with, a, mid, ##ter, ##mina, ##l, spine, (, ant, ##y, ##go, ##mona, ##s, and, ze, ##link, ##ade, ##res, ), or, an, inverted, y, -, like, bi, ##fur, ##cation, in, species, without, a, mid, ##ter, ##mina, ##l, spine, (, ec, ##hin, ##oder, ##es, and, set, ##ap, ##hy, ##es, ), [, 29, ], ., as, suggested, above, ,, there, appears, to, be, important, correlation, ##s, between, neural, organization, and, species, -, specific, cut, ##icular, structures, (, e, ., g, ., terminal, spines, ), situated, at, the, posterior, end, of, kin, ##or, ##hy, ##nch, ##s, ., in, the, case, of, 5, ##ht, -, li, ##r, ,, we, find, evidence, for, potential, links, between, terminal, anatomy, of, the, ventral, nerve, cord, and, functional, morphology, of, app, ##end, ##age, -, like, characters, in, mud, dragons, ., table, 1, ##com, ##par, ##ison, of, nervous, system, architecture, within, kin, ##or, ##hy, ##nch, ##a, ., abbreviation, ##s, :, np, ,, ne, ##uro, ##pi, ##l, ;, ios, ,, inner, oral, styles, ;, o, ##os, ,, outer, oral, styles, ;, so, ,, so, ##mata, ;, ss, ,, sensory, spots, ;, v, ##nc, ,, ventral, nerve, cord, ., question, marks, represent, absence, of, data, ##sp, ##ec, ##ies, ##da, ##ta, source, ##bra, ##inn, ##umber, of, longitudinal, nerves, ##tra, ##ns, ##verse, ne, ##uri, ##tes, (, com, ##mis, ##sure, ##s, ), v, ##nc, ##inn, ##er, ##vation, of, intro, ##vert, sc, ##ali, ##ds, ##inn, ##er, ##vation, mouth, cone, ##inn, ##er, ##vation, of, neck, ##inn, ##er, ##vation, of, trunk, cut, ##icular, structures, ##re, ##ference, ##sa, ., paula, ##ec, ##ls, ##mc, ##ir, ##cum, ##pha, ##ryn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ?, ?, paired, origin, of, v, ##nc, ?, ser, ##oton, ##in, positive, nerve, ring, ?, ?, [, 29, ], e, ., capita, ##tus, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ten, lo, ##bbed, anterior, so, ##mata, ##10, fu, ##sing, into, 5, (, 2, sub, ##dor, ##sal, ,, 2, vent, ##rol, ##ater, ##al, and, 1, v, ##nc, ), 2, per, trunk, segment, ##pa, ##ired, origin, of, v, ##nc, ##sing, ##le, gang, ##lion, per, segment, ##ne, ##uri, ##tes, from, the, 10, longitudinal, nerves, ##9, nerves, inner, ##vating, the, o, ##os, from, the, “, hind, ##bra, ##in, ”, fu, ##sing, into, 5, nerves, inner, ##vating, ios, ##pro, ##xi, ##mal, and, terminal, nerve, ring, ##10, longitudinal, nerves, ##sp, ##ines, ,, tubes, (, named, “, set, ##ae, ”, ), and, ss, inner, ##vate, ##d, from, the, 5, longitudinal, nerves, of, the, trunk, [, 24, ,, 25, ,, 38, ], e, ., a, ##quil, ##oni, ##ust, ##em, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 8, “, circular, nerve, fibers, ”, in, each, segment, ##pa, ##ired, origin, of, v, ##nc, ##dou, ##ble, gang, ##lia, per, segment, ##ne, ##uri, ##tes, from, the, anterior, per, ##ika, ##rya, of, the, brain, ##10, nerves, inner, ##vating, the, o, ##os, from, the, \", fore, ##bra, ##in, \", pro, ##xi, ##mal, and, terminal, nerve, ring, ##ne, ##uri, ##tes, from, the, longitudinal, nerves, ##sp, ##ines, ,, ss, ,, tubes, inner, ##vate, ##d, from, the, mid, ##dor, ##sal, ,, later, ##od, ##ors, ##al, and, vent, ##rol, ##ater, ##al, cords, [, 26, ], e, ., horn, ##i, e, ., spin, ##if, ##ur, ##ca, e, ., oh, ##tsu, ##kai, ##cl, ##sm, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ten, lo, ##bbed, anterior, so, ##mata, ##10, fu, ##sing, into, 5, (, 2, sub, ##dor, ##sal, ,, 2, vent, ##rol, ##ater, ##al, and, 1, v, ##nc, ), 2, per, trunk, segment, (, except, for, segments, 1, ,, 10, -, 11, ), paired, origin, of, v, ##nc, ##sing, ##le, gang, ##lion, per, segment, ##rad, ##ial, ##ly, arranged, ne, ##uri, ##tes, arising, from, the, ne, ##uro, ##pi, ##l, ##9, nerves, inner, ##vating, the, o, ##os, arising, from, the, ne, ##uro, ##pi, ##lan, ##ter, ##ior, nerve, ring, ##10, longitudinal, nerves, +, 2, circular, ##ne, ##uri, ##tes, ##sp, ##ines, ,, ss, ,, tubes, ,, and, ne, ##ph, ##rid, ##ia, inner, ##vate, ##d, from, transverse, ne, ##uri, ##test, ##er, ##mina, ##l, spines, inner, ##vate, ##d, from, longitudinal, ne, ##uri, ##tes, from, the, v, ##nc, ##pres, ##ent, study, ,, [, 29, ], p, ., greenland, ##icus, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 8, “, circular, nerve, fibers, ”, in, each, segment, ##pa, ##ired, origin, of, v, ##nc, ##dou, ##ble, gang, ##lia, per, segment, ##ne, ##uri, ##tes, from, the, anterior, per, ##ika, ##rya, of, the, brain, ##10, nerves, inner, ##vating, the, o, ##os, from, the, \", fore, ##bra, ##in, \", pro, ##xi, ##mal, and, terminal, nerve, ring, ##ne, ##uri, ##tes, from, the, longitudinal, nerves, ##sp, ##ines, ,, ss, ,, tubes, inner, ##vate, ##d, from, the, longitudinal, cords, [, 26, ,, 48, ], p, ., dent, ##atus, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 7, ?, paired, origin, of, v, ##nc, (, only, illustrated, ), ?, 9, nerves, inner, ##vating, the, o, ##os, from, the, posterior, brain, region, ?, ?, [, 34, ,, 49, ], s, ., kiel, ##ensis, ##tem, ,, cl, ##sm, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 8, (, te, ##m, ), at, least, one, “, nerve, ”, per, segment, (, cl, ##sm, ), paired, origin, of, v, ##nc, (, only, illustrated, ), (, te, ##m, ), 1, gang, ##lion, per, segment, (, te, ##m, ), /, 1, gang, ##lion, in, v, ##nc, segment, 6, (, cl, ##sm, ), ?, 9, nerves, inner, ##vating, the, o, ##os, (, te, ##m, ), ?, ?, [, 28, ,, 48, ], z, ., bright, ##ae, ##cl, ##sm, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ?, ?, paired, origin, of, v, ##nc, ?, ser, ##oton, ##in, positive, nerve, ring, ?, ?, [, 29, ], z, ., fl, ##ori, ##den, ##sis, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 12, ?, ?, ?, 9, nerves, inner, ##vating, the, o, ##os, ?, ?, [, 49, ]'},\n", + " {'article_id': '992bfa0b2a3e7bd521e302775dfc0ea8',\n", + " 'section_name': 'FMRFamidergic nervous system',\n", + " 'text': 'Within the brain, FMRF-LIR is localized primarily in the neuropil, and in a combination of at least six or more perikarya and associated neurites within the anterior brain region (Figs. 6b-e, g, h and 7c-c’). FMRF-LIR in the neuropil reveals a broad series of dorsal rings that narrow midventrally along the anterior-posterior axis (Fig. 6h). The associated perikarya extend neurites to dorsal, lateral and ventrolateral locations along the anterior side of the neuropil (Fig. 6c, e, h). All of these anterior perikarya are similar in size, with the exception of a comparatively larger pair of bipolar cells (bpc) that are located at midlateral positions along the brain (Fig. 6b, c, h also indicated with arrowheads). Compared with other cell bodies showing FMRF-LIR, the two bipolar cells are positioned more distally from the neuropil, closer to the base of the introvert scalids, with each cell extending one neurite anteriorly that innervates the first spinoscalids of the introvert (Figs. 6b and 7c-c’). FMRF-LIR was also detected as a thin ring within the basal part of the mouth cone (mcnr) (Figs. 6h and 7c-c’), which appears to correlate with the positions of mouth-cone nerve rings showing acTub-LIR and 5HT-LIR. The two convergent neurites (cne) that extend from the neuropil toward their connections with the ventral nerve cord also showed FMRF-LIR.Fig. 6FMRF-LIR in the nervous system of Echinoderes. Confocal z-stack projections co-labeled for FMRF-LIR (b-e, g-h), acTub-LIR (a, f) and/or DNA (a-b, f-g). Anterior is to the top in (a-b, e-h); dorsal is to the top in (c-d). Specimen silhouettes with dashed squares indicate the axial region of each z-stack. Color legend applies to all panels. a-d\\nEchinoderes spinifurca. e-h\\nEchinoderes horni. a-b Segments 1–9 in dorsal views with head retracted. FMRF-LIR is detected in the neuropil and several somata associated with the anterior end of the brain and introvert. FMRF-LIR is correlated with acTub-LIR within subdorsal nerves (a). c-d Anterior views of cross sections through the brain corresponding to axial positions (c and d) in (b). c multiple FMRF^+ somata (asterisks, arrowheads) anterior to the neuropil. d FMRF^+ ring-like neuropil and ventral nerve cord. The outer contour in c and d is cuticular autofluorescence. e Dorsal view of FMRF-LIR in the neuropil and associated somata (asterisks). f-g Segments 4–8 in ventral view of the same specimen showing acTub-LIR (f) and FMRF-LIR (g) along the ganglionated ventral nerve cord. h Segments 1–4 in ventral view with head retracted showing FMRF-LIR within the neuropil and associated somata (asterisks). Arrowheads mark the position of FMRF^+ bipolar somata. Note the pair of FMRF^+ somata (vncs) in segment 4 along the ventral nerve cord. Scale bars, 20 μm in all panels. Abbreviations: aso, anterior somata; bpc, FMRF^+ bipolar cells; mcnr, mouth cone nerve ring; mdg, middorsal ganglion; np, neuropil; psn, primary spinoscalid neurite; pso, posterior somata; s1–9, segments 1–9; sdn, subdorsal longitudinal nerve; vnc, ventral nerve cord; vncg, ventral nerve cord ganglion; vncs, ventral nerve cord FMRF^+ somataFig. 7Schematic representations of acetylated α-tubulin-LIR, Serotonin-LIR and FMRF-LIR in Echinoderes. a-c Lateral overviews with the head extended. a’-c’ Ventral views of the head. Anterior is to the top in all panels. b-c’ 5HT-LIR and FMRF-LIR are overlaid upon a background of acTub-LIR (gray). The number of 5HT^+ and FMRF^+ somata (vncs) along the ventral nerve cord (b, c) varies among specimens and are representative here. Note the approximate orientations and arrangements of 5HT^+ ventromedial somata (b’) and FMRF^+ bipolar cells (c’) relative to neural rings of the neuropil. Abbreviations: bpc, FMRF^+ bipolar cells; cne, convergent neurites; cnr, complete neural ring; gn, gonad neurite; inr, incomplete neural ring; lnb, longitudinal neurite bundle; mcnr, mouth cone nerve ring; mdsn, middorsal spine neurite; ncn, neck circular neurite; nen, nephridial neurite; np, neuropil; pen, penile spine neurite; sdn, subdorsal longitudinal nerve; tn, transverse neurite; tsn, terminal spine neurite; vln, ventrolateral nerve; vms, 5HT^+ ventromedial somata; vnc, ventral nerve cord; vncs, ventral nerve cord FMRF^+ somata',\n", + " 'paragraph_id': 17,\n", + " 'tokenizer': 'within, the, brain, ,, fm, ##rf, -, li, ##r, is, localized, primarily, in, the, ne, ##uro, ##pi, ##l, ,, and, in, a, combination, of, at, least, six, or, more, per, ##ika, ##rya, and, associated, ne, ##uri, ##tes, within, the, anterior, brain, region, (, fig, ##s, ., 6, ##b, -, e, ,, g, ,, h, and, 7, ##c, -, c, ’, ), ., fm, ##rf, -, li, ##r, in, the, ne, ##uro, ##pi, ##l, reveals, a, broad, series, of, dorsal, rings, that, narrow, mid, ##vent, ##ral, ##ly, along, the, anterior, -, posterior, axis, (, fig, ., 6, ##h, ), ., the, associated, per, ##ika, ##rya, extend, ne, ##uri, ##tes, to, dorsal, ,, lateral, and, vent, ##rol, ##ater, ##al, locations, along, the, anterior, side, of, the, ne, ##uro, ##pi, ##l, (, fig, ., 6, ##c, ,, e, ,, h, ), ., all, of, these, anterior, per, ##ika, ##rya, are, similar, in, size, ,, with, the, exception, of, a, comparatively, larger, pair, of, bipolar, cells, (, bp, ##c, ), that, are, located, at, mid, ##lateral, positions, along, the, brain, (, fig, ., 6, ##b, ,, c, ,, h, also, indicated, with, arrow, ##heads, ), ., compared, with, other, cell, bodies, showing, fm, ##rf, -, li, ##r, ,, the, two, bipolar, cells, are, positioned, more, distal, ##ly, from, the, ne, ##uro, ##pi, ##l, ,, closer, to, the, base, of, the, intro, ##vert, sc, ##ali, ##ds, ,, with, each, cell, extending, one, ne, ##uri, ##te, anterior, ##ly, that, inner, ##vate, ##s, the, first, spin, ##os, ##cal, ##ids, of, the, intro, ##vert, (, fig, ##s, ., 6, ##b, and, 7, ##c, -, c, ’, ), ., fm, ##rf, -, li, ##r, was, also, detected, as, a, thin, ring, within, the, basal, part, of, the, mouth, cone, (, mc, ##nr, ), (, fig, ##s, ., 6, ##h, and, 7, ##c, -, c, ’, ), ,, which, appears, to, co, ##rre, ##late, with, the, positions, of, mouth, -, cone, nerve, rings, showing, act, ##ub, -, li, ##r, and, 5, ##ht, -, li, ##r, ., the, two, converge, ##nt, ne, ##uri, ##tes, (, cn, ##e, ), that, extend, from, the, ne, ##uro, ##pi, ##l, toward, their, connections, with, the, ventral, nerve, cord, also, showed, fm, ##rf, -, li, ##r, ., fig, ., 6, ##fm, ##rf, -, li, ##r, in, the, nervous, system, of, ec, ##hin, ##oder, ##es, ., con, ##fo, ##cal, z, -, stack, projections, co, -, labeled, for, fm, ##rf, -, li, ##r, (, b, -, e, ,, g, -, h, ), ,, act, ##ub, -, li, ##r, (, a, ,, f, ), and, /, or, dna, (, a, -, b, ,, f, -, g, ), ., anterior, is, to, the, top, in, (, a, -, b, ,, e, -, h, ), ;, dorsal, is, to, the, top, in, (, c, -, d, ), ., specimen, silhouette, ##s, with, dashed, squares, indicate, the, axial, region, of, each, z, -, stack, ., color, legend, applies, to, all, panels, ., a, -, d, ec, ##hin, ##oder, ##es, spin, ##if, ##ur, ##ca, ., e, -, h, ec, ##hin, ##oder, ##es, horn, ##i, ., a, -, b, segments, 1, –, 9, in, dorsal, views, with, head, retracted, ., fm, ##rf, -, li, ##r, is, detected, in, the, ne, ##uro, ##pi, ##l, and, several, so, ##mata, associated, with, the, anterior, end, of, the, brain, and, intro, ##vert, ., fm, ##rf, -, li, ##r, is, correlated, with, act, ##ub, -, li, ##r, within, sub, ##dor, ##sal, nerves, (, a, ), ., c, -, d, anterior, views, of, cross, sections, through, the, brain, corresponding, to, axial, positions, (, c, and, d, ), in, (, b, ), ., c, multiple, fm, ##rf, ^, +, so, ##mata, (, as, ##ter, ##isk, ##s, ,, arrow, ##heads, ), anterior, to, the, ne, ##uro, ##pi, ##l, ., d, fm, ##rf, ^, +, ring, -, like, ne, ##uro, ##pi, ##l, and, ventral, nerve, cord, ., the, outer, con, ##tour, in, c, and, d, is, cut, ##icular, auto, ##fl, ##uo, ##res, ##cence, ., e, dorsal, view, of, fm, ##rf, -, li, ##r, in, the, ne, ##uro, ##pi, ##l, and, associated, so, ##mata, (, as, ##ter, ##isk, ##s, ), ., f, -, g, segments, 4, –, 8, in, ventral, view, of, the, same, specimen, showing, act, ##ub, -, li, ##r, (, f, ), and, fm, ##rf, -, li, ##r, (, g, ), along, the, gang, ##lion, ##ated, ventral, nerve, cord, ., h, segments, 1, –, 4, in, ventral, view, with, head, retracted, showing, fm, ##rf, -, li, ##r, within, the, ne, ##uro, ##pi, ##l, and, associated, so, ##mata, (, as, ##ter, ##isk, ##s, ), ., arrow, ##heads, mark, the, position, of, fm, ##rf, ^, +, bipolar, so, ##mata, ., note, the, pair, of, fm, ##rf, ^, +, so, ##mata, (, v, ##nc, ##s, ), in, segment, 4, along, the, ventral, nerve, cord, ., scale, bars, ,, 20, μ, ##m, in, all, panels, ., abbreviation, ##s, :, as, ##o, ,, anterior, so, ##mata, ;, bp, ##c, ,, fm, ##rf, ^, +, bipolar, cells, ;, mc, ##nr, ,, mouth, cone, nerve, ring, ;, md, ##g, ,, mid, ##dor, ##sal, gang, ##lion, ;, np, ,, ne, ##uro, ##pi, ##l, ;, ps, ##n, ,, primary, spin, ##os, ##cal, ##id, ne, ##uri, ##te, ;, ps, ##o, ,, posterior, so, ##mata, ;, s, ##1, –, 9, ,, segments, 1, –, 9, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, v, ##nc, ,, ventral, nerve, cord, ;, v, ##nc, ##g, ,, ventral, nerve, cord, gang, ##lion, ;, v, ##nc, ##s, ,, ventral, nerve, cord, fm, ##rf, ^, +, so, ##mata, ##fi, ##g, ., 7, ##sche, ##matic, representations, of, ace, ##ty, ##lated, α, -, tub, ##ulin, -, li, ##r, ,, ser, ##oton, ##in, -, li, ##r, and, fm, ##rf, -, li, ##r, in, ec, ##hin, ##oder, ##es, ., a, -, c, lateral, overview, ##s, with, the, head, extended, ., a, ’, -, c, ’, ventral, views, of, the, head, ., anterior, is, to, the, top, in, all, panels, ., b, -, c, ’, 5, ##ht, -, li, ##r, and, fm, ##rf, -, li, ##r, are, over, ##laid, upon, a, background, of, act, ##ub, -, li, ##r, (, gray, ), ., the, number, of, 5, ##ht, ^, +, and, fm, ##rf, ^, +, so, ##mata, (, v, ##nc, ##s, ), along, the, ventral, nerve, cord, (, b, ,, c, ), varies, among, specimens, and, are, representative, here, ., note, the, approximate, orientation, ##s, and, arrangements, of, 5, ##ht, ^, +, vent, ##rom, ##ed, ##ial, so, ##mata, (, b, ’, ), and, fm, ##rf, ^, +, bipolar, cells, (, c, ’, ), relative, to, neural, rings, of, the, ne, ##uro, ##pi, ##l, ., abbreviation, ##s, :, bp, ##c, ,, fm, ##rf, ^, +, bipolar, cells, ;, cn, ##e, ,, converge, ##nt, ne, ##uri, ##tes, ;, cn, ##r, ,, complete, neural, ring, ;, g, ##n, ,, go, ##nad, ne, ##uri, ##te, ;, in, ##r, ,, incomplete, neural, ring, ;, l, ##nb, ,, longitudinal, ne, ##uri, ##te, bundle, ;, mc, ##nr, ,, mouth, cone, nerve, ring, ;, md, ##s, ##n, ,, mid, ##dor, ##sal, spine, ne, ##uri, ##te, ;, nc, ##n, ,, neck, circular, ne, ##uri, ##te, ;, ne, ##n, ,, ne, ##ph, ##rid, ##ial, ne, ##uri, ##te, ;, np, ,, ne, ##uro, ##pi, ##l, ;, pen, ,, pen, ##ile, spine, ne, ##uri, ##te, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, tn, ,, transverse, ne, ##uri, ##te, ;, ts, ##n, ,, terminal, spine, ne, ##uri, ##te, ;, v, ##ln, ,, vent, ##rol, ##ater, ##al, nerve, ;, v, ##ms, ,, 5, ##ht, ^, +, vent, ##rom, ##ed, ##ial, so, ##mata, ;, v, ##nc, ,, ventral, nerve, cord, ;, v, ##nc, ##s, ,, ventral, nerve, cord, fm, ##rf, ^, +, so, ##mata'},\n", + " {'article_id': '0a905352272e1a0791679c71588f27f6',\n", + " 'section_name': 'Figure Caption',\n", + " 'text': 'Humans are equipped with high-threshold and very fast conducting primary afferents.(A) Location of myelinated HTMR receptive fields from recordings in the peroneal and radial nerves. Each red dot represents the location of an individual A-HTMR (n = 18). The pattern of receptive field spots, mapped with a Semmes-Weinstein monofilament, is shown for two A-HTMRs (marked by arrows; top, radial; bottom, peroneal). Receptive field spots were redrawn on photographic images so they can easily be seen. The horizontal lines represent the medial-lateral dimension, and the vertical lines represent the proximal-distal dimension. The average size of an A-HTMR receptive field, mapped using a filament force six times higher than that for an A-LTMR, was 26.8 mm^2 (±6.9; n = 9). This was significantly smaller than the receptive field of field afferents (100.5 ± 7.2 mm^2; n = 51; P < 0.0001, Dunnett’s test) but was not different from that of SA1 afferents (41.6 ± 7.5 mm^2; n = 17; P > 0.05, Dunnett’s test). (B) Brush responses of an A-HTMR and a field afferent. Using a soft or a coarse brush, the skin area centered on the receptive field of the recorded afferent was gently stroked at 3 cm/s. The field afferent responded vigorously to soft brush stroking. The A-HTMR did not respond to soft brush stroking, but it did respond to coarse brush stroking. The mechanical threshold of this A-HTMR was 4 mN, and the conduction velocity was 52 m/s. It responded to pinching, and its receptive field moved with skin translocation. Freq, frequency. (C) Mechanical threshold distribution of HTMRs and LTMRs in the recorded sample. For RA1 afferents, the preferred stimulus is hair movement, so monofilament thresholds were not measured. For A-HTMR, the median mechanical threshold was 10.0 mN (Q, 5.5–20.0; n = 18). This was significantly higher than the mechanical thresholds of all tested A-LTMR types (at least P < 0.001 for all individual comparisons, Dunn’s test) but was not different from C-HTMRs (10.0 mN; Q, 10.0–27.0; n = 5). (D) Spike activity of an A-HTMR to electrical and mechanical stimulations of the receptive field. Individual electrically and mechanically evoked spikes were superimposed on an expanded time scale to show that the electrically stimulated spike (used for latency measurement) was from the same unit as the one that was mechanically probed at the receptive field. (E) Conduction velocities of HTMRs and LTMRs to surface electrical stimulation (and monofilament tapping in case of one HTMR, conducting at 30 m/s). The data show individual and average (±SEM) conduction velocities of single afferents from peroneal (circles) and radial (diamonds) nerves. Conduction velocities of peroneal A-HTMRs (33.5 ± 2.1; n = 13) were statistically indistinguishable from peroneal A-LTMRs [SA1: 39.8 ± 2.3, n = 10; SA2: 38.6 ± 4.0, n = 4; RA1: 36.8 ± 2.8, n = 6; field: 34.3 ± 1.3, n = 18; F(4,46) = 1.70; P = 0.17, one-way analysis of variance (ANOVA)]. All three peroneal C-HTMRs were conducting at 0.9 m/s. In comparison to the peroneal nerve, conduction velocities of A-fiber types were faster in the radial nerve as expected (A-HTMR: 54.5 ± 2.4, n = 4; SA1: 56.8 m/s, n = 1; SA2: 53.0 ± 3.3, n = 3; RA1: 48.7 ± 1.6, n = 3; field: 47.3 ± 0.2, n = 2) (46). Both radial C-HTMRs were conducting at 1.1 m/s. Conduction velocity of RA2 afferents was not measured. (F) Slowly adapting properties of an A-HTMR at higher indentation forces. Spike activity of a field afferent and an A-HTMR during monofilament stimulation at three different forces, applied using electronic filaments with force feedback. Compared to the field afferent, the A-HTMR showed a sustained response at a lower indentation force (see also fig. S1).',\n", + " 'paragraph_id': 51,\n", + " 'tokenizer': 'humans, are, equipped, with, high, -, threshold, and, very, fast, conducting, primary, af, ##fer, ##ents, ., (, a, ), location, of, my, ##elin, ##ated, h, ##tm, ##r, rec, ##eptive, fields, from, recordings, in, the, per, ##one, ##al, and, radial, nerves, ., each, red, dot, represents, the, location, of, an, individual, a, -, h, ##tm, ##r, (, n, =, 18, ), ., the, pattern, of, rec, ##eptive, field, spots, ,, mapped, with, a, se, ##mme, ##s, -, wei, ##nstein, mono, ##fi, ##lam, ##ent, ,, is, shown, for, two, a, -, h, ##tm, ##rs, (, marked, by, arrows, ;, top, ,, radial, ;, bottom, ,, per, ##one, ##al, ), ., rec, ##eptive, field, spots, were, red, ##ra, ##wn, on, photographic, images, so, they, can, easily, be, seen, ., the, horizontal, lines, represent, the, medial, -, lateral, dimension, ,, and, the, vertical, lines, represent, the, pro, ##xi, ##mal, -, distal, dimension, ., the, average, size, of, an, a, -, h, ##tm, ##r, rec, ##eptive, field, ,, mapped, using, a, fi, ##lam, ##ent, force, six, times, higher, than, that, for, an, a, -, lt, ##m, ##r, ,, was, 26, ., 8, mm, ^, 2, (, ±, ##6, ., 9, ;, n, =, 9, ), ., this, was, significantly, smaller, than, the, rec, ##eptive, field, of, field, af, ##fer, ##ents, (, 100, ., 5, ±, 7, ., 2, mm, ^, 2, ;, n, =, 51, ;, p, <, 0, ., 000, ##1, ,, dunne, ##tt, ’, s, test, ), but, was, not, different, from, that, of, sa, ##1, af, ##fer, ##ents, (, 41, ., 6, ±, 7, ., 5, mm, ^, 2, ;, n, =, 17, ;, p, >, 0, ., 05, ,, dunne, ##tt, ’, s, test, ), ., (, b, ), brush, responses, of, an, a, -, h, ##tm, ##r, and, a, field, af, ##fer, ##ent, ., using, a, soft, or, a, coarse, brush, ,, the, skin, area, centered, on, the, rec, ##eptive, field, of, the, recorded, af, ##fer, ##ent, was, gently, stroked, at, 3, cm, /, s, ., the, field, af, ##fer, ##ent, responded, vigorously, to, soft, brush, stroking, ., the, a, -, h, ##tm, ##r, did, not, respond, to, soft, brush, stroking, ,, but, it, did, respond, to, coarse, brush, stroking, ., the, mechanical, threshold, of, this, a, -, h, ##tm, ##r, was, 4, mn, ,, and, the, conduct, ##ion, velocity, was, 52, m, /, s, ., it, responded, to, pinch, ##ing, ,, and, its, rec, ##eptive, field, moved, with, skin, trans, ##lo, ##cation, ., fr, ##e, ##q, ,, frequency, ., (, c, ), mechanical, threshold, distribution, of, h, ##tm, ##rs, and, lt, ##m, ##rs, in, the, recorded, sample, ., for, ra, ##1, af, ##fer, ##ents, ,, the, preferred, stimulus, is, hair, movement, ,, so, mono, ##fi, ##lam, ##ent, threshold, ##s, were, not, measured, ., for, a, -, h, ##tm, ##r, ,, the, median, mechanical, threshold, was, 10, ., 0, mn, (, q, ,, 5, ., 5, –, 20, ., 0, ;, n, =, 18, ), ., this, was, significantly, higher, than, the, mechanical, threshold, ##s, of, all, tested, a, -, lt, ##m, ##r, types, (, at, least, p, <, 0, ., 001, for, all, individual, comparisons, ,, dunn, ’, s, test, ), but, was, not, different, from, c, -, h, ##tm, ##rs, (, 10, ., 0, mn, ;, q, ,, 10, ., 0, –, 27, ., 0, ;, n, =, 5, ), ., (, d, ), spike, activity, of, an, a, -, h, ##tm, ##r, to, electrical, and, mechanical, stimulation, ##s, of, the, rec, ##eptive, field, ., individual, electrically, and, mechanically, ev, ##oked, spikes, were, super, ##im, ##posed, on, an, expanded, time, scale, to, show, that, the, electrically, stimulated, spike, (, used, for, late, ##ncy, measurement, ), was, from, the, same, unit, as, the, one, that, was, mechanically, probe, ##d, at, the, rec, ##eptive, field, ., (, e, ), conduct, ##ion, ve, ##lo, ##cit, ##ies, of, h, ##tm, ##rs, and, lt, ##m, ##rs, to, surface, electrical, stimulation, (, and, mono, ##fi, ##lam, ##ent, tapping, in, case, of, one, h, ##tm, ##r, ,, conducting, at, 30, m, /, s, ), ., the, data, show, individual, and, average, (, ±, ##se, ##m, ), conduct, ##ion, ve, ##lo, ##cit, ##ies, of, single, af, ##fer, ##ents, from, per, ##one, ##al, (, circles, ), and, radial, (, diamonds, ), nerves, ., conduct, ##ion, ve, ##lo, ##cit, ##ies, of, per, ##one, ##al, a, -, h, ##tm, ##rs, (, 33, ., 5, ±, 2, ., 1, ;, n, =, 13, ), were, statistical, ##ly, ind, ##ist, ##ing, ##uis, ##hab, ##le, from, per, ##one, ##al, a, -, lt, ##m, ##rs, [, sa, ##1, :, 39, ., 8, ±, 2, ., 3, ,, n, =, 10, ;, sa, ##2, :, 38, ., 6, ±, 4, ., 0, ,, n, =, 4, ;, ra, ##1, :, 36, ., 8, ±, 2, ., 8, ,, n, =, 6, ;, field, :, 34, ., 3, ±, 1, ., 3, ,, n, =, 18, ;, f, (, 4, ,, 46, ), =, 1, ., 70, ;, p, =, 0, ., 17, ,, one, -, way, analysis, of, variance, (, an, ##ova, ), ], ., all, three, per, ##one, ##al, c, -, h, ##tm, ##rs, were, conducting, at, 0, ., 9, m, /, s, ., in, comparison, to, the, per, ##one, ##al, nerve, ,, conduct, ##ion, ve, ##lo, ##cit, ##ies, of, a, -, fiber, types, were, faster, in, the, radial, nerve, as, expected, (, a, -, h, ##tm, ##r, :, 54, ., 5, ±, 2, ., 4, ,, n, =, 4, ;, sa, ##1, :, 56, ., 8, m, /, s, ,, n, =, 1, ;, sa, ##2, :, 53, ., 0, ±, 3, ., 3, ,, n, =, 3, ;, ra, ##1, :, 48, ., 7, ±, 1, ., 6, ,, n, =, 3, ;, field, :, 47, ., 3, ±, 0, ., 2, ,, n, =, 2, ), (, 46, ), ., both, radial, c, -, h, ##tm, ##rs, were, conducting, at, 1, ., 1, m, /, s, ., conduct, ##ion, velocity, of, ra, ##2, af, ##fer, ##ents, was, not, measured, ., (, f, ), slowly, adapting, properties, of, an, a, -, h, ##tm, ##r, at, higher, ind, ##entation, forces, ., spike, activity, of, a, field, af, ##fer, ##ent, and, an, a, -, h, ##tm, ##r, during, mono, ##fi, ##lam, ##ent, stimulation, at, three, different, forces, ,, applied, using, electronic, fi, ##lam, ##ents, with, force, feedback, ., compared, to, the, field, af, ##fer, ##ent, ,, the, a, -, h, ##tm, ##r, showed, a, sustained, response, at, a, lower, ind, ##entation, force, (, see, also, fig, ., s, ##1, ), .'},\n", + " {'article_id': '8e025c7b000befe6eff45d14ce01b82d',\n", + " 'section_name': 'Figure Caption',\n", + " 'text': 'Illustrations of four key MEMRI applications for studying the visual system, from neuroarchitecture detection (A), to neuronal tract tracing (B), neuronal activity detection (C) and glial activity identification (D). (A) represents detection of neuroarchitecture in the rodent retina and the primate visual cortex. Top row of (A) shows MEMRI detection of distinct bands of the normal (left and middle) and degenerated rodent retinas (right) with alternating dark and light intensity signals, as denoted by the numbering of layers. Note the compromised photoreceptor layer “D” upon degeneration in the Royal College of Surgeons (RCS) rats at postnatal day (P) 90. Bottom row of (A) represents in vivo T1-weighted MRI of the marmoset occipital cortex before (left) and after (middle) systemic Mn^2+ administration. The corresponding histological section stained for cytochrome oxidase activity is shown on the right. The arrows indicate the primary/secondary visual cortex (V1/V2) border; I–III, IV, and V–VI indicate the cortical layers; and WM represents white matter. V1 detected in the T1-enhanced MEMRI scans agrees with the V1 identified in the histological section. The cortical layer IV experiences the strongest layer-specific enhancement, defining the extent of V1. (B) represents the use of MEMRI tract tracing for retinotopic mapping of normal and injured central visual pathways in Sprague-Dawley rats. MEMRI was performed 1 week after partial transection to the right superior intraorbital optic nerve (ON_io) in a,b as shown by the yellow arrowhead in a, and to the temporal and nasal regions of the right optic nerve in c,d, respectively. After intravitreal Mn^2+ injection into both eyes, the intact central visual pathway projected from the left eye could be traced from the left retina to the left optic nerve (ON), optic chiasm (OC), right optic tract (OT), right lateral geniculate nucleus (LGN), right pretectum (PT), and right superior colliculus (SC) in a. In contrast, reduced anterograde Mn^2+ transport was found beyond the site of partial transection in the central visual pathway projected from the right eye in a retinotopic manner following the schematics in the insert in a. b–d in the right column highlight the reduced Mn^2+ enhancement in the lateral, rostral and caudal regions of the left SC, denoted by the solid arrows. Open arrows indicate the hypointensity in the left LGN. (C) shows the use of MEMRI for detection of neuronal activity in the retina (top 2 rows) and the visual cortex (bottom row) of rodents. The heat maps on the top 2 rows of (C) visualize retinal adaptation by MEMRI in either light or dark condition. The horizontal white arrows mark the enhanced inner retina 4 h after systemic Mn^2+ administration (right column) as compared to the control condition without Mn^2+ administration (left column), while the vertical white arrows point to the outer retina that has higher intensity in dark-adapted than light-adapted conditions. The optic nerve (ON) is identified by a black arrow in each image. The bottom row of (C) represents neuronal activity of the visual cortex after systemic Mn^2+ administration and awake visual stimulation. The left image shows the anatomy of cortical regions of interest (ROIs) in terms of Brodmann areas: blue for the binocular division of the primary visual cortex (Area 17), cyan for the lateral division of the accessory visual cortex (Area 18), red for the primary somatosensory cortex (Area 2), and green for the primary auditory cortex (Area 41). A superimposed drawing shows the relevant surface topography. On the right is a voxel-wise analysis of activity-dependent Mn^2+ enhancement in one hemisphere centered in layer IV of the primary visual cortex at a depth from 480 to 690 μm. The top of the image is the rostral side of the cortex while the left side depicts the position of the longitudinal fissure. Values of the P-threshold are indicated on the bottom. The primary visual cortex, represented by the leftmost green open circle, had the highest density of below-threshold voxels. The green shaded band to the left, centered at the longitudinal fissure, is a buffer of the unanalyzed space. (D) shows a series of T1-weighted images of neonatal rats at 3 h, and 7 and 8 days after mild hypoxic-ischemia (H-I) insult at postnatal day (P) 7. The injury was induced by unilateral carotid artery occlusion and exposure to hypoxia at 35°C for 1 h. After MRI scans at day 7, systemic Mn^2+ administration was performed, and the image at day 8 represents MEMRI enhancement. The white arrow points to gray matter injuries in the ipsilesional hemisphere around the visual cortex. This type of gray matter lesion is not visible in the images from hour 3 and day 7 post-insult. Immunohistology of the same rats suggested co-localization of overexpressed glial activity in the same lesion area in MEMRI (not shown). (A–D) are reproduced with permissions from Berkowitz et al. (2006), Yang and Wu (2007), Bissig and Berkowitz (2009); Bock et al. (2009), Chan et al. (2011), and Nair et al. (2011).',\n", + " 'paragraph_id': 46,\n", + " 'tokenizer': 'illustrations, of, four, key, me, ##m, ##ri, applications, for, studying, the, visual, system, ,, from, ne, ##uro, ##ar, ##chi, ##tec, ##ture, detection, (, a, ), ,, to, ne, ##uron, ##al, tract, tracing, (, b, ), ,, ne, ##uron, ##al, activity, detection, (, c, ), and, g, ##lia, ##l, activity, identification, (, d, ), ., (, a, ), represents, detection, of, ne, ##uro, ##ar, ##chi, ##tec, ##ture, in, the, rode, ##nt, re, ##tina, and, the, primate, visual, cortex, ., top, row, of, (, a, ), shows, me, ##m, ##ri, detection, of, distinct, bands, of, the, normal, (, left, and, middle, ), and, de, ##gen, ##erated, rode, ##nt, re, ##tina, ##s, (, right, ), with, alternating, dark, and, light, intensity, signals, ,, as, denoted, by, the, numbering, of, layers, ., note, the, compromised, photo, ##re, ##ce, ##pt, ##or, layer, “, d, ”, upon, de, ##gen, ##eration, in, the, royal, college, of, surgeons, (, rc, ##s, ), rats, at, post, ##nat, ##al, day, (, p, ), 90, ., bottom, row, of, (, a, ), represents, in, vivo, t, ##1, -, weighted, mri, of, the, mar, ##mos, ##et, o, ##cci, ##pit, ##al, cortex, before, (, left, ), and, after, (, middle, ), systemic, mn, ^, 2, +, administration, ., the, corresponding, his, ##to, ##logical, section, stained, for, cy, ##to, ##chrome, ox, ##ida, ##se, activity, is, shown, on, the, right, ., the, arrows, indicate, the, primary, /, secondary, visual, cortex, (, v, ##1, /, v, ##2, ), border, ;, i, –, iii, ,, iv, ,, and, v, –, vi, indicate, the, co, ##rti, ##cal, layers, ;, and, w, ##m, represents, white, matter, ., v, ##1, detected, in, the, t, ##1, -, enhanced, me, ##m, ##ri, scans, agrees, with, the, v, ##1, identified, in, the, his, ##to, ##logical, section, ., the, co, ##rti, ##cal, layer, iv, experiences, the, strongest, layer, -, specific, enhancement, ,, defining, the, extent, of, v, ##1, ., (, b, ), represents, the, use, of, me, ##m, ##ri, tract, tracing, for, re, ##tino, ##top, ##ic, mapping, of, normal, and, injured, central, visual, pathways, in, sp, ##rag, ##ue, -, da, ##wley, rats, ., me, ##m, ##ri, was, performed, 1, week, after, partial, trans, ##ection, to, the, right, superior, intra, ##or, ##bit, ##al, optic, nerve, (, on, _, io, ), in, a, ,, b, as, shown, by, the, yellow, arrow, ##head, in, a, ,, and, to, the, temporal, and, nasal, regions, of, the, right, optic, nerve, in, c, ,, d, ,, respectively, ., after, intra, ##vi, ##tre, ##al, mn, ^, 2, +, injection, into, both, eyes, ,, the, intact, central, visual, pathway, projected, from, the, left, eye, could, be, traced, from, the, left, re, ##tina, to, the, left, optic, nerve, (, on, ), ,, optic, chi, ##as, ##m, (, o, ##c, ), ,, right, optic, tract, (, ot, ), ,, right, lateral, gen, ##iculate, nucleus, (, l, ##gn, ), ,, right, pre, ##tec, ##tum, (, pt, ), ,, and, right, superior, col, ##lic, ##ulus, (, sc, ), in, a, ., in, contrast, ,, reduced, ant, ##ero, ##grade, mn, ^, 2, +, transport, was, found, beyond, the, site, of, partial, trans, ##ection, in, the, central, visual, pathway, projected, from, the, right, eye, in, a, re, ##tino, ##top, ##ic, manner, following, the, sc, ##hema, ##tics, in, the, insert, in, a, ., b, –, d, in, the, right, column, highlight, the, reduced, mn, ^, 2, +, enhancement, in, the, lateral, ,, ro, ##stra, ##l, and, ca, ##uda, ##l, regions, of, the, left, sc, ,, denoted, by, the, solid, arrows, ., open, arrows, indicate, the, h, ##yp, ##oint, ##ens, ##ity, in, the, left, l, ##gn, ., (, c, ), shows, the, use, of, me, ##m, ##ri, for, detection, of, ne, ##uron, ##al, activity, in, the, re, ##tina, (, top, 2, rows, ), and, the, visual, cortex, (, bottom, row, ), of, rodents, ., the, heat, maps, on, the, top, 2, rows, of, (, c, ), visual, ##ize, re, ##tina, ##l, adaptation, by, me, ##m, ##ri, in, either, light, or, dark, condition, ., the, horizontal, white, arrows, mark, the, enhanced, inner, re, ##tina, 4, h, after, systemic, mn, ^, 2, +, administration, (, right, column, ), as, compared, to, the, control, condition, without, mn, ^, 2, +, administration, (, left, column, ), ,, while, the, vertical, white, arrows, point, to, the, outer, re, ##tina, that, has, higher, intensity, in, dark, -, adapted, than, light, -, adapted, conditions, ., the, optic, nerve, (, on, ), is, identified, by, a, black, arrow, in, each, image, ., the, bottom, row, of, (, c, ), represents, ne, ##uron, ##al, activity, of, the, visual, cortex, after, systemic, mn, ^, 2, +, administration, and, awake, visual, stimulation, ., the, left, image, shows, the, anatomy, of, co, ##rti, ##cal, regions, of, interest, (, roi, ##s, ), in, terms, of, bro, ##dman, ##n, areas, :, blue, for, the, bin, ##oc, ##ular, division, of, the, primary, visual, cortex, (, area, 17, ), ,, cy, ##an, for, the, lateral, division, of, the, accessory, visual, cortex, (, area, 18, ), ,, red, for, the, primary, so, ##mat, ##ose, ##nsor, ##y, cortex, (, area, 2, ), ,, and, green, for, the, primary, auditory, cortex, (, area, 41, ), ., a, super, ##im, ##posed, drawing, shows, the, relevant, surface, topography, ., on, the, right, is, a, vox, ##el, -, wise, analysis, of, activity, -, dependent, mn, ^, 2, +, enhancement, in, one, hemisphere, centered, in, layer, iv, of, the, primary, visual, cortex, at, a, depth, from, 480, to, 690, μ, ##m, ., the, top, of, the, image, is, the, ro, ##stra, ##l, side, of, the, cortex, while, the, left, side, depicts, the, position, of, the, longitudinal, fis, ##sure, ., values, of, the, p, -, threshold, are, indicated, on, the, bottom, ., the, primary, visual, cortex, ,, represented, by, the, left, ##most, green, open, circle, ,, had, the, highest, density, of, below, -, threshold, vox, ##els, ., the, green, shaded, band, to, the, left, ,, centered, at, the, longitudinal, fis, ##sure, ,, is, a, buffer, of, the, una, ##nal, ##y, ##zed, space, ., (, d, ), shows, a, series, of, t, ##1, -, weighted, images, of, neon, ##atal, rats, at, 3, h, ,, and, 7, and, 8, days, after, mild, h, ##yp, ##ox, ##ic, -, is, ##che, ##mia, (, h, -, i, ), insult, at, post, ##nat, ##al, day, (, p, ), 7, ., the, injury, was, induced, by, un, ##ila, ##tera, ##l, car, ##ot, ##id, artery, o, ##cc, ##lusion, and, exposure, to, h, ##yp, ##ox, ##ia, at, 35, ##°, ##c, for, 1, h, ., after, mri, scans, at, day, 7, ,, systemic, mn, ^, 2, +, administration, was, performed, ,, and, the, image, at, day, 8, represents, me, ##m, ##ri, enhancement, ., the, white, arrow, points, to, gray, matter, injuries, in, the, ip, ##sil, ##es, ##ional, hemisphere, around, the, visual, cortex, ., this, type, of, gray, matter, les, ##ion, is, not, visible, in, the, images, from, hour, 3, and, day, 7, post, -, insult, ., im, ##mun, ##oh, ##isto, ##logy, of, the, same, rats, suggested, co, -, local, ##ization, of, over, ##ex, ##pressed, g, ##lia, ##l, activity, in, the, same, les, ##ion, area, in, me, ##m, ##ri, (, not, shown, ), ., (, a, –, d, ), are, reproduced, with, permission, ##s, from, be, ##rk, ##ow, ##itz, et, al, ., (, 2006, ), ,, yang, and, wu, (, 2007, ), ,, bis, ##si, ##g, and, be, ##rk, ##ow, ##itz, (, 2009, ), ;, bo, ##ck, et, al, ., (, 2009, ), ,, chan, et, al, ., (, 2011, ), ,, and, nair, et, al, ., (, 2011, ), .'},\n", + " {'article_id': '55db915e9bddb8a4270a57b3de30a9a1',\n", + " 'section_name': 'Decision utility in rats',\n", + " 'text': 'A series of experiments (Caprioli et al. 2007a, 2008, 2009; Celentano et al. 2009; Montanari et al. 2015; Avvisati et al. 2016; De Luca et al. 2019) were conducted in male Sprague–Dawley rats to assess the decision utility of heroin versus cocaine (or amphetamine). Also in these experiments, the rats were tested either at home or outside the home. Decision utility was assessed using different procedures.Between-subject procedures were used to assess the rats’ willingness to pay for heroin or cocaine, as a function of setting. In some experiments (Caprioli et al. 2007a, 2008), the rats were given the choice between a lever that triggered a drug infusion and a control lever that triggered an infusion of vehicle, and the work necessary to obtain the drug was increased progressively across sessions and within session, using a break-point procedure. The rats’ decision to self-administer heroin or cocaine was influenced in an opposite manner by the setting. Rats tested at home self-administered more heroin at home than rats tested outside the home. In contrast, the rats took more cocaine (and amphetamine) outside the home than at home. Furthermore, the rats worked harder for heroin at home than outside the home and for cocaine (or amphetamine) outside the home than at home.Within-subject procedures were used to compare the rats’ willingness to pay for heroin versus cocaine, as a function of setting. In these experiments (Caprioli et al. 2009; Celentano et al. 2009; Montanari et al. 2015; Avvisati et al. 2016), the rats were trained to press on alternate days for heroin and cocaine. One lever was paired with heroin and the other with cocaine (in a counterbalanced fashion), and the work necessary to obtain each drug was increased progressively across sessions. Also, in this case, the rats’ decision was a function of context, which influenced in an opposite manner heroin versus cocaine intake, and of workload. The ratio of cocaine to heroin infusions was greater outside the home than at home (indirectly indicating a preference) and became progressively larger with the increase in workload.Within-subject choice procedures were used in some studies to assess the rats’ preference for heroin or for cocaine. To the best of our knowledge, these are the first and only studies to have directly compared the rewarding effects of heroin and cocaine. In one of these studies (Caprioli et al. 2009), the rats were first trained to self-administer heroin and cocaine on alternate days, as previously described. The rats were then given the opportunity to choose between heroin and cocaine within the same session for several sessions. At the end of the choice sessions, the rats were classified, using a straightforward bootstrapping procedure (Wilson 1927; Newcombe 1988), as cocaine-preferring, heroin-preferring, or nonpreferring. The preference for one drug or the other was influenced in opposite directions by the context. At home, the rats tended to prefer heroin to cocaine; outside the home, the rats tended to prefer cocaine to heroin. Strikingly, the same double dissociation in decision-making was observed when we used an experimental design (see Fig. 3) in which rats were trained to receive the same drug (heroin for some, cocaine for other rats, Figs. 3A–C, 4) when pressing on either lever (De Luca et al. 2019). The rats were then offered the choice between heroin and cocaine, as described above (Fig. 3D). Also in this case, the rats tested at home tended to prefer heroin to cocaine, whereas the rats tested outside the home tended to prefer cocaine to heroin (Fig. 5). In summary, drug preference appears to be influenced to a much greater extent by the context of drug use than by the history of drug use.We also quantified the decision utility of heroin seeking and cocaine seeking after a period of abstinence from the drug (Montanari et al. 2015). The rats were first trained to self-administer heroin and cocaine on alternate days (Fig. 6A–C) and then underwent an extinction procedure (Fig. 6D), during which lever pressing did not result in drug infusion even in the presence of drug-paired cues (e.g., lever extension, cue lights, infusion of vehicle). The rats were then tested in a reinstatement procedure (Fig. 6E), developed to model relapse into drug seeking after a period of abstinence (de Wit and Stewart 1981; Shaham et al. 2003). The ability of a single, noncontingent intravenous drug infusion (drug priming) to precipitate drug seeking was assessed by comparing lever pressing during the reinstatement session to lever pressing under extinction conditions. Heroin priming precipitated heroin seeking in rats tested at home but not in rats tested outside the home, whereas the opposite was observed for cocaine: cocaine priming precipitated cocaine seeking outside the home but not at home (Fig. 7).It is important to notice that rats were able to update the decision utility of a given lever when one drug was substituted for another. When rats that had worked more vigorously for heroin at home than outside the home were shifted to amphetamine self-administration (after a period of washout), the opposite pattern was observed, as they took more amphetamine outside the home than at home (Caprioli et al. 2008).Fig. 3Experimental design of a within-subject study concerned with heroin versus cocaine choice in rats. A-C The rats were first trained to self-administer heroin (25 μg/kg per infusion) and cocaine (400 μg/kg per infusion), on alternate sessions, either at home or outside the home. The training lasted for 12 sessions (see Fig. 4 for results). D The rats were then given the opportunity to choose between heroin and cocaine for seven consecutive sessions. At the end of the choice sessions, the rats were classified as cocaine-preferring, heroin-preferring, or nonpreferring (see Fig. 5 for results). Modified from De Luca et al. (2019)Fig. 4Rats were tested as described in Fig. 3A–C. Mean (±SEM) number of infusions during the training phase for the heroin- and cocaine-trained groups, as a function of setting, time-out (TO) period, maximum number of infusions, and fixed ratio (FR). Single and double asterisks indicate significant effect setting (p < 0.05 and p < 0.01, respectively). Consistent with previous findings (Caprioli et al. 2007a, 2008) and despite the constraints in the maximum number of infusions, rats at home self-administered more heroin than rats outside the home, whereas rats outside the home self-administered more cocaine than rats at home. Modified from De Luca et al. (2019)Fig. 5Rats were tested as described in Fig. 3D. Drug preferences in individual rats (calculated using bootstrapping analysis), as a function of setting and drug history (see text for details). The preference for one drug or the other was influenced in opposite directions by the context. At home, 57.7% rats preferred heroin to cocaine, whereas only 23.1% preferred cocaine to heroin. Outside the home, 60% rats preferred cocaine to heroin, whereas only 16.7% preferred heroin to cocaine. Some rats (19.2% at home and 23.3% outside the home) did not exhibit a significant preference for either drug. Modified from De Luca et al. (2019)Fig. 6Experimental design aimed at quantifying the decision utility of heroin seeking and cocaine seeking after a period of abstinence from the drug (Montanari et al. 2015). The rats were first trained to self-administer heroin and cocaine on alternate days (A–C) and then underwent an extinction procedure (D), during which lever pressing did not result in drug infusion even in the presence of drug-paired cues (e.g., lever extension, cue lights, infusion of vehicle). The rats were then tested in a reinstatement procedure (E), developed to model relapse into drug seeking after a period of abstinence. The ability of a single, noncontingent intravenous drug infusion (drug priming) to precipitate drug seeking was assessed by comparing lever pressing during the reinstatement session to lever pressing under extinction conditions (for results, see Fig. 7)Fig. 7Mean (±SEM) number of lever presses during the first hour of the last extinction session (white bars) versus the reinstatement session (black bars) for rats tested at home versus rats outside the home (see Fig. 6). At the beginning of the reinstatement session, independent groups of rats (N values are indicated by the numbers within the white bars) received noncontingent intravenous (i.v.) infusions of one of three doses of cocaine (top panels) or heroin (bottom panels). Significant (##p ≤ 0.01 and ####p ≤ 0.0001) main effect of priming. Data from Montanari et al. (2015)',\n", + " 'paragraph_id': 18,\n", + " 'tokenizer': 'a, series, of, experiments, (, cap, ##rio, ##li, et, al, ., 2007, ##a, ,, 2008, ,, 2009, ;, ce, ##lent, ##ano, et, al, ., 2009, ;, montana, ##ri, et, al, ., 2015, ;, av, ##vis, ##ati, et, al, ., 2016, ;, de, luca, et, al, ., 2019, ), were, conducted, in, male, sp, ##rag, ##ue, –, da, ##wley, rats, to, assess, the, decision, utility, of, heroin, versus, cocaine, (, or, amp, ##het, ##amine, ), ., also, in, these, experiments, ,, the, rats, were, tested, either, at, home, or, outside, the, home, ., decision, utility, was, assessed, using, different, procedures, ., between, -, subject, procedures, were, used, to, assess, the, rats, ’, willingness, to, pay, for, heroin, or, cocaine, ,, as, a, function, of, setting, ., in, some, experiments, (, cap, ##rio, ##li, et, al, ., 2007, ##a, ,, 2008, ), ,, the, rats, were, given, the, choice, between, a, lever, that, triggered, a, drug, in, ##fusion, and, a, control, lever, that, triggered, an, in, ##fusion, of, vehicle, ,, and, the, work, necessary, to, obtain, the, drug, was, increased, progressively, across, sessions, and, within, session, ,, using, a, break, -, point, procedure, ., the, rats, ’, decision, to, self, -, administer, heroin, or, cocaine, was, influenced, in, an, opposite, manner, by, the, setting, ., rats, tested, at, home, self, -, administered, more, heroin, at, home, than, rats, tested, outside, the, home, ., in, contrast, ,, the, rats, took, more, cocaine, (, and, amp, ##het, ##amine, ), outside, the, home, than, at, home, ., furthermore, ,, the, rats, worked, harder, for, heroin, at, home, than, outside, the, home, and, for, cocaine, (, or, amp, ##het, ##amine, ), outside, the, home, than, at, home, ., within, -, subject, procedures, were, used, to, compare, the, rats, ’, willingness, to, pay, for, heroin, versus, cocaine, ,, as, a, function, of, setting, ., in, these, experiments, (, cap, ##rio, ##li, et, al, ., 2009, ;, ce, ##lent, ##ano, et, al, ., 2009, ;, montana, ##ri, et, al, ., 2015, ;, av, ##vis, ##ati, et, al, ., 2016, ), ,, the, rats, were, trained, to, press, on, alternate, days, for, heroin, and, cocaine, ., one, lever, was, paired, with, heroin, and, the, other, with, cocaine, (, in, a, counter, ##balance, ##d, fashion, ), ,, and, the, work, necessary, to, obtain, each, drug, was, increased, progressively, across, sessions, ., also, ,, in, this, case, ,, the, rats, ’, decision, was, a, function, of, context, ,, which, influenced, in, an, opposite, manner, heroin, versus, cocaine, intake, ,, and, of, work, ##load, ., the, ratio, of, cocaine, to, heroin, in, ##fusion, ##s, was, greater, outside, the, home, than, at, home, (, indirectly, indicating, a, preference, ), and, became, progressively, larger, with, the, increase, in, work, ##load, ., within, -, subject, choice, procedures, were, used, in, some, studies, to, assess, the, rats, ’, preference, for, heroin, or, for, cocaine, ., to, the, best, of, our, knowledge, ,, these, are, the, first, and, only, studies, to, have, directly, compared, the, reward, ##ing, effects, of, heroin, and, cocaine, ., in, one, of, these, studies, (, cap, ##rio, ##li, et, al, ., 2009, ), ,, the, rats, were, first, trained, to, self, -, administer, heroin, and, cocaine, on, alternate, days, ,, as, previously, described, ., the, rats, were, then, given, the, opportunity, to, choose, between, heroin, and, cocaine, within, the, same, session, for, several, sessions, ., at, the, end, of, the, choice, sessions, ,, the, rats, were, classified, ,, using, a, straightforward, boots, ##tra, ##pping, procedure, (, wilson, 1927, ;, new, ##combe, 1988, ), ,, as, cocaine, -, preferring, ,, heroin, -, preferring, ,, or, non, ##pre, ##fer, ##ring, ., the, preference, for, one, drug, or, the, other, was, influenced, in, opposite, directions, by, the, context, ., at, home, ,, the, rats, tended, to, prefer, heroin, to, cocaine, ;, outside, the, home, ,, the, rats, tended, to, prefer, cocaine, to, heroin, ., striking, ##ly, ,, the, same, double, di, ##sso, ##ciation, in, decision, -, making, was, observed, when, we, used, an, experimental, design, (, see, fig, ., 3, ), in, which, rats, were, trained, to, receive, the, same, drug, (, heroin, for, some, ,, cocaine, for, other, rats, ,, fig, ##s, ., 3a, –, c, ,, 4, ), when, pressing, on, either, lever, (, de, luca, et, al, ., 2019, ), ., the, rats, were, then, offered, the, choice, between, heroin, and, cocaine, ,, as, described, above, (, fig, ., 3d, ), ., also, in, this, case, ,, the, rats, tested, at, home, tended, to, prefer, heroin, to, cocaine, ,, whereas, the, rats, tested, outside, the, home, tended, to, prefer, cocaine, to, heroin, (, fig, ., 5, ), ., in, summary, ,, drug, preference, appears, to, be, influenced, to, a, much, greater, extent, by, the, context, of, drug, use, than, by, the, history, of, drug, use, ., we, also, quan, ##ti, ##fied, the, decision, utility, of, heroin, seeking, and, cocaine, seeking, after, a, period, of, abs, ##tine, ##nce, from, the, drug, (, montana, ##ri, et, al, ., 2015, ), ., the, rats, were, first, trained, to, self, -, administer, heroin, and, cocaine, on, alternate, days, (, fig, ., 6, ##a, –, c, ), and, then, underwent, an, extinction, procedure, (, fig, ., 6, ##d, ), ,, during, which, lever, pressing, did, not, result, in, drug, in, ##fusion, even, in, the, presence, of, drug, -, paired, cues, (, e, ., g, ., ,, lever, extension, ,, cue, lights, ,, in, ##fusion, of, vehicle, ), ., the, rats, were, then, tested, in, a, reins, ##tate, ##ment, procedure, (, fig, ., 6, ##e, ), ,, developed, to, model, re, ##la, ##pse, into, drug, seeking, after, a, period, of, abs, ##tine, ##nce, (, de, wit, and, stewart, 1981, ;, shah, ##am, et, al, ., 2003, ), ., the, ability, of, a, single, ,, non, ##con, ##ting, ##ent, intra, ##ven, ##ous, drug, in, ##fusion, (, drug, pri, ##ming, ), to, pre, ##ci, ##pit, ##ate, drug, seeking, was, assessed, by, comparing, lever, pressing, during, the, reins, ##tate, ##ment, session, to, lever, pressing, under, extinction, conditions, ., heroin, pri, ##ming, pre, ##ci, ##pit, ##ated, heroin, seeking, in, rats, tested, at, home, but, not, in, rats, tested, outside, the, home, ,, whereas, the, opposite, was, observed, for, cocaine, :, cocaine, pri, ##ming, pre, ##ci, ##pit, ##ated, cocaine, seeking, outside, the, home, but, not, at, home, (, fig, ., 7, ), ., it, is, important, to, notice, that, rats, were, able, to, update, the, decision, utility, of, a, given, lever, when, one, drug, was, substituted, for, another, ., when, rats, that, had, worked, more, vigorously, for, heroin, at, home, than, outside, the, home, were, shifted, to, amp, ##het, ##amine, self, -, administration, (, after, a, period, of, wash, ##out, ), ,, the, opposite, pattern, was, observed, ,, as, they, took, more, amp, ##het, ##amine, outside, the, home, than, at, home, (, cap, ##rio, ##li, et, al, ., 2008, ), ., fig, ., 3, ##ex, ##per, ##ime, ##ntal, design, of, a, within, -, subject, study, concerned, with, heroin, versus, cocaine, choice, in, rats, ., a, -, c, the, rats, were, first, trained, to, self, -, administer, heroin, (, 25, μ, ##g, /, kg, per, in, ##fusion, ), and, cocaine, (, 400, μ, ##g, /, kg, per, in, ##fusion, ), ,, on, alternate, sessions, ,, either, at, home, or, outside, the, home, ., the, training, lasted, for, 12, sessions, (, see, fig, ., 4, for, results, ), ., d, the, rats, were, then, given, the, opportunity, to, choose, between, heroin, and, cocaine, for, seven, consecutive, sessions, ., at, the, end, of, the, choice, sessions, ,, the, rats, were, classified, as, cocaine, -, preferring, ,, heroin, -, preferring, ,, or, non, ##pre, ##fer, ##ring, (, see, fig, ., 5, for, results, ), ., modified, from, de, luca, et, al, ., (, 2019, ), fig, ., 4, ##rat, ##s, were, tested, as, described, in, fig, ., 3a, –, c, ., mean, (, ±, ##se, ##m, ), number, of, in, ##fusion, ##s, during, the, training, phase, for, the, heroin, -, and, cocaine, -, trained, groups, ,, as, a, function, of, setting, ,, time, -, out, (, to, ), period, ,, maximum, number, of, in, ##fusion, ##s, ,, and, fixed, ratio, (, fr, ), ., single, and, double, as, ##ter, ##isk, ##s, indicate, significant, effect, setting, (, p, <, 0, ., 05, and, p, <, 0, ., 01, ,, respectively, ), ., consistent, with, previous, findings, (, cap, ##rio, ##li, et, al, ., 2007, ##a, ,, 2008, ), and, despite, the, constraints, in, the, maximum, number, of, in, ##fusion, ##s, ,, rats, at, home, self, -, administered, more, heroin, than, rats, outside, the, home, ,, whereas, rats, outside, the, home, self, -, administered, more, cocaine, than, rats, at, home, ., modified, from, de, luca, et, al, ., (, 2019, ), fig, ., 5, ##rat, ##s, were, tested, as, described, in, fig, ., 3d, ., drug, preferences, in, individual, rats, (, calculated, using, boots, ##tra, ##pping, analysis, ), ,, as, a, function, of, setting, and, drug, history, (, see, text, for, details, ), ., the, preference, for, one, drug, or, the, other, was, influenced, in, opposite, directions, by, the, context, ., at, home, ,, 57, ., 7, %, rats, preferred, heroin, to, cocaine, ,, whereas, only, 23, ., 1, %, preferred, cocaine, to, heroin, ., outside, the, home, ,, 60, %, rats, preferred, cocaine, to, heroin, ,, whereas, only, 16, ., 7, %, preferred, heroin, to, cocaine, ., some, rats, (, 19, ., 2, %, at, home, and, 23, ., 3, %, outside, the, home, ), did, not, exhibit, a, significant, preference, for, either, drug, ., modified, from, de, luca, et, al, ., (, 2019, ), fig, ., 6, ##ex, ##per, ##ime, ##ntal, design, aimed, at, quan, ##tify, ##ing, the, decision, utility, of, heroin, seeking, and, cocaine, seeking, after, a, period, of, abs, ##tine, ##nce, from, the, drug, (, montana, ##ri, et, al, ., 2015, ), ., the, rats, were, first, trained, to, self, -, administer, heroin, and, cocaine, on, alternate, days, (, a, –, c, ), and, then, underwent, an, extinction, procedure, (, d, ), ,, during, which, lever, pressing, did, not, result, in, drug, in, ##fusion, even, in, the, presence, of, drug, -, paired, cues, (, e, ., g, ., ,, lever, extension, ,, cue, lights, ,, in, ##fusion, of, vehicle, ), ., the, rats, were, then, tested, in, a, reins, ##tate, ##ment, procedure, (, e, ), ,, developed, to, model, re, ##la, ##pse, into, drug, seeking, after, a, period, of, abs, ##tine, ##nce, ., the, ability, of, a, single, ,, non, ##con, ##ting, ##ent, intra, ##ven, ##ous, drug, in, ##fusion, (, drug, pri, ##ming, ), to, pre, ##ci, ##pit, ##ate, drug, seeking, was, assessed, by, comparing, lever, pressing, during, the, reins, ##tate, ##ment, session, to, lever, pressing, under, extinction, conditions, (, for, results, ,, see, fig, ., 7, ), fig, ., 7, ##me, ##an, (, ±, ##se, ##m, ), number, of, lever, presses, during, the, first, hour, of, the, last, extinction, session, (, white, bars, ), versus, the, reins, ##tate, ##ment, session, (, black, bars, ), for, rats, tested, at, home, versus, rats, outside, the, home, (, see, fig, ., 6, ), ., at, the, beginning, of, the, reins, ##tate, ##ment, session, ,, independent, groups, of, rats, (, n, values, are, indicated, by, the, numbers, within, the, white, bars, ), received, non, ##con, ##ting, ##ent, intra, ##ven, ##ous, (, i, ., v, ., ), in, ##fusion, ##s, of, one, of, three, doses, of, cocaine, (, top, panels, ), or, heroin, (, bottom, panels, ), ., significant, (, #, #, p, ≤, 0, ., 01, and, #, #, #, #, p, ≤, 0, ., 000, ##1, ), main, effect, of, pri, ##ming, ., data, from, montana, ##ri, et, al, ., (, 2015, )'},\n", + " {'article_id': '2afd98c52706b12bad139a461e64e517',\n", + " 'section_name': 'Functional characterization of NAP genes',\n", + " 'text': 'Sub-clustering of the 147 unique human orthologs within the PLN network reveals nine functionally distinct gene modules (Fig. 5a). Similar mouse modules were uncovered when grouping NAP genes based on gene expression dynamics across the developing mouse CNS (Supplementary Fig. 8), reinforcing the relevance of translational studies between human and mouse. The human module 2 was enriched for cell cycle-related GO annotations specifically the G2/M checkpoint (Fig. 5a; Supplementary Data 18), implicating these genes in early neurodevelopmental processes. By contrast, human modules 0 and 7 exhibit an excess of brain-specific (p = 0.002 and p = 0.045, respectively; right-tailed Fisher’s test) and human orthologs of FMRP target genes (p = 7.81E−04 and p = 0.030, respectively; Fig. 5b; right-tailed Fisher test). Moreover, module 0 is also enriched for human orthologs of mouse PSD and synaptosome genes (p = 7.81E−04 and p = 0.019, respectively; Fig. 5b; right-tailed Fisher’s test) and the associated genes are functionally annotated with the GO terms PSD (BH-p = 0.0015; right-tailed hypergeometric test), cell projection (BH-p = 0.040; right-tailed hypergeometric test), and cytoskeleton (BH-p = 0.026; right-tailed hypergeometric test) (Supplementary Data 18). While both modules possess neuronal functions, genes from module 0 are upregulated postnatally, while those in module 7 are upregulated in the fetal brain (Fig. 5c), suggesting that each module contributes to distinct neurodevelopmental and mature synaptic functions. Accordingly, modules 7 and 0 are enriched in different subsets of fetally and postnatally expressed FMRP target genes (p = 0.0038 and p = 0.0055, respectively; Fig. 5b; right-tailed Fisher test). In humans, disruptions of genes within the same neurodevelopmental pathway cause a similar pattern of pleiotropic phenotypes^33. Correspondingly, while no specific neuroanatomical abnormality was overrepresented among mouse models of orthologs belonging to the same human functional modules, an overall phenotypic convergence was observed for modules 2, 7, and 8 (Fig. 5d; Supplementary Notes) revealing neurodevelopmental pathway/phenotype relationships. Specifically, mouse orthologs of modules 2 and 7 yielded more similar brain abnormalities than other NAP genes across Bregma +0.98 mm but not Bregma −1.34 mm, while the opposite pattern was found for module 8 orthologs (Fig. 5d). Congruently, while genes from human modules 2 and 7 are more strongly expressed across tissues mapping to Bregma +0.98 mm than Bregma −1.34 mm, those from module 8 are more highly expressed across Bregma −1.34 mm tissues (Fig. 5c).Fig. 5Functional characterization of human gene modules. a The PLN (Phenotypic Linkage Network) identifies 381 functional links between 121 human orthologs of NeuroAnatomical Phenotype (NAP) genes, which partitioned into the 9 modules of closely related genes (illustrated by the color of the nodes). The thickness of each edge is proportional to the functional similarity score, as given by the PLN, and the color of each edge indicates the largest contributing information source. Red borders depict known ID-associated genes, whereas blue and green borders refer to the set of embryonically expressed and mature Fragile X Mental Retardation Protein (FMRP) target genes, respectively. Module descriptions were added, where clearly discernable. b Gene set enrichment analysis across the nine human modules. c Spatiotemporal expression dynamics of module genes compared to the remaining NAP orthologs. d The heat map depicts the similarity of brain abnormalities caused by module genes in the critical sections 1 and 2 (Bregma +0.98 mm and −1.34 mm, respectively). The color code corresponds to the adjusted p value with double S (§) referring to BH-p < 0.05 (c, d; permutation test). e New neuroanatomical study of Fmr1^−/Y in the coronal plane (n = 4 wild types (WTs) and n = 6 Fmr1^−/Y, male). Top: Schematic representation of the affected brain parameters at Bregma +0.98 mm and −1.34 mm. Numbers refer to the same brain parameters from Fig. 2b and Supplementary Fig. 2b, c. The color code indicates the unadjusted p value. Bottom: Histograms showing the percentage of increase/decrease of the brain parameters compared to WTs',\n", + " 'paragraph_id': 19,\n", + " 'tokenizer': 'sub, -, cluster, ##ing, of, the, 147, unique, human, or, ##th, ##olo, ##gs, within, the, pl, ##n, network, reveals, nine, functional, ##ly, distinct, gene, modules, (, fig, ., 5, ##a, ), ., similar, mouse, modules, were, uncovered, when, grouping, nap, genes, based, on, gene, expression, dynamics, across, the, developing, mouse, cn, ##s, (, supplementary, fig, ., 8, ), ,, rein, ##for, ##cing, the, relevance, of, translation, ##al, studies, between, human, and, mouse, ., the, human, module, 2, was, enriched, for, cell, cycle, -, related, go, ann, ##ota, ##tions, specifically, the, g, ##2, /, m, checkpoint, (, fig, ., 5, ##a, ;, supplementary, data, 18, ), ,, imp, ##lica, ##ting, these, genes, in, early, ne, ##uro, ##dev, ##elo, ##pment, ##al, processes, ., by, contrast, ,, human, modules, 0, and, 7, exhibit, an, excess, of, brain, -, specific, (, p, =, 0, ., 00, ##2, and, p, =, 0, ., 04, ##5, ,, respectively, ;, right, -, tailed, fisher, ’, s, test, ), and, human, or, ##th, ##olo, ##gs, of, fm, ##rp, target, genes, (, p, =, 7, ., 81, ##e, ##−, ##0, ##4, and, p, =, 0, ., 03, ##0, ,, respectively, ;, fig, ., 5, ##b, ;, right, -, tailed, fisher, test, ), ., moreover, ,, module, 0, is, also, enriched, for, human, or, ##th, ##olo, ##gs, of, mouse, ps, ##d, and, syn, ##ap, ##tos, ##ome, genes, (, p, =, 7, ., 81, ##e, ##−, ##0, ##4, and, p, =, 0, ., 01, ##9, ,, respectively, ;, fig, ., 5, ##b, ;, right, -, tailed, fisher, ’, s, test, ), and, the, associated, genes, are, functional, ##ly, ann, ##ota, ##ted, with, the, go, terms, ps, ##d, (, b, ##h, -, p, =, 0, ., 001, ##5, ;, right, -, tailed, hyper, ##ge, ##ometric, test, ), ,, cell, projection, (, b, ##h, -, p, =, 0, ., 04, ##0, ;, right, -, tailed, hyper, ##ge, ##ometric, test, ), ,, and, cy, ##tos, ##kel, ##eto, ##n, (, b, ##h, -, p, =, 0, ., 02, ##6, ;, right, -, tailed, hyper, ##ge, ##ometric, test, ), (, supplementary, data, 18, ), ., while, both, modules, possess, ne, ##uron, ##al, functions, ,, genes, from, module, 0, are, up, ##re, ##gul, ##ated, post, ##nat, ##ally, ,, while, those, in, module, 7, are, up, ##re, ##gul, ##ated, in, the, fetal, brain, (, fig, ., 5, ##c, ), ,, suggesting, that, each, module, contributes, to, distinct, ne, ##uro, ##dev, ##elo, ##pment, ##al, and, mature, syn, ##ap, ##tic, functions, ., accordingly, ,, modules, 7, and, 0, are, enriched, in, different, subset, ##s, of, fetal, ##ly, and, post, ##nat, ##ally, expressed, fm, ##rp, target, genes, (, p, =, 0, ., 00, ##38, and, p, =, 0, ., 00, ##55, ,, respectively, ;, fig, ., 5, ##b, ;, right, -, tailed, fisher, test, ), ., in, humans, ,, disruption, ##s, of, genes, within, the, same, ne, ##uro, ##dev, ##elo, ##pment, ##al, pathway, cause, a, similar, pattern, of, pl, ##ei, ##ot, ##rop, ##ic, ph, ##eno, ##type, ##s, ^, 33, ., corresponding, ##ly, ,, while, no, specific, ne, ##uro, ##ana, ##tom, ##ical, abnormal, ##ity, was, over, ##re, ##pres, ##ented, among, mouse, models, of, or, ##th, ##olo, ##gs, belonging, to, the, same, human, functional, modules, ,, an, overall, ph, ##eno, ##typic, convergence, was, observed, for, modules, 2, ,, 7, ,, and, 8, (, fig, ., 5, ##d, ;, supplementary, notes, ), revealing, ne, ##uro, ##dev, ##elo, ##pment, ##al, pathway, /, ph, ##eno, ##type, relationships, ., specifically, ,, mouse, or, ##th, ##olo, ##gs, of, modules, 2, and, 7, yielded, more, similar, brain, abnormalities, than, other, nap, genes, across, br, ##eg, ##ma, +, 0, ., 98, mm, but, not, br, ##eg, ##ma, −, ##1, ., 34, mm, ,, while, the, opposite, pattern, was, found, for, module, 8, or, ##th, ##olo, ##gs, (, fig, ., 5, ##d, ), ., cong, ##ru, ##ently, ,, while, genes, from, human, modules, 2, and, 7, are, more, strongly, expressed, across, tissues, mapping, to, br, ##eg, ##ma, +, 0, ., 98, mm, than, br, ##eg, ##ma, −, ##1, ., 34, mm, ,, those, from, module, 8, are, more, highly, expressed, across, br, ##eg, ##ma, −, ##1, ., 34, mm, tissues, (, fig, ., 5, ##c, ), ., fig, ., 5, ##fu, ##nction, ##al, characterization, of, human, gene, modules, ., a, the, pl, ##n, (, ph, ##eno, ##typic, link, ##age, network, ), identifies, 381, functional, links, between, 121, human, or, ##th, ##olo, ##gs, of, ne, ##uro, ##ana, ##tom, ##ical, ph, ##eno, ##type, (, nap, ), genes, ,, which, partition, ##ed, into, the, 9, modules, of, closely, related, genes, (, illustrated, by, the, color, of, the, nodes, ), ., the, thickness, of, each, edge, is, proportional, to, the, functional, similarity, score, ,, as, given, by, the, pl, ##n, ,, and, the, color, of, each, edge, indicates, the, largest, contributing, information, source, ., red, borders, depict, known, id, -, associated, genes, ,, whereas, blue, and, green, borders, refer, to, the, set, of, embryo, ##nical, ##ly, expressed, and, mature, fragile, x, mental, re, ##tar, ##dation, protein, (, fm, ##rp, ), target, genes, ,, respectively, ., module, descriptions, were, added, ,, where, clearly, disc, ##ern, ##able, ., b, gene, set, enrichment, analysis, across, the, nine, human, modules, ., c, spat, ##iot, ##em, ##por, ##al, expression, dynamics, of, module, genes, compared, to, the, remaining, nap, or, ##th, ##olo, ##gs, ., d, the, heat, map, depicts, the, similarity, of, brain, abnormalities, caused, by, module, genes, in, the, critical, sections, 1, and, 2, (, br, ##eg, ##ma, +, 0, ., 98, mm, and, −, ##1, ., 34, mm, ,, respectively, ), ., the, color, code, corresponds, to, the, adjusted, p, value, with, double, s, (, §, ), referring, to, b, ##h, -, p, <, 0, ., 05, (, c, ,, d, ;, per, ##mut, ##ation, test, ), ., e, new, ne, ##uro, ##ana, ##tom, ##ical, study, of, fm, ##r, ##1, ^, −, /, y, in, the, corona, ##l, plane, (, n, =, 4, wild, types, (, w, ##ts, ), and, n, =, 6, fm, ##r, ##1, ^, −, /, y, ,, male, ), ., top, :, sc, ##hema, ##tic, representation, of, the, affected, brain, parameters, at, br, ##eg, ##ma, +, 0, ., 98, mm, and, −, ##1, ., 34, mm, ., numbers, refer, to, the, same, brain, parameters, from, fig, ., 2, ##b, and, supplementary, fig, ., 2, ##b, ,, c, ., the, color, code, indicates, the, una, ##d, ##just, ##ed, p, value, ., bottom, :, his, ##to, ##gram, ##s, showing, the, percentage, of, increase, /, decrease, of, the, brain, parameters, compared, to, w, ##ts'},\n", + " {'article_id': '2fa692af7a18169772b20d2215d57106',\n", + " 'section_name': 'Atypical channel behavior of Q/R-edited GluA2',\n", + " 'text': 'When recording glutamate-evoked currents (10 mM,100 ms, –60 mV) in outside-out patches excised from HEK293 cells expressing homomeric GluA2 with and without γ-2, γ-8, or GSG1L, we observed unexpected differences in the behavior of the unedited (Q) and edited (R) forms (Fig. 1). Compared with that of the Q-forms, GluA2(R) desensitization was slower (Fig. 1a–c). The mean differences in the weighed time constants of desensitization (τ_w, des) between the R- and Q-forms were 4.53 ms (95% confidence interval, 3.71–5.35) for GluA2 alone, 2.13 ms (95% confidence interval, 0.49–3.90) for GluA2/γ-2, 6.36 ms (95% confidence interval, 2.91–9.65) for GluA2/γ-8, and 2.83 ms (95% confidence interval, 1.28–4.56) for GluA2/GSG1L. This slowing of desensitization by Q/R site editing was accompanied by a striking increase in fractional steady-state current for GluA2, GluA2/γ-2, and GluA2/γ-8 (Fig. 1a, b, d). The mean differences in I_SS (% peak) between the R- and Q-forms were 9.2 (95% confidence interval, 6.6–11.1) for GluA2 alone, 33.9 (95% confidence interval, 29.2–38.4) for GluA2/γ-2, and 24.2 (95% confidence interval, 18.5–30.1) for GluA2/γ-8. By contrast, I_SS was not increased in the case of GluA2/GSG1L (1.43; 95% confidence interval, –0.35; 3.25) (Fig. 1d). Of note (except for GluA2/GSG1L) Q/R site editing had a much more pronounced effect on the steady-state currents (~400–600% increase) than on the desensitization time course (~30–90% slowing).Fig. 1Q/R editing affects the kinetics and variance of GluA2 currents. a Representative outside-out patch response (10 mM glutamate, 100 ms, –60 mV; gray bar) from a HEK293 cell transfected with GluA2(Q)/γ-2 (average current, black; five individual responses, grays). Inset: current–variance relationship (dotted line indicates background variance and red circle indicates expected origin). b As a, but for GluA2(R)/γ-2. Note that the data cannot be fitted with a parabolic relationship passing through the origin. c Pooled τ_w,des data for GluA2 alone (n = 12 Q-form and 9 R-form), GluA2/γ-2 (n = 21 and 27), GluA2/γ-8 (n = 7 and 10), and GluA2/GSG1L (n = 6 and 13). Box-and-whisker plots indicate the median (black line), the 25–75th percentiles (box), and the 10–90th percentiles (whiskers); filled circles are data from individual patches and open circles indicate means. Two-way ANOVA revealed an effect of Q/R editing (F_1,97 = 111.34, P < 0.0001), an effect of auxiliary subunit type (F_3,97 = 32.3, P < 0.0001) and an interaction (F_3,97 = 2.84, P = 0.041). d Pooled data for I_ss. Box-and-whisker plots and n numbers as in c. Two-way ANOVA indicated an effect of Q/R editing (F_1,97 = 129.98, P < 0.0001), an effect of auxiliary subunit type (F_3,97 = 58.30, P < 0.0001), and an interaction (F_3,97 = 58.67, P < 0.0001). e Doubly normalized and averaged current–variance relationships (desensitizing current phase only) from GluA2(Q) and GluA2(R) expressed alone (n = 12 and 9), with γ-2 (n = 19 and 23), with γ-8 (n = 7 and 10), or with GSG1L (n = 6 and 13). Error bars are s.e.m.s. All Q-forms can be fitted with parabolic relationships passing through the origin, while R-forms cannot. f Pooled NSFA conductance estimates for GluA2(Q) alone, GluA2(Q)/γ-2, GluA2(Q)/γ-8, and GluA2(Q)/GSG1L (n = 12, 18, 7, and 6, respectively). Box-and-whisker plots as in c. Indicated P values are from Wilcoxon rank sum tests. Source data are provided as a Source Data file',\n", + " 'paragraph_id': 4,\n", + " 'tokenizer': 'when, recording, g, ##lu, ##tama, ##te, -, ev, ##oked, currents, (, 10, mm, ,, 100, ms, ,, –, 60, mv, ), in, outside, -, out, patches, ex, ##cise, ##d, from, he, ##k, ##29, ##3, cells, expressing, homo, ##meric, g, ##lu, ##a, ##2, with, and, without, γ, -, 2, ,, γ, -, 8, ,, or, gs, ##g, ##1, ##l, ,, we, observed, unexpected, differences, in, the, behavior, of, the, une, ##dit, ##ed, (, q, ), and, edited, (, r, ), forms, (, fig, ., 1, ), ., compared, with, that, of, the, q, -, forms, ,, g, ##lu, ##a, ##2, (, r, ), des, ##ens, ##iti, ##zation, was, slower, (, fig, ., 1a, –, c, ), ., the, mean, differences, in, the, weighed, time, constant, ##s, of, des, ##ens, ##iti, ##zation, (, τ, _, w, ,, des, ), between, the, r, -, and, q, -, forms, were, 4, ., 53, ms, (, 95, %, confidence, interval, ,, 3, ., 71, –, 5, ., 35, ), for, g, ##lu, ##a, ##2, alone, ,, 2, ., 13, ms, (, 95, %, confidence, interval, ,, 0, ., 49, –, 3, ., 90, ), for, g, ##lu, ##a, ##2, /, γ, -, 2, ,, 6, ., 36, ms, (, 95, %, confidence, interval, ,, 2, ., 91, –, 9, ., 65, ), for, g, ##lu, ##a, ##2, /, γ, -, 8, ,, and, 2, ., 83, ms, (, 95, %, confidence, interval, ,, 1, ., 28, –, 4, ., 56, ), for, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, ., this, slowing, of, des, ##ens, ##iti, ##zation, by, q, /, r, site, editing, was, accompanied, by, a, striking, increase, in, fraction, ##al, steady, -, state, current, for, g, ##lu, ##a, ##2, ,, g, ##lu, ##a, ##2, /, γ, -, 2, ,, and, g, ##lu, ##a, ##2, /, γ, -, 8, (, fig, ., 1a, ,, b, ,, d, ), ., the, mean, differences, in, i, _, ss, (, %, peak, ), between, the, r, -, and, q, -, forms, were, 9, ., 2, (, 95, %, confidence, interval, ,, 6, ., 6, –, 11, ., 1, ), for, g, ##lu, ##a, ##2, alone, ,, 33, ., 9, (, 95, %, confidence, interval, ,, 29, ., 2, –, 38, ., 4, ), for, g, ##lu, ##a, ##2, /, γ, -, 2, ,, and, 24, ., 2, (, 95, %, confidence, interval, ,, 18, ., 5, –, 30, ., 1, ), for, g, ##lu, ##a, ##2, /, γ, -, 8, ., by, contrast, ,, i, _, ss, was, not, increased, in, the, case, of, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, (, 1, ., 43, ;, 95, %, confidence, interval, ,, –, 0, ., 35, ;, 3, ., 25, ), (, fig, ., 1, ##d, ), ., of, note, (, except, for, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, ), q, /, r, site, editing, had, a, much, more, pronounced, effect, on, the, steady, -, state, currents, (, ~, 400, –, 600, %, increase, ), than, on, the, des, ##ens, ##iti, ##zation, time, course, (, ~, 30, –, 90, %, slowing, ), ., fig, ., 1, ##q, /, r, editing, affects, the, kinetic, ##s, and, variance, of, g, ##lu, ##a, ##2, currents, ., a, representative, outside, -, out, patch, response, (, 10, mm, g, ##lu, ##tama, ##te, ,, 100, ms, ,, –, 60, mv, ;, gray, bar, ), from, a, he, ##k, ##29, ##3, cell, trans, ##fect, ##ed, with, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, (, average, current, ,, black, ;, five, individual, responses, ,, gray, ##s, ), ., ins, ##et, :, current, –, variance, relationship, (, dotted, line, indicates, background, variance, and, red, circle, indicates, expected, origin, ), ., b, as, a, ,, but, for, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, ., note, that, the, data, cannot, be, fitted, with, a, para, ##bolic, relationship, passing, through, the, origin, ., c, poole, ##d, τ, _, w, ,, des, data, for, g, ##lu, ##a, ##2, alone, (, n, =, 12, q, -, form, and, 9, r, -, form, ), ,, g, ##lu, ##a, ##2, /, γ, -, 2, (, n, =, 21, and, 27, ), ,, g, ##lu, ##a, ##2, /, γ, -, 8, (, n, =, 7, and, 10, ), ,, and, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, (, n, =, 6, and, 13, ), ., box, -, and, -, w, ##his, ##ker, plots, indicate, the, median, (, black, line, ), ,, the, 25, –, 75th, percent, ##ile, ##s, (, box, ), ,, and, the, 10, –, 90, ##th, percent, ##ile, ##s, (, w, ##his, ##kers, ), ;, filled, circles, are, data, from, individual, patches, and, open, circles, indicate, means, ., two, -, way, an, ##ova, revealed, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 97, =, 111, ., 34, ,, p, <, 0, ., 000, ##1, ), ,, an, effect, of, auxiliary, subunit, type, (, f, _, 3, ,, 97, =, 32, ., 3, ,, p, <, 0, ., 000, ##1, ), and, an, interaction, (, f, _, 3, ,, 97, =, 2, ., 84, ,, p, =, 0, ., 04, ##1, ), ., d, poole, ##d, data, for, i, _, ss, ., box, -, and, -, w, ##his, ##ker, plots, and, n, numbers, as, in, c, ., two, -, way, an, ##ova, indicated, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 97, =, 129, ., 98, ,, p, <, 0, ., 000, ##1, ), ,, an, effect, of, auxiliary, subunit, type, (, f, _, 3, ,, 97, =, 58, ., 30, ,, p, <, 0, ., 000, ##1, ), ,, and, an, interaction, (, f, _, 3, ,, 97, =, 58, ., 67, ,, p, <, 0, ., 000, ##1, ), ., e, do, ##ub, ##ly, normal, ##ized, and, averaged, current, –, variance, relationships, (, des, ##ens, ##iti, ##zing, current, phase, only, ), from, g, ##lu, ##a, ##2, (, q, ), and, g, ##lu, ##a, ##2, (, r, ), expressed, alone, (, n, =, 12, and, 9, ), ,, with, γ, -, 2, (, n, =, 19, and, 23, ), ,, with, γ, -, 8, (, n, =, 7, and, 10, ), ,, or, with, gs, ##g, ##1, ##l, (, n, =, 6, and, 13, ), ., error, bars, are, s, ., e, ., m, ., s, ., all, q, -, forms, can, be, fitted, with, para, ##bolic, relationships, passing, through, the, origin, ,, while, r, -, forms, cannot, ., f, poole, ##d, ns, ##fa, conduct, ##ance, estimates, for, g, ##lu, ##a, ##2, (, q, ), alone, ,, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, ,, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 8, ,, and, g, ##lu, ##a, ##2, (, q, ), /, gs, ##g, ##1, ##l, (, n, =, 12, ,, 18, ,, 7, ,, and, 6, ,, respectively, ), ., box, -, and, -, w, ##his, ##ker, plots, as, in, c, ., indicated, p, values, are, from, wilcox, ##on, rank, sum, tests, ., source, data, are, provided, as, a, source, data, file'},\n", + " {'article_id': '2fa692af7a18169772b20d2215d57106',\n", + " 'section_name': 'Low conductance steady-state openings follow desensitization',\n", + " 'text': 'As conventional current–variance relationships could be produced only from GluA2(R)/γ-2 activation and not desensitization (nor indeed from deactivation, during which there is a degree of desensitization) we speculated that desensitization itself may provide the key to our unexpected results. We hypothesized that the conformational rearrangements of the LBDs which normally trigger desensitization might not fully close the ion channel, such that the GluA2(R)/γ-2 receptors could adopt a conducting desensitized state, giving rise to the large fractional steady-state current and the anomalous current–variance relationships. If this were the case, and the shift from large resolvable channel openings to smaller openings was linked to the process of desensitization, a decline in GluA2(R)/γ-2 single-channel conductance (and therefore macroscopic current) would not be expected if desensitization was blocked. In the presence of cyclothiazide, which inhibits desensitization by stabilizing the upper LBD dimer interface^14, we found that GluA2(R)/γ-2 macroscopic currents (10 mM glutamate, 1 s) did not decay (Fig. 4a). Likewise, if the low-noise steady-state current of GluA2(R)/γ-2 arose from conducting desensitized channels, then we would expect the steady-state current to remain when desensitization was enhanced. To test this idea, we used the point mutation S754D. This weakens the upper LBD dimer interface, accelerating desensitization and reducing steady-state currents of GluA2(Q)^14. For both GluA2(Q)/γ-2 and GluA2(R)/γ-2 the S754D mutation produced a near 20-fold acceleration of desensitization (Fig. 4b, c) and a greater than twofold slowing of recovery from desensitization (Fig. 4d). As anticipated, GluA2(Q) S754D/γ-2 produced a negligible steady-state current (Fig. 4b, e). In marked contrast, GluA2(R) S754D/γ-2 exhibited an appreciable steady-state current (Fig. 4b, e). The presence of a large steady-state current with GluA2(R)/γ-2 under conditions strongly favoring desensitization is consistent with the view that desensitized channels can conduct.Fig. 4Large steady-state GluA2(R)/γ-2 currents are observed even in conditions favoring desensitization. a Representative GluA2(R)/γ-2 current (–60 mV) evoked by 10 mM glutamate (gray bar) in the presence of 50 μM cyclothiazide (green bar). Note the minimal current decay when desensitization is inhibited (for pooled data I_SS/I_peak = 93.4 ± 1.6%, n = 6) (mean ± s.e.m. from n patches). b Representative glutamate-evoked currents from Q- and R-forms of GluA2 S754D/γ-2. Both forms exhibit very fast desensitization, but the R-form has an appreciable steady-state current. c Pooled data showing desensitization kinetics (τ_w,des) for wild-type (wt; n = 6 and 5) and mutant (S754D; n = 5 and 5) forms of GluA2(Q)/γ-2 and GluA2(R)/γ-2. Box-and-whisker plots as in Fig. 1c. Two-way ANOVA indicated an effect of Q/R editing (F_1, 17 = 10.56, P = 0.0047), an effect of the mutation (F_1, 17 = 43.19, P < 0.0001) but no interaction (F_1, 17 = 2.63, P = 0.12). The mean difference between S754D and wild type was –8.1 ms (95% confidence interval, –10.9 to –6.0) for Q and –14.1 ms (95% confidence interval, –20.0 to –9.3) for R. d Pooled data (as in c) for recovery kinetics (τ_w,recov). Two-way ANOVA indicated no effect of Q/R editing (F_1, 17 = 0.13, P = 0.72), an effect of the mutation (F_1, 17 = 31.67, P < 0.0001) but no interaction (F_1, 17 = 1.65, P = 0.22). The mean difference between S754D and wild type was 24.1 ms (95% confidence interval, 15.3 to 33.2) for Q and 38.7 ms (95% confidence interval, 23.7 to 53.9) for R. e Pooled data (as in c) for the fractional steady-state current (I_SS). Two-way ANOVA indicated an effect of Q/R editing (F_1, 17 = 65.37, P < 0.0001), an effect of the mutation (F_1, 17 = 28.37, P < 0.0001), and an interaction (F_1, 17 = 14.93, P = 0.0012). The mean difference in I_SS (% of peak) between S754D and wild type was –7.7 (95% confidence interval, –11.2 to –5.2) for Q and –37.9 (95% confidence interval, –49.2 to –25.8) for R. Indicated P values are from Welch t-tests. Source data are provided as a Source Data file',\n", + " 'paragraph_id': 11,\n", + " 'tokenizer': 'as, conventional, current, –, variance, relationships, could, be, produced, only, from, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, activation, and, not, des, ##ens, ##iti, ##zation, (, nor, indeed, from, dea, ##ct, ##ivation, ,, during, which, there, is, a, degree, of, des, ##ens, ##iti, ##zation, ), we, speculated, that, des, ##ens, ##iti, ##zation, itself, may, provide, the, key, to, our, unexpected, results, ., we, h, ##yp, ##oth, ##es, ##ized, that, the, conform, ##ation, ##al, rear, ##rang, ##ement, ##s, of, the, lb, ##ds, which, normally, trigger, des, ##ens, ##iti, ##zation, might, not, fully, close, the, ion, channel, ,, such, that, the, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, receptors, could, adopt, a, conducting, des, ##ens, ##iti, ##zed, state, ,, giving, rise, to, the, large, fraction, ##al, steady, -, state, current, and, the, an, ##oma, ##lous, current, –, variance, relationships, ., if, this, were, the, case, ,, and, the, shift, from, large, res, ##ol, ##vable, channel, openings, to, smaller, openings, was, linked, to, the, process, of, des, ##ens, ##iti, ##zation, ,, a, decline, in, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, single, -, channel, conduct, ##ance, (, and, therefore, macro, ##scopic, current, ), would, not, be, expected, if, des, ##ens, ##iti, ##zation, was, blocked, ., in, the, presence, of, cy, ##cloth, ##ia, ##zi, ##de, ,, which, inhibit, ##s, des, ##ens, ##iti, ##zation, by, stab, ##ili, ##zing, the, upper, lb, ##d, dime, ##r, interface, ^, 14, ,, we, found, that, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, macro, ##scopic, currents, (, 10, mm, g, ##lu, ##tama, ##te, ,, 1, s, ), did, not, decay, (, fig, ., 4a, ), ., likewise, ,, if, the, low, -, noise, steady, -, state, current, of, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, arose, from, conducting, des, ##ens, ##iti, ##zed, channels, ,, then, we, would, expect, the, steady, -, state, current, to, remain, when, des, ##ens, ##iti, ##zation, was, enhanced, ., to, test, this, idea, ,, we, used, the, point, mutation, s, ##75, ##4, ##d, ., this, weaken, ##s, the, upper, lb, ##d, dime, ##r, interface, ,, accelerating, des, ##ens, ##iti, ##zation, and, reducing, steady, -, state, currents, of, g, ##lu, ##a, ##2, (, q, ), ^, 14, ., for, both, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, and, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, the, s, ##75, ##4, ##d, mutation, produced, a, near, 20, -, fold, acceleration, of, des, ##ens, ##iti, ##zation, (, fig, ., 4, ##b, ,, c, ), and, a, greater, than, two, ##fold, slowing, of, recovery, from, des, ##ens, ##iti, ##zation, (, fig, ., 4, ##d, ), ., as, anticipated, ,, g, ##lu, ##a, ##2, (, q, ), s, ##75, ##4, ##d, /, γ, -, 2, produced, a, ne, ##gli, ##gible, steady, -, state, current, (, fig, ., 4, ##b, ,, e, ), ., in, marked, contrast, ,, g, ##lu, ##a, ##2, (, r, ), s, ##75, ##4, ##d, /, γ, -, 2, exhibited, an, app, ##re, ##cia, ##ble, steady, -, state, current, (, fig, ., 4, ##b, ,, e, ), ., the, presence, of, a, large, steady, -, state, current, with, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, under, conditions, strongly, favor, ##ing, des, ##ens, ##iti, ##zation, is, consistent, with, the, view, that, des, ##ens, ##iti, ##zed, channels, can, conduct, ., fig, ., 4, ##lar, ##ge, steady, -, state, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, currents, are, observed, even, in, conditions, favor, ##ing, des, ##ens, ##iti, ##zation, ., a, representative, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, current, (, –, 60, mv, ), ev, ##oked, by, 10, mm, g, ##lu, ##tama, ##te, (, gray, bar, ), in, the, presence, of, 50, μ, ##m, cy, ##cloth, ##ia, ##zi, ##de, (, green, bar, ), ., note, the, minimal, current, decay, when, des, ##ens, ##iti, ##zation, is, inhibit, ##ed, (, for, poole, ##d, data, i, _, ss, /, i, _, peak, =, 93, ., 4, ±, 1, ., 6, %, ,, n, =, 6, ), (, mean, ±, s, ., e, ., m, ., from, n, patches, ), ., b, representative, g, ##lu, ##tama, ##te, -, ev, ##oked, currents, from, q, -, and, r, -, forms, of, g, ##lu, ##a, ##2, s, ##75, ##4, ##d, /, γ, -, 2, ., both, forms, exhibit, very, fast, des, ##ens, ##iti, ##zation, ,, but, the, r, -, form, has, an, app, ##re, ##cia, ##ble, steady, -, state, current, ., c, poole, ##d, data, showing, des, ##ens, ##iti, ##zation, kinetic, ##s, (, τ, _, w, ,, des, ), for, wild, -, type, (, w, ##t, ;, n, =, 6, and, 5, ), and, mutant, (, s, ##75, ##4, ##d, ;, n, =, 5, and, 5, ), forms, of, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, and, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, ., box, -, and, -, w, ##his, ##ker, plots, as, in, fig, ., 1, ##c, ., two, -, way, an, ##ova, indicated, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 17, =, 10, ., 56, ,, p, =, 0, ., 00, ##47, ), ,, an, effect, of, the, mutation, (, f, _, 1, ,, 17, =, 43, ., 19, ,, p, <, 0, ., 000, ##1, ), but, no, interaction, (, f, _, 1, ,, 17, =, 2, ., 63, ,, p, =, 0, ., 12, ), ., the, mean, difference, between, s, ##75, ##4, ##d, and, wild, type, was, –, 8, ., 1, ms, (, 95, %, confidence, interval, ,, –, 10, ., 9, to, –, 6, ., 0, ), for, q, and, –, 14, ., 1, ms, (, 95, %, confidence, interval, ,, –, 20, ., 0, to, –, 9, ., 3, ), for, r, ., d, poole, ##d, data, (, as, in, c, ), for, recovery, kinetic, ##s, (, τ, _, w, ,, rec, ##ov, ), ., two, -, way, an, ##ova, indicated, no, effect, of, q, /, r, editing, (, f, _, 1, ,, 17, =, 0, ., 13, ,, p, =, 0, ., 72, ), ,, an, effect, of, the, mutation, (, f, _, 1, ,, 17, =, 31, ., 67, ,, p, <, 0, ., 000, ##1, ), but, no, interaction, (, f, _, 1, ,, 17, =, 1, ., 65, ,, p, =, 0, ., 22, ), ., the, mean, difference, between, s, ##75, ##4, ##d, and, wild, type, was, 24, ., 1, ms, (, 95, %, confidence, interval, ,, 15, ., 3, to, 33, ., 2, ), for, q, and, 38, ., 7, ms, (, 95, %, confidence, interval, ,, 23, ., 7, to, 53, ., 9, ), for, r, ., e, poole, ##d, data, (, as, in, c, ), for, the, fraction, ##al, steady, -, state, current, (, i, _, ss, ), ., two, -, way, an, ##ova, indicated, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 17, =, 65, ., 37, ,, p, <, 0, ., 000, ##1, ), ,, an, effect, of, the, mutation, (, f, _, 1, ,, 17, =, 28, ., 37, ,, p, <, 0, ., 000, ##1, ), ,, and, an, interaction, (, f, _, 1, ,, 17, =, 14, ., 93, ,, p, =, 0, ., 001, ##2, ), ., the, mean, difference, in, i, _, ss, (, %, of, peak, ), between, s, ##75, ##4, ##d, and, wild, type, was, –, 7, ., 7, (, 95, %, confidence, interval, ,, –, 11, ., 2, to, –, 5, ., 2, ), for, q, and, –, 37, ., 9, (, 95, %, confidence, interval, ,, –, 49, ., 2, to, –, 25, ., 8, ), for, r, ., indicated, p, values, are, from, welch, t, -, tests, ., source, data, are, provided, as, a, source, data, file'},\n", + " {'article_id': 'a0f24e75876344036375246a431899e7',\n", + " 'section_name': 'Monomeric Olfm1^Olf',\n", + " 'text': 'We determined a high-resolution crystal structure of Endo-H-deglycosylated Olfm1^Olf (Fig. 4), which leaves a single acetylglucosamine (GlcNAc) attached to glycosylated asparagines. The deglycosylation step often aids crystallisation. Our best crystal diffracted to 1.25 Å resolution (Table 1), representing the highest resolution crystal structure of an Olfactomedin domain to date. The highly conserved monomeric Olf domain has a five-bladed β-propeller fold with a central metal ion binding site [29–34, 50]. The structure shows a high degree of similarity to the Olf-domain dimer in our previously-determined structure of a dimeric Olfm1^coil-Olf (PDB 5AMO) [6] (C_α RMSD of 0.55 Å, Fig. 5). A human Olfm1 Olf domain structure derived from bacterially-expressed protein [35] has a very similar structure to our mouse Olfm1^Olf (C_α RMSD of 0.44 Å, Fig. 6), other than it lacking N-linked glycosylation as a result of the expression system. Comparing the structures of mouse Olfm1^Olf and human Olfm1^Olf [35] with that of Olfm1^coil-Olf, reveals structural rearrangements arising from the coordination of the Ca^2+ and Na^+ ions, that are not present in our previously determined structure of Olfm1^coil-Olf [6].\\nFig. 4High-resolution crystal structure of Olfm1^Olf to 1.25 Å with bound Na^+ and Ca^2+ ions reveals a structured switch loop and a water tunnel running to the metal ion binding sites. a Overview of the Olfm1^Olf β-propeller domain with the bound Na^+ (purple) and Ca^2+ (green) ions. The switch loop is indicated in violet, the water tunnel in green, the hydrophobic plug residues closing the tunnel in dark red and individual water molecules in the tunnel are represented as red spheres. The intra-chain disulfide between Cys227 and Cys409 is shown in sticks representation. b Close-up of the metal ion binding site with 2F_o-F_c electron density contoured at 2.5 σ. Metal ion-coordinating interactions are shown as black dashes and the hydrogen bond of the coordinating carboxylic acid group of Asp356 with the hydroxyl group of Tyr347 in the switch loop is indicated in green. c Analysis of the tunnel radius by HOLE [48]\\nTable 1Data collection and processing statisticsData CollectionPDB ID6QHJ (Olfm1^Olf)6QM3 (Olfm1^coil-Olf)BeamlineESRF ID30A-3DLS I03Resolution range (Å)^a36.76–1.25 (1.29–1.25)75.99–1.89 (2.10–1.89)Wavelength (Å)0.96770.9762Space GroupI222C2Unit Cell Dimensionsa, b, c (Å)61.79, 79.63, 111.72160.7, 47.0, 105.0α, β, γ90.0, 90.0, 90.090.0, 117.4, 90.0Measured reflections416,91095,762Unique reflections72,02829,117Mean I/σ13.7 (1.0)10.3 (1.7)Completeness (%)94.6 (63.9)92.2 (77.2)Redundancy5.8 (2.4)3.3 (3.4)R_merge (%)8.4 (90.8)6.0 (75.1)CC_1/20.998 (0.445)0.998 (0.551)Data RefinementResolution Range (Å)33.75–1.2571.30–2.00Total reflections72,02728,629Test set36231459R_work0.1240.179R_free0.1410.216No. of protein atoms43744321No. of ligand atoms156133No. of water atoms29899RMSD from idealBonds (Å)0.0100.007Angles (°)1.1680.852Mean B factor (Å^2)17.2549.09RamachandranFavoured (%)96.896.4Outliers (%)0.40.0Clashscore^b1.113.58^aNumbers in parentheses correspond to values for the highest resolution shell^bValue calculated by MolProbity [49]\\nFig. 5Comparison of Olfm1^Olf domain in the Ca^2+- and Na^+-bound state in grey with the previously-published apo state in teal [6]. The switch loop (violet) is only resolved in the Ca^2+- and Na^+-bound state. In the apo state, the negatively-charged side chains of Asp356, Glu404 and Asp453 are pushed outward in the absence of compensating positive charges from the Na^+ and Ca^2+ ions (indicated by arrows in the right panel). This most likely destabilises the conformation of the switch loop (violet) via Tyr347, which consequently is unstructured (indicated by a dashed line in the left panel) and thus not observed in the electron density of the apo form [6]. The intra-chain disulfide between Cys227 and Cys409 is shown in stick representation\\nFig. 6Mouse Olfm1^Olf and human Olfm1^Olf are very similar. Structural comparison of mouse Olfm1^Olf produced in mammalian (HEK293) cell line (grey) with human Olfm1^Olf produced in a bacterial expression system (PDB 4XAT, yellow) [35], both with bound Na^+ and Ca^2+, shows a high degree of similarity (C_α RMSD of 0.44). The switch loop (violet) is stabilised by bound Ca^2+ and Na^+ ions in both structures',\n", + " 'paragraph_id': 19,\n", + " 'tokenizer': 'we, determined, a, high, -, resolution, crystal, structure, of, end, ##o, -, h, -, de, ##gly, ##cos, ##yla, ##ted, ol, ##fm, ##1, ^, ol, ##f, (, fig, ., 4, ), ,, which, leaves, a, single, ace, ##ty, ##l, ##gl, ##uc, ##osa, ##mine, (, g, ##lc, ##nac, ), attached, to, g, ##ly, ##cos, ##yla, ##ted, as, ##para, ##gin, ##es, ., the, de, ##gly, ##cos, ##yla, ##tion, step, often, aids, crystal, ##lis, ##ation, ., our, best, crystal, di, ##ff, ##rac, ##ted, to, 1, ., 25, a, resolution, (, table, 1, ), ,, representing, the, highest, resolution, crystal, structure, of, an, ol, ##fa, ##ct, ##ome, ##din, domain, to, date, ., the, highly, conserved, mono, ##meric, ol, ##f, domain, has, a, five, -, bladed, β, -, propeller, fold, with, a, central, metal, ion, binding, site, [, 29, –, 34, ,, 50, ], ., the, structure, shows, a, high, degree, of, similarity, to, the, ol, ##f, -, domain, dime, ##r, in, our, previously, -, determined, structure, of, a, dime, ##ric, ol, ##fm, ##1, ^, coil, -, ol, ##f, (, pd, ##b, 5, ##amo, ), [, 6, ], (, c, _, α, rms, ##d, of, 0, ., 55, a, ,, fig, ., 5, ), ., a, human, ol, ##fm, ##1, ol, ##f, domain, structure, derived, from, bacterial, ##ly, -, expressed, protein, [, 35, ], has, a, very, similar, structure, to, our, mouse, ol, ##fm, ##1, ^, ol, ##f, (, c, _, α, rms, ##d, of, 0, ., 44, a, ,, fig, ., 6, ), ,, other, than, it, lacking, n, -, linked, g, ##ly, ##cos, ##yla, ##tion, as, a, result, of, the, expression, system, ., comparing, the, structures, of, mouse, ol, ##fm, ##1, ^, ol, ##f, and, human, ol, ##fm, ##1, ^, ol, ##f, [, 35, ], with, that, of, ol, ##fm, ##1, ^, coil, -, ol, ##f, ,, reveals, structural, rear, ##rang, ##ement, ##s, arising, from, the, coordination, of, the, ca, ^, 2, +, and, na, ^, +, ions, ,, that, are, not, present, in, our, previously, determined, structure, of, ol, ##fm, ##1, ^, coil, -, ol, ##f, [, 6, ], ., fig, ., 4, ##hi, ##gh, -, resolution, crystal, structure, of, ol, ##fm, ##1, ^, ol, ##f, to, 1, ., 25, a, with, bound, na, ^, +, and, ca, ^, 2, +, ions, reveals, a, structured, switch, loop, and, a, water, tunnel, running, to, the, metal, ion, binding, sites, ., a, overview, of, the, ol, ##fm, ##1, ^, ol, ##f, β, -, propeller, domain, with, the, bound, na, ^, +, (, purple, ), and, ca, ^, 2, +, (, green, ), ions, ., the, switch, loop, is, indicated, in, violet, ,, the, water, tunnel, in, green, ,, the, hydro, ##phobic, plug, residues, closing, the, tunnel, in, dark, red, and, individual, water, molecules, in, the, tunnel, are, represented, as, red, spheres, ., the, intra, -, chain, di, ##sul, ##fide, between, cy, ##s, ##22, ##7, and, cy, ##s, ##40, ##9, is, shown, in, sticks, representation, ., b, close, -, up, of, the, metal, ion, binding, site, with, 2, ##f, _, o, -, f, _, c, electron, density, con, ##tour, ##ed, at, 2, ., 5, σ, ., metal, ion, -, coordinating, interactions, are, shown, as, black, dash, ##es, and, the, hydrogen, bond, of, the, coordinating, car, ##box, ##yl, ##ic, acid, group, of, as, ##p, ##35, ##6, with, the, hydro, ##xy, ##l, group, of, ty, ##r, ##34, ##7, in, the, switch, loop, is, indicated, in, green, ., c, analysis, of, the, tunnel, radius, by, hole, [, 48, ], table, 1, ##da, ##ta, collection, and, processing, statistics, ##da, ##ta, collection, ##pd, ##b, id, ##6, ##q, ##h, ##j, (, ol, ##fm, ##1, ^, ol, ##f, ), 6, ##q, ##m, ##3, (, ol, ##fm, ##1, ^, coil, -, ol, ##f, ), beam, ##line, ##es, ##rf, id, ##30, ##a, -, 3d, ##ls, i, ##0, ##3, ##res, ##ol, ##ution, range, (, a, ), ^, a, ##36, ., 76, –, 1, ., 25, (, 1, ., 29, –, 1, ., 25, ), 75, ., 99, –, 1, ., 89, (, 2, ., 10, –, 1, ., 89, ), wavelength, (, a, ), 0, ., 96, ##7, ##70, ., 97, ##6, ##2, ##space, group, ##i, ##22, ##2, ##c, ##2, ##uni, ##t, cell, dimensions, ##a, ,, b, ,, c, (, a, ), 61, ., 79, ,, 79, ., 63, ,, 111, ., 72, ##16, ##0, ., 7, ,, 47, ., 0, ,, 105, ., 0, ##α, ,, β, ,, γ, ##90, ., 0, ,, 90, ., 0, ,, 90, ., 09, ##0, ., 0, ,, 117, ., 4, ,, 90, ., 0, ##me, ##as, ##ured, reflections, ##41, ##6, ,, 910, ##9, ##5, ,, 76, ##2, ##uni, ##que, reflections, ##7, ##2, ,, 02, ##8, ##29, ,, 117, ##me, ##an, i, /, σ, ##13, ., 7, (, 1, ., 0, ), 10, ., 3, (, 1, ., 7, ), complete, ##ness, (, %, ), 94, ., 6, (, 63, ., 9, ), 92, ., 2, (, 77, ., 2, ), red, ##unda, ##ncy, ##5, ., 8, (, 2, ., 4, ), 3, ., 3, (, 3, ., 4, ), r, _, merge, (, %, ), 8, ., 4, (, 90, ., 8, ), 6, ., 0, (, 75, ., 1, ), cc, _, 1, /, 20, ., 99, ##8, (, 0, ., 44, ##5, ), 0, ., 99, ##8, (, 0, ., 55, ##1, ), data, ref, ##ine, ##ment, ##res, ##ol, ##ution, range, (, a, ), 33, ., 75, –, 1, ., 257, ##1, ., 30, –, 2, ., 00, ##to, ##tal, reflections, ##7, ##2, ,, 02, ##7, ##28, ,, 62, ##9, ##test, set, ##36, ##23, ##14, ##59, ##r, _, work, ##0, ., 124, ##0, ., 179, ##r, _, free, ##0, ., 141, ##0, ., 216, ##no, ., of, protein, atoms, ##43, ##7, ##44, ##32, ##1, ##no, ., of, ligand, atoms, ##15, ##6, ##13, ##3, ##no, ., of, water, atoms, ##29, ##8, ##9, ##9, ##rm, ##sd, from, ideal, ##bon, ##ds, (, a, ), 0, ., 01, ##00, ., 00, ##7, ##ang, ##les, (, °, ), 1, ., 1680, ., 85, ##2, ##me, ##an, b, factor, (, a, ^, 2, ), 17, ., 254, ##9, ., 09, ##rama, ##chan, ##dran, ##fa, ##vo, ##ured, (, %, ), 96, ., 89, ##6, ., 4, ##out, ##lier, ##s, (, %, ), 0, ., 40, ., 0, ##cl, ##ash, ##sco, ##re, ^, b1, ., 113, ., 58, ^, an, ##umber, ##s, in, parentheses, correspond, to, values, for, the, highest, resolution, shell, ^, b, ##val, ##ue, calculated, by, mo, ##lp, ##ro, ##bit, ##y, [, 49, ], fig, ., 5, ##com, ##par, ##ison, of, ol, ##fm, ##1, ^, ol, ##f, domain, in, the, ca, ^, 2, +, -, and, na, ^, +, -, bound, state, in, grey, with, the, previously, -, published, ap, ##o, state, in, tea, ##l, [, 6, ], ., the, switch, loop, (, violet, ), is, only, resolved, in, the, ca, ^, 2, +, -, and, na, ^, +, -, bound, state, ., in, the, ap, ##o, state, ,, the, negatively, -, charged, side, chains, of, as, ##p, ##35, ##6, ,, g, ##lu, ##40, ##4, and, as, ##p, ##45, ##3, are, pushed, outward, in, the, absence, of, com, ##pen, ##sat, ##ing, positive, charges, from, the, na, ^, +, and, ca, ^, 2, +, ions, (, indicated, by, arrows, in, the, right, panel, ), ., this, most, likely, des, ##ta, ##bilis, ##es, the, conform, ##ation, of, the, switch, loop, (, violet, ), via, ty, ##r, ##34, ##7, ,, which, consequently, is, un, ##st, ##ructured, (, indicated, by, a, dashed, line, in, the, left, panel, ), and, thus, not, observed, in, the, electron, density, of, the, ap, ##o, form, [, 6, ], ., the, intra, -, chain, di, ##sul, ##fide, between, cy, ##s, ##22, ##7, and, cy, ##s, ##40, ##9, is, shown, in, stick, representation, fig, ., 6, ##mous, ##e, ol, ##fm, ##1, ^, ol, ##f, and, human, ol, ##fm, ##1, ^, ol, ##f, are, very, similar, ., structural, comparison, of, mouse, ol, ##fm, ##1, ^, ol, ##f, produced, in, mammalian, (, he, ##k, ##29, ##3, ), cell, line, (, grey, ), with, human, ol, ##fm, ##1, ^, ol, ##f, produced, in, a, bacterial, expression, system, (, pd, ##b, 4, ##xa, ##t, ,, yellow, ), [, 35, ], ,, both, with, bound, na, ^, +, and, ca, ^, 2, +, ,, shows, a, high, degree, of, similarity, (, c, _, α, rms, ##d, of, 0, ., 44, ), ., the, switch, loop, (, violet, ), is, stab, ##ilised, by, bound, ca, ^, 2, +, and, na, ^, +, ions, in, both, structures'},\n", + " {'article_id': 'a0f24e75876344036375246a431899e7',\n", + " 'section_name': 'Monomeric Olfm1^Olf',\n", + " 'text': 'Because of the high resolution of our Olfm1^Olf diffraction data to 1.25 Å, we can unambiguously assign a Na^+ and a Ca^2+ ion bound in the central cavity of the β-propeller. Metal ion assignment was based on previous binding data [6, 35], coordination distances (Table 2) [51] and fit to the electron density. The Ca^2+ ion is coordinated by the negatively-charged carboxyl groups of the side chains of Asp356, Asp453 and Glu404, as well as by the backbone carbonyl groups of Ala405 and Leu452 and a single water molecule (Fig. 4b and Table 2 for coordination distances and angles). The Na^+ ion is also coordinated by the carboxylic acid groups of the side chains of both Asp356 and Asp453, as well as by the backbone carbonyl group of Leu357 and a different water molecule than the one coordinating the calcium ion (Fig. 4b, Table 2). In sum, three formal negative charges of the carboxylic acid groups of the side chains of Asp356, Asp453 and Glu404 are compensated by three formal positive charges of the bound Ca^2+ and Na^+ ions.\\nTable 2Distances and angles of metal ion coordination in the Olfm1^Olf crystal structureDistances:Angles:distance (Å)angle (°)CalciumASP356 O_(carboxylate)2.3ASP356 O_(carboxylate)CalciumGLU404 O_(carboxylate)86.7CalciumGLU404 O_(carboxylate)2.3ASP356 O_(carboxylate)CalciumALA405 O_(carbonyl)93.1CalciumALA405 O_(carbonyl)2.3ASP356 O_(carboxylate)CalciumASP453 O_(carboxylate)105.5CalciumLEU452 O_(carbonyl)2.3ASP356 O_(carboxylate)CalciumH_2O94.1CalciumASP453 O_(carboxylate)2.3GLU404 O_(carboxylate)CalciumALA405 O_(carbonyl)83.0CalciumH_2O2.4GLU404 O_(carboxylate)CalciumLEU452 O_(carbonyl)83.7GLU404 O_(carboxylate)CalciumH_2O82.7SodiumGLY302 O_(carbonyl)2.9ALA405 O_(carbonyl)CalciumLEU452 O_(carbonyl)89.2SodiumGLN303 O_(carbonyl)3.0ALA405 O_(carbonyl)CalciumASP453 O_(carboxylate)103.8SodiumASP356 O_(carboxylate)2.3LEU452 O_(carbonyl)CalciumH_2O81.4SodiumLEU357 O_(carbonyl)2.2LEU452 O_(carbonyl)CalciumASP453 O_(carboxylate)83.6SodiumASP453 O_(carboxylate)2.3ASP453 O_(carboxylate)CalciumH_2O88.4SodiumH_2O2.4GLY302 O_(carbonyl)SodiumGLN303 O_(carbonyl)66.6ASP356 O_(carboxylate)TYR347 O_(hydroxyl)2.7GLY302 O_(carbonyl)SodiumASP356 O_(carboxylate)88.5GLY302 O_(carbonyl)SodiumLEU357 O_(carbonyl)78.3GLY302 O_(carbonyl)SodiumH_2O98.6GLN303 O_(carbonyl)SodiumLEU357 O_(carbonyl)88.4GLN303 O (carbonyl)SodiumASP453 O_(carboxylate)95.8GLN303 O (carbonyl)SodiumH_2O71.0ASP356 O_(carboxylate)SodiumLEU357 O_(carbonyl)101.4ASP356 O_(carboxylate)SodiumASP453 O_(carboxylate)109.4ASP356 O_(carboxylate)SodiumH_2O99.9LEU357 O_(carbonyl)SodiumASP453 O_(carboxylate)98.5ASP453 O_(carboxylate)SodiumH_2O77.8',\n", + " 'paragraph_id': 20,\n", + " 'tokenizer': 'because, of, the, high, resolution, of, our, ol, ##fm, ##1, ^, ol, ##f, di, ##ff, ##raction, data, to, 1, ., 25, a, ,, we, can, una, ##mb, ##ig, ##uously, assign, a, na, ^, +, and, a, ca, ^, 2, +, ion, bound, in, the, central, cavity, of, the, β, -, propeller, ., metal, ion, assignment, was, based, on, previous, binding, data, [, 6, ,, 35, ], ,, coordination, distances, (, table, 2, ), [, 51, ], and, fit, to, the, electron, density, ., the, ca, ^, 2, +, ion, is, coordinated, by, the, negatively, -, charged, car, ##box, ##yl, groups, of, the, side, chains, of, as, ##p, ##35, ##6, ,, as, ##p, ##45, ##3, and, g, ##lu, ##40, ##4, ,, as, well, as, by, the, backbone, carbon, ##yl, groups, of, ala, ##40, ##5, and, le, ##u, ##45, ##2, and, a, single, water, molecule, (, fig, ., 4, ##b, and, table, 2, for, coordination, distances, and, angles, ), ., the, na, ^, +, ion, is, also, coordinated, by, the, car, ##box, ##yl, ##ic, acid, groups, of, the, side, chains, of, both, as, ##p, ##35, ##6, and, as, ##p, ##45, ##3, ,, as, well, as, by, the, backbone, carbon, ##yl, group, of, le, ##u, ##35, ##7, and, a, different, water, molecule, than, the, one, coordinating, the, calcium, ion, (, fig, ., 4, ##b, ,, table, 2, ), ., in, sum, ,, three, formal, negative, charges, of, the, car, ##box, ##yl, ##ic, acid, groups, of, the, side, chains, of, as, ##p, ##35, ##6, ,, as, ##p, ##45, ##3, and, g, ##lu, ##40, ##4, are, compensated, by, three, formal, positive, charges, of, the, bound, ca, ^, 2, +, and, na, ^, +, ions, ., table, 2d, ##istan, ##ces, and, angles, of, metal, ion, coordination, in, the, ol, ##fm, ##1, ^, ol, ##f, crystal, structured, ##istan, ##ces, :, angles, :, distance, (, a, ), angle, (, °, ), calcium, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), 86, ., 7, ##cal, ##ci, ##um, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), 93, ., 1, ##cal, ##ci, ##uma, ##la, ##40, ##5, o, _, (, carbon, ##yl, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 105, ., 5, ##cal, ##ci, ##um, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##h, _, 2, ##o, ##9, ##4, ., 1, ##cal, ##ci, ##uma, ##sp, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), 83, ., 0, ##cal, ##ci, ##um, ##h, _, 2, ##o, ##2, ., 4, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), 83, ., 7, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##h, _, 2, ##o, ##8, ##2, ., 7, ##so, ##dium, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), 2, ., 9, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), calcium, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), 89, ., 2, ##so, ##dium, ##gl, ##n, ##30, ##3, o, _, (, carbon, ##yl, ), 3, ., 0, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), calcium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 103, ., 8, ##so, ##dium, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), calcium, ##h, _, 2, ##o, ##8, ##1, ., 4, ##so, ##dium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 2, ., 2, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), calcium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 83, ., 6, ##so, ##dium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3a, ##sp, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##h, _, 2, ##o, ##8, ##8, ., 4, ##so, ##dium, ##h, _, 2, ##o, ##2, ., 4, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##gl, ##n, ##30, ##3, o, _, (, carbon, ##yl, ), 66, ., 6, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), ty, ##r, ##34, ##7, o, _, (, hydro, ##xy, ##l, ), 2, ., 7, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), 88, ., 5, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 78, ., 3, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##h, _, 2, ##o, ##9, ##8, ., 6, ##gl, ##n, ##30, ##3, o, _, (, carbon, ##yl, ), sodium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 88, ., 4, ##gl, ##n, ##30, ##3, o, (, carbon, ##yl, ), sodium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 95, ., 8, ##gl, ##n, ##30, ##3, o, (, carbon, ##yl, ), sodium, ##h, _, 2, ##o, ##7, ##1, ., 0, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 101, ., 4a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 109, ., 4a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##h, _, 2, ##o, ##9, ##9, ., 9, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), sodium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 98, ., 5, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##h, _, 2, ##o, ##7, ##7, ., 8'},\n", + " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", + " 'section_name': 'Disruption of the EphB2–NMDAR interaction',\n", + " 'text': 'Phosphorylation of EphB2 Y504 and a negative charge at Y504 are required for interaction with the NMDAR^19. To test how the charge of Y504 affects the EphB2–NMDAR interaction, PLA was performed on HEK293T cells transfected with EphB2 WT, EphB2 Y504E, or EphB2 Y504F, and WT Myc-GluN1, GluN2B, and EGFP (Fig. 6a). As expected, cells transfected with the more positively charged EphB2 phospho-null mutant (Y405F) had significantly fewer PLA puncta than both WT EphB2 and the more negatively charged phosphomimetic (Y504E) EphB2 (Fig. 6b, ****p < 0.0001, ANOVA). To specifically test the role of a negative charge at EphB2 Y504 in relation to the GluN1 charge mutants, PLA was performed on HEK293T cells transfected with EphB2 Y504E, GluN2B, EGFP and Myc-GluN1 WT or GluN1 point mutants (Fig. 6c, e). Consistent with the model that the negative charge of phosphomimetic EphB2 Y504E interacts with the positive potential of the GluN1 NTD hinge region, mutations in GluN1 that result in larger negative shifts of surface potential interact with EphB2 Y504E less well than those with smaller differences (Fig. 6d, f, WT vs. N273A, *p < 0.05; WT vs. R337D, ***p < 0.005; WT vs. N273A/R337D, ****p < 0.0001; ANOVA). Unfortunately, mutations of Y504 to a positively charged amino acid failed to reach the cell surface. Together these results suggest that the positively charged hinge region of GluN1 interacts with the negatively charged phosphorylated Y504 of EphB2 and this interaction is disrupted when GluN1 is mutated to become more negatively charged.Fig. 6EphB2–GluN1 interaction in HEK293T cells is charge-dependent.a Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated FLAG-EphB2 single point mutants (WT, Y504E, or Y504F), together with Myc-GluN1 WT, GluN2B, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. b Quantification of the effects of EphB2 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition. (****p < 0.0001, ANOVA; n = 30 cells for each condition). c Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 single point mutants, together with GluN2B, FLAG-EphB2 Y504E, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. d Quantification of the effects of GluN1 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition. (*p < 0.05, ***p < 0.005, ANOVA; n = 30 cells for each condition). e Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 double point mutants, together with GluN2B, FLAG-EphB2 Y504E, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. f Quantification of the effects of GluN1 mutants on PLA puncta number (*p = 0.0219, ****p < 0.0001, ANOVA; green dots represent n = 30 cells for each condition).',\n", + " 'paragraph_id': 18,\n", + " 'tokenizer': 'ph, ##os, ##ph, ##ory, ##lation, of, ep, ##h, ##b, ##2, y, ##50, ##4, and, a, negative, charge, at, y, ##50, ##4, are, required, for, interaction, with, the, nm, ##dar, ^, 19, ., to, test, how, the, charge, of, y, ##50, ##4, affects, the, ep, ##h, ##b, ##2, –, nm, ##dar, interaction, ,, pl, ##a, was, performed, on, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, ep, ##h, ##b, ##2, w, ##t, ,, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, or, ep, ##h, ##b, ##2, y, ##50, ##4, ##f, ,, and, w, ##t, my, ##c, -, g, ##lun, ##1, ,, g, ##lun, ##2, ##b, ,, and, e, ##gf, ##p, (, fig, ., 6, ##a, ), ., as, expected, ,, cells, trans, ##fect, ##ed, with, the, more, positively, charged, ep, ##h, ##b, ##2, ph, ##os, ##ph, ##o, -, null, mutant, (, y, ##40, ##5, ##f, ), had, significantly, fewer, pl, ##a, pun, ##cta, than, both, w, ##t, ep, ##h, ##b, ##2, and, the, more, negatively, charged, ph, ##os, ##ph, ##omi, ##met, ##ic, (, y, ##50, ##4, ##e, ), ep, ##h, ##b, ##2, (, fig, ., 6, ##b, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ), ., to, specifically, test, the, role, of, a, negative, charge, at, ep, ##h, ##b, ##2, y, ##50, ##4, in, relation, to, the, g, ##lun, ##1, charge, mutants, ,, pl, ##a, was, performed, on, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, g, ##lun, ##2, ##b, ,, e, ##gf, ##p, and, my, ##c, -, g, ##lun, ##1, w, ##t, or, g, ##lun, ##1, point, mutants, (, fig, ., 6, ##c, ,, e, ), ., consistent, with, the, model, that, the, negative, charge, of, ph, ##os, ##ph, ##omi, ##met, ##ic, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, interact, ##s, with, the, positive, potential, of, the, g, ##lun, ##1, nt, ##d, hi, ##nge, region, ,, mutations, in, g, ##lun, ##1, that, result, in, larger, negative, shifts, of, surface, potential, interact, with, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, less, well, than, those, with, smaller, differences, (, fig, ., 6, ##d, ,, f, ,, w, ##t, vs, ., n, ##27, ##3, ##a, ,, *, p, <, 0, ., 05, ;, w, ##t, vs, ., r, ##33, ##7, ##d, ,, *, *, *, p, <, 0, ., 00, ##5, ;, w, ##t, vs, ., n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, ,, *, *, *, *, p, <, 0, ., 000, ##1, ;, an, ##ova, ), ., unfortunately, ,, mutations, of, y, ##50, ##4, to, a, positively, charged, amino, acid, failed, to, reach, the, cell, surface, ., together, these, results, suggest, that, the, positively, charged, hi, ##nge, region, of, g, ##lun, ##1, interact, ##s, with, the, negatively, charged, ph, ##os, ##ph, ##ory, ##lated, y, ##50, ##4, of, ep, ##h, ##b, ##2, and, this, interaction, is, disrupted, when, g, ##lun, ##1, is, mu, ##tated, to, become, more, negatively, charged, ., fig, ., 6, ##ep, ##h, ##b, ##2, –, g, ##lun, ##1, interaction, in, he, ##k, ##29, ##3, ##t, cells, is, charge, -, dependent, ., a, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, flag, -, ep, ##h, ##b, ##2, single, point, mutants, (, w, ##t, ,, y, ##50, ##4, ##e, ,, or, y, ##50, ##4, ##f, ), ,, together, with, my, ##c, -, g, ##lun, ##1, w, ##t, ,, g, ##lun, ##2, ##b, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., b, quan, ##ti, ##fication, of, the, effects, of, ep, ##h, ##b, ##2, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, ., (, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, n, =, 30, cells, for, each, condition, ), ., c, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, single, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., d, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, ., (, *, p, <, 0, ., 05, ,, *, *, *, p, <, 0, ., 00, ##5, ,, an, ##ova, ;, n, =, 30, cells, for, each, condition, ), ., e, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, double, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., f, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, (, *, p, =, 0, ., 02, ##19, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), .'},\n", + " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", + " 'section_name': 'Impact on synaptic stability of the NMDAR',\n", + " 'text': 'Disrupting the EphB2–NMDAR interaction by mutating the hinge region of GluN1 results in increased mobility of NMDARs found in dendritic spines. We next asked whether the GluN1 N273A/R337D charge mutant is sufficient to increase the mobility of the NMDAR in dendritic spines. To test this, neurons were transfected with either WT EGFP–GluN1, EGFP–GluN1 I272A, or EGFP–GluN1 N273A/R337D, and GluN2B, mCherry, and GluN1 CRISPR. No significant differences were found between levels of WT or mutant EGFP–GluN1 in the dendritic shaft (Supplementary Fig. 9c, d), but there was a decrease in spine density in N237A/R337D expressing neurons (Supplementary Fig. 9e, f). EGFP–GluN1 mobility in dendritic spines was examined by FRAP, and images of EGFP–GluN1 puncta were collected once every 10 s for 15 min after bleaching. Fluorescence recovery of both WT and I272A EGFP–GluN1 was indistinguishable (Fig. 8a, b). In contrast, EGFP–GluN1 N273A/R337D recovered significantly more than WT (Fig. 8b, ****p < 0.0001, KS test; 15 min time point, *p < 0.05, ANOVA). These results suggest converting the surface charge in the hinge region of the GluN1 NTD increases NMDAR mobility at spines.Fig. 8GluN1 charge mutants show increased mobility due to disrupted EphB–NMDAR interaction.a Representative FRAP images at different time points of DIV21–23 cortical neurons transfected with EGFP–GluN1 (WT, I272A, or N273A/R337D) together with GluN2B, CRISPR construct targeting endogenous GluN1, and mCherry. Recovery of bleached spine puncta (magenta circle) was monitored for 15 min at 10s intervals. Scale bar = 2 μm. b Quantification of the recovery curve of different GluN1 mutants in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit (****p < 0.0001, Kolmogorov–Smirnov (KS) nonparametric test). Inset: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min after photobleaching in EGFP–GluN1 mutant transfected cells compared to WT EGFP–GluN1 in DIV21–23 cortical neurons (*p < 0.05, ANOVA; green dots represent WT n = 33 puncta; I272A n = 12; N273A/R337D n = 12). Error bars show S.E.M. c Representative FRAP images at different time points of DIV21–23 cortical neurons transfected with EGFP–GluN1 (WT, WT+EphB2 knockdown, N273A/R337D + EphB2 knockdown, WT+EphB2 knockdown rescued by RNAi insensitive EphB2) together with GluN2B, CRISPR construct targeting endogenous GluN1, and mCherry. FRAP was conducted on serveral puncta in different dendritic branches. Recovery of bleached spine puncta (magenta circle) was monitored for 15 min at 10s intervals. Scale bar = 2 μm. d Quantification of the recovery curve of different GluN1 mutants in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit (****p < 0.0001, Kolmogorov–Smirnov (KS) nonparametric test). Inset: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min after bleaching in EGFP–GluN1 mutant transfected cells compared to WT EGFP–GluN1 in DIV21–23 cortical neurons (*p < 0.05, ANOVA; green dots represent WT n = 33 puncta; WT+EphB2 K.D. n = 12; N273A/R337D+EphB2 K.D. n = 21; rescue n = 22). Error bars show S.E.M.',\n", + " 'paragraph_id': 20,\n", + " 'tokenizer': 'disrupt, ##ing, the, ep, ##h, ##b, ##2, –, nm, ##dar, interaction, by, mu, ##tat, ##ing, the, hi, ##nge, region, of, g, ##lun, ##1, results, in, increased, mobility, of, nm, ##dar, ##s, found, in, den, ##dr, ##itic, spines, ., we, next, asked, whether, the, g, ##lun, ##1, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, charge, mutant, is, sufficient, to, increase, the, mobility, of, the, nm, ##dar, in, den, ##dr, ##itic, spines, ., to, test, this, ,, neurons, were, trans, ##fect, ##ed, with, either, w, ##t, e, ##gf, ##p, –, g, ##lun, ##1, ,, e, ##gf, ##p, –, g, ##lun, ##1, i, ##27, ##2, ##a, ,, or, e, ##gf, ##p, –, g, ##lun, ##1, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, ,, and, g, ##lun, ##2, ##b, ,, mc, ##her, ##ry, ,, and, g, ##lun, ##1, crisp, ##r, ., no, significant, differences, were, found, between, levels, of, w, ##t, or, mutant, e, ##gf, ##p, –, g, ##lun, ##1, in, the, den, ##dr, ##itic, shaft, (, supplementary, fig, ., 9, ##c, ,, d, ), ,, but, there, was, a, decrease, in, spine, density, in, n, ##23, ##7, ##a, /, r, ##33, ##7, ##d, expressing, neurons, (, supplementary, fig, ., 9, ##e, ,, f, ), ., e, ##gf, ##p, –, g, ##lun, ##1, mobility, in, den, ##dr, ##itic, spines, was, examined, by, fra, ##p, ,, and, images, of, e, ##gf, ##p, –, g, ##lun, ##1, pun, ##cta, were, collected, once, every, 10, s, for, 15, min, after, b, ##lea, ##ching, ., flu, ##orescence, recovery, of, both, w, ##t, and, i, ##27, ##2, ##a, e, ##gf, ##p, –, g, ##lun, ##1, was, ind, ##ist, ##ing, ##uis, ##hab, ##le, (, fig, ., 8, ##a, ,, b, ), ., in, contrast, ,, e, ##gf, ##p, –, g, ##lun, ##1, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, recovered, significantly, more, than, w, ##t, (, fig, ., 8, ##b, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, ks, test, ;, 15, min, time, point, ,, *, p, <, 0, ., 05, ,, an, ##ova, ), ., these, results, suggest, converting, the, surface, charge, in, the, hi, ##nge, region, of, the, g, ##lun, ##1, nt, ##d, increases, nm, ##dar, mobility, at, spines, ., fig, ., 8, ##gl, ##un, ##1, charge, mutants, show, increased, mobility, due, to, disrupted, ep, ##h, ##b, –, nm, ##dar, interaction, ., a, representative, fra, ##p, images, at, different, time, points, of, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, trans, ##fect, ##ed, with, e, ##gf, ##p, –, g, ##lun, ##1, (, w, ##t, ,, i, ##27, ##2, ##a, ,, or, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, ), together, with, g, ##lun, ##2, ##b, ,, crisp, ##r, construct, targeting, end, ##ogen, ##ous, g, ##lun, ##1, ,, and, mc, ##her, ##ry, ., recovery, of, b, ##lea, ##ched, spine, pun, ##cta, (, mage, ##nta, circle, ), was, monitored, for, 15, min, at, 10, ##s, intervals, ., scale, bar, =, 2, μ, ##m, ., b, quan, ##ti, ##fication, of, the, recovery, curve, of, different, g, ##lun, ##1, mutants, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., ins, ##et, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, after, photo, ##ble, ##achi, ##ng, in, e, ##gf, ##p, –, g, ##lun, ##1, mutant, trans, ##fect, ##ed, cells, compared, to, w, ##t, e, ##gf, ##p, –, g, ##lun, ##1, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, (, *, p, <, 0, ., 05, ,, an, ##ova, ;, green, dots, represent, w, ##t, n, =, 33, pun, ##cta, ;, i, ##27, ##2, ##a, n, =, 12, ;, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, n, =, 12, ), ., error, bars, show, s, ., e, ., m, ., c, representative, fra, ##p, images, at, different, time, points, of, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, trans, ##fect, ##ed, with, e, ##gf, ##p, –, g, ##lun, ##1, (, w, ##t, ,, w, ##t, +, ep, ##h, ##b, ##2, knock, ##down, ,, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, +, ep, ##h, ##b, ##2, knock, ##down, ,, w, ##t, +, ep, ##h, ##b, ##2, knock, ##down, rescued, by, rna, ##i, ins, ##ens, ##itive, ep, ##h, ##b, ##2, ), together, with, g, ##lun, ##2, ##b, ,, crisp, ##r, construct, targeting, end, ##ogen, ##ous, g, ##lun, ##1, ,, and, mc, ##her, ##ry, ., fra, ##p, was, conducted, on, server, ##al, pun, ##cta, in, different, den, ##dr, ##itic, branches, ., recovery, of, b, ##lea, ##ched, spine, pun, ##cta, (, mage, ##nta, circle, ), was, monitored, for, 15, min, at, 10, ##s, intervals, ., scale, bar, =, 2, μ, ##m, ., d, quan, ##ti, ##fication, of, the, recovery, curve, of, different, g, ##lun, ##1, mutants, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., ins, ##et, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, after, b, ##lea, ##ching, in, e, ##gf, ##p, –, g, ##lun, ##1, mutant, trans, ##fect, ##ed, cells, compared, to, w, ##t, e, ##gf, ##p, –, g, ##lun, ##1, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, (, *, p, <, 0, ., 05, ,, an, ##ova, ;, green, dots, represent, w, ##t, n, =, 33, pun, ##cta, ;, w, ##t, +, ep, ##h, ##b, ##2, k, ., d, ., n, =, 12, ;, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, +, ep, ##h, ##b, ##2, k, ., d, ., n, =, 21, ;, rescue, n, =, 22, ), ., error, bars, show, s, ., e, ., m, .'},\n", + " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", + " 'section_name': 'Antibodies',\n", + " 'text': 'The following primary antibodies and dilutions were used: mouse monoclonal (IgG1) anti-GluN1 (1:500 (WB), BioLegend, clone R1JHL, cat# 828201, lot# B212895), goat polyclonal anti-EphB2 (1:1200 (ICC, PLA), R&D Systems, cat# AF467, lot# CVT0315041), mouse monoclonal (IgG1) anti-EphB2 (1:500 (WB), Invitrogen, clone 1A6C9, cat# 37-1700, lot# RD215698), rabbit polyclonal anti-Myc (1:3000 (ICC, PLA), Abcam, Cambridge, MA, cat# ab9103, lot# 2932489), mouse monoclonal (IgG2b) anti-GluN2B (1:500 (WB), Neuromab, UC Davis, Davis, CA, clone N59/36, cat# 75-101, lot# 455-10JD-82), mouse monoclonal (IgG2A) anti-PSD-95 (1:2500 (WB), Neuromab, UC Davis, Davis, CA, clone 28/43, cat# 75-028, lot# 455.7JD.22f), mouse monoclonal (IgG1) anti-Synaptophysin-1 (1:5000 (WB), Synaptic Systems, Gottingen, Germany, clone 7.2, cat# 101 111, lot# 101011/1-43), guinea pig polyclonal anti-vesicular glutamate transporter 1 (vGlut1; 1:5000 (WB, ICC), EMD Millipore, Temecula, CA, cat# AB5905, lot# 2932489), rabbit polyclonal anti-GFP (1:3000 (ICC), Life Technologies, cat# A6455, lot# 1736965), mouse monoclonal (IgG1) anti-GAPDH (1:500 (WB), EMD Millipore, Temecula, CA, cat# MAB374, lot# 2910381), rabbit polyclonal anti-Tubulin (1:10,000 (WB), Abcam, Cambridge, MA, cat# ab18251, lot# GR235480-2), rabbit polyclonal anti-actin (1:2000 (ICC), Sigma, cat# A2103, lot# 115M4865V), rabbit polyclonal anti-FLAG (1:1000 (IP, WB), Sigma, Cat# F7425, lot# 097M4882V). The following secondary antibodies were used: Donkey anti-mouse-HRP (1:10,000 (WB), Jackson ImmunoResearch, cat# 715-035-151, lot# 128396), Donkey anti-rabbit-HRP (1:10,000 (WB), Jackson ImmunoResearch, cat# 711-035-152, lot# 132960), Donkey anti-goat-HRP (1:10,000 (WB), Jackson ImmunoResearch, cat# 705-035-147, lot# 112876), Donkey anti-rabbit unconjugated (1:100 (ICC), Jackson ImmunoResearch, cat# 711-005-152 lot# 125861), Donkey anti-mouse AlexaFluor-488 (1:500 (ICC), Jackson ImmunoResearch, cat# 715-545-150, lot# 11603), Donkey anti-rabbit AlexaFluor-488 (1:500 (ICC), Jackson ImmunoResearch, cat# 711-545-152, lot# 126601), Donkey anti-goat Cy3 (1:500 (ICC), Jackson ImmunoResearch, cat# 705-166-147, lot# 107019), Donkey anti-rabbit Cy3 (1:500 (ICC), Jackson ImmunoResearch, cat# 711-165-152, lot# 123091), Donkey anti-guinea pig AlexaFluor-647 (1:500 (ICC), Jackson ImmunoResearch, cat# 706-605-148, lot# 116734), Donkey anti-goat AlexaFluor-647 (1:500 (ICC), Jackson ImmunoResearch, cat# 706-606-147, lot# 124186).',\n", + " 'paragraph_id': 46,\n", + " 'tokenizer': 'the, following, primary, antibodies, and, dil, ##ution, ##s, were, used, :, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, g, ##lun, ##1, (, 1, :, 500, (, wb, ), ,, bio, ##leg, ##end, ,, clone, r, ##1, ##jhl, ,, cat, #, 82, ##8, ##20, ##1, ,, lot, #, b, ##21, ##28, ##9, ##5, ), ,, goat, poly, ##cl, ##onal, anti, -, ep, ##h, ##b, ##2, (, 1, :, 1200, (, icc, ,, pl, ##a, ), ,, r, &, d, systems, ,, cat, #, af, ##46, ##7, ,, lot, #, cv, ##t, ##0, ##31, ##50, ##41, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, ep, ##h, ##b, ##2, (, 1, :, 500, (, wb, ), ,, in, ##vi, ##tro, ##gen, ,, clone, 1a, ##6, ##c, ##9, ,, cat, #, 37, -, 1700, ,, lot, #, rd, ##21, ##56, ##9, ##8, ), ,, rabbit, poly, ##cl, ##onal, anti, -, my, ##c, (, 1, :, 3000, (, icc, ,, pl, ##a, ), ,, abc, ##am, ,, cambridge, ,, ma, ,, cat, #, ab, ##9, ##10, ##3, ,, lot, #, 293, ##24, ##8, ##9, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##2, ##b, ), anti, -, g, ##lun, ##2, ##b, (, 1, :, 500, (, wb, ), ,, ne, ##uro, ##ma, ##b, ,, uc, davis, ,, davis, ,, ca, ,, clone, n, ##59, /, 36, ,, cat, #, 75, -, 101, ,, lot, #, 45, ##5, -, 10, ##j, ##d, -, 82, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##2, ##a, ), anti, -, ps, ##d, -, 95, (, 1, :, 2500, (, wb, ), ,, ne, ##uro, ##ma, ##b, ,, uc, davis, ,, davis, ,, ca, ,, clone, 28, /, 43, ,, cat, #, 75, -, 02, ##8, ,, lot, #, 45, ##5, ., 7, ##j, ##d, ., 22, ##f, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, syn, ##ap, ##top, ##hy, ##sin, -, 1, (, 1, :, 5000, (, wb, ), ,, syn, ##ap, ##tic, systems, ,, gottingen, ,, germany, ,, clone, 7, ., 2, ,, cat, #, 101, 111, ,, lot, #, 101, ##01, ##1, /, 1, -, 43, ), ,, guinea, pig, poly, ##cl, ##onal, anti, -, ve, ##sic, ##ular, g, ##lu, ##tama, ##te, transport, ##er, 1, (, v, ##gl, ##ut, ##1, ;, 1, :, 5000, (, wb, ,, icc, ), ,, em, ##d, mill, ##ip, ##ore, ,, te, ##me, ##cula, ,, ca, ,, cat, #, ab, ##59, ##0, ##5, ,, lot, #, 293, ##24, ##8, ##9, ), ,, rabbit, poly, ##cl, ##onal, anti, -, g, ##fp, (, 1, :, 3000, (, icc, ), ,, life, technologies, ,, cat, #, a, ##64, ##55, ,, lot, #, 1736, ##9, ##65, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, gap, ##dh, (, 1, :, 500, (, wb, ), ,, em, ##d, mill, ##ip, ##ore, ,, te, ##me, ##cula, ,, ca, ,, cat, #, mab, ##37, ##4, ,, lot, #, 291, ##0, ##38, ##1, ), ,, rabbit, poly, ##cl, ##onal, anti, -, tub, ##ulin, (, 1, :, 10, ,, 000, (, wb, ), ,, abc, ##am, ,, cambridge, ,, ma, ,, cat, #, ab, ##18, ##25, ##1, ,, lot, #, gr, ##23, ##54, ##80, -, 2, ), ,, rabbit, poly, ##cl, ##onal, anti, -, act, ##in, (, 1, :, 2000, (, icc, ), ,, sigma, ,, cat, #, a2, ##10, ##3, ,, lot, #, 115, ##m, ##48, ##65, ##v, ), ,, rabbit, poly, ##cl, ##onal, anti, -, flag, (, 1, :, 1000, (, ip, ,, wb, ), ,, sigma, ,, cat, #, f, ##7, ##42, ##5, ,, lot, #, 09, ##7, ##m, ##48, ##8, ##2, ##v, ), ., the, following, secondary, antibodies, were, used, :, donkey, anti, -, mouse, -, hr, ##p, (, 1, :, 10, ,, 000, (, wb, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##5, -, 03, ##5, -, 151, ,, lot, #, 128, ##39, ##6, ), ,, donkey, anti, -, rabbit, -, hr, ##p, (, 1, :, 10, ,, 000, (, wb, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 03, ##5, -, 152, ,, lot, #, 132, ##9, ##60, ), ,, donkey, anti, -, goat, -, hr, ##p, (, 1, :, 10, ,, 000, (, wb, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##5, -, 03, ##5, -, 147, ,, lot, #, 112, ##8, ##7, ##6, ), ,, donkey, anti, -, rabbit, un, ##con, ##ju, ##gated, (, 1, :, 100, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 00, ##5, -, 152, lot, #, 125, ##86, ##1, ), ,, donkey, anti, -, mouse, alexa, ##fl, ##uo, ##r, -, 48, ##8, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##5, -, 54, ##5, -, 150, ,, lot, #, 116, ##0, ##3, ), ,, donkey, anti, -, rabbit, alexa, ##fl, ##uo, ##r, -, 48, ##8, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 54, ##5, -, 152, ,, lot, #, 126, ##60, ##1, ), ,, donkey, anti, -, goat, cy, ##3, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##5, -, 166, -, 147, ,, lot, #, 107, ##01, ##9, ), ,, donkey, anti, -, rabbit, cy, ##3, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 165, -, 152, ,, lot, #, 123, ##0, ##9, ##1, ), ,, donkey, anti, -, guinea, pig, alexa, ##fl, ##uo, ##r, -, 64, ##7, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##6, -, 60, ##5, -, 148, ,, lot, #, 116, ##7, ##34, ), ,, donkey, anti, -, goat, alexa, ##fl, ##uo, ##r, -, 64, ##7, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##6, -, 60, ##6, -, 147, ,, lot, #, 124, ##18, ##6, ), .'},\n", + " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", + " 'section_name': 'The amino acids required for the EphB2–GluN1 interaction',\n", + " 'text': 'To begin to determine which amino acids in the NTD hinge region might mediate the EphB–NMDAR interaction, we generated six individual point mutants to each of the amino acids that form the area of positive surface charge (I272A, N273A, T335A, G336A, R337A, R337D). These mutants were chosen because they affect surface charge and not the glycosylation state of the GluN1 subunit. Each of these mutants trafficked to the cell surface at similar levels and ran as expected on western blots (Supplementary Fig. 7a–d, 7c, p = 0.0613; 7d, p = 0.1349; ANOVA). APBS models showed that mutations to N273 and R337 had the largest impact on the surface potential (N273A, R337A, and R337D) (Fig. 5a). If the positive surface charge of the GluN1 NTD hinge region mediates the EphB–NMDAR interaction, then the three GluN1 mutants that affect surface potential the most should disrupt the EphB2–NMDAR interaction. To test whether those charge mutants affect the interaction, PLA was performed on HEK293T cells transfected with each of the GluN1 single mutants (I272A, N273A, T335A, G336A, R337A, R337D), together with GluN2B, EphB2, and EGFP (Fig. 5b). Consistent with the charge-based model for the EphB–NMDAR interaction, the GluN1 mutants with the largest apparent effect on surface charge, N273A, R337A, and R337D, had significantly fewer PLA puncta per cell than WT (Fig. 5c, ****p < 0.0001, ANOVA). Mutations that did not alter the surface charge did not impact the number of PLA puncta (Fig. 5c, I272A vs. WT, p = 1.000; T335A vs. WT, p = 0.999; G336A vs. WT, p = 0.1489; ANOVA). Similarly, Myc-GluN1 N273 and R337 mutants co-immunoprecipitated FLAG-EphB2 less well than WT Myc-GluN1 (Supplementary Fig. 8). These data suggest that a positive surface potential in the NTD hinge region is necessary for the EphB–NMDAR interaction.Fig. 5Specific hinge region amino acid residues are responsible for the EphB2–GluN1 interaction in HEK293T cells.a Surface charge maps of GluN1 NTD hinge region of the indicated GluN1 single point mutants in order of increasing negative charged in the hinge region (left (positive) to right (negative)), with blue representing positive charge and red representing negative charge. Yellow outline indicates the location of the six key hinge region amino acids in WT GluN1. b Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 single point mutants, together with GluN2B, FLAG-EphB2, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. c Quantification of the effects of GluN1 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition (****p < 0.0001, ANOVA; green dots represent n = 30 cells for each condition). d Surface charge maps of GluN1 NTD hinge region of the indicated GluN1 double point mutants as in a (left (positive) to right (negative)). Yellow outline indicates the location of the six key hinge region amino acids in WT GluN1. e Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 double point mutants, together with GluN2B, FLAG-EphB2, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. f Quantification of the effects of GluN1 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition (****p < 0.0001, ANOVA; green dots represent n = 30 cells for each condition).',\n", + " 'paragraph_id': 16,\n", + " 'tokenizer': 'to, begin, to, determine, which, amino, acids, in, the, nt, ##d, hi, ##nge, region, might, media, ##te, the, ep, ##h, ##b, –, nm, ##dar, interaction, ,, we, generated, six, individual, point, mutants, to, each, of, the, amino, acids, that, form, the, area, of, positive, surface, charge, (, i, ##27, ##2, ##a, ,, n, ##27, ##3, ##a, ,, t, ##33, ##5, ##a, ,, g, ##33, ##6, ##a, ,, r, ##33, ##7, ##a, ,, r, ##33, ##7, ##d, ), ., these, mutants, were, chosen, because, they, affect, surface, charge, and, not, the, g, ##ly, ##cos, ##yla, ##tion, state, of, the, g, ##lun, ##1, subunit, ., each, of, these, mutants, traffic, ##ked, to, the, cell, surface, at, similar, levels, and, ran, as, expected, on, western, b, ##lot, ##s, (, supplementary, fig, ., 7, ##a, –, d, ,, 7, ##c, ,, p, =, 0, ., 06, ##13, ;, 7, ##d, ,, p, =, 0, ., 134, ##9, ;, an, ##ova, ), ., ap, ##bs, models, showed, that, mutations, to, n, ##27, ##3, and, r, ##33, ##7, had, the, largest, impact, on, the, surface, potential, (, n, ##27, ##3, ##a, ,, r, ##33, ##7, ##a, ,, and, r, ##33, ##7, ##d, ), (, fig, ., 5, ##a, ), ., if, the, positive, surface, charge, of, the, g, ##lun, ##1, nt, ##d, hi, ##nge, region, media, ##tes, the, ep, ##h, ##b, –, nm, ##dar, interaction, ,, then, the, three, g, ##lun, ##1, mutants, that, affect, surface, potential, the, most, should, disrupt, the, ep, ##h, ##b, ##2, –, nm, ##dar, interaction, ., to, test, whether, those, charge, mutants, affect, the, interaction, ,, pl, ##a, was, performed, on, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, each, of, the, g, ##lun, ##1, single, mutants, (, i, ##27, ##2, ##a, ,, n, ##27, ##3, ##a, ,, t, ##33, ##5, ##a, ,, g, ##33, ##6, ##a, ,, r, ##33, ##7, ##a, ,, r, ##33, ##7, ##d, ), ,, together, with, g, ##lun, ##2, ##b, ,, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, (, fig, ., 5, ##b, ), ., consistent, with, the, charge, -, based, model, for, the, ep, ##h, ##b, –, nm, ##dar, interaction, ,, the, g, ##lun, ##1, mutants, with, the, largest, apparent, effect, on, surface, charge, ,, n, ##27, ##3, ##a, ,, r, ##33, ##7, ##a, ,, and, r, ##33, ##7, ##d, ,, had, significantly, fewer, pl, ##a, pun, ##cta, per, cell, than, w, ##t, (, fig, ., 5, ##c, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ), ., mutations, that, did, not, alter, the, surface, charge, did, not, impact, the, number, of, pl, ##a, pun, ##cta, (, fig, ., 5, ##c, ,, i, ##27, ##2, ##a, vs, ., w, ##t, ,, p, =, 1, ., 000, ;, t, ##33, ##5, ##a, vs, ., w, ##t, ,, p, =, 0, ., 999, ;, g, ##33, ##6, ##a, vs, ., w, ##t, ,, p, =, 0, ., 148, ##9, ;, an, ##ova, ), ., similarly, ,, my, ##c, -, g, ##lun, ##1, n, ##27, ##3, and, r, ##33, ##7, mutants, co, -, im, ##mun, ##op, ##re, ##ci, ##pit, ##ated, flag, -, ep, ##h, ##b, ##2, less, well, than, w, ##t, my, ##c, -, g, ##lun, ##1, (, supplementary, fig, ., 8, ), ., these, data, suggest, that, a, positive, surface, potential, in, the, nt, ##d, hi, ##nge, region, is, necessary, for, the, ep, ##h, ##b, –, nm, ##dar, interaction, ., fig, ., 5, ##sp, ##ec, ##ific, hi, ##nge, region, amino, acid, residues, are, responsible, for, the, ep, ##h, ##b, ##2, –, g, ##lun, ##1, interaction, in, he, ##k, ##29, ##3, ##t, cells, ., a, surface, charge, maps, of, g, ##lun, ##1, nt, ##d, hi, ##nge, region, of, the, indicated, g, ##lun, ##1, single, point, mutants, in, order, of, increasing, negative, charged, in, the, hi, ##nge, region, (, left, (, positive, ), to, right, (, negative, ), ), ,, with, blue, representing, positive, charge, and, red, representing, negative, charge, ., yellow, outline, indicates, the, location, of, the, six, key, hi, ##nge, region, amino, acids, in, w, ##t, g, ##lun, ##1, ., b, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, single, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., c, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), ., d, surface, charge, maps, of, g, ##lun, ##1, nt, ##d, hi, ##nge, region, of, the, indicated, g, ##lun, ##1, double, point, mutants, as, in, a, (, left, (, positive, ), to, right, (, negative, ), ), ., yellow, outline, indicates, the, location, of, the, six, key, hi, ##nge, region, amino, acids, in, w, ##t, g, ##lun, ##1, ., e, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, double, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., f, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), .'},\n", + " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", + " 'section_name': 'The EphB–NMDAR interaction is charge-dependent',\n", + " 'text': 'The predicted structure of the charged hinge domain indicates that mutation of R337 results in modification of a feature formed by the arginine side chain (Figs. 5a and 9c). To achieve a dynamically modifiable surface charge, we took advantage of the pK_a of the side chain of histidine (Fig. 9d). The pK_a of histidine is 6.0. At a pH of 7.3, the deprotonated form of histidine is dominant (95% deprotonated) and the charge of histidine is neutral. At a pH of 5.0, the imidazole group of histidine is protonated (91% protonated) and is positively charged. Substituting histidine at GluN1 hinge region residues should generate a pH-sensitive molecular switch for the EphB-NMDAR interaction^48–50. Because low pH (<6.0) would also alter the pK_a of any exposed histidine residues in the extracellular domain, and is known to result in rearrangements of the NMDAR ectodomain^51, we generated three histidine point mutants in the GluN1 hinge region: I272H, N273H, and R337H. We expect that the WT and I272H mutant GluN1 should interact at both pH 5 and pH 7.3, controlling for the effects of rearrangements. If the EphB–NMDAR interaction is mediated by a positive surface charge in the hinge region, N273H and R337H mutants should interact with EphB2 at pH 5.0 but not at the physiological histidine-neutral pH 7.3.Fig. 9pH-sensitive histidine mutants in the hinge region elucidate a charge-dependent mechanism.a Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 single point mutants, together with GluN2B, FLAG-EphB2, and EGFP. Cells were treated with media at either pH 5.0 or pH 7.3 for 30 min before PLA. Upper panels: PLA signal alone. Lower panels: merge of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. b Quantification of the effects of GluN1 mutants and pH on PLA puncta number (****p < 0.0005, ANOVA; green dots represent n = 30 cells for each condition). c Surface representation models (top) and charge maps (bottom) of WT GluN1 and R337H GluN1 predicted at neutral pH. d Model of experimental design. The same neurons were imaged for both pH conditions. e Representative FRAP images at different time points of DIV21–23 cortical neurons transfected with EGFP–GluN1 (WT or R337H) together with GluN2B, CRISPR construct targeting endogenous GluN1, and mCherry. FRAP of GluN1 puncta was conducted in the same neurons at pH 5.0 (H-positive) and pH 7.3 (H-neutral) and the order of pH presentation varied. Recovery of bleached spine puncta (magenta circle) was monitored for 15 min at 10s intervals. Scale bar = 2 μm. f Left: Quantification of the recovery curve of GluN1 WT or R337H mutant in ACSF at pH 7.3 and pH 5.0 in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit (****p < 0.0001, Kolmogorov–Smirnov (KS) nonparametric test). Right: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min after photobleaching (*p = 0.0398, WT-pH7.3 vs. R337H-pH7.3; ANOVA; green dots represent WT-pH5.0 n = 26 puncta; R337H-pH5.0 n = 24; WT-pH7.3 n = 23; R337H-pH7.3 n = 35). Error bars show S.E.M. g Left: Quantification of the recovery curve of GluN1 WT or I272H mutant in ACSF at pH7.3 and pH5.0 in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit. (p = 0.8148, WT-pH7.3 vs. I272H-pH7.3, Kolmogorov–Smirnov (KS) nonparametric test). Right: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min of FRAP (p = 0.9839; WT-pH7.3 vs. I272H-pH7.3; ANOVA; green dots represent WT-pH5.0 n = 26 puncta; I272H-pH5.0 n = 22; WT-pH7.3 n = 23; I272H-pH7.3 n = 30). Error bars show S.E.M.',\n", + " 'paragraph_id': 23,\n", + " 'tokenizer': 'the, predicted, structure, of, the, charged, hi, ##nge, domain, indicates, that, mutation, of, r, ##33, ##7, results, in, modification, of, a, feature, formed, by, the, ar, ##gin, ##ine, side, chain, (, fig, ##s, ., 5, ##a, and, 9, ##c, ), ., to, achieve, a, dynamic, ##ally, mod, ##if, ##iable, surface, charge, ,, we, took, advantage, of, the, p, ##k, _, a, of, the, side, chain, of, his, ##ti, ##dine, (, fig, ., 9, ##d, ), ., the, p, ##k, _, a, of, his, ##ti, ##dine, is, 6, ., 0, ., at, a, ph, of, 7, ., 3, ,, the, de, ##pro, ##ton, ##ated, form, of, his, ##ti, ##dine, is, dominant, (, 95, %, de, ##pro, ##ton, ##ated, ), and, the, charge, of, his, ##ti, ##dine, is, neutral, ., at, a, ph, of, 5, ., 0, ,, the, im, ##ida, ##zo, ##le, group, of, his, ##ti, ##dine, is, proton, ##ated, (, 91, %, proton, ##ated, ), and, is, positively, charged, ., sub, ##stituting, his, ##ti, ##dine, at, g, ##lun, ##1, hi, ##nge, region, residues, should, generate, a, ph, -, sensitive, molecular, switch, for, the, ep, ##h, ##b, -, nm, ##dar, interaction, ^, 48, –, 50, ., because, low, ph, (, <, 6, ., 0, ), would, also, alter, the, p, ##k, _, a, of, any, exposed, his, ##ti, ##dine, residues, in, the, extra, ##cellular, domain, ,, and, is, known, to, result, in, rear, ##rang, ##ement, ##s, of, the, nm, ##dar, ec, ##to, ##dom, ##ain, ^, 51, ,, we, generated, three, his, ##ti, ##dine, point, mutants, in, the, g, ##lun, ##1, hi, ##nge, region, :, i, ##27, ##2, ##h, ,, n, ##27, ##3, ##h, ,, and, r, ##33, ##7, ##h, ., we, expect, that, the, w, ##t, and, i, ##27, ##2, ##h, mutant, g, ##lun, ##1, should, interact, at, both, ph, 5, and, ph, 7, ., 3, ,, controlling, for, the, effects, of, rear, ##rang, ##ement, ##s, ., if, the, ep, ##h, ##b, –, nm, ##dar, interaction, is, mediated, by, a, positive, surface, charge, in, the, hi, ##nge, region, ,, n, ##27, ##3, ##h, and, r, ##33, ##7, ##h, mutants, should, interact, with, ep, ##h, ##b, ##2, at, ph, 5, ., 0, but, not, at, the, physiological, his, ##ti, ##dine, -, neutral, ph, 7, ., 3, ., fig, ., 9, ##ph, -, sensitive, his, ##ti, ##dine, mutants, in, the, hi, ##nge, region, el, ##uc, ##ida, ##te, a, charge, -, dependent, mechanism, ., a, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, single, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, ., cells, were, treated, with, media, at, either, ph, 5, ., 0, or, ph, 7, ., 3, for, 30, min, before, pl, ##a, ., upper, panels, :, pl, ##a, signal, alone, ., lower, panels, :, merge, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., b, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, and, ph, on, pl, ##a, pun, ##cta, number, (, *, *, *, *, p, <, 0, ., 000, ##5, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), ., c, surface, representation, models, (, top, ), and, charge, maps, (, bottom, ), of, w, ##t, g, ##lun, ##1, and, r, ##33, ##7, ##h, g, ##lun, ##1, predicted, at, neutral, ph, ., d, model, of, experimental, design, ., the, same, neurons, were, image, ##d, for, both, ph, conditions, ., e, representative, fra, ##p, images, at, different, time, points, of, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, trans, ##fect, ##ed, with, e, ##gf, ##p, –, g, ##lun, ##1, (, w, ##t, or, r, ##33, ##7, ##h, ), together, with, g, ##lun, ##2, ##b, ,, crisp, ##r, construct, targeting, end, ##ogen, ##ous, g, ##lun, ##1, ,, and, mc, ##her, ##ry, ., fra, ##p, of, g, ##lun, ##1, pun, ##cta, was, conducted, in, the, same, neurons, at, ph, 5, ., 0, (, h, -, positive, ), and, ph, 7, ., 3, (, h, -, neutral, ), and, the, order, of, ph, presentation, varied, ., recovery, of, b, ##lea, ##ched, spine, pun, ##cta, (, mage, ##nta, circle, ), was, monitored, for, 15, min, at, 10, ##s, intervals, ., scale, bar, =, 2, μ, ##m, ., f, left, :, quan, ##ti, ##fication, of, the, recovery, curve, of, g, ##lun, ##1, w, ##t, or, r, ##33, ##7, ##h, mutant, in, ac, ##sf, at, ph, 7, ., 3, and, ph, 5, ., 0, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., right, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, after, photo, ##ble, ##achi, ##ng, (, *, p, =, 0, ., 03, ##9, ##8, ,, w, ##t, -, ph, ##7, ., 3, vs, ., r, ##33, ##7, ##h, -, ph, ##7, ., 3, ;, an, ##ova, ;, green, dots, represent, w, ##t, -, ph, ##5, ., 0, n, =, 26, pun, ##cta, ;, r, ##33, ##7, ##h, -, ph, ##5, ., 0, n, =, 24, ;, w, ##t, -, ph, ##7, ., 3, n, =, 23, ;, r, ##33, ##7, ##h, -, ph, ##7, ., 3, n, =, 35, ), ., error, bars, show, s, ., e, ., m, ., g, left, :, quan, ##ti, ##fication, of, the, recovery, curve, of, g, ##lun, ##1, w, ##t, or, i, ##27, ##2, ##h, mutant, in, ac, ##sf, at, ph, ##7, ., 3, and, ph, ##5, ., 0, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, ., (, p, =, 0, ., 81, ##48, ,, w, ##t, -, ph, ##7, ., 3, vs, ., i, ##27, ##2, ##h, -, ph, ##7, ., 3, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., right, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, of, fra, ##p, (, p, =, 0, ., 98, ##39, ;, w, ##t, -, ph, ##7, ., 3, vs, ., i, ##27, ##2, ##h, -, ph, ##7, ., 3, ;, an, ##ova, ;, green, dots, represent, w, ##t, -, ph, ##5, ., 0, n, =, 26, pun, ##cta, ;, i, ##27, ##2, ##h, -, ph, ##5, ., 0, n, =, 22, ;, w, ##t, -, ph, ##7, ., 3, n, =, 23, ;, i, ##27, ##2, ##h, -, ph, ##7, ., 3, n, =, 30, ), ., error, bars, show, s, ., e, ., m, .'},\n", + " {'article_id': '72a6fa0f75cc78645fa609d5a4d17a5c',\n", + " 'section_name': 'Alzheimer’s dementia ORs',\n", + " 'text': 'Table 1 and Supplementary Table 3 show Alzheimer’s dementia ORs for each APOE genotype and allelic doses (i.e., the number of APOE2 alleles in APOE4 non-carriers and the number of APOE4 alleles in APOE2 non-carriers) before and after adjustment for age and sex in the neuropathologically confirmed and unconfirmed groups before and after adjustment for age and sex, compared to the common APOE3/3 genotype. ORs associated with APOE2 allelic dose in APOE4 non-carriers (APOE2/2 < 2/3 < 3/3) and APOE4 allelic dose in APOE2 non-carriers (APOE4/4 > 3/4 > 3/3) were generated using allelic association tests in an additive genetic model. As discussed below, APOE2/2, APOE2/3, and APOE2 allelic dose ORs were significantly lower, and APOE3/4, APOE4/4, and APOE4 allelic dose ORs were significantly higher, in the neuropathologically confirmed group than in the unconfirmed group. While ORs for the other APOE genotypes were similar to those that we had reported in a small number of cases and controls, the number of APOE2 homozygotes in the earlier study was too small to provide an accurate OR estimate^1,11. Table 2 shows Alzheimer’s dementia ORs for each APOE genotype compared to the relatively low-risk APOE2/3 and highest risk APOE4 genotypes in the neuropathologically confirmed cohort. As discussed below, these ORs permitted us to confirm our primary hypothesis that APOE2/2 is associated with a significantly lower OR compared to APOE3/3 and to demonstrate an exceptionally low OR compared to APOE4/4. Supplementary Table 4 shows Alzheimer’s dementia ORs for each APOE genotype in the combined group, compared to APOE3/3, and for APOE2 and APOE4 allelic dose before and after adjustment for age, sex, and autopsy/non-autopsy group.Table 1Association of APOE genotypes and allelic doses compared to the APOE3/3 genotype.APOENeuropathologically confirmed groupNeuropathologically unconfirmed groupOR95% CIPOR95% CIPGenotype2/20.130.05–0.366.3 × 10^−50.520.30–0.900.022/30.390.30–0.501.6 × 10^−120.630.53–0.752.2 × 10^−72/42.681.65–4.367.5 × 10^−52.472.02–3.015.7 × 10^−193/46.135.08–7.412.2 × 10^−753.553.17–3.982.3 × 10^−1054/431.2216.59–58.754.9 × 10^−2610.709.12–12.567.5 × 10^−186Allelic dose20.380.30–0.481.1 × 10^−150.640.58–0.722.2 × 10^−1646.005.06–7.123.4 × 10^−903.433.26–3.60<10^−300For genotypic association tests, odds ratio (OR), 95% confidence interval (CI), and P value (P) for each APOE genotype compared to the APOE3/3 genotype were calculated under a logistic regression model.For allelic association tests, OR, CI, and P associated with APOE2 allelic dose in APOE4 non-carriers (APOE2/2 < 2/3 < 3/3) and APOE4 allelic dose in APOE2 non-carriers (APOE4/4 > 3/4 > 3/3) in an additive genetic model were generated under a logistic regression model.Table 2Association of each APOE genotype in the neuropathologically confirmed group.APOECompared to APOE2/3Compared to APOE4/4OR95% CIPOR95% CIP2/20.340.12–0.950.040.0040.001–0.0146.0 × 10^−192/3Ref.Ref.Ref.0.0120.006–0.0241.2 × 10^−343/32.602.00–3.381.6 × 10^−120.0320.017–0.0604.9 × 10^−262/46.964.06–11.927.5 × 10^−120.0860.039–0.1891.6 × 10^−93/415.9211.85–21.381.4 × 10^−700.1960.103–0.3758.4 × 10^−74/481.0541.39–158.681.2 × 10^−34Ref.Ref.Ref.Alzheimer’s dementia odds ratios (ORs), 95% confidence intervals (CIs), and P value (P) for each APOE genotype compared to the APOE2/3 or 4/4 genotype as a reference (Ref.) in the neuropathologically confirmed group were calculated under a logistic regression model.',\n", + " 'paragraph_id': 5,\n", + " 'tokenizer': 'table, 1, and, supplementary, table, 3, show, alzheimer, ’, s, dementia, or, ##s, for, each, ap, ##oe, gen, ##otype, and, all, ##eli, ##c, doses, (, i, ., e, ., ,, the, number, of, ap, ##oe, ##2, all, ##eles, in, ap, ##oe, ##4, non, -, carriers, and, the, number, of, ap, ##oe, ##4, all, ##eles, in, ap, ##oe, ##2, non, -, carriers, ), before, and, after, adjustment, for, age, and, sex, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, and, un, ##con, ##firmed, groups, before, and, after, adjustment, for, age, and, sex, ,, compared, to, the, common, ap, ##oe, ##3, /, 3, gen, ##otype, ., or, ##s, associated, with, ap, ##oe, ##2, all, ##eli, ##c, dose, in, ap, ##oe, ##4, non, -, carriers, (, ap, ##oe, ##2, /, 2, <, 2, /, 3, <, 3, /, 3, ), and, ap, ##oe, ##4, all, ##eli, ##c, dose, in, ap, ##oe, ##2, non, -, carriers, (, ap, ##oe, ##4, /, 4, >, 3, /, 4, >, 3, /, 3, ), were, generated, using, all, ##eli, ##c, association, tests, in, an, additive, genetic, model, ., as, discussed, below, ,, ap, ##oe, ##2, /, 2, ,, ap, ##oe, ##2, /, 3, ,, and, ap, ##oe, ##2, all, ##eli, ##c, dose, or, ##s, were, significantly, lower, ,, and, ap, ##oe, ##3, /, 4, ,, ap, ##oe, ##4, /, 4, ,, and, ap, ##oe, ##4, all, ##eli, ##c, dose, or, ##s, were, significantly, higher, ,, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, group, than, in, the, un, ##con, ##firmed, group, ., while, or, ##s, for, the, other, ap, ##oe, gen, ##otype, ##s, were, similar, to, those, that, we, had, reported, in, a, small, number, of, cases, and, controls, ,, the, number, of, ap, ##oe, ##2, homo, ##zy, ##go, ##tes, in, the, earlier, study, was, too, small, to, provide, an, accurate, or, estimate, ^, 1, ,, 11, ., table, 2, shows, alzheimer, ’, s, dementia, or, ##s, for, each, ap, ##oe, gen, ##otype, compared, to, the, relatively, low, -, risk, ap, ##oe, ##2, /, 3, and, highest, risk, ap, ##oe, ##4, gen, ##otype, ##s, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, co, ##hort, ., as, discussed, below, ,, these, or, ##s, permitted, us, to, confirm, our, primary, hypothesis, that, ap, ##oe, ##2, /, 2, is, associated, with, a, significantly, lower, or, compared, to, ap, ##oe, ##3, /, 3, and, to, demonstrate, an, exceptionally, low, or, compared, to, ap, ##oe, ##4, /, 4, ., supplementary, table, 4, shows, alzheimer, ’, s, dementia, or, ##s, for, each, ap, ##oe, gen, ##otype, in, the, combined, group, ,, compared, to, ap, ##oe, ##3, /, 3, ,, and, for, ap, ##oe, ##2, and, ap, ##oe, ##4, all, ##eli, ##c, dose, before, and, after, adjustment, for, age, ,, sex, ,, and, autopsy, /, non, -, autopsy, group, ., table, 1a, ##sso, ##ciation, of, ap, ##oe, gen, ##otype, ##s, and, all, ##eli, ##c, doses, compared, to, the, ap, ##oe, ##3, /, 3, gen, ##otype, ., ap, ##oe, ##ne, ##uro, ##path, ##ological, ##ly, confirmed, group, ##ne, ##uro, ##path, ##ological, ##ly, un, ##con, ##firmed, group, ##or, ##9, ##5, %, ci, ##por, ##9, ##5, %, ci, ##pg, ##eno, ##type, ##2, /, 20, ., 130, ., 05, –, 0, ., 36, ##6, ., 3, ×, 10, ^, −, ##50, ., 520, ., 30, –, 0, ., 900, ., 02, ##2, /, 30, ., 390, ., 30, –, 0, ., 501, ., 6, ×, 10, ^, −, ##12, ##0, ., 630, ., 53, –, 0, ., 75, ##2, ., 2, ×, 10, ^, −, ##7, ##2, /, 42, ., 68, ##1, ., 65, –, 4, ., 36, ##7, ., 5, ×, 10, ^, −, ##52, ., 47, ##2, ., 02, –, 3, ., 01, ##5, ., 7, ×, 10, ^, −, ##19, ##3, /, 46, ., 135, ., 08, –, 7, ., 412, ., 2, ×, 10, ^, −, ##75, ##3, ., 55, ##3, ., 17, –, 3, ., 98, ##2, ., 3, ×, 10, ^, −, ##10, ##54, /, 43, ##1, ., 221, ##6, ., 59, –, 58, ., 75, ##4, ., 9, ×, 10, ^, −, ##26, ##10, ., 70, ##9, ., 12, –, 12, ., 56, ##7, ., 5, ×, 10, ^, −, ##18, ##6, ##alle, ##lic, dose, ##20, ., 380, ., 30, –, 0, ., 48, ##1, ., 1, ×, 10, ^, −, ##15, ##0, ., 640, ., 58, –, 0, ., 72, ##2, ., 2, ×, 10, ^, −, ##16, ##46, ., 00, ##5, ., 06, –, 7, ., 123, ., 4, ×, 10, ^, −, ##90, ##3, ., 43, ##3, ., 26, –, 3, ., 60, <, 10, ^, −, ##30, ##0, ##for, gen, ##ot, ##yp, ##ic, association, tests, ,, odds, ratio, (, or, ), ,, 95, %, confidence, interval, (, ci, ), ,, and, p, value, (, p, ), for, each, ap, ##oe, gen, ##otype, compared, to, the, ap, ##oe, ##3, /, 3, gen, ##otype, were, calculated, under, a, log, ##istic, regression, model, ., for, all, ##eli, ##c, association, tests, ,, or, ,, ci, ,, and, p, associated, with, ap, ##oe, ##2, all, ##eli, ##c, dose, in, ap, ##oe, ##4, non, -, carriers, (, ap, ##oe, ##2, /, 2, <, 2, /, 3, <, 3, /, 3, ), and, ap, ##oe, ##4, all, ##eli, ##c, dose, in, ap, ##oe, ##2, non, -, carriers, (, ap, ##oe, ##4, /, 4, >, 3, /, 4, >, 3, /, 3, ), in, an, additive, genetic, model, were, generated, under, a, log, ##istic, regression, model, ., table, 2a, ##sso, ##ciation, of, each, ap, ##oe, gen, ##otype, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, group, ., ap, ##oe, ##com, ##par, ##ed, to, ap, ##oe, ##2, /, 3, ##com, ##par, ##ed, to, ap, ##oe, ##4, /, 4, ##or, ##9, ##5, %, ci, ##por, ##9, ##5, %, ci, ##p, ##2, /, 20, ., 340, ., 12, –, 0, ., 950, ., 04, ##0, ., 00, ##40, ., 001, –, 0, ., 01, ##46, ., 0, ×, 10, ^, −, ##19, ##2, /, 3, ##re, ##f, ., ref, ., ref, ., 0, ., 01, ##20, ., 00, ##6, –, 0, ., 02, ##41, ., 2, ×, 10, ^, −, ##34, ##3, /, 32, ., 60, ##2, ., 00, –, 3, ., 381, ., 6, ×, 10, ^, −, ##12, ##0, ., 03, ##20, ., 01, ##7, –, 0, ., 06, ##0, ##4, ., 9, ×, 10, ^, −, ##26, ##2, /, 46, ., 96, ##4, ., 06, –, 11, ., 92, ##7, ., 5, ×, 10, ^, −, ##12, ##0, ., 08, ##60, ., 03, ##9, –, 0, ., 1891, ., 6, ×, 10, ^, −, ##9, ##3, /, 415, ., 92, ##11, ., 85, –, 21, ., 381, ., 4, ×, 10, ^, −, ##70, ##0, ., 1960, ., 103, –, 0, ., 375, ##8, ., 4, ×, 10, ^, −, ##7, ##4, /, 48, ##1, ., 05, ##41, ., 39, –, 158, ., 68, ##1, ., 2, ×, 10, ^, −, ##34, ##re, ##f, ., ref, ., ref, ., alzheimer, ’, s, dementia, odds, ratios, (, or, ##s, ), ,, 95, %, confidence, intervals, (, cis, ), ,, and, p, value, (, p, ), for, each, ap, ##oe, gen, ##otype, compared, to, the, ap, ##oe, ##2, /, 3, or, 4, /, 4, gen, ##otype, as, a, reference, (, ref, ., ), in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, group, were, calculated, under, a, log, ##istic, regression, model, .'},\n", + " {'article_id': '8ac4fbd9ed9f0baa294353544aae74fc',\n", + " 'section_name': 'Metabolic defects in ob/ob; Pomc-Cre; Atg7^loxP/loxP mice',\n", + " 'text': 'To further investigate the relationship between leptin deficiency, ER stress and autophagy in vivo, we generated ob/ob mice that lack the autophagy gene Atg7 in POMC neurons (ob/ob; Pomc-Cre; Atg7^loxP/loxP mice). The rationale for focusing on POMC neurons, specifically, is because we found that TUDCA treatment only rescues POMC projections in ob/ob mice (see results above), and we previously reported that Atg7 in POMC neurons is required for normal metabolic regulation and neuronal development^24. We confirmed that these mice are indeed autophagy-defective by analyzing the expression of the polyubiquitin-binding protein p62, which links ubiquitinated proteins to the autophagy apparatus^25. We found that ob/ob; Pomc-Cre; Atg7^loxP/loxP mice displayed higher levels of p62-IR in the ARH compared to WT and ob/ob mice (Fig. 6a). The ob/ob; Pomc-Cre; Atg7^loxP/loxP mice were born normal and survived to adulthood. In addition, these mutant mice had body weights indistinguishable from those of their ob/ob control littermates during the preweaning period and in adulthood (Fig. 6b, c). However, when exposed to a glucose challenge, ob/ob; Pomc-Cre; Atg7^loxP/loxP mice displayed impaired glucose tolerance compared to ob/ob mice (Fig. 6d). Serum insulin levels appeared normal in fed ob/ob; Pomc-Cre; Atg7^loxP/loxP mice (Fig. 6e). In addition, food intake and fat mass were increased in 10-week-old and 4-week-old, ob/ob; Pomc-Cre; Atg7^loxP/loxP mice (Fig. 6f, g), but the body composition became normal in 10-week-old mice (Fig. 6g). We also treated ob/ob; Pomc-Cre; Atg7^loxP/loxP mice with TUDCA daily from P4 to P16 and found that neonatal TUDCA treatment reduced arcuate p62-IR, body weight, serum insulin levels, food intake, and body composition and improved glucose tolerance (Fig. 6a–g).Fig. 6Neonatal tauroursodeoxycholic acid treatment ameliorates metabolic defects inob/ob;Pomc-Cre;Atg7^loxP/loxPmice.a Representative images and quantification of ubiquitin-binding protein (p62) immunoreactivity (red) in the arcuate nucleus (ARH) of 10-week-old wild-type (WT) mice, leptin-deficient (ob/ob) mice treated neonatally with vehicle or tauroursodeoxycholic acid (TUDCA), and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 5–7 per group). b Pre- (ob/ob, ob/ob; Pomc-Cre; Atg7^loxP/loxP + Vehicle: n = 9, ob/ob; Pomc-Cre; Atg7^loxP/loxP + TUDCA: n = 8 per group) and (c) post-weaning growth curves of ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (ob/ob, ob/ob; Pomc-Cre; Atg7^loxP/loxP + Vehicle: n = 7, ob/ob; Pomc-Cre; Atg7^loxP/loxP + TUDCA: n = 6 per group). d Blood glucose concentration after intraperitoneal injection of glucose and area under the glucose tolerance test (GTT) curve (AUC) (ob/ob, ob/ob; Pomc-Cre; Atg7^loxP/loxP + TUDCA: n = 6, ob/ob; Pomc-Cre; Atg7^loxP/loxP + Vehicle: n = 10 per group) and e serum insulin levels of 8-week-old fed ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 7 per group). f Food intake of 10-week-old ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 3–5 per group). g Body composition of 4- (n = 3 per group) and 10-week-old ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 4–5 per group). Error bars represent the SEM. *P ≤ 0.05, and **P < 0.01 versus all groups (a), *P ≤ 0.05, **P < 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 versus vehicle-treated ob/ob; Pomc-Cre; Atg7^loxP/loxP mice (b–g), ^#P < 0.05, ^##P ≤ 0.01, ^###P ≤ 0.001, and ^####P ≤ 0.0001 versus WT mice (d). Statistical significance between groups was determined using one-way ANOVA (a, AUC in d, e–g) and two-way ANOVA (b–d) followed by Tukey’s multiple comparison test. ARH, arcuate nucleus of the hypothalamus; me, median eminence; V3, third ventricle. Scale bar, 50 μm (a). Source data are provided as a Source Data file.',\n", + " 'paragraph_id': 14,\n", + " 'tokenizer': 'to, further, investigate, the, relationship, between, le, ##pt, ##in, deficiency, ,, er, stress, and, auto, ##pha, ##gy, in, vivo, ,, we, generated, ob, /, ob, mice, that, lack, the, auto, ##pha, ##gy, gene, at, ##g, ##7, in, po, ##mc, neurons, (, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, ), ., the, rational, ##e, for, focusing, on, po, ##mc, neurons, ,, specifically, ,, is, because, we, found, that, tu, ##dc, ##a, treatment, only, rescues, po, ##mc, projections, in, ob, /, ob, mice, (, see, results, above, ), ,, and, we, previously, reported, that, at, ##g, ##7, in, po, ##mc, neurons, is, required, for, normal, metabolic, regulation, and, ne, ##uron, ##al, development, ^, 24, ., we, confirmed, that, these, mice, are, indeed, auto, ##pha, ##gy, -, defective, by, analyzing, the, expression, of, the, poly, ##ub, ##iq, ##uit, ##in, -, binding, protein, p, ##6, ##2, ,, which, links, u, ##bi, ##qui, ##tina, ##ted, proteins, to, the, auto, ##pha, ##gy, apparatus, ^, 25, ., we, found, that, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, displayed, higher, levels, of, p, ##6, ##2, -, ir, in, the, ar, ##h, compared, to, w, ##t, and, ob, /, ob, mice, (, fig, ., 6, ##a, ), ., the, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, were, born, normal, and, survived, to, adulthood, ., in, addition, ,, these, mutant, mice, had, body, weights, ind, ##ist, ##ing, ##uis, ##hab, ##le, from, those, of, their, ob, /, ob, control, litter, ##mates, during, the, pre, ##we, ##ani, ##ng, period, and, in, adulthood, (, fig, ., 6, ##b, ,, c, ), ., however, ,, when, exposed, to, a, glucose, challenge, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, displayed, impaired, glucose, tolerance, compared, to, ob, /, ob, mice, (, fig, ., 6, ##d, ), ., serum, insulin, levels, appeared, normal, in, fed, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, (, fig, ., 6, ##e, ), ., in, addition, ,, food, intake, and, fat, mass, were, increased, in, 10, -, week, -, old, and, 4, -, week, -, old, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, (, fig, ., 6, ##f, ,, g, ), ,, but, the, body, composition, became, normal, in, 10, -, week, -, old, mice, (, fig, ., 6, ##g, ), ., we, also, treated, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, with, tu, ##dc, ##a, daily, from, p, ##4, to, p, ##16, and, found, that, neon, ##atal, tu, ##dc, ##a, treatment, reduced, arc, ##uate, p, ##6, ##2, -, ir, ,, body, weight, ,, serum, insulin, levels, ,, food, intake, ,, and, body, composition, and, improved, glucose, tolerance, (, fig, ., 6, ##a, –, g, ), ., fig, ., 6, ##neo, ##nat, ##al, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, treatment, am, ##eli, ##ora, ##tes, metabolic, defects, in, ##ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##pm, ##ice, ., a, representative, images, and, quan, ##ti, ##fication, of, u, ##bi, ##qui, ##tin, -, binding, protein, (, p, ##6, ##2, ), im, ##mun, ##ore, ##act, ##ivity, (, red, ), in, the, arc, ##uate, nucleus, (, ar, ##h, ), of, 10, -, week, -, old, wild, -, type, (, w, ##t, ), mice, ,, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), mice, treated, neon, ##atal, ##ly, with, vehicle, or, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, (, tu, ##dc, ##a, ), ,, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 5, –, 7, per, group, ), ., b, pre, -, (, ob, /, ob, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, vehicle, :, n, =, 9, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, tu, ##dc, ##a, :, n, =, 8, per, group, ), and, (, c, ), post, -, we, ##ani, ##ng, growth, curves, of, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, ob, /, ob, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, vehicle, :, n, =, 7, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, tu, ##dc, ##a, :, n, =, 6, per, group, ), ., d, blood, glucose, concentration, after, intra, ##per, ##ito, ##nea, ##l, injection, of, glucose, and, area, under, the, glucose, tolerance, test, (, gt, ##t, ), curve, (, au, ##c, ), (, ob, /, ob, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, tu, ##dc, ##a, :, n, =, 6, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, vehicle, :, n, =, 10, per, group, ), and, e, serum, insulin, levels, of, 8, -, week, -, old, fed, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 7, per, group, ), ., f, food, intake, of, 10, -, week, -, old, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 3, –, 5, per, group, ), ., g, body, composition, of, 4, -, (, n, =, 3, per, group, ), and, 10, -, week, -, old, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 4, –, 5, per, group, ), ., error, bars, represent, the, se, ##m, ., *, p, ≤, 0, ., 05, ,, and, *, *, p, <, 0, ., 01, versus, all, groups, (, a, ), ,, *, p, ≤, 0, ., 05, ,, *, *, p, <, 0, ., 01, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, treated, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, (, b, –, g, ), ,, ^, #, p, <, 0, ., 05, ,, ^, #, #, p, ≤, 0, ., 01, ,, ^, #, #, #, p, ≤, 0, ., 001, ,, and, ^, #, #, #, #, p, ≤, 0, ., 000, ##1, versus, w, ##t, mice, (, d, ), ., statistical, significance, between, groups, was, determined, using, one, -, way, an, ##ova, (, a, ,, au, ##c, in, d, ,, e, –, g, ), and, two, -, way, an, ##ova, (, b, –, d, ), followed, by, tu, ##key, ’, s, multiple, comparison, test, ., ar, ##h, ,, arc, ##uate, nucleus, of, the, h, ##yp, ##oth, ##ala, ##mus, ;, me, ,, median, emi, ##nen, ##ce, ;, v, ##3, ,, third, vent, ##ric, ##le, ., scale, bar, ,, 50, μ, ##m, (, a, ), ., source, data, are, provided, as, a, source, data, file, .'},\n", + " {'article_id': '8ac4fbd9ed9f0baa294353544aae74fc',\n", + " 'section_name': 'Leptin deficiency induces early life ER stress',\n", + " 'text': 'To examine whether leptin deficiency causes ER stress during critical periods of development, we measured the expression levels of the following ER stress markers: activating transcription factor 4 (Atf4), 6 (Atf6), X-box binding protein (Xbp1), glucose regulated protein GRP78 (referred to as Bip), and CCAAT-enhancer-binding protein homologous protein (Chop), in the embryonic, postnatal and adult hypothalamus of leptin-deficient (ob/ob) and wild-type (WT) mice. The levels of ER stress gene expression were not significantly changed in the hypothalamus of E14.5 ob/ob embryos (Fig. 1a) or in the arcuate nucleus of the hypothalamus (ARH) of postnatal day (P) 0 ob/ob mice (Fig. 1b). In contrast, all ER stress markers examined were significantly elevated in the ARH of P10 ob/ob mice (Fig. 1c). We next assessed ER stress marker expression specifically in arcuate Pomc and Agrp neurons and found that the levels of Atf4, Atf6, Xbp1, and Bip mRNAs were higher in these two neuronal populations in P10 ob/ob mice (Fig. 1d). During adulthood, leptin deficiency only caused an increase in Xbp1 and Bip mRNA expression in the ARH (Fig. 1e). In addition, Xbp1 mRNA levels were significantly higher in the paraventricular nucleus of the hypothalamus (PVH) of P0 (Fig. 1f) and P10 ob/ob mice (Fig. 1g), but none of the ER stress markers studied were significantly elevated in the PVH of adult ob/ob mice (Fig. 1h). We also examined ER stress markers in metabolically relevant peripheral tissues and found that Xbp1 gene expression was upregulated in the liver and adipose tissue of P10 ob/ob mice and that Atf4 mRNA levels were increased in the livers of P10 ob/ob mice (Supplementary Fig. 1a, b). In contrast, most of the ER stress markers studied were downregulated in the liver and adipose tissue of adult ob/ob mice (Supplementary Fig. 1c, d).Fig. 1Leptin deficiency increases endoplasmic reticulum stress markers in the developing hypothalamus.Relative expression of activating transcription factor 4 (Atf4), 6 (Atf6), X-box binding protein (Xbp1), glucose regulated protein GRP78 (referred to as Bip), and CCAAT-enhancer-binding protein homologous protein (Chop) mRNA a in the hypothalamus of embryonic day (E)14.5 mice (n = 4–5 per group) and b in the arcuate nucleus (ARH) of postnatal day (P) 0 wild-type (WT) and leptin-deficient (ob/ob) mice (n = 5–6 per group). c Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in the ARH of P10 WT mice and ob/ob mice treated neonatally either vehicle or tauroursodeoxycholic acid (TUDCA) or leptin (WT, ob/ob + Vehicle, ob/ob + TUDCA n = 4, ob/ob + Leptin: n = 5 per group). d Representative images and quantification of Atf4, Atf6, Xbp1, Bip, and Chop mRNA (green) in arcuate pro-opiomelanocortin (Pomc)- (white) and agouti-related peptide (Agrp) (red) mRNA-expressing cells of WT and ob/ob mice at P10 (n = 3–4 per group). e Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in the ARH of 10-week-old adult WT mice and ob/ob mice treated neonatally either vehicle or TUDCA (n = 6 per group). Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in the paraventricular nucleus (PVH) of f P0 (n = 4 per group), g P10 (n = 6 per group), and h 10-week-old adult WT mice and ob/ob mice treated neonatally either vehicle or TUDCA (n = 6 per group). i Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in hypothalamic mHypoE-N43/5 cell lysates treated with dimethyl sulfoxide (DMSO, control) or leptin (LEP, 100 ng/ml) or tunicamycin (TUN, 0.1 μg/ml) or TUN + LEP for 5 h (n = 4 per group). Error bars represent the SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 versus ob/ob mice (d, f), *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001 versus vehicle-injected ob/ob mice (c, e, g, h). **P ≤ 0.01 and ****P ≤ 0.0001 versus tunicamycin treated group (i). Statistical significance was determined using two-way ANOVA followed by Tukey’s Multiple Comparison test (a–i). Scale bar, 5 μm (d). Source data are provided as a Source Data file.',\n", + " 'paragraph_id': 4,\n", + " 'tokenizer': 'to, examine, whether, le, ##pt, ##in, deficiency, causes, er, stress, during, critical, periods, of, development, ,, we, measured, the, expression, levels, of, the, following, er, stress, markers, :, act, ##ivating, transcription, factor, 4, (, at, ##f, ##4, ), ,, 6, (, at, ##f, ##6, ), ,, x, -, box, binding, protein, (, x, ##b, ##p, ##1, ), ,, glucose, regulated, protein, gr, ##p, ##7, ##8, (, referred, to, as, bi, ##p, ), ,, and, cc, ##aa, ##t, -, enhance, ##r, -, binding, protein, homo, ##log, ##ous, protein, (, chop, ), ,, in, the, embryo, ##nic, ,, post, ##nat, ##al, and, adult, h, ##yp, ##oth, ##ala, ##mus, of, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), and, wild, -, type, (, w, ##t, ), mice, ., the, levels, of, er, stress, gene, expression, were, not, significantly, changed, in, the, h, ##yp, ##oth, ##ala, ##mus, of, e, ##14, ., 5, ob, /, ob, embryo, ##s, (, fig, ., 1a, ), or, in, the, arc, ##uate, nucleus, of, the, h, ##yp, ##oth, ##ala, ##mus, (, ar, ##h, ), of, post, ##nat, ##al, day, (, p, ), 0, ob, /, ob, mice, (, fig, ., 1b, ), ., in, contrast, ,, all, er, stress, markers, examined, were, significantly, elevated, in, the, ar, ##h, of, p, ##10, ob, /, ob, mice, (, fig, ., 1, ##c, ), ., we, next, assessed, er, stress, marker, expression, specifically, in, arc, ##uate, po, ##mc, and, ag, ##rp, neurons, and, found, that, the, levels, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, and, bi, ##p, mrna, ##s, were, higher, in, these, two, ne, ##uron, ##al, populations, in, p, ##10, ob, /, ob, mice, (, fig, ., 1, ##d, ), ., during, adulthood, ,, le, ##pt, ##in, deficiency, only, caused, an, increase, in, x, ##b, ##p, ##1, and, bi, ##p, mrna, expression, in, the, ar, ##h, (, fig, ., 1, ##e, ), ., in, addition, ,, x, ##b, ##p, ##1, mrna, levels, were, significantly, higher, in, the, para, ##vent, ##ric, ##ular, nucleus, of, the, h, ##yp, ##oth, ##ala, ##mus, (, pv, ##h, ), of, p, ##0, (, fig, ., 1, ##f, ), and, p, ##10, ob, /, ob, mice, (, fig, ., 1, ##g, ), ,, but, none, of, the, er, stress, markers, studied, were, significantly, elevated, in, the, pv, ##h, of, adult, ob, /, ob, mice, (, fig, ., 1, ##h, ), ., we, also, examined, er, stress, markers, in, metabolic, ##ally, relevant, peripheral, tissues, and, found, that, x, ##b, ##p, ##1, gene, expression, was, up, ##re, ##gul, ##ated, in, the, liver, and, adi, ##pose, tissue, of, p, ##10, ob, /, ob, mice, and, that, at, ##f, ##4, mrna, levels, were, increased, in, the, liver, ##s, of, p, ##10, ob, /, ob, mice, (, supplementary, fig, ., 1a, ,, b, ), ., in, contrast, ,, most, of, the, er, stress, markers, studied, were, down, ##re, ##gul, ##ated, in, the, liver, and, adi, ##pose, tissue, of, adult, ob, /, ob, mice, (, supplementary, fig, ., 1, ##c, ,, d, ), ., fig, ., 1, ##le, ##pt, ##in, deficiency, increases, end, ##op, ##las, ##mic, re, ##tic, ##ulum, stress, markers, in, the, developing, h, ##yp, ##oth, ##ala, ##mus, ., relative, expression, of, act, ##ivating, transcription, factor, 4, (, at, ##f, ##4, ), ,, 6, (, at, ##f, ##6, ), ,, x, -, box, binding, protein, (, x, ##b, ##p, ##1, ), ,, glucose, regulated, protein, gr, ##p, ##7, ##8, (, referred, to, as, bi, ##p, ), ,, and, cc, ##aa, ##t, -, enhance, ##r, -, binding, protein, homo, ##log, ##ous, protein, (, chop, ), mrna, a, in, the, h, ##yp, ##oth, ##ala, ##mus, of, embryo, ##nic, day, (, e, ), 14, ., 5, mice, (, n, =, 4, –, 5, per, group, ), and, b, in, the, arc, ##uate, nucleus, (, ar, ##h, ), of, post, ##nat, ##al, day, (, p, ), 0, wild, -, type, (, w, ##t, ), and, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), mice, (, n, =, 5, –, 6, per, group, ), ., c, relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, the, ar, ##h, of, p, ##10, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, either, vehicle, or, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, (, tu, ##dc, ##a, ), or, le, ##pt, ##in, (, w, ##t, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, n, =, 4, ,, ob, /, ob, +, le, ##pt, ##in, :, n, =, 5, per, group, ), ., d, representative, images, and, quan, ##ti, ##fication, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, (, green, ), in, arc, ##uate, pro, -, op, ##iom, ##ela, ##no, ##cor, ##tin, (, po, ##mc, ), -, (, white, ), and, ago, ##uti, -, related, peptide, (, ag, ##rp, ), (, red, ), mrna, -, expressing, cells, of, w, ##t, and, ob, /, ob, mice, at, p, ##10, (, n, =, 3, –, 4, per, group, ), ., e, relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, the, ar, ##h, of, 10, -, week, -, old, adult, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, either, vehicle, or, tu, ##dc, ##a, (, n, =, 6, per, group, ), ., relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, the, para, ##vent, ##ric, ##ular, nucleus, (, pv, ##h, ), of, f, p, ##0, (, n, =, 4, per, group, ), ,, g, p, ##10, (, n, =, 6, per, group, ), ,, and, h, 10, -, week, -, old, adult, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, either, vehicle, or, tu, ##dc, ##a, (, n, =, 6, per, group, ), ., i, relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, h, ##yp, ##oth, ##ala, ##mic, m, ##hy, ##po, ##e, -, n, ##43, /, 5, cell, l, ##ys, ##ates, treated, with, dime, ##thy, ##l, sul, ##fo, ##xide, (, d, ##ms, ##o, ,, control, ), or, le, ##pt, ##in, (, le, ##p, ,, 100, ng, /, ml, ), or, tunic, ##amy, ##cin, (, tun, ,, 0, ., 1, μ, ##g, /, ml, ), or, tun, +, le, ##p, for, 5, h, (, n, =, 4, per, group, ), ., error, bars, represent, the, se, ##m, ., *, p, ≤, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, ob, /, ob, mice, (, d, ,, f, ), ,, *, p, ≤, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, injected, ob, /, ob, mice, (, c, ,, e, ,, g, ,, h, ), ., *, *, p, ≤, 0, ., 01, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, tunic, ##amy, ##cin, treated, group, (, i, ), ., statistical, significance, was, determined, using, two, -, way, an, ##ova, followed, by, tu, ##key, ’, s, multiple, comparison, test, (, a, –, i, ), ., scale, bar, ,, 5, μ, ##m, (, d, ), ., source, data, are, provided, as, a, source, data, file, .'},\n", + " {'article_id': '8ac4fbd9ed9f0baa294353544aae74fc',\n", + " 'section_name': 'Neonatal TUDCA treatment improves energy balance',\n", + " 'text': 'Beginning at 3 weeks of age, the TUDCA-treated ob/ob neonates had significantly lower body weights than the control ob/ob mice, and this reduction in body weight persisted until 6 weeks of age (Fig. 2a). Neonatal TUDCA treatment also reduced the daily food intake in 10-week-old ob/ob mice (Fig. 2b). Moreover, 4-week-old ob/ob mice treated with TUDCA neonatally displayed a reduction in fat mass, but this effect was not observed in 10-week-old animals (Fig. 2c). Similarly, respiratory quotient, energy expenditure, and locomotor activity during the light phase appeared comparable between control and TUDCA-treated ob/ob mice (Fig. 2d–f). However, locomotor activity during the dark phase was slightly reduced in TUDCA-treated mice (Fig. 2f). To examine whether relieving ER stress neonatally also had consequences on glucose homeostasis, we performed glucose- and insulin-tolerance tests. When exposed to a glucose or an insulin challenge, adult ob/ob mice neonatally treated with TUDCA displayed improved glucose and insulin tolerance, respectively, compared to control ob/ob mice (Fig. 2g–i). In addition, neonatal TUDCA treatment reduced insulin levels in adult fed ob/ob mice (Fig. 2j).Fig. 2Neonatal TUDCA treatment causes long-term beneficial metabolic effects inob/obmice.a Growth curves of wild-type (WT) mice and leptin-deficient (ob/ob) mice treated neonatally with vehicle or tauroursodeoxycholic acid (TUDCA) (n = 8 per group). b Food intake (WT: n = 5, ob/ob + Vehicle, ob/ob + TUDCA: n = 4 per group) and c body composition of 4- (n = 3 per group) and 10-week-old (n = 4–5 per group) WT mice and ob/ob mice treated neonatally with vehicle or TUDCA. d Respiratory exchange ratio (WT: n = 5, ob/ob + Vehicle, ob/ob + TUDCA: n = 4 per group), e energy expenditure (WT: n = 7, ob/ob + Vehicle, ob/ob + TUDCA: n = 3 per group), and f locomotor activity of 6-week-old WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (WT: n = 7, ob/ob + Vehicle, ob/ob + TUDCA: n = 3 per group). g, h Glucose tolerance tests (GTT) and area under the curve (AUC) quantification of 4-week-old (WT: n = 5, ob/ob + Vehicle, ob/ob + TUDCA: n = 8 per group) (g) and 8-week-old (WT: n = 5, ob/ob + Vehicle: n = 6, ob/ob + TUDCA: n = 10 per group) (h) WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (n = 5–10 per group). i Insulin tolerance test (ITT) and area under the ITT curve (AUC) of 9-week-old WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (WT, ob/ob + Vehicle: n = 5, ob/ob + TUDCA: n = 9 per group). j Serum insulin levels of 10- to 12-week-old fed WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (n = 7 per group). Error bars represent the SEM. *P < 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 versus vehicle-injected ob/ob mice (a, g–i), ^#P < 0.05, ^##P ≤ 0.01, ^###P ≤ 0.001, and ^####P ≤ 0.0001 versus WT mice (a, g–i). *P < 0.05, ***P ≤ 0.001, and ****P ≤ 0.0001 versus WT mice and *P < 0.05, **P ≤ 0.01, and ****P ≤ 0.0001 versus vehicle-injected ob/ob mice (b–f, j). Statistical significance between groups was determined using two-tailed Student’s t test (f), one-way ANOVA (b, c, e, f, j) and AUCs in g–j and two-way ANOVA (a, d, g–i) followed by Tukey’s multiple comparison test. Source data are provided as a Source Data file.',\n", + " 'paragraph_id': 7,\n", + " 'tokenizer': 'beginning, at, 3, weeks, of, age, ,, the, tu, ##dc, ##a, -, treated, ob, /, ob, neon, ##ates, had, significantly, lower, body, weights, than, the, control, ob, /, ob, mice, ,, and, this, reduction, in, body, weight, persisted, until, 6, weeks, of, age, (, fig, ., 2a, ), ., neon, ##atal, tu, ##dc, ##a, treatment, also, reduced, the, daily, food, intake, in, 10, -, week, -, old, ob, /, ob, mice, (, fig, ., 2, ##b, ), ., moreover, ,, 4, -, week, -, old, ob, /, ob, mice, treated, with, tu, ##dc, ##a, neon, ##atal, ##ly, displayed, a, reduction, in, fat, mass, ,, but, this, effect, was, not, observed, in, 10, -, week, -, old, animals, (, fig, ., 2, ##c, ), ., similarly, ,, respiratory, quo, ##tie, ##nt, ,, energy, expenditure, ,, and, loco, ##moto, ##r, activity, during, the, light, phase, appeared, comparable, between, control, and, tu, ##dc, ##a, -, treated, ob, /, ob, mice, (, fig, ., 2d, –, f, ), ., however, ,, loco, ##moto, ##r, activity, during, the, dark, phase, was, slightly, reduced, in, tu, ##dc, ##a, -, treated, mice, (, fig, ., 2, ##f, ), ., to, examine, whether, re, ##lie, ##ving, er, stress, neon, ##atal, ##ly, also, had, consequences, on, glucose, home, ##osta, ##sis, ,, we, performed, glucose, -, and, insulin, -, tolerance, tests, ., when, exposed, to, a, glucose, or, an, insulin, challenge, ,, adult, ob, /, ob, mice, neon, ##atal, ##ly, treated, with, tu, ##dc, ##a, displayed, improved, glucose, and, insulin, tolerance, ,, respectively, ,, compared, to, control, ob, /, ob, mice, (, fig, ., 2, ##g, –, i, ), ., in, addition, ,, neon, ##atal, tu, ##dc, ##a, treatment, reduced, insulin, levels, in, adult, fed, ob, /, ob, mice, (, fig, ., 2, ##j, ), ., fig, ., 2, ##neo, ##nat, ##al, tu, ##dc, ##a, treatment, causes, long, -, term, beneficial, metabolic, effects, in, ##ob, /, ob, ##mic, ##e, ., a, growth, curves, of, wild, -, type, (, w, ##t, ), mice, and, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), mice, treated, neon, ##atal, ##ly, with, vehicle, or, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, (, tu, ##dc, ##a, ), (, n, =, 8, per, group, ), ., b, food, intake, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 4, per, group, ), and, c, body, composition, of, 4, -, (, n, =, 3, per, group, ), and, 10, -, week, -, old, (, n, =, 4, –, 5, per, group, ), w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, ., d, respiratory, exchange, ratio, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 4, per, group, ), ,, e, energy, expenditure, (, w, ##t, :, n, =, 7, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 3, per, group, ), ,, and, f, loco, ##moto, ##r, activity, of, 6, -, week, -, old, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, w, ##t, :, n, =, 7, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 3, per, group, ), ., g, ,, h, glucose, tolerance, tests, (, gt, ##t, ), and, area, under, the, curve, (, au, ##c, ), quan, ##ti, ##fication, of, 4, -, week, -, old, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 8, per, group, ), (, g, ), and, 8, -, week, -, old, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, :, n, =, 6, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 10, per, group, ), (, h, ), w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 5, –, 10, per, group, ), ., i, insulin, tolerance, test, (, it, ##t, ), and, area, under, the, it, ##t, curve, (, au, ##c, ), of, 9, -, week, -, old, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, w, ##t, ,, ob, /, ob, +, vehicle, :, n, =, 5, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 9, per, group, ), ., j, serum, insulin, levels, of, 10, -, to, 12, -, week, -, old, fed, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 7, per, group, ), ., error, bars, represent, the, se, ##m, ., *, p, <, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, injected, ob, /, ob, mice, (, a, ,, g, –, i, ), ,, ^, #, p, <, 0, ., 05, ,, ^, #, #, p, ≤, 0, ., 01, ,, ^, #, #, #, p, ≤, 0, ., 001, ,, and, ^, #, #, #, #, p, ≤, 0, ., 000, ##1, versus, w, ##t, mice, (, a, ,, g, –, i, ), ., *, p, <, 0, ., 05, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, w, ##t, mice, and, *, p, <, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, injected, ob, /, ob, mice, (, b, –, f, ,, j, ), ., statistical, significance, between, groups, was, determined, using, two, -, tailed, student, ’, s, t, test, (, f, ), ,, one, -, way, an, ##ova, (, b, ,, c, ,, e, ,, f, ,, j, ), and, au, ##cs, in, g, –, j, and, two, -, way, an, ##ova, (, a, ,, d, ,, g, –, i, ), followed, by, tu, ##key, ’, s, multiple, comparison, test, ., source, data, are, provided, as, a, source, data, file, .'},\n", + " {'article_id': 'b7bfa0c785ac14cbcc984dd2d223647c',\n", + " 'section_name': 'Protein Delivery to the Cytosol or Nucleus',\n", + " 'text': 'Methods for protein delivery include approaches based on physical membrane disruption and approaches that rely on the endocytotic uptake of cargo with subsequent endosomal release [100]. For the latter class, endosomal entrapment has in the past been found to pose a major block to delivery efficiency [101, 102]. Further delivery methods include approaches that combine physical methods with chemicals, such as the application of graphene quantum dots to cells and laser irradiation [103], or use microorganisms to deliver cargoes [104]. Among the many proposed approaches to the cytosolic delivery of proteins, disruption of the membrane has proven particularly efficient for the delivery of proteins into cells [3, 105, 106]. With an efficiency of up to 90–99%, high cell viability of 80–90% [107, 108] and validation in many cell types over the last 20 years (Table 3), electroporation is a robust approach for delivering antibodies into the cytosol. Further physical methods include microinjection or microfluidic cell squeezing, which are either applicable to lower cell numbers or require special equipment [106]. Delivered antibodies remain functional in the cytosol in spite of the reducing environment. The half-life of antibodies in the cytosol is long and they bind to their targets even 3–4 days after electroporation [3, 105]. This suggests that degradation might be even slower than dilution of the antibody by cell division. Compared with DNA that has integrated into the genome, protein delivery is not permanent but transient and depends on the half-life of the delivered protein. The time-limited activity of a protein drug offers the opportunity for better control over therapy and thus higher safety.Table 3Antibodies or proteins delivered by electroporationDelivered proteinCell typeReferencesAsparagine synthetase antibodyHeLa, HT-5, and L5178Y DlO/R[107]p21^ras antibodyB16BL6 mouse melanoma cells[322]Various antibodiesHuman cells[323]MLCK antibody, constitutively active form of MLCKMacrophages[324]Various antibodies and proteinsPheochromocytoma, other cultured cells[325]p21^ras antibodyB16BL6 mouse melanoma cells[326]Tubulin antibodyCHO cells[327]TK enzymeTK-deficient mammalian cell line[328]Lipoxygenase antibodyLentil protoplasts[329]Vimentin antibody, RNAse AFibroblasts[330]Lipoxygenase antibodyLentil protoplasts[331]Cyclin D1 antibodyMouse embryo and SKUT1B cells[332]TGN38-, p200- and VSV-G antibodiesNRK-6G cells[333]Tropomodulin, antibodies specific to: tropomodulin, talin, vinculin and a-actininFibroblasts[334]Lucifer yellow, IgGSW 3T3, NIH 3T3, dHL60, A7r5, BASM[335]MAP kinase antibodyMDCK cells[336]Anti-M-line protein, titin antibodiesChicken cardiomyocytes[337]Various antibodiesChicken cardiomyocytes[338]Wild-type STAT1, mutated STAT1, STAT1 antibodyRat mesangial cells[339]DNase I, restriction enzymesJurkat cells[340]c-Src antibodyHuman vascular smooth muscle cells[341]TFAR19 antibodyHeLa[342]c-Fos antibodySpinal neuronal cells[37]STIM1 antibodyPlatelets[343]Orai1 antibodyPlatelets[344]EGFPHeLa[345]Orai1 antibodyPlatelets[346]HPV16 E6 oncoprotein, PCNA, RNA polymerase II largest subunitHeLa, CaSki, H1299, MEL501 and U2OS[105]Fc-Cre, tubulin antibody, myosin antibodySC1 REW22, HeLa[3]PCNA, DNA polymerase alphaHeLa, US2-OS[317]Pericentrin, mTOR, IκBα, NLRP3, anti-IKKα antibodiesNIH3T3, HEK293T, human monocyte-derived macrophages[8]RBP1, TBP and TAF10 antibodiesVarious mammalian or Drosophila melanogaster cell types[108]γ H2AX antibodyU2-OS[347]Various recombinant proteinsVarious cell lines[348]BASM bovine aortic smooth muscle, CHO Chinese hamster ovary, c-Src cellular Src, EGFP enhanced green fluorescent protein, H2AX H2A.X variant histone, HPV16 human papillomavirus 16, IKKα IκB kinase α, MAP mitogen-activated protein, MDCK Madin-Darby canine kidney, MLCK myosin light chain kinase, mTOR mammalian target of rapamycin, NLRP3 NLR family pyrin domain containing 3, NRK normal rat kidney, Orai1 ORAI calcium release-activated calcium modulator 1, PCNA proliferating cell nuclear antigen, RBP1 retinol binding protein 1, STAT signal transducer and activator of transcription, STIM1 stromal interaction molecule 1, TAF10 TATA-box binding protein associated factor 10, TBP TATA box binding protein, TFAR19 TF-1 apoptosis-related gene 19, TK thymidine kinase',\n", + " 'paragraph_id': 17,\n", + " 'tokenizer': 'methods, for, protein, delivery, include, approaches, based, on, physical, membrane, disruption, and, approaches, that, rely, on, the, end, ##oc, ##yt, ##otic, up, ##take, of, cargo, with, subsequent, end, ##osomal, release, [, 100, ], ., for, the, latter, class, ,, end, ##osomal, en, ##tra, ##pment, has, in, the, past, been, found, to, pose, a, major, block, to, delivery, efficiency, [, 101, ,, 102, ], ., further, delivery, methods, include, approaches, that, combine, physical, methods, with, chemicals, ,, such, as, the, application, of, graph, ##ene, quantum, dots, to, cells, and, laser, ir, ##rad, ##iation, [, 103, ], ,, or, use, micro, ##org, ##ani, ##sms, to, deliver, cargo, ##es, [, 104, ], ., among, the, many, proposed, approaches, to, the, cy, ##tos, ##olic, delivery, of, proteins, ,, disruption, of, the, membrane, has, proven, particularly, efficient, for, the, delivery, of, proteins, into, cells, [, 3, ,, 105, ,, 106, ], ., with, an, efficiency, of, up, to, 90, –, 99, %, ,, high, cell, via, ##bility, of, 80, –, 90, %, [, 107, ,, 108, ], and, validation, in, many, cell, types, over, the, last, 20, years, (, table, 3, ), ,, electro, ##por, ##ation, is, a, robust, approach, for, delivering, antibodies, into, the, cy, ##tos, ##ol, ., further, physical, methods, include, micro, ##in, ##ject, ##ion, or, micro, ##fl, ##uid, ##ic, cell, squeezing, ,, which, are, either, applicable, to, lower, cell, numbers, or, require, special, equipment, [, 106, ], ., delivered, antibodies, remain, functional, in, the, cy, ##tos, ##ol, in, spite, of, the, reducing, environment, ., the, half, -, life, of, antibodies, in, the, cy, ##tos, ##ol, is, long, and, they, bind, to, their, targets, even, 3, –, 4, days, after, electro, ##por, ##ation, [, 3, ,, 105, ], ., this, suggests, that, degradation, might, be, even, slower, than, dil, ##ution, of, the, antibody, by, cell, division, ., compared, with, dna, that, has, integrated, into, the, genome, ,, protein, delivery, is, not, permanent, but, transient, and, depends, on, the, half, -, life, of, the, delivered, protein, ., the, time, -, limited, activity, of, a, protein, drug, offers, the, opportunity, for, better, control, over, therapy, and, thus, higher, safety, ., table, 3a, ##nti, ##bo, ##dies, or, proteins, delivered, by, electro, ##por, ##ation, ##del, ##iver, ##ed, protein, ##cel, ##l, type, ##re, ##ference, ##sas, ##para, ##gin, ##e, synth, ##eta, ##se, antibody, ##hel, ##a, ,, h, ##t, -, 5, ,, and, l, ##51, ##7, ##8, ##y, dl, ##o, /, r, [, 107, ], p, ##21, ^, ras, antibody, ##b, ##16, ##bl, ##6, mouse, mel, ##ano, ##ma, cells, [, 322, ], various, antibodies, ##hum, ##an, cells, [, 323, ], ml, ##ck, antibody, ,, con, ##sti, ##tu, ##tively, active, form, of, ml, ##ck, ##mac, ##rop, ##ha, ##ges, [, 324, ], various, antibodies, and, proteins, ##ph, ##eo, ##ch, ##rom, ##oc, ##yt, ##oma, ,, other, culture, ##d, cells, [, 325, ], p, ##21, ^, ras, antibody, ##b, ##16, ##bl, ##6, mouse, mel, ##ano, ##ma, cells, [, 326, ], tub, ##ulin, antibody, ##cho, cells, [, 327, ], t, ##k, enzyme, ##t, ##k, -, def, ##icient, mammalian, cell, line, [, 328, ], lip, ##ox, ##y, ##genase, antibody, ##lent, ##il, proto, ##pl, ##ast, ##s, [, 329, ], vi, ##ment, ##in, antibody, ,, rna, ##se, afi, ##bro, ##bla, ##sts, [, 330, ], lip, ##ox, ##y, ##genase, antibody, ##lent, ##il, proto, ##pl, ##ast, ##s, [, 331, ], cy, ##cl, ##in, d, ##1, antibody, ##mous, ##e, embryo, and, sk, ##ut, ##1, ##b, cells, [, 332, ], t, ##gn, ##38, -, ,, p, ##200, -, and, vs, ##v, -, g, antibodies, ##nr, ##k, -, 6, ##g, cells, [, 333, ], tr, ##op, ##omo, ##du, ##lin, ,, antibodies, specific, to, :, tr, ##op, ##omo, ##du, ##lin, ,, tal, ##in, ,, vin, ##cu, ##lin, and, a, -, act, ##ini, ##n, ##fi, ##bro, ##bla, ##sts, [, 334, ], lucifer, yellow, ,, i, ##ggs, ##w, 3, ##t, ##3, ,, ni, ##h, 3, ##t, ##3, ,, dh, ##l, ##60, ,, a, ##7, ##r, ##5, ,, bas, ##m, [, 335, ], map, kinase, antibody, ##md, ##ck, cells, [, 336, ], anti, -, m, -, line, protein, ,, ti, ##tin, antibodies, ##chi, ##cken, card, ##iom, ##yo, ##cytes, [, 337, ], various, antibodies, ##chi, ##cken, card, ##iom, ##yo, ##cytes, [, 338, ], wild, -, type, stat, ##1, ,, mu, ##tated, stat, ##1, ,, stat, ##1, antibody, ##rat, mesa, ##ng, ##ial, cells, [, 339, ], dna, ##se, i, ,, restriction, enzymes, ##ju, ##rka, ##t, cells, [, 340, ], c, -, sr, ##c, antibody, ##hum, ##an, vascular, smooth, muscle, cells, [, 341, ], t, ##far, ##19, antibody, ##hel, ##a, [, 34, ##2, ], c, -, f, ##os, antibody, ##sp, ##inal, ne, ##uron, ##al, cells, [, 37, ], st, ##im, ##1, antibody, ##plate, ##lets, [, 343, ], or, ##ai, ##1, antibody, ##plate, ##lets, [, 344, ], e, ##gf, ##ph, ##ela, [, 345, ], or, ##ai, ##1, antibody, ##plate, ##lets, [, 34, ##6, ], hp, ##v, ##16, e, ##6, on, ##co, ##pro, ##tein, ,, pc, ##na, ,, rna, polymer, ##ase, ii, largest, subunit, ##hel, ##a, ,, cas, ##ki, ,, h, ##12, ##9, ##9, ,, mel, ##50, ##1, and, u2, ##os, [, 105, ], fc, -, cr, ##e, ,, tub, ##ulin, antibody, ,, my, ##osi, ##n, antibody, ##sc, ##1, re, ##w, ##22, ,, he, ##la, [, 3, ], pc, ##na, ,, dna, polymer, ##ase, alpha, ##hel, ##a, ,, us, ##2, -, os, [, 317, ], per, ##ice, ##nt, ##rin, ,, mt, ##or, ,, i, ##κ, ##b, ##α, ,, nl, ##rp, ##3, ,, anti, -, ik, ##k, ##α, antibodies, ##ni, ##h, ##3, ##t, ##3, ,, he, ##k, ##29, ##3, ##t, ,, human, mono, ##cy, ##te, -, derived, macro, ##pha, ##ges, [, 8, ], rb, ##p, ##1, ,, tb, ##p, and, ta, ##f, ##10, antibodies, ##var, ##ious, mammalian, or, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, cell, types, [, 108, ], γ, h, ##2, ##ax, antibody, ##u, ##2, -, os, [, 34, ##7, ], various, rec, ##om, ##bina, ##nt, proteins, ##var, ##ious, cell, lines, [, 34, ##8, ], bas, ##m, bo, ##vine, ao, ##rti, ##c, smooth, muscle, ,, cho, chinese, ham, ##ster, o, ##vary, ,, c, -, sr, ##c, cellular, sr, ##c, ,, e, ##gf, ##p, enhanced, green, fluorescent, protein, ,, h, ##2, ##ax, h, ##2, ##a, ., x, variant, his, ##tone, ,, hp, ##v, ##16, human, pa, ##pi, ##llo, ##ma, ##virus, 16, ,, ik, ##k, ##α, i, ##κ, ##b, kinase, α, ,, map, mit, ##ogen, -, activated, protein, ,, md, ##ck, mad, ##in, -, darby, canine, kidney, ,, ml, ##ck, my, ##osi, ##n, light, chain, kinase, ,, mt, ##or, mammalian, target, of, rap, ##amy, ##cin, ,, nl, ##rp, ##3, nl, ##r, family, p, ##yr, ##in, domain, containing, 3, ,, nr, ##k, normal, rat, kidney, ,, or, ##ai, ##1, or, ##ai, calcium, release, -, activated, calcium, mod, ##ulator, 1, ,, pc, ##na, pro, ##life, ##rating, cell, nuclear, antigen, ,, rb, ##p, ##1, re, ##tino, ##l, binding, protein, 1, ,, stat, signal, trans, ##du, ##cer, and, act, ##iva, ##tor, of, transcription, ,, st, ##im, ##1, st, ##rom, ##al, interaction, molecule, 1, ,, ta, ##f, ##10, tata, -, box, binding, protein, associated, factor, 10, ,, tb, ##p, tata, box, binding, protein, ,, t, ##far, ##19, t, ##f, -, 1, ap, ##op, ##tosis, -, related, gene, 19, ,, t, ##k, thy, ##mi, ##dine, kinase'},\n", + " {'article_id': '0f95431b101de7554500eebfc9ad3378',\n", + " 'section_name': 'Results',\n", + " 'text': \"The median age of the 43 patients was 76 years (IQR 70–86; range 51–94), 16 (37%) patients were women and 27 (63%) were men. 40 (93%) had relevant pre-existing chronic medical conditions (mainly cardiorespiratory problems), and 13 (30%) had pre-existing neurological diseases, such as neurodegenerative disease or epilepsy (table\\n). 11 patients (26%) died outside of a hospital (five at home and six in a nursing facility) and 32 (74%) died in a hospital. 12 (28%) patients who died in hospital were treated in intensive care units (ICUs). Cause of death was mainly attributed to the respiratory system, with viral pneumonia as the underlying condition in most cases (table).TableSummary of cases and brain autopsy findingsSexAge, yearsPlace of deathPost-mortem interval, daysCause of deathComorbiditiesBrain weight, gBrain oedemaBrain atrophyArteriosclerosisMacroscopic findingsCase 1Female87Nursing home0PneumoniaCOPD, dementia, IHD, renal insufficiency1215NoneMildModerateNoneCase 2Female85Hospital ward0PneumoniaAtrial fibrillation, cardiac insufficiency, IHD, myelofibrosis, renal insufficiency1240NoneMildModerateFresh infarction in territory of PCACase 3Male88Hospital ward5PneumoniaEmphysema, IHD, renal insufficiency1490ModerateNoneModerateFresh infarction in territory of MCACase 4Male75ICU4Pulmonary arterial embolism, pneumoniaAtrial fibrillation, emphysema, hypertension, renal insufficiency1475MildNoneModerateFresh infarction in territory of PCACase 5Female86Nursing home0PneumoniaCOPD, dementia, IHD1250NoneMildSevereFresh infarction in territory of PCACase 6Male90Nursing home2PneumoniaAtrial fibrillation, dementia, diabetes, history of stroke1015NoneModerateSevereOld infarctions in territory of PCACase 7Male90Hospital ward3Emphysema with respiratory decompensationCardiac insufficiency, COPD1440NoneMildModerateNoneCase 8Male77Hospital ward2PneumoniaAortic aneurysm, atrial flutter, cardiac hypertrophy, emphysema, renal insufficiency1590ModerateNoneModerateNoneCase 9Male76ICU3Pulmonary arterial embolism, respiratory tract infectionCardiac insufficiency, COPD1460MildNoneModerateNoneCase 10Male76ICU3Sepsis, aortic valve endocarditis, pneumoniaAML, cardiomyopathy, thyroid cancer1270NoneMildMildNoneCase 11Male70Hospital ward1Pneumonia (aspiration)Cardiac insufficiency, COPD, IHD, Parkinson's disease1430MildNoneSevereNoneCase 12Male93Hospital ward3PneumoniaDiabetes, hypertension1400MildNoneModerateNoneCase 13Male66Emergency room2PneumoniaDiabetes, IHD1450MildNoneSevereNoneCase 14Female54Hospital ward1PneumoniaTrisomy 21, epilepsy950NoneSevereMildGrey matter heterotopiaCase 15Male82Hospital ward1PneumoniaDiabetes, IHD, Parkinson's disease1170NoneMildModerateOld infarctions in territory of PCACase 16Male86Nursing home2Sepsis, pneumoniaEmphysema, epilepsy, hypoxic brain damage, IHD, renal insufficiency1210NoneMildModerateNoneCase 17Female87Home1PneumoniaCardiac insufficiency, COPD1180NoneMildSevereNoneCase 18Female70ICU3PneumoniaCardiac insufficiency1150NoneMildModerateNoneCase 19Female75ICU4PneumoniaCardiac arrythmia, IHD1210NoneMildSevereNoneCase 20Male93Hospital ward2PneumoniaAtrial fibrillation, cardiac insufficiency, diabetes, IHD, obstructive sleep apnoea syndrome1000NoneModerateModerateOld cerebellar infarctionCase 21Female82Hospital ward4Purulent bronchitisCOPD, history of pulmonary embolism, renal insufficiency1080NoneModerateModerateNoneCase 22Male63ICU1Pulmonary arterial embolism, pneumoniaCardiac insufficiency1435MildNoneMildFresh infarction in territory of ACACase 23Male84Hospital ward5Pneumonia, septic encephalopathyDiabetes, history of stroke, hypertension, IHD, ulcerative colitis1350MildNoneSevereNoneCase 24Male71ICU2Pulmonary arterial embolism, pneumoniaCardiac insufficiency, diabetes, lung granuloma1665ModerateNoneMildNoneCase 25Male75Nursing home3Sudden cardiac deathParkinson's disease1110MildNoneModerateNoneCase 26Male52Home1Pulmonary arterial embolism, pneumoniaCardiac insufficiency1520ModerateNoneSevereNoneCase 27Male85ICU2PneumoniaCOPD, aortic valve replacement, hypertension, IHD1400MildNoneModerateNoneCase 28Female75Home2Pulmonary arterial embolismHypertension, IHD1095NoneModerateModerateNoneCase 29Male59Hospital ward12PneumoniaCardiomyopathy1575ModerateNoneMildNoneCase 30Male85Hospital ward15PneumoniaAtrial fibrillation, COPD, hypothyroidism, lung cancer, renal insufficiency1540ModerateNoneModerateCerebellar metastasis of non-small cell lung cancerCase 31Female76Hospital ward2PneumoniaBreast cancer, hypertension1180NoneMildModerateNoneCase 32Male73Home9Sudden cardiac deathCardiomyopathy, emphysema, IHD1430MildNoneSevereNoneCase 33Male70ICU9PneumoniaDementia, IHD, hypertension1370NoneNoneModerateNoneCase 34Female90Nursing home3PneumoniaCardiomyopathy, dementia, emphysema, renal insufficiency1090NoneSevereModerateNoneCase 35Female94Hospital ward2SepsisAtrial fibrillation, cardiac insufficiency, dementia, history of stroke, IHD, renal insufficiency1220MildMildModerateOld infarction in territory of PCACase 36Female87Hospital ward3Sepsis, pneumoniaColon cancer, emphysema, paranoid schizophrenia1310NoneNoneMildNoneCase 37Female54ICU1PneumoniaMild cardiomyopathy1470MildNoneMildNoneCase 38Female79Hospital ward5PneumoniaCOPD, myelodysplastic syndrome, IHD1290NoneMildMildNoneCase 39Male51Home8PneumoniaLiver cirrhosis1255MildMildMildNoneCase 40Male85Hospital ward3PneumoniaAtrial fibrillation, cardiac insufficiency, dysphagia, emphysema, hypertension, IHD1290MildNoneModerateNoneCase 41Male56Hospital ward3PneumoniaCardiac insufficiency, COPD, diabetes, IHD, renal insufficiency1230MildNoneMildOld infarctions in territory of PCA and lenticulostriate arteriesCase 42Male76ICU3Aortic valve endocarditis, pneumoniaAML, cardiomyopathy, thyroid cancer1270MildNoneMildNoneCase 43Female59ICU1PneumoniaMultiple myeloma1220MildNoneMildFresh infarction in territory of MCACOPD=chronic obstructive pulmonary disease. IHD=ischaemic heart disease. PCA=posterior cerebral artery. MCA=middle cerebral artery. ICU=intensive care unit. AML=acute myeloid leukaemia. ACA=anterior cerebral artery.\",\n", + " 'paragraph_id': 18,\n", + " 'tokenizer': \"the, median, age, of, the, 43, patients, was, 76, years, (, iq, ##r, 70, –, 86, ;, range, 51, –, 94, ), ,, 16, (, 37, %, ), patients, were, women, and, 27, (, 63, %, ), were, men, ., 40, (, 93, %, ), had, relevant, pre, -, existing, chronic, medical, conditions, (, mainly, card, ##ior, ##es, ##pi, ##rator, ##y, problems, ), ,, and, 13, (, 30, %, ), had, pre, -, existing, neurological, diseases, ,, such, as, ne, ##uro, ##de, ##gen, ##erative, disease, or, ep, ##ile, ##psy, (, table, ), ., 11, patients, (, 26, %, ), died, outside, of, a, hospital, (, five, at, home, and, six, in, a, nursing, facility, ), and, 32, (, 74, %, ), died, in, a, hospital, ., 12, (, 28, %, ), patients, who, died, in, hospital, were, treated, in, intensive, care, units, (, ic, ##us, ), ., cause, of, death, was, mainly, attributed, to, the, respiratory, system, ,, with, viral, pneumonia, as, the, underlying, condition, in, most, cases, (, table, ), ., tables, ##um, ##mar, ##y, of, cases, and, brain, autopsy, findings, ##se, ##xa, ##ge, ,, years, ##pl, ##ace, of, death, ##post, -, mort, ##em, interval, ,, days, ##ca, ##use, of, death, ##com, ##or, ##bid, ##ities, ##bra, ##in, weight, ,, gb, ##rain, o, ##ede, ##ma, ##bra, ##in, at, ##rop, ##hya, ##rter, ##ios, ##cle, ##rosis, ##mac, ##ros, ##copic, findings, ##case, 1, ##fe, ##mal, ##e, ##8, ##7, ##nu, ##rs, ##ing, home, ##0, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, dementia, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##15, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 2, ##fe, ##mal, ##e, ##85, ##hos, ##pit, ##al, ward, ##0, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, i, ##hd, ,, my, ##elo, ##fi, ##bro, ##sis, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##40, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##fr, ##esh, in, ##far, ##ction, in, territory, of, pc, ##aca, ##se, 3, ##mal, 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##ld, ##gre, ##y, matter, het, ##ero, ##top, ##iac, ##ase, 15, ##mal, ##e, ##8, ##2, ##hos, ##pit, ##al, ward, ##1, ##p, ##ne, ##um, ##onia, ##dia, ##bet, ##es, ,, i, ##hd, ,, parkinson, ', s, disease, ##11, ##70, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##old, in, ##far, ##ctions, in, territory, of, pc, ##aca, ##se, 16, ##mal, ##e, ##86, ##nu, ##rs, ##ing, home, ##2, ##se, ##psis, ,, pneumonia, ##em, ##phy, ##se, ##ma, ,, ep, ##ile, ##psy, ,, h, ##yp, ##ox, ##ic, brain, damage, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##10, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 17, ##fe, ##mal, ##e, ##8, ##7, ##hom, ##e, ##1, ##p, ##ne, ##um, ##onia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ##11, ##80, ##non, ##emi, ##ld, ##se, ##vere, ##non, ##eca, ##se, 18, ##fe, ##mal, ##e, ##70, ##ic, ##u, ##3, ##p, ##ne, ##um, ##onia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ##11, ##50, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 19, ##fe, ##mal, 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##fr, ##esh, in, ##far, ##ction, in, territory, of, ac, ##aca, ##se, 23, ##mal, ##e, ##8, ##4, ##hos, ##pit, ##al, ward, ##5, ##p, ##ne, ##um, ##onia, ,, sept, ##ic, en, ##ce, ##pha, ##lo, ##pathy, ##dia, ##bet, ##es, ,, history, of, stroke, ,, hyper, ##tension, ,, i, ##hd, ,, ul, ##cera, ##tive, coli, ##tis, ##13, ##50, ##mi, ##ld, ##non, ##ese, ##vere, ##non, ##eca, ##se, 24, ##mal, ##e, ##7, ##1, ##ic, ##u, ##2, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, pneumonia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, diabetes, ,, lung, gran, ##ulo, ##ma, ##16, ##65, ##mo, ##der, ##ate, ##non, ##emi, ##ld, ##non, ##eca, ##se, 25, ##mal, ##e, ##75, ##nu, ##rs, ##ing, home, ##3, ##su, ##dden, cardiac, death, ##park, ##ins, ##on, ', s, disease, ##11, ##10, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 26, ##mal, ##e, ##52, ##hom, ##e, ##1, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, pneumonia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ##15, ##20, ##mo, ##der, ##ate, ##non, ##ese, ##vere, ##non, ##eca, ##se, 27, ##mal, ##e, ##85, ##ic, ##u, ##2, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, ao, ##rti, ##c, valve, replacement, ,, hyper, ##tension, ,, i, ##hd, ##14, ##00, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 28, ##fe, ##mal, ##e, ##75, ##hom, ##e, ##2, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ##hy, ##per, ##tension, ,, i, ##hd, ##10, ##9, ##5, ##non, ##em, ##oder, ##ate, ##mo, ##der, ##ate, ##non, ##eca, ##se, 29, ##mal, ##e, ##59, ##hos, ##pit, ##al, ward, ##12, ##p, ##ne, ##um, ##onia, ##card, ##iom, ##yo, ##pathy, ##15, ##75, ##mo, ##der, ##ate, ##non, ##emi, ##ld, ##non, ##eca, ##se, 30, ##mal, ##e, ##85, ##hos, ##pit, ##al, ward, ##15, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cop, ##d, ,, h, ##yp, ##oth, ##yr, ##oid, ##ism, ,, lung, cancer, ,, renal, ins, ##uf, ##fi, ##ciency, ##15, ##40, ##mo, ##der, ##ate, ##non, ##em, ##oder, ##ate, ##cer, ##eb, ##ella, ##r, meta, ##sta, ##sis, of, non, -, small, cell, lung, cancer, ##case, 31, ##fe, ##mal, ##e, ##7, ##6, ##hos, ##pit, ##al, ward, ##2, ##p, ##ne, ##um, ##onia, ##bre, ##ast, cancer, ,, hyper, ##tension, ##11, ##80, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 32, ##mal, ##e, ##7, ##3, ##hom, ##e, ##9, ##su, ##dden, cardiac, death, ##card, ##iom, ##yo, ##pathy, ,, em, ##phy, ##se, ##ma, ,, i, ##hd, ##14, ##30, ##mi, ##ld, ##non, ##ese, ##vere, ##non, ##eca, ##se, 33, ##mal, ##e, ##70, ##ic, ##u, ##9, ##p, ##ne, ##um, ##onia, ##de, ##ment, ##ia, ,, i, ##hd, ,, hyper, ##tension, ##13, ##70, ##non, ##eno, ##nem, ##oder, ##ate, ##non, ##eca, ##se, 34, ##fe, ##mal, ##e, ##90, ##nu, ##rs, ##ing, home, ##3, ##p, ##ne, ##um, ##onia, ##card, ##iom, ##yo, ##pathy, ,, dementia, ,, em, ##phy, ##se, ##ma, ,, renal, ins, ##uf, ##fi, ##ciency, ##10, ##90, ##non, ##ese, ##vere, ##mo, ##der, ##ate, ##non, ##eca, ##se, 35, ##fe, ##mal, ##e, ##9, ##4, ##hos, ##pit, ##al, ward, ##2, ##se, ##psis, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, dementia, ,, history, of, stroke, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##20, ##mi, ##ld, ##mi, ##ld, ##mo, ##der, ##ate, ##old, in, ##far, ##ction, in, territory, of, pc, ##aca, ##se, 36, ##fe, ##mal, ##e, ##8, ##7, ##hos, ##pit, ##al, ward, ##3, ##se, ##psis, ,, pneumonia, ##col, ##on, cancer, ,, em, ##phy, ##se, ##ma, ,, paranoid, schizophrenia, ##13, ##10, ##non, ##eno, ##nem, ##il, ##d, ##non, ##eca, ##se, 37, ##fe, ##mal, ##e, ##54, ##ic, ##u, ##1, ##p, ##ne, ##um, ##onia, ##mi, ##ld, card, ##iom, ##yo, ##pathy, ##14, ##70, ##mi, ##ld, ##non, ##emi, ##ld, ##non, ##eca, ##se, 38, ##fe, ##mal, ##e, ##7, ##9, ##hos, ##pit, ##al, ward, ##5, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, my, ##elo, ##dy, ##sp, ##lastic, syndrome, ,, i, ##hd, ##12, ##90, ##non, ##emi, ##ld, ##mi, ##ld, ##non, ##eca, ##se, 39, ##mal, ##e, ##51, ##hom, ##e, ##8, ##p, ##ne, ##um, ##onia, ##li, ##ver, ci, ##rr, ##hosis, ##12, ##55, ##mi, ##ld, ##mi, ##ld, ##mi, ##ld, ##non, ##eca, ##se, 40, ##mal, ##e, ##85, ##hos, ##pit, ##al, ward, ##3, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, d, ##ys, ##pha, ##gia, ,, em, ##phy, ##se, ##ma, ,, hyper, ##tension, ,, i, ##hd, ##12, ##90, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 41, ##mal, ##e, ##56, ##hos, ##pit, ##al, ward, ##3, ##p, ##ne, ##um, ##onia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ,, diabetes, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##30, ##mi, ##ld, ##non, ##emi, ##ld, ##old, in, ##far, ##ctions, in, territory, of, pc, ##a, and, lent, ##ic, ##ulo, ##st, ##ria, ##te, arteries, ##case, 42, ##mal, ##e, ##7, ##6, ##ic, ##u, ##3, ##ao, ##rti, ##c, valve, end, ##oca, ##rdi, ##tis, ,, pneumonia, ##am, ##l, ,, card, ##iom, ##yo, ##pathy, ,, thyroid, cancer, ##12, ##70, ##mi, ##ld, ##non, ##emi, ##ld, ##non, ##eca, ##se, 43, ##fe, ##mal, ##e, ##59, ##ic, ##u, ##1, ##p, ##ne, ##um, ##onia, ##mu, ##lt, ##ip, ##le, my, ##elo, ##ma, ##12, ##20, ##mi, ##ld, ##non, ##emi, ##ld, ##fr, ##esh, in, ##far, ##ction, in, territory, of, mca, ##co, ##pd, =, chronic, ob, ##st, ##ru, ##ctive, pulmonary, disease, ., i, ##hd, =, is, ##cha, ##emi, ##c, heart, disease, ., pc, ##a, =, posterior, cerebral, artery, ., mca, =, middle, cerebral, artery, ., ic, ##u, =, intensive, care, unit, ., am, ##l, =, acute, my, ##elo, ##id, le, ##uka, ##emia, ., ac, ##a, =, anterior, cerebral, artery, .\"}]" + ] + }, + "execution_count": 48, + "metadata": {}, + "output_type": "execute_result" + }, + { + "name": "stderr", + "output_type": "stream", + "text": [ + "Scanning paragraphs: 16199 Docs [00:16, 2773.05 Docs/s]" + ] + } + ], + "source": [ + "paragraphs" + ] + } + ], + "metadata": { + "kernelspec": { + "display_name": "Python 3.10.5 ('py10')", + "language": "python", + "name": "python3" + }, + "language_info": { + "codemirror_mode": { + "name": "ipython", + "version": 3 + }, + "file_extension": ".py", + "mimetype": "text/x-python", + "name": "python", + "nbconvert_exporter": "python", + "pygments_lexer": "ipython3", + "version": "3.10.5" + }, + "orig_nbformat": 4, + "vscode": { + "interpreter": { + "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" + } + } + }, + "nbformat": 4, + "nbformat_minor": 2 +} diff --git a/src/bluesearch/k8s/connect.py b/src/bluesearch/k8s/connect.py new file mode 100644 index 000000000..01fffa7e7 --- /dev/null +++ b/src/bluesearch/k8s/connect.py @@ -0,0 +1,15 @@ +import urllib3 +from decouple import config +from elasticsearch import Elasticsearch + +urllib3.disable_warnings() + + +def connect(): + """return a client connect to BBP K8S""" + client = Elasticsearch( + config("ES_URL"), + basic_auth=("elastic", config("ES_PASS")), + verify_certs=False, + ) + return client From d51ab55881becf90781199f13c52ff01705d4be0 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Thu, 15 Sep 2022 16:21:20 +0200 Subject: [PATCH 12/99] add initial embeddings k8s --- .mypy.ini | 3 + src/bluesearch/embedding_models.py | 92 ++++++++++++++++-------------- src/bluesearch/k8s/embedings.py | 13 +++++ 3 files changed, 66 insertions(+), 42 deletions(-) create mode 100644 src/bluesearch/k8s/embedings.py diff --git a/.mypy.ini b/.mypy.ini index bc99f1f8f..cf6fcd4fb 100644 --- a/.mypy.ini +++ b/.mypy.ini @@ -25,3 +25,6 @@ warn_unused_ignores = True show_error_codes = True plugins = sqlmypy exclude = benchmarks/conftest.py|data_and_models/pipelines/ner/transformers_vs_spacy/transformers/|data_and_models/pipelines/sentence_embedding/training_transformers/ +disallow_any_generics = True +disallow_incomplete_defs = True +disallow_untyped_defs = True \ No newline at end of file diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 8ef3555f8..0897060fb 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -22,10 +22,11 @@ import pathlib import pickle # nosec from abc import ABC, abstractmethod +from typing import Any, Optional import numpy as np -import sentence_transformers import sqlalchemy +from sentence_transformers import SentenceTransformer from bluesearch.sql import retrieve_sentences_from_sentence_ids from bluesearch.utils import H5 @@ -38,10 +39,10 @@ class EmbeddingModel(ABC): @property @abstractmethod - def dim(self): + def dim(self) -> int: """Return dimension of the embedding.""" - def preprocess(self, raw_sentence): + def preprocess(self, raw_sentence: str) -> str: """Preprocess the sentence (Tokenization, ...) if needed by the model. This is a default implementation that perform no preprocessing. @@ -59,7 +60,7 @@ def preprocess(self, raw_sentence): """ return raw_sentence - def preprocess_many(self, raw_sentences): + def preprocess_many(self, raw_sentences: list[str]) -> list[Any]: """Preprocess multiple sentences. This is a default implementation and can be overridden by children classes. @@ -77,7 +78,7 @@ def preprocess_many(self, raw_sentences): return [self.preprocess(sentence) for sentence in raw_sentences] @abstractmethod - def embed(self, preprocessed_sentence): + def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: """Compute the sentences embeddings for a given sentence. Parameters @@ -91,7 +92,7 @@ def embed(self, preprocessed_sentence): One dimensional vector representing the embedding of the given sentence. """ - def embed_many(self, preprocessed_sentences): + def embed_many(self, preprocessed_sentences: list[str]) -> np.ndarray[Any, Any]: """Compute sentence embeddings for all provided sentences. This is a default implementation. Children classes can implement more @@ -124,18 +125,20 @@ class SentTransformer(EmbeddingModel): https://github.com/UKPLab/sentence-transformers """ - def __init__(self, model_name_or_path, device=None): + def __init__( + self, model_name_or_path: pathlib.Path | str, device: Optional[str] = None + ): - self.senttransf_model = sentence_transformers.SentenceTransformer( + self.senttransf_model = SentenceTransformer( str(model_name_or_path), device=device ) @property - def dim(self): + def dim(self) -> int: """Return dimension of the embedding.""" - return 768 + return self.senttransf_model.get_sentence_embedding_dimension() - def embed(self, preprocessed_sentence): + def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: """Compute the sentences embeddings for a given sentence. Parameters @@ -150,7 +153,7 @@ def embed(self, preprocessed_sentence): """ return self.embed_many([preprocessed_sentence]).squeeze() - def embed_many(self, preprocessed_sentences): + def embed_many(self, preprocessed_sentences: list[str]) -> np.ndarray[Any, Any]: """Compute sentence embeddings for multiple sentences. Parameters @@ -177,13 +180,13 @@ class SklearnVectorizer(EmbeddingModel): The path of the scikit-learn model to use for the embeddings in Pickle format. """ - def __init__(self, checkpoint_path): + def __init__(self, checkpoint_path: pathlib.Path | str): self.checkpoint_path = pathlib.Path(checkpoint_path) with self.checkpoint_path.open("rb") as f: self.model = pickle.load(f) # nosec @property - def dim(self): + def dim(self) -> int: """Return dimension of the embedding. Returns @@ -201,7 +204,7 @@ def dim(self): f"{type(self.model)} could not be computed." ) - def embed(self, preprocessed_sentence): + def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: """Embed one given sentence. Parameters @@ -218,7 +221,7 @@ def embed(self, preprocessed_sentence): embedding = self.embed_many([preprocessed_sentence]) return embedding.squeeze() - def embed_many(self, preprocessed_sentences): + def embed_many(self, preprocessed_sentences: list[str]) -> np.ndarray[Any, Any]: """Compute sentence embeddings for multiple sentences. Parameters @@ -237,7 +240,12 @@ def embed_many(self, preprocessed_sentences): return embeddings -def compute_database_embeddings(connection, model, indices, batch_size=10): +def compute_database_embeddings( + connection: sqlalchemy.engine.Engine, + model: EmbeddingModel, + indices: np.ndarray[Any, Any], + batch_size: int = 10, +) -> tuple[np.ndarray[Any, Any], np.ndarray[Any, Any]]: """Compute sentences embeddings. The embeddings are computed for a given model and a given database @@ -298,7 +306,7 @@ def compute_database_embeddings(connection, model, indices, batch_size=10): def get_embedding_model( model_name_or_class: str, - checkpoint_path: pathlib.Path | str | None = None, + checkpoint_path: pathlib.Path | str, device: str = "cpu", ) -> EmbeddingModel: """Load a sentence embedding model from its name or its class and checkpoint. @@ -404,20 +412,20 @@ class MPEmbedder: def __init__( self, - database_url, - model_name_or_class, - indices, - h5_path_output, - batch_size_inference=16, - batch_size_transfer=1000, - n_processes=2, - checkpoint_path=None, - gpus=None, - delete_temp=True, - temp_folder=None, - h5_dataset_name=None, - start_method="forkserver", - preinitialize=True, + database_url: str, + model_name_or_class: str, + indices: np.ndarray[Any, Any], + h5_path_output: pathlib.Path, + checkpoint_path: pathlib.Path | str, + batch_size_inference: int = 16, + batch_size_transfer: int = 1000, + n_processes: int = 2, + gpus: Optional[list[Any]] = None, + delete_temp: bool = True, + temp_folder: Optional[pathlib.Path] = None, + h5_dataset_name: Optional[str] = None, + start_method: str = "forkserver", + preinitialize: bool = True, ): self.database_url = database_url self.model_name_or_class = model_name_or_class @@ -445,7 +453,7 @@ def __init__( self.gpus = gpus - def do_embedding(self): + def do_embedding(self) -> None: """Do the parallelized embedding.""" if self.preinitialize: self.logger.info("Preinitializing model (download of checkpoints)") @@ -507,15 +515,15 @@ def do_embedding(self): @staticmethod def run_embedding_worker( - database_url, - model_name_or_class, - indices, - temp_h5_path, - batch_size, - checkpoint_path, - gpu, - h5_dataset_name, - ): + database_url: str, + model_name_or_class: str, + indices: np.ndarray[Any, Any], + temp_h5_path: pathlib.Path, + batch_size: int, + checkpoint_path: pathlib.Path, + gpu: int, + h5_dataset_name: str, + ) -> None: """Run per worker function. Parameters diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embedings.py new file mode 100644 index 000000000..2c02f1d63 --- /dev/null +++ b/src/bluesearch/k8s/embedings.py @@ -0,0 +1,13 @@ +import logging + +logger = logging.getLogger(__name__) + +from sentence_transformers import SentenceTransformer +from bluesearch.embedding_models import SentTransformer + +def embed_locally(model_name, client): + + + model = SentenceTransformer('sentence-transformers/multi-qa-MiniLM-L6-cos-v1') + + model.add_module \ No newline at end of file From 9e7927dcdfae1d0a3f11656f2f40d381de843c63 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 16 Sep 2022 10:51:14 +0200 Subject: [PATCH 13/99] add embedding model --- src/bluesearch/embedding_models.py | 4 +++- src/bluesearch/k8s/embedings.py | 33 +++++++++++++++++++++++++----- 2 files changed, 31 insertions(+), 6 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 0897060fb..c921dff1b 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -583,7 +583,9 @@ def run_embedding_worker( batch_size = min(n_indices, batch_size) logger.info("Populating h5 files") - splits = np.array_split(np.arange(n_indices), n_indices / batch_size) + splits = np.array_split( + np.arange(n_indices), n_indices / batch_size + ) # type:ignore splits = [split for split in splits if len(split) > 0] for split_ix, pos_indices in enumerate(splits): diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embedings.py index 2c02f1d63..cc729ab2f 100644 --- a/src/bluesearch/k8s/embedings.py +++ b/src/bluesearch/k8s/embedings.py @@ -1,13 +1,36 @@ import logging -logger = logging.getLogger(__name__) +import elasticsearch +import tqdm +from elasticsearch.helpers import scan -from sentence_transformers import SentenceTransformer from bluesearch.embedding_models import SentTransformer -def embed_locally(model_name, client): +logger = logging.getLogger(__name__) + + +def embed_locally( + client: elasticsearch.Elasticsearch, + model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", +) -> None: + model = SentTransformer(model_name) - model = SentenceTransformer('sentence-transformers/multi-qa-MiniLM-L6-cos-v1') + # get paragraphs without embeddings + query = {"query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}}} + paragraph_count = client.count(index="paragraphs", query=query)["count"] + print(f"There are {paragraph_count} paragraphs without embeddings") - model.add_module \ No newline at end of file + # creates embeddings for all the documents without embeddings and updates them + progress = tqdm.tqdm( + total=paragraph_count, + position=0, + unit=" Paragraphs", + desc="Updating embeddings", + ) + for hit in scan(client, query=query, index="paragraphs"): + emb = model.embed(hit["_source"]["text"]) + client.update( + index="paragraphs", doc={"embedding": emb.tolist()}, id=hit["_id"] + ) + progress.update(1) From 9fca694d720c537a4158656b70fadc76621ea4ff Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 16 Sep 2022 11:38:13 +0200 Subject: [PATCH 14/99] add embedding locally --- src/bluesearch/k8s/connect.py | 2 +- src/bluesearch/k8s/create_indices.ipynb | 4 ++-- src/bluesearch/k8s/embedings.py | 15 +++++++++++---- 3 files changed, 14 insertions(+), 7 deletions(-) diff --git a/src/bluesearch/k8s/connect.py b/src/bluesearch/k8s/connect.py index 01fffa7e7..6bd030e69 100644 --- a/src/bluesearch/k8s/connect.py +++ b/src/bluesearch/k8s/connect.py @@ -5,7 +5,7 @@ urllib3.disable_warnings() -def connect(): +def connect() -> Elasticsearch: """return a client connect to BBP K8S""" client = Elasticsearch( config("ES_URL"), diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb index 2a087c3f5..6fe65fc12 100644 --- a/src/bluesearch/k8s/create_indices.ipynb +++ b/src/bluesearch/k8s/create_indices.ipynb @@ -9,7 +9,7 @@ }, { "cell_type": "code", - "execution_count": 2, + "execution_count": 1, "metadata": {}, "outputs": [], "source": [ @@ -20,7 +20,7 @@ }, { "cell_type": "code", - "execution_count": 1, + "execution_count": 2, "metadata": {}, "outputs": [], "source": [ diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embedings.py index cc729ab2f..49201e40c 100644 --- a/src/bluesearch/k8s/embedings.py +++ b/src/bluesearch/k8s/embedings.py @@ -5,12 +5,13 @@ from elasticsearch.helpers import scan from bluesearch.embedding_models import SentTransformer +from bluesearch.k8s.connect import connect logger = logging.getLogger(__name__) def embed_locally( - client: elasticsearch.Elasticsearch, + client: elasticsearch.Elasticsearch = connect(), model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", ) -> None: @@ -18,10 +19,12 @@ def embed_locally( # get paragraphs without embeddings query = {"query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}}} - paragraph_count = client.count(index="paragraphs", query=query)["count"] - print(f"There are {paragraph_count} paragraphs without embeddings") + paragraph_count = client.count(index="paragraphs", body=query)[ # type: ignore + "count" + ] + logger.info("There are {paragraph_count} paragraphs without embeddings") - # creates embeddings for all the documents without embeddings and updates them + # creates embeddings for all the documents withouts embeddings and updates them progress = tqdm.tqdm( total=paragraph_count, position=0, @@ -34,3 +37,7 @@ def embed_locally( index="paragraphs", doc={"embedding": emb.tolist()}, id=hit["_id"] ) progress.update(1) + + +if __name__ == "__main__": + embed_locally() From fb8c372b58736e69eebafffc1900def8392ad210 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 19 Sep 2022 11:22:57 +0200 Subject: [PATCH 15/99] add normalization check --- src/bluesearch/embedding_models.py | 8 ++++++++ src/bluesearch/k8s/embedings.py | 3 +++ 2 files changed, 11 insertions(+) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index c921dff1b..92e343cb1 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -138,6 +138,14 @@ def dim(self) -> int: """Return dimension of the embedding.""" return self.senttransf_model.get_sentence_embedding_dimension() + @property + def normalized(self) -> bool: + """Return true is the model as a normalization module""" + for _, module in self.senttransf_model._modules.items(): + if str(module) == "Normalize()": + return True + return False + def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: """Compute the sentences embeddings for a given sentence. diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embedings.py index 49201e40c..8984dc178 100644 --- a/src/bluesearch/k8s/embedings.py +++ b/src/bluesearch/k8s/embedings.py @@ -1,6 +1,7 @@ import logging import elasticsearch +import numpy as np import tqdm from elasticsearch.helpers import scan @@ -33,6 +34,8 @@ def embed_locally( ) for hit in scan(client, query=query, index="paragraphs"): emb = model.embed(hit["_source"]["text"]) + if not model.normalized: + emb /= np.linalg.norm(emb) client.update( index="paragraphs", doc={"embedding": emb.tolist()}, id=hit["_id"] ) From ed3156d23a9c913736a5c3cff48056c137ce7d4c Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 20 Sep 2022 16:54:47 +0200 Subject: [PATCH 16/99] adjustments after PR review --- .gitignore | 3 - notebooks/check_paragrapha_size.ipynb | 231 +++++ setup.py | 1 - src/bluesearch/embedding_models.py | 10 +- .../k8s/check_paragrapha_size.ipynb | 902 ------------------ src/bluesearch/k8s/create_indices.ipynb | 283 ------ src/bluesearch/k8s/embedings.py | 8 +- 7 files changed, 240 insertions(+), 1198 deletions(-) create mode 100644 notebooks/check_paragrapha_size.ipynb delete mode 100644 src/bluesearch/k8s/check_paragrapha_size.ipynb delete mode 100644 src/bluesearch/k8s/create_indices.ipynb diff --git a/.gitignore b/.gitignore index 097d9fa95..6301e8019 100644 --- a/.gitignore +++ b/.gitignore @@ -151,9 +151,6 @@ venv.bak/ # mkdocs documentation /site -# trunk -.trunk - # mypy .mypy_cache/ .dmypy.json diff --git a/notebooks/check_paragrapha_size.ipynb b/notebooks/check_paragrapha_size.ipynb new file mode 100644 index 000000000..37a690f96 --- /dev/null +++ b/notebooks/check_paragrapha_size.ipynb @@ -0,0 +1,231 @@ +{ + "cells": [ + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# connect to ES" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "from bluesearch.k8s.connect import connect" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "client = connect()" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# tokenize all the paragraphs" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "import tqdm\n", + "from elasticsearch.helpers import scan" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "from transformers import AutoTokenizer" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "tokenizer = AutoTokenizer.from_pretrained(\"sentence-transformers/multi-qa-MiniLM-L6-cos-v1\")" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "lens = []\n", + "progress = tqdm.tqdm(position=0, unit=\" Docs\", desc=\"Scanning paragraphs\")\n", + "body = {\"query\":{\"match_all\":{}}}\n", + "for hit in scan(client, query=body, index=\"paragraphs\"):\n", + " emb = tokenizer.tokenize(hit['_source']['text'])\n", + " lens.append(len(emb))\n", + " progress.update(1)" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# plot results" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "import matplotlib.pyplot as plt\n", + "import seaborn as sns\n", + "sns.set()" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "plt.boxplot(lens)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "plt.boxplot(lens)\n", + "plt.ylim([0, 512])" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "plt.hist(lens)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "plt.hist(lens, bins=100)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "plt.hist(lens, bins=100)\n", + "plt.xlim([0, 512])" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "import numpy as np" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "lens=np.array(lens)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "len(lens[np.array(lens)>512]) / len(lens) * 100" + ] + }, + { + "cell_type": "markdown", + "metadata": {}, + "source": [ + "# get biggest paragraphs" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "paragraphs = []\n", + "progress = tqdm.tqdm(position=0, unit=\" Docs\", desc=\"Scanning paragraphs\")\n", + "body = {\"query\":{\"match_all\":{}}}\n", + "for hit in scan(client, query=body, index=\"paragraphs\"):\n", + " emb = tokenizer.tokenize(hit['_source']['text'])\n", + " hit['_source']['tokenizer'] = ', '.join(emb)\n", + " progress.update(1)\n", + " if len(emb) > 1000:\n", + " paragraphs.append(hit['_source'])" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "paragraphs" + ] + } + ], + "metadata": { + "kernelspec": { + "display_name": "Python 3.10.5 ('py10')", + "language": "python", + "name": "python3" + }, + "language_info": { + "codemirror_mode": { + "name": "ipython", + "version": 3 + }, + "file_extension": ".py", + "mimetype": "text/x-python", + "name": "python", + "nbconvert_exporter": "python", + "pygments_lexer": "ipython3", + "version": "3.10.5" + }, + "orig_nbformat": 4, + "vscode": { + "interpreter": { + "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" + } + } + }, + "nbformat": 4, + "nbformat_minor": 2 +} diff --git a/setup.py b/setup.py index 6cb1efeda..aecd7cbe0 100644 --- a/setup.py +++ b/setup.py @@ -67,7 +67,6 @@ "numpy>=1.20.1", "pandas>=1", "pg8000", - "python-decouple==3.6", "python-dotenv", "requests", "scikit-learn", diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 92e343cb1..0814f2050 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -22,7 +22,7 @@ import pathlib import pickle # nosec from abc import ABC, abstractmethod -from typing import Any, Optional +from typing import Any import numpy as np import sqlalchemy @@ -126,7 +126,7 @@ class SentTransformer(EmbeddingModel): """ def __init__( - self, model_name_or_path: pathlib.Path | str, device: Optional[str] = None + self, model_name_or_path: pathlib.Path | str, device: str | None = None ): self.senttransf_model = SentenceTransformer( @@ -428,10 +428,10 @@ def __init__( batch_size_inference: int = 16, batch_size_transfer: int = 1000, n_processes: int = 2, - gpus: Optional[list[Any]] = None, + gpus: list[Any] | None = None, delete_temp: bool = True, - temp_folder: Optional[pathlib.Path] = None, - h5_dataset_name: Optional[str] = None, + temp_folder: pathlib.Path | None = None, + h5_dataset_name: str | None = None, start_method: str = "forkserver", preinitialize: bool = True, ): diff --git a/src/bluesearch/k8s/check_paragrapha_size.ipynb b/src/bluesearch/k8s/check_paragrapha_size.ipynb deleted file mode 100644 index 55d6a42c5..000000000 --- a/src/bluesearch/k8s/check_paragrapha_size.ipynb +++ /dev/null @@ -1,902 +0,0 @@ -{ - "cells": [ - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# connect to ES" - ] - }, - { - "cell_type": "code", - "execution_count": 7, - "metadata": {}, - "outputs": [], - "source": [ - "from bluesearch.k8s.connect import connect" - ] - }, - { - "cell_type": "code", - "execution_count": 8, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/elasticsearch/_sync/client/__init__.py:395: SecurityWarning: Connecting to 'https://ml-elasticsearch.kcp.bbp.epfl.ch:443' using TLS with verify_certs=False is insecure\n", - " _transport = transport_class(\n" - ] - } - ], - "source": [ - "client = connect()" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# tokenize all the paragraphs" - ] - }, - { - "cell_type": "code", - "execution_count": 9, - "metadata": {}, - "outputs": [], - "source": [ - "import tqdm\n", - "from elasticsearch.helpers import scan" - ] - }, - { - "cell_type": "code", - "execution_count": 10, - "metadata": {}, - "outputs": [], - "source": [ - "from transformers import AutoTokenizer" - ] - }, - { - "cell_type": "code", - "execution_count": 11, - "metadata": {}, - "outputs": [], - "source": [ - "tokenizer = AutoTokenizer.from_pretrained(\"sentence-transformers/multi-qa-MiniLM-L6-cos-v1\")" - ] - }, - { - "cell_type": "code", - "execution_count": 16, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "Scanning paragraphs: 1 Docs [23:25, 1405.53s/ Docs]\n", - "Scanning paragraphs: 294 Docs [00:00, 2936.98 Docs/s]Token indices sequence length is longer than the specified maximum sequence length for this model (825 > 512). Running this sequence through the model will result in indexing errors\n", - "Scanning paragraphs: 16006 Docs [00:06, 2740.84 Docs/s]" - ] - } - ], - "source": [ - "lens = []\n", - "progress = tqdm.tqdm(position=0, unit=\" Docs\", desc=\"Scanning paragraphs\")\n", - "body = {\"query\":{\"match_all\":{}}}\n", - "for hit in scan(client, query=body, index=\"paragraphs\"):\n", - " emb = tokenizer.tokenize(hit['_source']['text'])\n", - " lens.append(len(emb))\n", - " progress.update(1)" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# plot results" - ] - }, - { - "cell_type": "code", - "execution_count": 19, - "metadata": {}, - "outputs": [], - "source": [ - "import matplotlib.pyplot as plt\n", - "import seaborn as sns\n", - "sns.set()" - ] - }, - { - "cell_type": "code", - "execution_count": 21, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "{'whiskers': [,\n", - " ],\n", - " 'caps': [,\n", - " ],\n", - " 'boxes': [],\n", - " 'medians': [],\n", - " 'fliers': [],\n", - " 'means': []}" - ] - }, - "execution_count": 21, - "metadata": {}, - "output_type": "execute_result" - }, - { - "data": { - "image/png": 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9.54900e+03]),\n", - " )" - ] - }, - "execution_count": 24, - "metadata": {}, - "output_type": "execute_result" - }, - { - "data": { - "image/png": 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" - ] - }, - "metadata": { - "needs_background": "light" - }, - "output_type": "display_data" - } - ], - "source": [ - "plt.hist(lens, bins=100)" - ] - }, - { - "cell_type": "code", - "execution_count": 25, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "(0.0, 512.0)" - ] - }, - "execution_count": 25, - "metadata": {}, - "output_type": "execute_result" - }, - { - "data": { - "image/png": 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+E2EMeBF4ODNfW+8+DFUoSJI21tAcPpIkbTxDQZJUGAqSpMJQkCQVhoIkqTAUJEmFoSBJKgwFSVLx/1T9D0vAZS73AAAAAElFTkSuQmCC", - "text/plain": [ - "
" - ] - }, - "metadata": { - "needs_background": "light" - }, - "output_type": "display_data" - } - ], - "source": [ - "plt.hist(lens, bins=100)\n", - "plt.xlim([0, 512])" - ] - }, - { - "cell_type": "code", - "execution_count": 28, - "metadata": {}, - "outputs": [], - "source": [ - "import numpy as np" - ] - }, - { - "cell_type": "code", - "execution_count": 32, - "metadata": {}, - "outputs": [], - "source": [ - "lens=np.array(lens)" - ] - }, - { - "cell_type": "code", - "execution_count": 36, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "4.475584912648929" - ] - }, - "execution_count": 36, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "len(lens[np.array(lens)>512]) / len(lens) * 100" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# get biggest paragraphs" - ] - }, - { - "cell_type": "code", - "execution_count": 47, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "Scanning paragraphs: 16199 Docs [01:21, 199.60 Docs/s] \n", - "Scanning paragraphs: 15986 Docs [00:06, 2773.05 Docs/s]" - ] - } - ], - "source": [ - "paragraphs = []\n", - "progress = tqdm.tqdm(position=0, unit=\" Docs\", desc=\"Scanning paragraphs\")\n", - "body = {\"query\":{\"match_all\":{}}}\n", - "for hit in scan(client, query=body, index=\"paragraphs\"):\n", - " emb = tokenizer.tokenize(hit['_source']['text'])\n", - " hit['_source']['tokenizer'] = ', '.join(emb)\n", - " progress.update(1)\n", - " if len(emb) > 1000:\n", - " paragraphs.append(hit['_source'])" - ] - }, - { - "cell_type": "code", - "execution_count": 48, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "[{'article_id': 'a155049713201921a7cc41b64ccbf8fc',\n", - " 'section_name': 'Many other peptides in gonadotrophs may stimulate lactotroph function, but none have been shown to be involved yet',\n", - " 'text': 'An impressive number of peptides have been identified in gonadotrophs and, as they are secreted (183), they are potential candidates for a paracrine action on lactotrophs (Fig. 1), namely angiotensin II (184), neurotensin (185, 186), pituitary adenylate cyclase-activating peptide (PACAP) (187, 188), calcitonin (189), calcitonin gene-related peptide (CGRP) (190), atrial natriuretic peptide (ANP) (191), C-type natriuretic peptide (CNP) (192), proenkephalin A and B-derived peptides (193–195), cocaine and amphetamine-regulated transcript (CART) (196), NPY (197), endothelins (ET) (198, 199) and leptin (200, 201). TRH has been located in gonadotrophs maintained in culture, although this observation was not confirmed yet (202). Among these peptides, angiotensin II (184) and neurotensin (203–206) have well documented PRL-releasing activity in in vitro pituitary cell systems from adult rats. However, expression of neurotensin in gonadotrophs in vivo coincides with the prepubertal rise in plasma oestradiol throughout the second and third weeks in both sexes (185, 186) whereas, in the intact pituitary, the PRL response to GnRH is already decreasing by that time (see above). PACAP effects on PRL release are controversial and depend on the test system used (207–211). Whereas PACAP inhibits PRL release in monolayer cell cultures, it stimulates release in aggregate cell cultures and in vivo (207, 212). In studies where a stimulation of PRL release by PACAP was found in monolayer culture, the effect is probably on PRL gene expression and translation as it was only found after several hours of treatment (213). PACAP activates PRL gene expression (209, 214, 215) and is therefore a candidate peptide to participate in gonadotroph-mediated increase in PRL mRNA levels. ANP has no PRL-releasing action in mammals (216, 217) and whether CNP has such an effect seems unknown for mammals. In fish, ANP was reported to have PRL-releasing activity, although only after hours of exposure and not acutely as seen in our experiments (217). Leptin may be involved as it has been found to strongly stimulate PRL release (218). NPY is also reported to be stimulatory for basal PRL release by some investigators but others found it to inhibit basal and TRH-stimulated PRL release (219). CART has been reported to stimulate PRL release by some investigators but others found it to be inhibitory (196, 220). As to angiotensin II, a debate has going on for many years on whether or not there is an independent renin–angiotensin system expressed in the pituitary and in which cell types the different components are located (184). According to recent studies, there are two different renin-angiotensin systems (221): one is fully expressed within the gonadotrophs, with both renin and angiotensin II detectable in the regulated secretory pathway, but angiotensinogen appears to sort into the constitutive secretory pathway, raising a puzzling question how angiotensin II can then be formed within the regulated pathway. The second system seems to be extracellular with angiotensinogen located in perisinusoidal cells and angiotensin produced by circulating renin in the sinusoid lumen after release of angiotensinogen (221). Angiotensin II could then affect various other cell types downstream in the gland. Several investigators have reported PRL-releasing activity in response to GnRH in pituitary monolayer cultures, although only upon using a very high dose of GnRH (222). In reaggregate cell cultures kept in serum-free medium, we found that physiological doses of GnRH stimulate PRL release and, at these doses, neither an angiotensin-converting enzyme inhibitor, nor angiotensin receptor-1 antagonists were capable of inhibiting the GnRH-stimulated PRL release (222). Only at 100 nm GnRH could a partial inhibition of the PRL response by angiotensin receptor-1 antagonists be detected (222). Thus, angiotensin II may be involved in GnRH-stimulation of PRL release, but it seems to play only an accessory role at high concentration of GnRH. Possibly, the more physiologically relevant effect of GnRH is not involving the local renin–angiotensin system at all and gonadotroph-mediated stimulation of PRL release is mediated by another molecule or by a combination of substances.',\n", - " 'paragraph_id': 43,\n", - " 'tokenizer': 'an, impressive, number, of, peptide, ##s, have, been, identified, in, go, ##nad, ##ot, ##rop, ##hs, and, ,, as, they, are, secret, ##ed, (, 183, ), ,, they, are, potential, candidates, for, a, para, ##cr, ##ine, action, on, lac, ##to, ##tro, ##phs, (, fig, ., 1, ), ,, namely, ang, ##iot, ##ens, ##in, ii, (, 184, ), ,, ne, ##uro, ##tens, ##in, (, 185, ,, 186, ), ,, pit, ##uit, ##ary, aden, ##yla, ##te, cy, ##cl, ##ase, -, act, ##ivating, peptide, (, pac, ##ap, ), (, 187, ,, 188, ), ,, cal, ##cit, ##oni, ##n, (, 189, ), ,, cal, ##cit, ##oni, ##n, gene, -, related, peptide, (, c, ##gr, ##p, ), (, 190, ), ,, at, ##rial, nat, ##ri, ##ure, ##tic, peptide, (, an, ##p, ), (, 191, ), ,, c, -, type, nat, ##ri, ##ure, ##tic, peptide, (, cn, ##p, ), (, 192, ), ,, pro, ##en, ##ke, ##pha, ##lin, a, and, b, -, derived, peptide, ##s, (, 193, –, 195, ), ,, cocaine, and, amp, ##het, ##amine, -, regulated, transcript, (, cart, ), (, 196, ), ,, np, ##y, (, 197, ), ,, end, ##oth, ##elin, ##s, (, et, ), (, 198, ,, 199, ), and, le, ##pt, ##in, (, 200, ,, 201, ), ., tr, ##h, has, been, located, in, go, ##nad, ##ot, ##rop, ##hs, maintained, in, culture, ,, although, this, observation, was, not, confirmed, yet, (, 202, ), ., among, these, peptide, ##s, ,, ang, ##iot, ##ens, ##in, ii, (, 184, ), and, ne, ##uro, ##tens, ##in, (, 203, –, 206, ), have, well, documented, pr, ##l, -, releasing, activity, in, in, vitro, pit, ##uit, ##ary, cell, systems, from, adult, rats, ., however, ,, expression, of, ne, ##uro, ##tens, ##in, in, go, ##nad, ##ot, ##rop, ##hs, in, vivo, coincide, ##s, with, the, prep, ##uber, ##tal, rise, in, plasma, o, ##estra, ##dio, ##l, throughout, the, second, and, third, weeks, in, both, sexes, (, 185, ,, 186, ), whereas, ,, in, the, intact, pit, ##uit, ##ary, ,, the, pr, ##l, response, to, g, ##nr, ##h, is, already, decreasing, by, that, time, (, see, above, ), ., pac, ##ap, effects, on, pr, ##l, release, are, controversial, and, depend, on, the, test, system, used, (, 207, –, 211, ), ., whereas, pac, ##ap, inhibit, ##s, pr, ##l, release, in, mono, ##layer, cell, cultures, ,, it, stimulate, ##s, release, in, aggregate, cell, cultures, and, in, vivo, (, 207, ,, 212, ), ., in, studies, where, a, stimulation, of, pr, ##l, release, by, pac, ##ap, was, found, in, mono, ##layer, culture, ,, the, effect, is, probably, on, pr, ##l, gene, expression, and, translation, as, it, was, only, found, after, several, hours, of, treatment, (, 213, ), ., pac, ##ap, activate, ##s, pr, ##l, gene, expression, (, 209, ,, 214, ,, 215, ), and, is, therefore, a, candidate, peptide, to, participate, in, go, ##nad, ##ot, ##rop, ##h, -, mediated, increase, in, pr, ##l, mrna, levels, ., an, ##p, has, no, pr, ##l, -, releasing, action, in, mammals, (, 216, ,, 217, ), and, whether, cn, ##p, has, such, an, effect, seems, unknown, for, mammals, ., in, fish, ,, an, ##p, was, reported, to, have, pr, ##l, -, releasing, activity, ,, although, only, after, hours, of, exposure, and, not, acute, ##ly, as, seen, in, our, experiments, (, 217, ), ., le, ##pt, ##in, may, be, involved, as, it, has, been, found, to, strongly, stimulate, pr, ##l, release, (, 218, ), ., np, ##y, is, also, reported, to, be, st, ##im, ##ulator, ##y, for, basal, pr, ##l, release, by, some, investigators, but, others, found, it, to, inhibit, basal, and, tr, ##h, -, stimulated, pr, ##l, release, (, 219, ), ., cart, has, been, reported, to, stimulate, pr, ##l, release, by, some, investigators, but, others, found, it, to, be, inhibitor, ##y, (, 196, ,, 220, ), ., as, to, ang, ##iot, ##ens, ##in, ii, ,, a, debate, has, going, on, for, many, years, on, whether, or, not, there, is, an, independent, ren, ##in, –, ang, ##iot, ##ens, ##in, system, expressed, in, the, pit, ##uit, ##ary, and, in, which, cell, types, the, different, components, are, located, (, 184, ), ., according, to, recent, studies, ,, there, are, two, different, ren, ##in, -, ang, ##iot, ##ens, ##in, systems, (, 221, ), :, one, is, fully, expressed, within, the, go, ##nad, ##ot, ##rop, ##hs, ,, with, both, ren, ##in, and, ang, ##iot, ##ens, ##in, ii, detect, ##able, in, the, regulated, secret, ##ory, pathway, ,, but, ang, ##iot, ##ens, ##ino, ##gen, appears, to, sort, into, the, con, ##sti, ##tu, ##tive, secret, ##ory, pathway, ,, raising, a, pu, ##zzling, question, how, ang, ##iot, ##ens, ##in, ii, can, then, be, formed, within, the, regulated, pathway, ., the, second, system, seems, to, be, extra, ##cellular, with, ang, ##iot, ##ens, ##ino, ##gen, located, in, per, ##isi, ##nus, ##oid, ##al, cells, and, ang, ##iot, ##ens, ##in, produced, by, circulating, ren, ##in, in, the, sin, ##uso, ##id, lu, ##men, after, release, of, ang, ##iot, ##ens, ##ino, ##gen, (, 221, ), ., ang, ##iot, ##ens, ##in, ii, could, then, affect, various, other, cell, types, downstream, in, the, gland, ., several, investigators, have, reported, pr, ##l, -, releasing, activity, in, response, to, g, ##nr, ##h, in, pit, ##uit, ##ary, mono, ##layer, cultures, ,, although, only, upon, using, a, very, high, dose, of, g, ##nr, ##h, (, 222, ), ., in, re, ##ag, ##gre, ##gate, cell, cultures, kept, in, serum, -, free, medium, ,, we, found, that, physiological, doses, of, g, ##nr, ##h, stimulate, pr, ##l, release, and, ,, at, these, doses, ,, neither, an, ang, ##iot, ##ens, ##in, -, converting, enzyme, inhibitor, ,, nor, ang, ##iot, ##ens, ##in, receptor, -, 1, antagonist, ##s, were, capable, of, inhibit, ##ing, the, g, ##nr, ##h, -, stimulated, pr, ##l, release, (, 222, ), ., only, at, 100, nm, g, ##nr, ##h, could, a, partial, inhibition, of, the, pr, ##l, response, by, ang, ##iot, ##ens, ##in, receptor, -, 1, antagonist, ##s, be, detected, (, 222, ), ., thus, ,, ang, ##iot, ##ens, ##in, ii, may, be, involved, in, g, ##nr, ##h, -, stimulation, of, pr, ##l, release, ,, but, it, seems, to, play, only, an, accessory, role, at, high, concentration, of, g, ##nr, ##h, ., possibly, ,, the, more, physiological, ##ly, relevant, effect, of, g, ##nr, ##h, is, not, involving, the, local, ren, ##in, –, ang, ##iot, ##ens, ##in, system, at, all, and, go, ##nad, ##ot, ##rop, ##h, -, mediated, stimulation, of, pr, ##l, release, is, mediated, by, another, molecule, or, by, a, combination, of, substances, .'},\n", - " {'article_id': 'abb03d386e8326ec19c7392d2a382d80',\n", - " 'section_name': 'Respiratory physiology (1965–75) and myasthenia at the National Hospital',\n", - " 'text': \"Tom Sears, JND's MD supervisor, friend and colleague, describes their work together.\\n‘Moran Campbell had carried out experiments testing the ability of human subjects to perceive increased resistive or elastic loading of the airways; and he had drawn on contemporary ideas of the ‘length follow-up servo control of movement’ to propose imaginatively that perception depended on ‘length–tension’ inappropriateness to account for the results. However, the servo theory at the time conceived a muscle spindle-dependent reflex mechanism automatically subserving motor control without conscious intervention. In fact the conscious response to loading of limb muscles at that time was assigned to joint receptors with afferent pathways to the brain in the posterior columns. The neurologist Richard Godwin-Austen had recently finished a study of intercostal joint mechanoreceptors in the cat, examining these receptors as a possible source of chest wall proprioception to account for dyspnoeic sensibility. Around that time I was examining electromyographically the response of the intercostal muscles to altered mechanical loading (Sears, 1964). I therefore suggested to John that he should investigate the perception of load in patients with impaired position sense or other criteria of posterior column dysfunction. On alternate weeks John and I would impale each other with wire EMG electrodes, inserted in the external or internal intercostal muscles (sometimes with uncomfortable consequences, ANA; ), to examine their reflex responses to sudden changes in pressure, which could either assist or oppose the voluntary sustained lung volume, or a steadily decreasing or increasing one; similarly, a solenoid valve was used to increase or decrease the mechanical load (airway resistance). The research was based on insights gained from intracellular recordings of the central respiratory drive and the monosynaptic reflexes of intercostal motoneurons. In this way we were able to provide a comprehensive account of the segmental reflex responses of these muscles, particularly in relation to the topographical distribution of activities across the chest wall, as well as to the lung volume (% vital capacity) at which the perturbation was introduced ( and ). Thus our conceptual framework centred on the muscle spindle and John, who had access to human intercostal muscle biopsies, subsequently used the same experimental rig to examine the muscle spindles in these muscles, and provided the first account of their activation in his in vitro preparation (Tom Sears; ).From this experience John gained invaluable experience in electrophysiological measurements and subsequently became very interested in hiccup (), and described a new method to measure conduction velocity of human phrenic nerve fibres, which hitherto had depended on oesophageal electrodes (). Surface electrodes placed over the insertion of the diaphragm in the lower ribs provided clean EMG signals in response to stimulation of the phrenic nerve in the neck, thus providing objective data where the assessment of paradoxical movement was equivocal.In New York with Fred Plum from 1969–70, he carried out experiments on the anaesthetized cat to determine the trajectory of descending bulbospinal pathways responsible – firstly, for the ‘central respiratory drive’ to respiratory motoneurons in the spinal cord, and secondly, for those responsible for the cough reflex (). Both questions had their origin in work done at Queen Square, namely that of Peter Nathan on the pathways in man, as deduced from the effects of cervical tractotomy for the relief of intractable pain; and our studies on the effects of selective lesioning and stimulation experiments in the medulla studied. The experiments were meticulous and with excellent histological control to allow clear conclusions concerning the innervations of the diaphragm and abdominal muscles. Those responsible for the cough lay in the ventral quadrant of the cervical spinal cord, whereas those carrying the respiratory drive were in a ventrolateral location, just as Nathan had found for man (). These feline studies epitomized John's interest in seeking experimentally to discover mechanistic explanations to illuminate his clinical work.John's links with the emerging Department of Neurophysiology continued while he was Physician-in-Charge of the Batten Unit. He collaborated with the lecturer in Bioengineering in that department, David Stagg, who developed a comprehensive computer-based analysis of airflow and tidal volume in eupnoea to reveal a complex breath-by breath variation in such individual parameters as inspiratory and expiratory durations, cycle time, and their correlation with tidal volume (). Nevertheless, this seemingly random variability was such that mean inspiratory flow rate was held constant, the work providing a fresh insight concerning the homeostatic regulation of breathing. Mike Goldman, an expert on the use of ‘magnetometers’ for measuring body wall displacements, then at the Harvard School of Public Health, was encouraged to come to Queen Square. This led to a further collaboration in which John, David Stagg and Mike Goldman were able to show that magnetometers placed over the ribcage and abdomen to measure changes in their anterior/posterior diameters provided signals that, coupled to a calibration procedure, allowed the assessment of respiratory function without the need for face masks, a valuable method for sick patients’ (Tom Sears; and ).\",\n", - " 'paragraph_id': 15,\n", - " 'tokenizer': \"tom, sears, ,, j, ##nd, ', s, md, supervisor, ,, friend, and, colleague, ,, describes, their, work, together, ., ‘, moran, campbell, had, carried, out, experiments, testing, the, ability, of, human, subjects, to, perceive, increased, resist, ##ive, or, elastic, loading, of, the, airways, ;, and, he, had, drawn, on, contemporary, ideas, of, the, ‘, length, follow, -, up, ser, ##vo, control, of, movement, ’, to, propose, imaginative, ##ly, that, perception, depended, on, ‘, length, –, tension, ’, inappropriate, ##ness, to, account, for, the, results, ., however, ,, the, ser, ##vo, theory, at, the, time, conceived, a, muscle, spin, ##dle, -, dependent, reflex, mechanism, automatically, sub, ##ser, ##ving, motor, control, without, conscious, intervention, ., in, fact, the, conscious, response, to, loading, of, limb, muscles, at, that, time, was, assigned, to, joint, receptors, with, af, ##fer, ##ent, pathways, to, the, brain, in, the, posterior, columns, ., the, ne, ##uro, ##logist, richard, god, ##win, -, austen, had, recently, finished, a, study, of, inter, ##cos, ##tal, joint, me, ##chan, ##ore, ##ce, ##pt, ##ors, in, the, cat, ,, examining, these, receptors, as, a, possible, source, of, chest, wall, prop, ##rio, ##ception, to, account, for, d, ##ys, ##p, ##no, ##ei, ##c, sen, ##sibility, ., around, that, time, i, was, examining, electro, ##my, ##ographic, ##ally, the, response, of, the, inter, ##cos, ##tal, muscles, to, altered, mechanical, loading, (, sears, ,, 1964, ), ., i, therefore, suggested, to, john, that, he, should, investigate, the, perception, of, load, in, patients, with, impaired, position, sense, or, other, criteria, of, posterior, column, dysfunction, ., on, alternate, weeks, john, and, i, would, imp, ##ale, each, other, with, wire, em, ##g, electrode, ##s, ,, inserted, in, the, external, or, internal, inter, ##cos, ##tal, muscles, (, sometimes, with, uncomfortable, consequences, ,, ana, ;, ), ,, to, examine, their, reflex, responses, to, sudden, changes, in, pressure, ,, which, could, either, assist, or, oppose, the, voluntary, sustained, lung, volume, ,, or, a, steadily, decreasing, or, increasing, one, ;, similarly, ,, a, sole, ##no, ##id, valve, was, used, to, increase, or, decrease, the, mechanical, load, (, air, ##way, resistance, ), ., the, research, was, based, on, insights, gained, from, intra, ##cellular, recordings, of, the, central, respiratory, drive, and, the, mono, ##sy, ##na, ##ptic, reflex, ##es, of, inter, ##cos, ##tal, mo, ##tone, ##uron, ##s, ., in, this, way, we, were, able, to, provide, a, comprehensive, account, of, the, segment, ##al, reflex, responses, of, these, muscles, ,, particularly, in, relation, to, the, topographic, ##al, distribution, of, activities, across, the, chest, wall, ,, as, well, as, to, the, lung, volume, (, %, vital, capacity, ), at, which, the, per, ##tur, ##bation, was, introduced, (, and, ), ., thus, our, conceptual, framework, centred, on, the, muscle, spin, ##dle, and, john, ,, who, had, access, to, human, inter, ##cos, ##tal, muscle, bio, ##ps, ##ies, ,, subsequently, used, the, same, experimental, rig, to, examine, the, muscle, spin, ##dles, in, these, muscles, ,, and, provided, the, first, account, of, their, activation, in, his, in, vitro, preparation, (, tom, sears, ;, ), ., from, this, experience, john, gained, in, ##val, ##ua, ##ble, experience, in, electro, ##phy, ##sio, ##logical, measurements, and, subsequently, became, very, interested, in, hi, ##cc, ##up, (, ), ,, and, described, a, new, method, to, measure, conduct, ##ion, velocity, of, human, ph, ##ren, ##ic, nerve, fibre, ##s, ,, which, hit, ##her, ##to, had, depended, on, o, ##es, ##op, ##ha, ##ge, ##al, electrode, ##s, (, ), ., surface, electrode, ##s, placed, over, the, insertion, of, the, dia, ##ph, ##rag, ##m, in, the, lower, ribs, provided, clean, em, ##g, signals, in, response, to, stimulation, of, the, ph, ##ren, ##ic, nerve, in, the, neck, ,, thus, providing, objective, data, where, the, assessment, of, paradox, ##ical, movement, was, e, ##qui, ##vo, ##cal, ., in, new, york, with, fred, plum, from, 1969, –, 70, ,, he, carried, out, experiments, on, the, ana, ##est, ##het, ##ized, cat, to, determine, the, trajectory, of, descending, bulb, ##os, ##pina, ##l, pathways, responsible, –, firstly, ,, for, the, ‘, central, respiratory, drive, ’, to, respiratory, mo, ##tone, ##uron, ##s, in, the, spinal, cord, ,, and, secondly, ,, for, those, responsible, for, the, cough, reflex, (, ), ., both, questions, had, their, origin, in, work, done, at, queen, square, ,, namely, that, of, peter, nathan, on, the, pathways, in, man, ,, as, de, ##duced, from, the, effects, of, cervical, tract, ##oto, ##my, for, the, relief, of, intra, ##ctable, pain, ;, and, our, studies, on, the, effects, of, selective, les, ##ion, ##ing, and, stimulation, experiments, in, the, med, ##ulla, studied, ., the, experiments, were, met, ##ic, ##ulous, and, with, excellent, his, ##to, ##logical, control, to, allow, clear, conclusions, concerning, the, inner, ##vation, ##s, of, the, dia, ##ph, ##rag, ##m, and, abdominal, muscles, ., those, responsible, for, the, cough, lay, in, the, ventral, quadrant, of, the, cervical, spinal, cord, ,, whereas, those, carrying, the, respiratory, drive, were, in, a, vent, ##rol, ##ater, ##al, location, ,, just, as, nathan, had, found, for, man, (, ), ., these, fe, ##line, studies, ep, ##ito, ##mi, ##zed, john, ', s, interest, in, seeking, experimental, ##ly, to, discover, me, ##chan, ##istic, explanations, to, ill, ##umi, ##nate, his, clinical, work, ., john, ', s, links, with, the, emerging, department, of, ne, ##uro, ##phy, ##sio, ##logy, continued, while, he, was, physician, -, in, -, charge, of, the, bat, ##ten, unit, ., he, collaborated, with, the, lecturer, in, bio, ##eng, ##ine, ##ering, in, that, department, ,, david, st, ##ag, ##g, ,, who, developed, a, comprehensive, computer, -, based, analysis, of, air, ##flow, and, tidal, volume, in, eu, ##p, ##no, ##ea, to, reveal, a, complex, breath, -, by, breath, variation, in, such, individual, parameters, as, ins, ##pi, ##rator, ##y, and, ex, ##pi, ##rator, ##y, duration, ##s, ,, cycle, time, ,, and, their, correlation, with, tidal, volume, (, ), ., nevertheless, ,, this, seemingly, random, variability, was, such, that, mean, ins, ##pi, ##rator, ##y, flow, rate, was, held, constant, ,, the, work, providing, a, fresh, insight, concerning, the, home, ##osta, ##tic, regulation, of, breathing, ., mike, goldman, ,, an, expert, on, the, use, of, ‘, magnet, ##ometer, ##s, ’, for, measuring, body, wall, displacement, ##s, ,, then, at, the, harvard, school, of, public, health, ,, was, encouraged, to, come, to, queen, square, ., this, led, to, a, further, collaboration, in, which, john, ,, david, st, ##ag, ##g, and, mike, goldman, were, able, to, show, that, magnet, ##ometer, ##s, placed, over, the, rib, ##ca, ##ge, and, abdomen, to, measure, changes, in, their, anterior, /, posterior, diameter, ##s, provided, signals, that, ,, coupled, to, a, cal, ##ib, ##ration, procedure, ,, allowed, the, assessment, of, respiratory, function, without, the, need, for, face, masks, ,, a, valuable, method, for, sick, patients, ’, (, tom, sears, ;, and, ), .\"},\n", - " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", - " 'section_name': 'Potential clinical applications of optoprosthetics',\n", - " 'text': 'Recent publications underpin the possible role of optogenetics as a potential future therapeutic application. For example, electrical peripheral nerve stimulation has been used as an experimental treatment of patients with paralysis and muscle disease. A major drawback is random or reverse muscle recruitment by heterogeneous tissue excitation, resulting in high fatigability. Thy-1::ChR2YFP transgenic mice express ChR2-YFP in both the central and peripheral nervous system as well as in lower motor and dorsal root ganglion neurons. By an optical approach motor units can be recruited in an orderly manner favoring small, slow muscle fibers in comparison to random recruitment by electrical stimulation. This results in a markedly enhanced functional performance as muscle fatigability is strongly reduced by a more physiological recruitment pattern via optical stimulation. Taking into account recent advances in human gene therapy the authors point out an eventual therapeutic use of optogenetics as neuroprosthetics and suggest NpHR in the treatment of spastic movement disorders (Llewellyn et al. 2010). Another promising example of optical control replacing electrical stimulation is light-induced stimulation of the heart muscle. Bruegmann et al. (2010) transferred the optogenetic principle from neurons to cardiomyocytes. A ChR2-EYFP construct driven by the CAG promoter was electroporated into embryonic stem cells (ESCs). After ESC differentiation into cardiomyocytes ChR2 expression was limited to the cell membrane and pulsed in vitro optical stimulation triggered action potential-induced contractions with intercellular electrical spreading. The authors also generated transgenic CAG-ChR2-EYFP mice that showed robust rhodopsin expression in atrial and ventricular cardiomyoctes. By illuminating an area of only 0.05–0.2 mm with pulses as short as 1 ms, reliable action potentials were generated in a minimally delayed 1:1 manner in vitro and in vivo, allowing fast optical pacing limited only by the natural refractoriness of the cardiac cells. Thus, optogenetics could serve as an analytical tool for the study of pacemaking and arrhythmia in cardiology with a high potential for therapeutic use. There are several putative clinical applications of optogenetics also in neurodegenerative disorders. A recent work from Stroh et al. (2011) focuses on a restorative approach. Mouse ESCs were transduced in vitro via lentiviruses to express ChR2-YFP under the EF1α promoter. After a retinoic acid-based differentiation protocol, targeted cells were viable and electrophysiologically mature, similar to native cells. After FACS sorting ChR2-YFP expressing cells were transplanted into rat motor cortex and reacted toward blue light illumination after integration into the host environment. Depolarization and direct Ca^2+ influx via light-gated membrane proteins such as ChR2 could serve as a new tool for stem cell differentiation into neural and neuronal cells in vitro and in vivo, as various facts indicate an important role of Ca^2+ dependent cellular processes driving differentiation (e.g., D’Ascenzo et al. (2006). As functional integration of the transplant is the major goal of regenerative medicine, optogenetically induced differentiation, compared to unspecific chemically or electrically based protocols, just affects the genetically targeted graft cells within a heterogeneous cellular host environment, reducing undesirable side effects such as cell death or tumor growth (Stroh et al. 2011). In a previous study neurons derived from human ESCs were transduced with ChR2-mCherry and mature neurons were analyzed for synaptic integration and functional connectivity of the targeted graft cells into the host circuitry of immuno-depressed neonatal SCID mice (Weick et al. 2010). In vitro postmitotic neurons, both glutamatergic and GABAergic, showed typical electrophysiological responses upon illumination. When transplanted, ChR2 positive matured neurons not only displayed spontaneous action potentials and postsynaptic currents (PSCs) as a proof of input-specific graft integration, but furthermore, adjacent ChR2-negative cells likewise displayed PSCs upon light stimulation, indicating graft to host microcircuit connectivity also in an output-specific manner. By generating a pluripotent human ESC line, expressing ChR2-mCherry constitutively under the synapsin promoter, the authors could improve several drawbacks of viral based approaches such as low transduction efficiency. Yet further research is necessary to establish optogenetics as a standard examination and manipulation tool of functional graft to host integration and circuit plasticity in the context of stem cell based neuroregenerative strategies. Another example for a clinical application could be vision restoration in human subjects with retinal degeneration. ChR2- and NpHR-based approaches would, due to their simple monocomponent working principle with good immune compatibility, cell type specificity and high spatial resolution, compete with electrical stimulation in their ability of restoring photosensitivity. In blind mice lacking retinal photoreceptors (rd1 or Pde6b^rd1 mouse model, Bowes et al. 1990) photosensitivity was restored by heterologous expression of ChR2, either by transducing inner retinal neurons in a non-selective viral based strategy or by in vivo electroporating exclusively ON bipolar retinal cells using a specific promoter sequence (Bi et al. 2006, Lagali et al. 2008). Positive changes in a behavioral readout indicated improved vision and suggest the use of optogenetics in a translational approach also in humans. A major step toward applications in vivo, especially for therapeutic use in humans, would be the employment of highly light-sensitive rhodopsins with specifically defined response kinetics supporting optical control at a cell type-specific resolution. In general optogenetics would significantly benefit from ChRs with larger conductance and higher selectivity for Ca^2+, Na^+ or K^+ in combination with appropriate color and kinetics.',\n", - " 'paragraph_id': 8,\n", - " 'tokenizer': 'recent, publications, under, ##pin, the, possible, role, of, opt, ##ogen, ##etic, ##s, as, a, potential, future, therapeutic, application, ., for, example, ,, electrical, peripheral, nerve, stimulation, has, been, used, as, an, experimental, treatment, of, patients, with, paralysis, and, muscle, disease, ., a, major, draw, ##back, is, random, or, reverse, muscle, recruitment, by, het, ##ero, ##gen, ##eous, tissue, ex, ##cit, ##ation, ,, resulting, in, high, fat, ##iga, ##bility, ., thy, -, 1, :, :, ch, ##r, ##2, ##y, ##fp, trans, ##genic, mice, express, ch, ##r, ##2, -, y, ##fp, in, both, the, central, and, peripheral, nervous, system, as, well, as, in, lower, motor, and, dorsal, root, gang, ##lion, neurons, ., by, an, optical, approach, motor, units, can, be, recruited, in, an, orderly, manner, favor, ##ing, small, ,, slow, muscle, fibers, in, comparison, to, random, recruitment, by, electrical, stimulation, ., this, results, in, a, markedly, enhanced, functional, performance, as, muscle, fat, ##iga, ##bility, is, strongly, reduced, by, a, more, physiological, recruitment, pattern, via, optical, stimulation, ., taking, into, account, recent, advances, in, human, gene, therapy, the, authors, point, out, an, eventual, therapeutic, use, of, opt, ##ogen, ##etic, ##s, as, ne, ##uro, ##pro, ##st, ##hetic, ##s, and, suggest, np, ##hr, in, the, treatment, of, spa, ##stic, movement, disorders, (, ll, ##ew, ##ell, ##yn, et, al, ., 2010, ), ., another, promising, example, of, optical, control, replacing, electrical, stimulation, is, light, -, induced, stimulation, of, the, heart, muscle, ., br, ##ue, ##gman, ##n, et, al, ., (, 2010, ), transferred, the, opt, ##ogen, ##etic, principle, from, neurons, to, card, ##iom, ##yo, ##cytes, ., a, ch, ##r, ##2, -, e, ##y, ##fp, construct, driven, by, the, ca, ##g, promoter, was, electro, ##por, ##ated, into, embryo, ##nic, stem, cells, (, es, ##cs, ), ., after, es, ##c, differentiation, into, card, ##iom, ##yo, ##cytes, ch, ##r, ##2, expression, was, limited, to, the, cell, membrane, and, pulsed, in, vitro, optical, stimulation, triggered, action, potential, -, induced, contraction, ##s, with, inter, ##cellular, electrical, spreading, ., the, authors, also, generated, trans, ##genic, ca, ##g, -, ch, ##r, ##2, -, e, ##y, ##fp, mice, that, showed, robust, r, ##ho, ##do, ##ps, ##in, expression, in, at, ##rial, and, vent, ##ric, ##ular, card, ##iom, ##yo, ##ct, ##es, ., by, illuminating, an, area, of, only, 0, ., 05, –, 0, ., 2, mm, with, pulses, as, short, as, 1, ms, ,, reliable, action, potential, ##s, were, generated, in, a, minimal, ##ly, delayed, 1, :, 1, manner, in, vitro, and, in, vivo, ,, allowing, fast, optical, pacing, limited, only, by, the, natural, ref, ##rac, ##tori, ##ness, of, the, cardiac, cells, ., thus, ,, opt, ##ogen, ##etic, ##s, could, serve, as, an, analytical, tool, for, the, study, of, pace, ##making, and, ar, ##rh, ##yt, ##hmi, ##a, in, card, ##iology, with, a, high, potential, for, therapeutic, use, ., there, are, several, put, ##ative, clinical, applications, of, opt, ##ogen, ##etic, ##s, also, in, ne, ##uro, ##de, ##gen, ##erative, disorders, ., a, recent, work, from, st, ##ro, ##h, et, al, ., (, 2011, ), focuses, on, a, rest, ##ora, ##tive, approach, ., mouse, es, ##cs, were, trans, ##duced, in, vitro, via, lent, ##iv, ##irus, ##es, to, express, ch, ##r, ##2, -, y, ##fp, under, the, e, ##f, ##1, ##α, promoter, ., after, a, re, ##tino, ##ic, acid, -, based, differentiation, protocol, ,, targeted, cells, were, viable, and, electro, ##phy, ##sio, ##logical, ##ly, mature, ,, similar, to, native, cells, ., after, fa, ##cs, sorting, ch, ##r, ##2, -, y, ##fp, expressing, cells, were, transplant, ##ed, into, rat, motor, cortex, and, reacted, toward, blue, light, illumination, after, integration, into, the, host, environment, ., de, ##pol, ##ari, ##zation, and, direct, ca, ^, 2, +, influx, via, light, -, gate, ##d, membrane, proteins, such, as, ch, ##r, ##2, could, serve, as, a, new, tool, for, stem, cell, differentiation, into, neural, and, ne, ##uron, ##al, cells, in, vitro, and, in, vivo, ,, as, various, facts, indicate, an, important, role, of, ca, ^, 2, +, dependent, cellular, processes, driving, differentiation, (, e, ., g, ., ,, d, ’, as, ##cen, ##zo, et, al, ., (, 2006, ), ., as, functional, integration, of, the, transplant, is, the, major, goal, of, reg, ##ener, ##ative, medicine, ,, opt, ##ogen, ##etic, ##ally, induced, differentiation, ,, compared, to, un, ##sp, ##ec, ##ific, chemical, ##ly, or, electrically, based, protocols, ,, just, affects, the, genetically, targeted, graf, ##t, cells, within, a, het, ##ero, ##gen, ##eous, cellular, host, environment, ,, reducing, und, ##es, ##ira, ##ble, side, effects, such, as, cell, death, or, tumor, growth, (, st, ##ro, ##h, et, al, ., 2011, ), ., in, a, previous, study, neurons, derived, from, human, es, ##cs, were, trans, ##duced, with, ch, ##r, ##2, -, mc, ##her, ##ry, and, mature, neurons, were, analyzed, for, syn, ##ap, ##tic, integration, and, functional, connectivity, of, the, targeted, graf, ##t, cells, into, the, host, circuit, ##ry, of, im, ##mun, ##o, -, depressed, neon, ##atal, sci, ##d, mice, (, wei, ##ck, et, al, ., 2010, ), ., in, vitro, post, ##mit, ##otic, neurons, ,, both, g, ##lu, ##tama, ##ter, ##gic, and, ga, ##ba, ##er, ##gic, ,, showed, typical, electro, ##phy, ##sio, ##logical, responses, upon, illumination, ., when, transplant, ##ed, ,, ch, ##r, ##2, positive, mature, ##d, neurons, not, only, displayed, spontaneous, action, potential, ##s, and, posts, ##yna, ##ptic, currents, (, ps, ##cs, ), as, a, proof, of, input, -, specific, graf, ##t, integration, ,, but, furthermore, ,, adjacent, ch, ##r, ##2, -, negative, cells, likewise, displayed, ps, ##cs, upon, light, stimulation, ,, indicating, graf, ##t, to, host, micro, ##ci, ##rc, ##uit, connectivity, also, in, an, output, -, specific, manner, ., by, generating, a, pl, ##uri, ##pot, ##ent, human, es, ##c, line, ,, expressing, ch, ##r, ##2, -, mc, ##her, ##ry, con, ##sti, ##tu, ##tively, under, the, syn, ##ap, ##sin, promoter, ,, the, authors, could, improve, several, draw, ##backs, of, viral, based, approaches, such, as, low, trans, ##duction, efficiency, ., yet, further, research, is, necessary, to, establish, opt, ##ogen, ##etic, ##s, as, a, standard, examination, and, manipulation, tool, of, functional, graf, ##t, to, host, integration, and, circuit, plastic, ##ity, in, the, context, of, stem, cell, based, ne, ##uro, ##re, ##gen, ##erative, strategies, ., another, example, for, a, clinical, application, could, be, vision, restoration, in, human, subjects, with, re, ##tina, ##l, de, ##gen, ##eration, ., ch, ##r, ##2, -, and, np, ##hr, -, based, approaches, would, ,, due, to, their, simple, mono, ##com, ##pone, ##nt, working, principle, with, good, immune, compatibility, ,, cell, type, specific, ##ity, and, high, spatial, resolution, ,, compete, with, electrical, stimulation, in, their, ability, of, restoring, photos, ##ens, ##iti, ##vity, ., in, blind, mice, lacking, re, ##tina, ##l, photo, ##re, ##ce, ##pt, ##ors, (, rd, ##1, or, pd, ##e, ##6, ##b, ^, rd, ##1, mouse, model, ,, bow, ##es, et, al, ., 1990, ), photos, ##ens, ##iti, ##vity, was, restored, by, het, ##ero, ##log, ##ous, expression, of, ch, ##r, ##2, ,, either, by, trans, ##du, ##cing, inner, re, ##tina, ##l, neurons, in, a, non, -, selective, viral, based, strategy, or, by, in, vivo, electro, ##por, ##ating, exclusively, on, bipolar, re, ##tina, ##l, cells, using, a, specific, promoter, sequence, (, bi, et, al, ., 2006, ,, la, ##gal, ##i, et, al, ., 2008, ), ., positive, changes, in, a, behavioral, read, ##out, indicated, improved, vision, and, suggest, the, use, of, opt, ##ogen, ##etic, ##s, in, a, translation, ##al, approach, also, in, humans, ., a, major, step, toward, applications, in, vivo, ,, especially, for, therapeutic, use, in, humans, ,, would, be, the, employment, of, highly, light, -, sensitive, r, ##ho, ##do, ##ps, ##ins, with, specifically, defined, response, kinetic, ##s, supporting, optical, control, at, a, cell, type, -, specific, resolution, ., in, general, opt, ##ogen, ##etic, ##s, would, significantly, benefit, from, ch, ##rs, with, larger, conduct, ##ance, and, higher, select, ##ivity, for, ca, ^, 2, +, ,, na, ^, +, or, k, ^, +, in, combination, with, appropriate, color, and, kinetic, ##s, .'},\n", - " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", - " 'section_name': 'Introduction',\n", - " 'text': 'In recent years, optical control of genetically targeted biological systems has been a fast moving field of continuous progress. The combination of optics, genetics and bioengineering to either stimulate or inhibit cellular activity via light-sensitive microbial membrane proteins (opsins) gave birth to a new research discipline named “optogenetics” (Nagel et al. 2002, 2003; Boyden et al. 2005; Deisseroth et al. 2006). Optical control by microbial opsins has several advantages in comparison to classical electrical or multicomponent manipulation techniques. By genetic targeting, optogenetic stimulation and even inhibition of heterogeneous brain tissue can be achieved in a cell type-specific manner. In contrast, electrical stimulation unselectively interferes with all present cell types, regardless of their anatomical or genetic entity (for example excitatory versus inhibitory neurons and local neurons versus projections), thereby diluting the contribution of individual elements on brain circuitries on the overall effect. In opsins, sensor and effector are combined in a monocomponent system and no exogenous genetical or chemical substitution is necessary what makes it more suitable for in vivo experiments in contrast to multicomponent systems, which are limited rather to in vitro applications. As light of moderate intensity does not interfere with neuronal function and opsin latency upon illumination is very short, optogenetics uniquely combines cell type-specific control with millisecond time scale temporal resolution in a fully reversible manner. Once channelrhodopsin 2 (ChR2) and halorhodopsin (NpHR) had been recognized as multimodal optical interrogation tools in neuroscience, significant efforts have been made to lift the optogenetic approach to a level of broader applicability (Nagel et al. 2003; Boyden et al. 2005; Deisseroth et al. 2006; Zhang et al. 2007a). Bioengineering of existing opsin genes from different microorganisms generated a variety of chimeric rhodopsin versions with modified properties regarding trafficking, kinetics and light responsivity (Zhao et al. 2008; Airan et al. 2009; Berndt et al. 2008, 2011; Lin et al. 2009; Bamann et al. 2010; Gunaydin et al. 2010; Oh et al. 2010; Han et al. 2011; Kleinlogel et al. 2011; Schultheis et al. 2011; Yizhar et al. 2011a, b). In parallel, opsins from various species were screened for their optogenetic suitability. Channelrhodopsin from different species extended the optical spectrum of cellular excitation and the light-driven proton pumps Arch and ArchT enabled neuronal silencing in addition to halorhodopsin (Zhang et al. 2008; Chow et al. 2010; Govorunova et al. 2011; Han et al. 2011). Starting with proof of principle experiments in frog oocytes, optogenetics has been intensively used in vitro (Nagel et al. 2002; Boyden et al. 2005). With the creation of an optical neural interface, freely moving mammals can be studied in vivo, upgrading the optogenetic toolbox to an instrument for the analysis of such complex biological mechanisms such as animal behavior (for example Aravanis et al. 2007; Adamantidis et al. 2007; Tsai et al. 2009; Carter et al. 2010; Ciocchi et al. 2010; Tye et al. 2011). Beside its role in neuroscience, other research fields recently have started to illuminate ChR2-targeted tissues such as cardiomyocytes and embryonic stem cells, proving the universal capabilities of optogenetics (Bruegmann et al. 2010; Stroh et al. 2011). Continuous progress in optical technologies and opsin engineering will not only further consolidate optogenetics as an excellent experimental tool but will also lay the foundation for potential future therapeutic applications (Bi et al. 2006; Lagali et al. 2008; Llewellyn et al. 2010; Weick et al. 2010; Kleinlogel et al. 2011) (Table 1).Table 1Summary of optogenetic toolsOpsinGeneral descriptionOff-kineticsλ_max (nm)PropertiesReferenceFast activators (wild-type, chimeras, mutants and double mutants)ChR2Naturally occurring light-sensitive cation channel10 ± 1 ms470Standard, wild-typeLow photocurrents, slow recovery, spike failure >20 HzNagel et al. (2003)Boyden et al. (2005)ChR2 (H134R)Single mutated ChR2 variant19 ± 2 ms450Photocurrents ↑Slow kinetics, not suitablefor >20 Hz stimulationNagel et al. (2005)Gradinaru et al. (2007)ChETA (E123T)Single mutated ChR2 variant5 ± 1 ms500Reliable spiking ≤200 HzReduced photocurrents if not combined with H134R or T159CGunaydin et al. (2010)ChR2 (T159C)Single mutated ChR2 variant26 ms470Photocurrents ↑Light sensitivity ↑↑No high frequency spikingBerndt et al. (2011)CatCH (L132C)Single mutated ChR2 variant16 ± 3 ms^a474Photocurrents ↑, light sensitivity ↑↑Reliable spiking ≤ 50 HzCell tolerance to increased intracellular calcium?Kleinlogel et al. (2011)E123T + T159CDouble mutantDouble mutated ChR2 variant8 ms505Photocurrents = wild-typeReliable spiking ≤40 HzLimited spectral separation from inhibitory opsinsBerndt et al. (2011)ChIEFChimeric ChR1/ChR2 variant10 ± 1 ms450Photocurrents ↑Reliable spiking ≤25 HzReduced light sensitivityLin et al. (2009)ChR1/2_5/2ChR1/2_2/5Chimeric ChR1/ChR2 variants475 (505)470 (485)^cMight be used as a pH-sensitive light-gated channelTsunoda and Hegemann (2009)ChRGRChimeric ChR1/ChR2 variant8–10 ms505Photocurrents ↑Slow kineticsWang et al. (2009)Wen et al. (2010)VChR1Naturally occurring light-sensitive cation channel133 ms545Red-shifted spectrum, reduced photocurrentsWeak membrane expressionSlow kineticsZhang et al. (2008)C1V1Chimeric ChR1/VChR2 variant156 ms540Red-shifted spectrumPhotocurrents ↑Improved expressionYizhar et al. (2011a, b)MChR1^bNaturally occurring light-sensitive cation channel27 ms528Red-shifted spectrum, faster than VChR2Reduced photocurrents, not tested in neuronsGovorunova et al. (2011)Slow activators (Bistable, step-function opsins)ChR2 C128SSingle mutated ChR2 variant106 ± 9 sOn 470Off ~560Light sensitivity ↑↑↑↑Long term depolarisationNot suited for repeated stimulationBerndt et al. (2008)Bamann et al. (2010)ChR2 D156ASingle mutated ChR2 variant414 sOn 480Off 593Light sensitivity ↑↑↑↑Long term depolarisationNot suited for repeated stimulationBamann et al. (2010)C128S + D156ADouble mutantDouble mutated ChR2 variant29 minOn 445Off 590Light sensitivity ↑↑↑↑Long term depolarisationNot suited for repeated stimulationYizhar et al. (2011a, b)InhibitorsNpHRNaturally occurring light-sensitive chloride pump41 ms589Standard, wild-typeIntracellular blebbing, poor traffickingIncomplete silencingZhang et al. (2007a)eNpHR 3.0Mutated halorhodopsin4.2 ms590Light sensitivity ↑↑Photocurrents ↑↑↑Membrane trafficking ↑↑↑Gradinaru et al. (2010)ArchArchaerhodopsin-3Naturally occurring light-sensitive proton pump19 ms566Light sensitivity ↑↑Photocurrents ↑↑↑Fast recoverySuboptimal traffickingConstant illumination requiredChow et al. (2010)Arch TArchaerhodopsinNaturally occurring light-sensitive proton pump15 ± 4 ms566Light sensitivity ↑↑↑, photocurrents ↑↑↑, fast recoverySuboptimal traffickingConstant illumination requiredHan et al. (2011)Modulators of intracellular signalling, light-sensitive G protein-coupled receptorsOpto-α_1ARRhodopsin/α1 adrenergic receptor chimera3 s500Alpha_1-adrenergic receptor ⇒ activation of G_q protein signaling ⇒ induction of IP_3Affects behavior of freely moving mice.Airan et al. (2009)Opto-β_2ARRhodopsin/β2 adrenergic receptor chimera500 ms500Beta_2-adrenergic receptor ⇒ activation of G_s protein signaling ⇒ induction of cAMPAiran et al. (2009)Rh-CT_5-HT1ARhodopsin/serotonergic 1A receptor chimera3 s4855-HT_1A receptor ⇒ activation of G_i/o protein signaling ⇒ repression of cAMP. Induction of GIRK channel induced hyperpolarization in neurons of rodents.Oh et al. (2010)b-PACMicrobial photo-activated adenylyl cyclase12 s453Light-induced induction of cAMP in frog oocytes, rodent neuronsEffect on behavior of freely moving D. melanogaster.Stierl et al. (2011)^aOff data for CatCH was measured in X. laevis oocytes, not neurons^bData for MChR1 is from HEK 293 cells and MChR1 has not been evaluated in neurons^cMeasurments were performed at pH 7.5 (and pH 4.0)↑ indicates improvement in comparison to wild-type variant',\n", - " 'paragraph_id': 0,\n", - " 'tokenizer': 'in, recent, years, ,, optical, control, of, genetically, targeted, biological, systems, has, been, a, fast, moving, field, of, continuous, progress, ., the, combination, of, optics, ,, genetics, and, bio, ##eng, ##ine, ##ering, to, either, stimulate, or, inhibit, cellular, activity, via, light, -, sensitive, micro, ##bial, membrane, proteins, (, ops, ##ins, ), gave, birth, to, a, new, research, discipline, named, “, opt, ##ogen, ##etic, ##s, ”, (, na, ##gel, et, al, ., 2002, ,, 2003, ;, boyd, ##en, et, al, ., 2005, ;, dei, ##sser, ##oth, et, al, ., 2006, ), ., optical, control, by, micro, ##bial, ops, ##ins, has, several, advantages, in, comparison, to, classical, electrical, or, multi, ##com, ##pone, ##nt, manipulation, techniques, ., by, genetic, targeting, ,, opt, ##ogen, ##etic, stimulation, and, even, inhibition, of, het, ##ero, ##gen, ##eous, brain, tissue, can, be, achieved, in, a, cell, type, -, specific, manner, ., in, contrast, ,, electrical, stimulation, un, ##sel, ##ect, ##ively, interfere, ##s, with, all, present, cell, types, ,, regardless, of, their, anatomical, or, genetic, entity, (, for, example, ex, ##cit, ##atory, versus, inhibitor, ##y, neurons, and, local, neurons, versus, projections, ), ,, thereby, dil, ##uting, the, contribution, of, individual, elements, on, brain, circuit, ##ries, on, the, overall, effect, ., in, ops, ##ins, ,, sensor, and, effect, ##or, are, combined, in, a, mono, ##com, ##pone, ##nt, system, and, no, ex, ##ogen, ##ous, genetic, ##al, or, chemical, substitution, is, necessary, what, makes, it, more, suitable, for, in, vivo, experiments, in, contrast, to, multi, ##com, ##pone, ##nt, systems, ,, which, are, limited, rather, to, in, vitro, applications, ., as, light, of, moderate, intensity, does, not, interfere, with, ne, ##uron, ##al, function, and, ops, ##in, late, ##ncy, upon, illumination, is, very, short, ,, opt, ##ogen, ##etic, ##s, uniquely, combines, cell, type, -, specific, control, with, mill, ##ise, ##con, ##d, time, scale, temporal, resolution, in, a, fully, rev, ##ers, ##ible, manner, ., once, channel, ##rh, ##od, ##ops, ##in, 2, (, ch, ##r, ##2, ), and, halo, ##rh, ##od, ##ops, ##in, (, np, ##hr, ), had, been, recognized, as, multi, ##mo, ##dal, optical, interrogation, tools, in, neuroscience, ,, significant, efforts, have, been, made, to, lift, the, opt, ##ogen, ##etic, approach, to, a, level, of, broader, app, ##lica, ##bility, (, na, ##gel, et, al, ., 2003, ;, boyd, ##en, et, al, ., 2005, ;, dei, ##sser, ##oth, et, al, ., 2006, ;, zhang, et, al, ., 2007, ##a, ), ., bio, ##eng, ##ine, ##ering, of, existing, ops, ##in, genes, from, different, micro, ##org, ##ani, ##sms, generated, a, variety, of, chi, ##meric, r, ##ho, ##do, ##ps, ##in, versions, with, modified, properties, regarding, trafficking, ,, kinetic, ##s, and, light, res, ##pon, ##si, ##vity, (, zhao, et, al, ., 2008, ;, air, ##an, et, al, ., 2009, ;, bern, ##dt, et, al, ., 2008, ,, 2011, ;, lin, et, al, ., 2009, ;, bam, ##ann, et, al, ., 2010, ;, gun, ##ay, ##din, et, al, ., 2010, ;, oh, et, al, ., 2010, ;, han, et, al, ., 2011, ;, klein, ##log, ##el, et, al, ., 2011, ;, sc, ##hul, ##the, ##is, et, al, ., 2011, ;, yi, ##zh, ##ar, et, al, ., 2011, ##a, ,, b, ), ., in, parallel, ,, ops, ##ins, from, various, species, were, screened, for, their, opt, ##ogen, ##etic, suit, ##ability, ., channel, ##rh, ##od, ##ops, ##in, from, different, species, extended, the, optical, spectrum, of, cellular, ex, ##cit, ##ation, and, the, light, -, driven, proton, pumps, arch, and, arch, ##t, enabled, ne, ##uron, ##al, si, ##len, ##cing, in, addition, to, halo, ##rh, ##od, ##ops, ##in, (, zhang, et, al, ., 2008, ;, chow, et, al, ., 2010, ;, gov, ##or, ##uno, ##va, et, al, ., 2011, ;, han, et, al, ., 2011, ), ., starting, with, proof, of, principle, experiments, in, frog, o, ##ocytes, ,, opt, ##ogen, ##etic, ##s, has, been, intensive, ##ly, used, in, vitro, (, na, ##gel, et, al, ., 2002, ;, boyd, ##en, et, al, ., 2005, ), ., with, the, creation, of, an, optical, neural, interface, ,, freely, moving, mammals, can, be, studied, in, vivo, ,, upgrading, the, opt, ##ogen, ##etic, tool, ##box, to, an, instrument, for, the, analysis, of, such, complex, biological, mechanisms, such, as, animal, behavior, (, for, example, ara, ##vani, ##s, et, al, ., 2007, ;, adamant, ##idi, ##s, et, al, ., 2007, ;, ts, ##ai, et, al, ., 2009, ;, carter, et, al, ., 2010, ;, ci, ##oc, ##chi, et, al, ., 2010, ;, ty, ##e, et, al, ., 2011, ), ., beside, its, role, in, neuroscience, ,, other, research, fields, recently, have, started, to, ill, ##umi, ##nate, ch, ##r, ##2, -, targeted, tissues, such, as, card, ##iom, ##yo, ##cytes, and, embryo, ##nic, stem, cells, ,, proving, the, universal, capabilities, of, opt, ##ogen, ##etic, ##s, (, br, ##ue, ##gman, ##n, et, al, ., 2010, ;, st, ##ro, ##h, et, al, ., 2011, ), ., continuous, progress, in, optical, technologies, and, ops, ##in, engineering, will, not, only, further, consolidate, opt, ##ogen, ##etic, ##s, as, an, excellent, experimental, tool, but, will, also, lay, the, foundation, for, potential, future, therapeutic, applications, (, bi, et, al, ., 2006, ;, la, ##gal, ##i, et, al, ., 2008, ;, ll, ##ew, ##ell, ##yn, et, al, ., 2010, ;, wei, ##ck, et, al, ., 2010, ;, klein, ##log, ##el, et, al, ., 2011, ), (, table, 1, ), ., table, 1, ##sum, ##mar, ##y, of, opt, ##ogen, ##etic, tools, ##ops, ##ingen, ##eral, description, ##off, -, kinetic, ##s, ##λ, _, max, (, nm, ), properties, ##re, ##ference, ##fast, act, ##iva, ##tors, (, wild, -, type, ,, chi, ##mer, ##as, ,, mutants, and, double, mutants, ), ch, ##r, ##2, ##nat, ##ural, ##ly, occurring, light, -, sensitive, cat, ##ion, channel, ##10, ±, 1, ms, ##47, ##0s, ##tan, ##dar, ##d, ,, wild, -, type, ##low, photo, ##cu, ##rre, ##nts, ,, slow, recovery, ,, spike, failure, >, 20, hz, ##nage, ##l, et, al, ., (, 2003, ), boyd, ##en, et, al, ., (, 2005, ), ch, ##r, ##2, (, h, ##13, ##4, ##r, ), single, mu, ##tated, ch, ##r, ##2, variant, ##19, ±, 2, ms, ##45, ##0, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##slow, kinetic, ##s, ,, not, suitable, ##for, >, 20, hz, stimulation, ##nage, ##l, et, al, ., (, 2005, ), gr, ##adi, ##nar, ##u, et, al, ., (, 2007, ), chet, ##a, (, e, ##12, ##3, ##t, ), single, mu, ##tated, ch, ##r, ##2, variant, ##5, ±, 1, ms, ##500, ##rel, ##iable, sp, ##iki, ##ng, ≤, ##200, hz, ##red, ##uce, ##d, photo, ##cu, ##rre, ##nts, if, not, combined, with, h, ##13, ##4, ##r, or, t, ##15, ##9, ##c, ##gun, ##ay, ##din, et, al, ., (, 2010, ), ch, ##r, ##2, (, t, ##15, ##9, ##c, ), single, mu, ##tated, ch, ##r, ##2, variant, ##26, ms, ##47, ##0, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##light, sensitivity, ↑, ##↑, ##no, high, frequency, sp, ##iki, ##ng, ##ber, ##ndt, et, al, ., (, 2011, ), catch, (, l, ##13, ##2, ##c, ), single, mu, ##tated, ch, ##r, ##2, variant, ##16, ±, 3, ms, ^, a, ##47, ##4, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ,, light, sensitivity, ↑, ##↑, ##rel, ##iable, sp, ##iki, ##ng, ≤, 50, hz, ##cel, ##l, tolerance, to, increased, intra, ##cellular, calcium, ?, klein, ##log, ##el, et, al, ., (, 2011, ), e, ##12, ##3, ##t, +, t, ##15, ##9, ##cd, ##ou, ##ble, mutant, ##dou, ##ble, mu, ##tated, ch, ##r, ##2, variant, ##8, ms, ##50, ##5, ##ph, ##oto, ##cu, ##rre, ##nts, =, wild, -, type, ##rel, ##iable, sp, ##iki, ##ng, ≤, ##40, hz, ##lim, ##ited, spectral, separation, from, inhibitor, ##y, ops, ##ins, ##ber, ##ndt, et, al, ., (, 2011, ), chief, ##chi, ##meric, ch, ##r, ##1, /, ch, ##r, ##2, variant, ##10, ±, 1, ms, ##45, ##0, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##rel, ##iable, sp, ##iki, ##ng, ≤, ##25, hz, ##red, ##uce, ##d, light, sensitivity, ##lin, et, al, ., (, 2009, ), ch, ##r, ##1, /, 2, _, 5, /, 2, ##ch, ##r, ##1, /, 2, _, 2, /, 5, ##chi, ##meric, ch, ##r, ##1, /, ch, ##r, ##2, variants, ##47, ##5, (, 505, ), 470, (, 48, ##5, ), ^, cm, ##ight, be, used, as, a, ph, -, sensitive, light, -, gate, ##d, channel, ##tsu, ##no, ##da, and, he, ##ge, ##mann, (, 2009, ), ch, ##rg, ##rch, ##ime, ##ric, ch, ##r, ##1, /, ch, ##r, ##2, variant, ##8, –, 10, ms, ##50, ##5, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##slow, kinetic, ##sw, ##ang, et, al, ., (, 2009, ), wen, et, al, ., (, 2010, ), vc, ##hr, ##1, ##nat, ##ural, ##ly, occurring, light, -, sensitive, cat, ##ion, channel, ##13, ##3, ms, ##54, ##5, ##red, -, shifted, spectrum, ,, reduced, photo, ##cu, ##rre, ##nts, ##we, ##ak, membrane, expressions, ##low, kinetic, ##sz, ##hang, et, al, ., (, 2008, ), c1, ##v, ##1, ##chi, ##meric, ch, ##r, ##1, /, vc, ##hr, ##2, variant, ##15, ##6, ms, ##54, ##0, ##red, -, shifted, spectrum, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##im, ##pro, ##ved, expression, ##yi, ##zh, ##ar, et, al, ., (, 2011, ##a, ,, b, ), mc, ##hr, ##1, ^, bn, ##at, ##ural, ##ly, occurring, light, -, sensitive, cat, ##ion, channel, ##27, ms, ##52, ##8, ##red, -, shifted, spectrum, ,, faster, than, vc, ##hr, ##2, ##red, ##uce, ##d, photo, ##cu, ##rre, ##nts, ,, not, tested, in, neurons, ##go, ##vor, ##uno, ##va, et, al, ., (, 2011, ), slow, act, ##iva, ##tors, (, bis, ##table, ,, step, -, function, ops, ##ins, ), ch, ##r, ##2, c1, ##28, ##ssing, ##le, mu, ##tated, ch, ##r, ##2, variant, ##10, ##6, ±, 9, son, 470, ##off, ~, 560, ##light, sensitivity, ↑, ##↑, ##↑, ##↑, ##long, term, de, ##pol, ##aris, ##ation, ##not, suited, for, repeated, stimulation, ##ber, ##ndt, et, al, ., (, 2008, ), bam, ##ann, et, al, ., (, 2010, ), ch, ##r, ##2, d, ##15, ##6, ##asi, ##ng, ##le, mu, ##tated, ch, ##r, ##2, variant, ##41, ##4, son, 480, ##off, 59, ##3, ##light, sensitivity, ↑, ##↑, ##↑, ##↑, ##long, term, de, ##pol, ##aris, ##ation, ##not, suited, for, repeated, stimulation, ##ba, ##mann, et, al, ., (, 2010, ), c1, ##28, ##s, +, d, ##15, ##6, ##ado, ##ub, ##le, mutant, ##dou, ##ble, mu, ##tated, ch, ##r, ##2, variant, ##29, min, ##on, 44, ##5, ##off, 590, ##light, sensitivity, ↑, ##↑, ##↑, ##↑, ##long, term, de, ##pol, ##aris, ##ation, ##not, suited, for, repeated, stimulation, ##yi, ##zh, ##ar, et, al, ., (, 2011, ##a, ,, b, ), inhibitors, ##np, ##hr, ##nat, ##ural, ##ly, occurring, light, -, sensitive, chloride, pump, ##41, ms, ##58, ##9, ##stand, ##ard, ,, wild, -, type, ##int, ##race, ##ll, ##ular, b, ##le, ##bbing, ,, poor, trafficking, ##in, ##com, ##ple, ##te, si, ##len, ##cing, ##zh, ##ang, et, al, ., (, 2007, ##a, ), en, ##ph, ##r, 3, ., 0, ##mut, ##ated, halo, ##rh, ##od, ##ops, ##in, ##4, ., 2, ms, ##59, ##0, ##light, sensitivity, ↑, ##↑, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##↑, ##↑, ##me, ##mb, ##rane, trafficking, ↑, ##↑, ##↑, ##grad, ##ina, ##ru, et, al, ., (, 2010, ), arch, ##ar, ##cha, ##er, ##ho, ##do, ##ps, ##in, -, 3, ##nat, ##ural, ##ly, occurring, light, -, sensitive, proton, pump, ##19, ms, ##56, ##6, ##light, sensitivity, ↑, ##↑, ##ph, ##oto, ##cu, ##rre, ##nts, ↑, ##↑, ##↑, ##fast, recovery, ##su, ##bo, ##pt, ##ima, ##l, trafficking, ##con, ##stan, ##t, illumination, required, ##cho, ##w, et, al, ., (, 2010, ), arch, tar, ##cha, ##er, ##ho, ##do, ##ps, ##inn, ##at, ##ural, ##ly, occurring, light, -, sensitive, proton, pump, ##15, ±, 4, ms, ##56, ##6, ##light, sensitivity, ↑, ##↑, ##↑, ,, photo, ##cu, ##rre, ##nts, ↑, ##↑, ##↑, ,, fast, recovery, ##su, ##bo, ##pt, ##ima, ##l, trafficking, ##con, ##stan, ##t, illumination, required, ##han, et, al, ., (, 2011, ), mod, ##ulator, ##s, of, intra, ##cellular, signalling, ,, light, -, sensitive, g, protein, -, coupled, receptors, ##op, ##to, -, α, _, 1a, ##rr, ##ho, ##do, ##ps, ##in, /, α, ##1, ad, ##ren, ##er, ##gic, receptor, chi, ##mer, ##a, ##3, s, ##500, ##al, ##pha, _, 1, -, ad, ##ren, ##er, ##gic, receptor, ⇒, activation, of, g, _, q, protein, signaling, ⇒, induction, of, ip, _, 3a, ##ffe, ##cts, behavior, of, freely, moving, mice, ., air, ##an, et, al, ., (, 2009, ), opt, ##o, -, β, _, 2a, ##rr, ##ho, ##do, ##ps, ##in, /, β, ##2, ad, ##ren, ##er, ##gic, receptor, chi, ##mer, ##a, ##500, ms, ##500, ##bet, ##a, _, 2, -, ad, ##ren, ##er, ##gic, receptor, ⇒, activation, of, g, _, s, protein, signaling, ⇒, induction, of, camp, ##air, ##an, et, al, ., (, 2009, ), r, ##h, -, ct, _, 5, -, h, ##t, ##1, ##ar, ##ho, ##do, ##ps, ##in, /, ser, ##oton, ##er, ##gic, 1a, receptor, chi, ##mer, ##a, ##3, s, ##48, ##55, -, h, ##t, _, 1a, receptor, ⇒, activation, of, g, _, i, /, o, protein, signaling, ⇒, repression, of, camp, ., induction, of, gi, ##rk, channel, induced, hyper, ##pol, ##ari, ##zation, in, neurons, of, rodents, ., oh, et, al, ., (, 2010, ), b, -, pac, ##mic, ##ro, ##bial, photo, -, activated, aden, ##yl, ##yl, cy, ##cl, ##ase, ##12, s, ##45, ##3, ##light, -, induced, induction, of, camp, in, frog, o, ##ocytes, ,, rode, ##nt, neurons, ##ef, ##fect, on, behavior, of, freely, moving, d, ., mel, ##ano, ##gas, ##ter, ., st, ##ier, ##l, et, al, ., (, 2011, ), ^, ao, ##ff, data, for, catch, was, measured, in, x, ., la, ##ev, ##is, o, ##ocytes, ,, not, neurons, ^, b, ##da, ##ta, for, mc, ##hr, ##1, is, from, he, ##k, 293, cells, and, mc, ##hr, ##1, has, not, been, evaluated, in, neurons, ^, cm, ##ea, ##sur, ##ments, were, performed, at, ph, 7, ., 5, (, and, ph, 4, ., 0, ), ↑, indicates, improvement, in, comparison, to, wild, -, type, variant'},\n", - " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", - " 'section_name': 'Exploiting light-sensitive microbial membrane proteins',\n", - " 'text': 'With the identification of the gene for a light-responsive membrane protein in microorganisms called bacteriorhodopsin (BR), Stoeckenius and Oesterhelt (1971) set the foundation for a technology, which is today described by the term “optogenetics” (Oesterhelt and Stoeckenius 1973; Deisseroth et al. 2006). Three decades had passed until scientists were able to take advantage of the potential based on the working principle of this seven-transmembrane domain-containing light-transducing proton pump, which in nature serves microbes, among other things, as a regulator of homeostasis and phototrophy (Beja et al. 2000). Encoded by a single open reading frame, it works as an optical controller of transmembrane ion flow combining fast action and coupling of sensor and effector in a monocomponent system (Oesterhelt and Stoeckenius 1971). Later rhodopsin-mediated responses were also studied in the alga Chlamydomonas (Harz and Hegemann 1991) and since the photocurrets were ultra fast the authors claimed that rhodopsin and channel were intimately linked (Holland et al. 1996). Then Nagel and colleagues proved this concept by showing that the Rhodopsins are directly light-gated ion channels. They used amphibian and mammalian cells as hosts to express channelrhodopsin-1 (ChR1), a light-gated proton channel from the green algae Chlamydomonas reinhardtii. In a modified patch clamp set-up they substantiated that rhodopsins react functionally upon laser illumination also in mammalian cells (Nagel et al. 2002). What was initially used as an experimental model system to study channelrhodopsin function turned into the precursor of a novel scientific tool. With the functional characterization of ChR2, a directly light-gated cation-selective membrane channel, Nagel et al. (2003) showed that mammalian cells expressing ChR2 could be depolarized “simply by illumination”. The full conversion of this approach into an optical control device of cell activity happened in 2005 when it found its way into neuroscience. The Deisseroth lab applied lentiviral gene delivery to express ChR2 in rat hippocampal neurons. In combination with high-speed optical switching, neuronal spiking was elicited by photostimulation in a millisecond timescale (Boyden et al. 2005). In parallel, the labs of Yawo, Herlitze and Gottschalk independently demonstrated the feasibility of ChR2-based optical neuronal manipulation (Li et al. 2005; Nagel et al. 2005; Ishizuka et al. 2006). The interplay of optics, genetics, and bioengineering in this novel approach was the inspiration to coin the term “optogenetics”, which can be defined as optical control of cells achieved by the genetic introduction of light-sensitive proteins (Deisseroth et al. 2006). Another milestone in the evolution of optical control was the discovery of an inhibitory opponent of ChR2. Although relative reduction of neuronal activity had previously been shown for the Gi/o protein-coupled vertebrate rat opsin (Ro4, a type II opsin) by activating G protein-gated rectifying potassium channels and voltage-gated calcium channels (Li et al. 2005), complete and fast silencing was achieved by using a microbial (type I opsin) chloride pump. Halorhodopsin (HR) had been discovered decades before its conversion into a research tool (Matsuno-Yagi and Mukohata 1977). Expression of Natromonas pharaonis HR (NpHR) in neuronal tissue enables optically induced cellular hyperpolarization by pumping chloride into the cell. Consecutive inhibition of spontaneous neuronal firing can be achieved in a millisecond time scale (Zhang et al. 2007a, b; Han and Boyden 2007). A major advantage compared to Ro4 is the manipulation via Cl^−, an ion that is not involved in intracellular signaling such as calcium and the use of all-trans retinal instead of 11-cis which is functioning as a chromophore in Ro4. Due to spectrally separated activation maxima of ChR2 and NpHR bidirectional optical modulation is possible, offering excitation and silencing of the same target cell. Even more efficient optical silencers, the proton pumps Arch and ArchT, with similar activation spectra were found in archaebacteria after screening various species (prokaryotes, algae and fungi) for microbial type I opsins (Chow et al. 2010; Han et al. 2011). In an attempt to establish a simultaneous multi-excitatory optical control system by using spectrally separated opsins, red-shifted ChR1 from Volvox carteri (VChR1) was identified. VChR1 works like ChR2 as a cation channel and extended the optical spectrum of cellular excitation toward green light (Zhang et al. 2008). Yet VChR1 applicability in mammalian cells was strongly limited by small photocurrents due to insufficient membrane expression; a limitation that has been circumvented by the generation of a chimeric channelrhodopsin (C1V1) composed of channelrhodopsin-1 parts from Chlamydomonas reinhardtii and Volvox carteri (Yizhar et al. 2011b). In a very recent publication a new channelrhodopsin from Mesostigma viride (MChR1) with a similarly red-shifted action spectrum has been identified and mutated (Govorunova et al. 2011). Heterologous expression of native MChR1 in HEK293 cells indicated peak currents comparable to VChR1 with faster current kinetics making MChR1 a potential candidate for red-shifted optogenetic control, although toxicity and expression levels in neuronal tissue remain to be analyzed. Channelrhodopsins show structural homology to other type I opsins, however, in their working principle they fundamentally differ from NpHR and BRs like Arch and ArchT (Fig. 1). ChRs are non-selective cation channels that open when illuminated by green light with passive influx of predominantly Na^+ and, to a lesser extent, Ca^2+ ions along a membrane gradient resulting in the depolarization of cells expressing these molecules (Nagel et al. 2003). In contrast, HR and BR are ion pumps that work against an electrochemical gradient across the membrane (Racker and Stoeckenius 1974, Schobert and Lanyi 1982). With an excitation maximum at 589 nm NpHR pumps chloride into the cell when activated by yellow light causing a hyperpolarization with consecutive silencing of the target cell. Arch and ArchT also hyperpolarize cells, but by pumping H^+ outwards and in a more rapidly recovering manner. Excitation maxima are at approximately 566 nm for Arch and ArchT (Chow et al. 2010; Han et al. 2011).Fig. 1The optogenetic principle: changing the membrane voltage potential of excitable cells. a Activating tools—channelrhodopsins: channelrhodopsin-2 from Chlamydomoas reinhardtii (ChR2) and channelrhodopsin-1 Volvox carteri (VChR1) from nonselective cation channels leading to depolarization of target cells. Silencing tools—ion pumps: archaerhodopsin-3 (Arch) from Halorubrum sodomense works as a proton pump and leads to hyperpolarization of the target cell such as the chloride pump NpHR (NpHR) from Natronomonas pharaonis. b Spectral working properties of light-sensitive membrane proteins',\n", - " 'paragraph_id': 1,\n", - " 'tokenizer': 'with, the, identification, of, the, gene, for, a, light, -, responsive, membrane, protein, in, micro, ##org, ##ani, ##sms, called, ba, ##cter, ##ior, ##ho, ##do, ##ps, ##in, (, br, ), ,, st, ##oe, ##cken, ##ius, and, o, ##ester, ##hel, ##t, (, 1971, ), set, the, foundation, for, a, technology, ,, which, is, today, described, by, the, term, “, opt, ##ogen, ##etic, ##s, ”, (, o, ##ester, ##hel, ##t, and, st, ##oe, ##cken, ##ius, 1973, ;, dei, ##sser, ##oth, et, al, ., 2006, ), ., three, decades, had, passed, until, scientists, were, able, to, take, advantage, of, the, potential, based, on, the, working, principle, of, this, seven, -, trans, ##me, ##mb, ##rane, domain, -, containing, light, -, trans, ##du, ##cing, proton, pump, ,, which, in, nature, serves, micro, ##bes, ,, among, other, things, ,, as, a, regulator, of, home, ##osta, ##sis, and, photo, ##tro, ##phy, (, be, ##ja, et, al, ., 2000, ), ., encoded, by, a, single, open, reading, frame, ,, it, works, as, an, optical, controller, of, trans, ##me, ##mb, ##rane, ion, flow, combining, fast, action, and, coupling, of, sensor, and, effect, ##or, in, a, mono, ##com, ##pone, ##nt, system, (, o, ##ester, ##hel, ##t, and, st, ##oe, ##cken, ##ius, 1971, ), ., later, r, ##ho, ##do, ##ps, ##in, -, mediated, responses, were, also, studied, in, the, al, ##ga, ch, ##lam, ##yd, ##omo, ##nas, (, ha, ##rz, and, he, ##ge, ##mann, 1991, ), and, since, the, photo, ##cu, ##rret, ##s, were, ultra, fast, the, authors, claimed, that, r, ##ho, ##do, ##ps, ##in, and, channel, were, intimately, linked, (, holland, et, al, ., 1996, ), ., then, na, ##gel, and, colleagues, proved, this, concept, by, showing, that, the, r, ##ho, ##do, ##ps, ##ins, are, directly, light, -, gate, ##d, ion, channels, ., they, used, amp, ##hi, ##bian, and, mammalian, cells, as, hosts, to, express, channel, ##rh, ##od, ##ops, ##in, -, 1, (, ch, ##r, ##1, ), ,, a, light, -, gate, ##d, proton, channel, from, the, green, algae, ch, ##lam, ##yd, ##omo, ##nas, rein, ##hardt, ##ii, ., in, a, modified, patch, cl, ##amp, set, -, up, they, sub, ##stan, ##tia, ##ted, that, r, ##ho, ##do, ##ps, ##ins, react, functional, ##ly, upon, laser, illumination, also, in, mammalian, cells, (, na, ##gel, et, al, ., 2002, ), ., what, was, initially, used, as, an, experimental, model, system, to, study, channel, ##rh, ##od, ##ops, ##in, function, turned, into, the, precursor, of, a, novel, scientific, tool, ., with, the, functional, characterization, of, ch, ##r, ##2, ,, a, directly, light, -, gate, ##d, cat, ##ion, -, selective, membrane, channel, ,, na, ##gel, et, al, ., (, 2003, ), showed, that, mammalian, cells, expressing, ch, ##r, ##2, could, be, de, ##pol, ##ari, ##zed, “, simply, by, illumination, ”, ., the, full, conversion, of, this, approach, into, an, optical, control, device, of, cell, activity, happened, in, 2005, when, it, found, its, way, into, neuroscience, ., the, dei, ##sser, ##oth, lab, applied, lent, ##iv, ##ira, ##l, gene, delivery, to, express, ch, ##r, ##2, in, rat, hip, ##po, ##camp, ##al, neurons, ., in, combination, with, high, -, speed, optical, switching, ,, ne, ##uron, ##al, sp, ##iki, ##ng, was, eli, ##cite, ##d, by, photos, ##ti, ##mu, ##lation, in, a, mill, ##ise, ##con, ##d, times, ##cal, ##e, (, boyd, ##en, et, al, ., 2005, ), ., in, parallel, ,, the, labs, of, ya, ##wo, ,, her, ##litz, ##e, and, got, ##ts, ##chal, ##k, independently, demonstrated, the, feasibility, of, ch, ##r, ##2, -, based, optical, ne, ##uron, ##al, manipulation, (, li, et, al, ., 2005, ;, na, ##gel, et, al, ., 2005, ;, is, ##hi, ##zuka, et, al, ., 2006, ), ., the, inter, ##play, of, optics, ,, genetics, ,, and, bio, ##eng, ##ine, ##ering, in, this, novel, approach, was, the, inspiration, to, coin, the, term, “, opt, ##ogen, ##etic, ##s, ”, ,, which, can, be, defined, as, optical, control, of, cells, achieved, by, the, genetic, introduction, of, light, -, sensitive, proteins, (, dei, ##sser, ##oth, et, al, ., 2006, ), ., another, milestone, in, the, evolution, of, optical, control, was, the, discovery, of, an, inhibitor, ##y, opponent, of, ch, ##r, ##2, ., although, relative, reduction, of, ne, ##uron, ##al, activity, had, previously, been, shown, for, the, gi, /, o, protein, -, coupled, ve, ##rte, ##brate, rat, ops, ##in, (, ro, ##4, ,, a, type, ii, ops, ##in, ), by, act, ##ivating, g, protein, -, gate, ##d, rec, ##tify, ##ing, potassium, channels, and, voltage, -, gate, ##d, calcium, channels, (, li, et, al, ., 2005, ), ,, complete, and, fast, si, ##len, ##cing, was, achieved, by, using, a, micro, ##bial, (, type, i, ops, ##in, ), chloride, pump, ., halo, ##rh, ##od, ##ops, ##in, (, hr, ), had, been, discovered, decades, before, its, conversion, into, a, research, tool, (, mats, ##uno, -, ya, ##gi, and, mu, ##ko, ##hat, ##a, 1977, ), ., expression, of, nat, ##rom, ##ona, ##s, ph, ##ara, ##onis, hr, (, np, ##hr, ), in, ne, ##uron, ##al, tissue, enables, optical, ##ly, induced, cellular, hyper, ##pol, ##ari, ##zation, by, pumping, chloride, into, the, cell, ., consecutive, inhibition, of, spontaneous, ne, ##uron, ##al, firing, can, be, achieved, in, a, mill, ##ise, ##con, ##d, time, scale, (, zhang, et, al, ., 2007, ##a, ,, b, ;, han, and, boyd, ##en, 2007, ), ., a, major, advantage, compared, to, ro, ##4, is, the, manipulation, via, cl, ^, −, ,, an, ion, that, is, not, involved, in, intra, ##cellular, signaling, such, as, calcium, and, the, use, of, all, -, trans, re, ##tina, ##l, instead, of, 11, -, cis, which, is, functioning, as, a, ch, ##rom, ##op, ##hore, in, ro, ##4, ., due, to, spectral, ##ly, separated, activation, maxim, ##a, of, ch, ##r, ##2, and, np, ##hr, bid, ##ire, ##ction, ##al, optical, modulation, is, possible, ,, offering, ex, ##cit, ##ation, and, si, ##len, ##cing, of, the, same, target, cell, ., even, more, efficient, optical, silence, ##rs, ,, the, proton, pumps, arch, and, arch, ##t, ,, with, similar, activation, spectra, were, found, in, arch, ##ae, ##ba, ##cter, ##ia, after, screening, various, species, (, pro, ##kar, ##yo, ##tes, ,, algae, and, fungi, ), for, micro, ##bial, type, i, ops, ##ins, (, chow, et, al, ., 2010, ;, han, et, al, ., 2011, ), ., in, an, attempt, to, establish, a, simultaneous, multi, -, ex, ##cit, ##atory, optical, control, system, by, using, spectral, ##ly, separated, ops, ##ins, ,, red, -, shifted, ch, ##r, ##1, from, volvo, ##x, carter, ##i, (, vc, ##hr, ##1, ), was, identified, ., vc, ##hr, ##1, works, like, ch, ##r, ##2, as, a, cat, ##ion, channel, and, extended, the, optical, spectrum, of, cellular, ex, ##cit, ##ation, toward, green, light, (, zhang, et, al, ., 2008, ), ., yet, vc, ##hr, ##1, app, ##lica, ##bility, in, mammalian, cells, was, strongly, limited, by, small, photo, ##cu, ##rre, ##nts, due, to, insufficient, membrane, expression, ;, a, limitation, that, has, been, ci, ##rc, ##um, ##vent, ##ed, by, the, generation, of, a, chi, ##meric, channel, ##rh, ##od, ##ops, ##in, (, c1, ##v, ##1, ), composed, of, channel, ##rh, ##od, ##ops, ##in, -, 1, parts, from, ch, ##lam, ##yd, ##omo, ##nas, rein, ##hardt, ##ii, and, volvo, ##x, carter, ##i, (, yi, ##zh, ##ar, et, al, ., 2011, ##b, ), ., in, a, very, recent, publication, a, new, channel, ##rh, ##od, ##ops, ##in, from, me, ##sos, ##ti, ##gm, ##a, vi, ##ride, (, mc, ##hr, ##1, ), with, a, similarly, red, -, shifted, action, spectrum, has, been, identified, and, mu, ##tated, (, gov, ##or, ##uno, ##va, et, al, ., 2011, ), ., het, ##ero, ##log, ##ous, expression, of, native, mc, ##hr, ##1, in, he, ##k, ##29, ##3, cells, indicated, peak, currents, comparable, to, vc, ##hr, ##1, with, faster, current, kinetic, ##s, making, mc, ##hr, ##1, a, potential, candidate, for, red, -, shifted, opt, ##ogen, ##etic, control, ,, although, toxicity, and, expression, levels, in, ne, ##uron, ##al, tissue, remain, to, be, analyzed, ., channel, ##rh, ##od, ##ops, ##ins, show, structural, homo, ##logy, to, other, type, i, ops, ##ins, ,, however, ,, in, their, working, principle, they, fundamentally, differ, from, np, ##hr, and, br, ##s, like, arch, and, arch, ##t, (, fig, ., 1, ), ., ch, ##rs, are, non, -, selective, cat, ##ion, channels, that, open, when, illuminated, by, green, light, with, passive, influx, of, predominantly, na, ^, +, and, ,, to, a, lesser, extent, ,, ca, ^, 2, +, ions, along, a, membrane, gradient, resulting, in, the, de, ##pol, ##ari, ##zation, of, cells, expressing, these, molecules, (, na, ##gel, et, al, ., 2003, ), ., in, contrast, ,, hr, and, br, are, ion, pumps, that, work, against, an, electro, ##chemical, gradient, across, the, membrane, (, rack, ##er, and, st, ##oe, ##cken, ##ius, 1974, ,, sc, ##ho, ##bert, and, lan, ##yi, 1982, ), ., with, an, ex, ##cit, ##ation, maximum, at, 58, ##9, nm, np, ##hr, pumps, chloride, into, the, cell, when, activated, by, yellow, light, causing, a, hyper, ##pol, ##ari, ##zation, with, consecutive, si, ##len, ##cing, of, the, target, cell, ., arch, and, arch, ##t, also, hyper, ##pol, ##ari, ##ze, cells, ,, but, by, pumping, h, ^, +, outward, ##s, and, in, a, more, rapidly, recovering, manner, ., ex, ##cit, ##ation, maxim, ##a, are, at, approximately, 56, ##6, nm, for, arch, and, arch, ##t, (, chow, et, al, ., 2010, ;, han, et, al, ., 2011, ), ., fig, ., 1, ##the, opt, ##ogen, ##etic, principle, :, changing, the, membrane, voltage, potential, of, ex, ##cit, ##able, cells, ., a, act, ##ivating, tools, —, channel, ##rh, ##od, ##ops, ##ins, :, channel, ##rh, ##od, ##ops, ##in, -, 2, from, ch, ##lam, ##yd, ##omo, ##as, rein, ##hardt, ##ii, (, ch, ##r, ##2, ), and, channel, ##rh, ##od, ##ops, ##in, -, 1, volvo, ##x, carter, ##i, (, vc, ##hr, ##1, ), from, non, ##sel, ##ect, ##ive, cat, ##ion, channels, leading, to, de, ##pol, ##ari, ##zation, of, target, cells, ., si, ##len, ##cing, tools, —, ion, pumps, :, arch, ##aer, ##ho, ##do, ##ps, ##in, -, 3, (, arch, ), from, halo, ##ru, ##br, ##um, so, ##dome, ##nse, works, as, a, proton, pump, and, leads, to, hyper, ##pol, ##ari, ##zation, of, the, target, cell, such, as, the, chloride, pump, np, ##hr, (, np, ##hr, ), from, nat, ##ron, ##omo, ##nas, ph, ##ara, ##onis, ., b, spectral, working, properties, of, light, -, sensitive, membrane, proteins'},\n", - " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", - " 'section_name': 'Targeted delivery of optogenetic tools',\n", - " 'text': 'For most of the targeting, in vivo viral gene transfer has been effectively used in mice, rats and non human primates, especially adeno-associated viruses (AAV; e.g., Sohal et al. 2009; Carter et al. 2010) lentiviruses (e.g., Adamantidis et al. 2007; Han et al. 2009), and to a lesser extent also herpes simplex virus (HSV; e.g., Covington et al. 2010; Lobo et al. 2010). Advantages of viral expression are a straightforward experimental approach, which takes approximately 6 weeks from virus production to extensive long lasting opsin expression (four more weeks for HSV) and a broad applicableness regarding the subject, ranging from rodents to primates. Depending on the experimental setup either strong ubiquitous promoters such as elongation factor 1-alpha (EF1α), human synapsin, human thymocyte differentiation antigen 1 (Thy-1), a combination of chicken beta-actin promoter and cytomegalovirus immediate-early enhancer (CAG) or weaker cell type-specific promoters, for example α-calcium/calmodulin-dependent protein kinase II (CamKIIα) can be used (Fig. 2a; Xu et al. 2001; Jakobsson et al. 2003; Dittgen et al. 2004). AAVs are to some extent superior to lentiviruses due to the fact that AAV-based vectors remain episomally while lentiviral vectors are integrated into the host genome. Thus, the expression from lentiviral vectors is prone to influences of the surrounding chromatin and the integration could lead to an undesired disruption of host genes. General drawbacks are a limited packing volume of AAVs and lentiviruses and weak cell type-specific transcriptional promoter activity. For example, the smallest promoter targeting selectively inhibitory neurons is approximately 3 kilobase pairs (kb) in length, which interferes with the maximal capacity of AAVs and lentiviruses, which is about 5 and 8 kb, respectively (Nathanson et al. 2009; Dong et al. 2010). A limitation often seen in experiments using cell type-specific promoters is the need of high irradiance for optimal stimulation of larger brain areas. As light penetration is low in brain tissue, reaching deeper regions optically requires either higher expression levels of the rhodopsin (e.g., by using a strong exogenous promoter as indicated above) or higher levels of light energy. As an alternative to moderately active tissue- or cell type-specific promoters, strong conditional rhodopsin expression can be achieved by the use of transgenic cre recombinase driver mice (Fig. 2; Geschwind 2004; Gong et al. 2007). By using a cre-dependent viral construct like AAV-FlEx (Flip-Excision) or AAV-DIO (double floxed inverse open reading frame) driven by a strong promoter such as EF1α or CAG, cell and tissue specificity is provided by selective cre activity (Fig. 2b; Atasoy et al. 2008; Sohal et al. 2009). An alternative to viral injections is the use of transgenic animals, where rhodopsin expression occurs early in development. Several transgenic mouse lines exist, expressing channelrhodopsin or HR under the panneuronal Thy-1 promoter (Arenkiel et al. 2007; Wang et al. 2007; Zhao et al. 2008) or the glutamatergic Vglut2 promoter (Fig. 2c; Hagglund et al. 2010). In analogy to the above-mentioned cre-dependent conditional approach utilizing viral gene delivery systems, a cell type-specific expression could be achieved by using a strong panneuronal promoter such as EF1α or CAG in combination with the cre-loxP system. Breeding to selective cre driver mice will result in expression of ChR2 or NpHR driven by the panneural promoter, whereas the temporal and spatial expression will depend on the used cre driver line (Fig. 2d). For in vivo cell type-specific opsin expression in utero electroporation has been used. Lacking construct size limitations even large cell type-specific promoters can be used to drive expression. Depending on the day of embryonic development various brain areas and cell types can efficiently be targeted (Saito 2006; Gradinaru et al. 2007; Navarro-Quiroga et al. 2007; Petreanu et al. 2007). Besides cell type-specific control in different brain areas, circuit-specific targeting may be desirable to distinguish more precisely between neurons, which, although carrying the same cell-specific set of genetic markers, are heterogeneous regarding their afferent or efferent influences. By fusing cre recombinase to axonally transported proteins such as wheat germ agglutinin (WGA) and tetanus toxin fragment C (TTC) or using idiosyncratic antero-/retrograde viral axonal delivery, circuit connectivity can be analyzed by optogenetics in a transneuronal fashion. This transcellular approach in combination with conditional cre-dependent expression vectors represents a versatile tool for circuit mapping independent of the use of cre animals, extending the cell type-specific optogenetic approach to animals such as rats and primates, which have not been amenable to large-scale genetic manipulation (Gradinaru et al. 2010).Fig. 2Targeted delivery of opsins to the mouse brain based on adeno-associated viruses (AAV) or transgenic approaches. a Opsins can be expressed in specific types of neurons or glia using gene-specific promoter elements (e.g., CamKIIα). AAV-based expression vectors integrating such promoter elements are delivered via stereotactic injection into desired brain areas. b Stereotactic injection of AAV vectors, which combine a strong ubiquitous promoter (e.g., Ef1α or CAG) either with a “STOP” cassette (top) or with an AAV-FlEx/AAV-DIO system (bottom), into specific cre mouse lines will result in a strong opsin expression selectively in neurons expressing the cre recombinase. c Classical transgenesis via pronucleus injection using a gene-specific promoter (top) or targeted knock-in strategies in embryonic stem cells (bottom) will result in a neuron- or glia-specific opsin expression in transgenic mice. d Alternatively, the combination of a ubiquitous promoter with a “STOP” cassette (top) or with an AAV-FlEx/AAV-DIO system (bottom) can be applied also in a transgenic approach either in a random or targeted fashion, e.g., to the ubiquitously expressed ROSA26 locus. Only after breeding to desired cre driver lines a brain region- or cell type-specific expression of opsins will be activated. Mice expressing opsins can be recognized by the highlighted brain and an inset in the background showing hippocampal neurons expressing opsin-GFP fusion protein. AAV adeno-associated virus, BGHpA bovine growth hormone poly A signal, GOI gene of interest, GSP gene-specific promoter, IRES internal ribosomal entry side, ITR inverted terminal repeat, STOP transcriptional terminator, UBP: ubiquitous promoter, WPRE woodchuck hepatitis virus posttranscriptional regulatory element',\n", - " 'paragraph_id': 5,\n", - " 'tokenizer': 'for, most, of, the, targeting, ,, in, vivo, viral, gene, transfer, has, been, effectively, used, in, mice, ,, rats, and, non, human, primate, ##s, ,, especially, aden, ##o, -, associated, viruses, (, aa, ##v, ;, e, ., g, ., ,, so, ##hal, et, al, ., 2009, ;, carter, et, al, ., 2010, ), lent, ##iv, ##irus, ##es, (, e, ., g, ., ,, adamant, ##idi, ##s, et, al, ., 2007, ;, han, et, al, ., 2009, ), ,, and, to, a, lesser, extent, also, her, ##pes, simple, ##x, virus, (, hs, ##v, ;, e, ., g, ., ,, co, ##vington, et, al, ., 2010, ;, lo, ##bo, et, al, ., 2010, ), ., advantages, of, viral, expression, are, a, straightforward, experimental, approach, ,, which, takes, approximately, 6, weeks, from, virus, production, to, extensive, long, lasting, ops, ##in, expression, (, four, more, weeks, for, hs, ##v, ), and, a, broad, applicable, ##ness, regarding, the, subject, ,, ranging, from, rodents, to, primate, ##s, ., depending, on, the, experimental, setup, either, strong, ubiquitous, promoters, such, as, el, ##onga, ##tion, factor, 1, -, alpha, (, e, ##f, ##1, ##α, ), ,, human, syn, ##ap, ##sin, ,, human, thy, ##mo, ##cy, ##te, differentiation, antigen, 1, (, thy, -, 1, ), ,, a, combination, of, chicken, beta, -, act, ##in, promoter, and, cy, ##tom, ##ega, ##lov, ##irus, immediate, -, early, enhance, ##r, (, ca, ##g, ), or, weaker, cell, type, -, specific, promoters, ,, for, example, α, -, calcium, /, calm, ##od, ##ulin, -, dependent, protein, kinase, ii, (, cam, ##ki, ##i, ##α, ), can, be, used, (, fig, ., 2a, ;, xu, et, al, ., 2001, ;, jakob, ##sson, et, al, ., 2003, ;, di, ##tt, ##gen, et, al, ., 2004, ), ., aa, ##vs, are, to, some, extent, superior, to, lent, ##iv, ##irus, ##es, due, to, the, fact, that, aa, ##v, -, based, vectors, remain, ep, ##iso, ##mal, ##ly, while, lent, ##iv, ##ira, ##l, vectors, are, integrated, into, the, host, genome, ., thus, ,, the, expression, from, lent, ##iv, ##ira, ##l, vectors, is, prone, to, influences, of, the, surrounding, ch, ##rom, ##atin, and, the, integration, could, lead, to, an, und, ##es, ##ired, disruption, of, host, genes, ., general, draw, ##backs, are, a, limited, packing, volume, of, aa, ##vs, and, lent, ##iv, ##irus, ##es, and, weak, cell, type, -, specific, transcription, ##al, promoter, activity, ., for, example, ,, the, smallest, promoter, targeting, selective, ##ly, inhibitor, ##y, neurons, is, approximately, 3, ki, ##lo, ##base, pairs, (, kb, ), in, length, ,, which, interfere, ##s, with, the, maximal, capacity, of, aa, ##vs, and, lent, ##iv, ##irus, ##es, ,, which, is, about, 5, and, 8, kb, ,, respectively, (, nathan, ##son, et, al, ., 2009, ;, dong, et, al, ., 2010, ), ., a, limitation, often, seen, in, experiments, using, cell, type, -, specific, promoters, is, the, need, of, high, ir, ##rad, ##iance, for, optimal, stimulation, of, larger, brain, areas, ., as, light, penetration, is, low, in, brain, tissue, ,, reaching, deeper, regions, optical, ##ly, requires, either, higher, expression, levels, of, the, r, ##ho, ##do, ##ps, ##in, (, e, ., g, ., ,, by, using, a, strong, ex, ##ogen, ##ous, promoter, as, indicated, above, ), or, higher, levels, of, light, energy, ., as, an, alternative, to, moderately, active, tissue, -, or, cell, type, -, specific, promoters, ,, strong, conditional, r, ##ho, ##do, ##ps, ##in, expression, can, be, achieved, by, the, use, of, trans, ##genic, cr, ##e, rec, ##om, ##bina, ##se, driver, mice, (, fig, ., 2, ;, ge, ##sch, ##wind, 2004, ;, gong, et, al, ., 2007, ), ., by, using, a, cr, ##e, -, dependent, viral, construct, like, aa, ##v, -, flex, (, flip, -, ex, ##cision, ), or, aa, ##v, -, di, ##o, (, double, fl, ##ox, ##ed, inverse, open, reading, frame, ), driven, by, a, strong, promoter, such, as, e, ##f, ##1, ##α, or, ca, ##g, ,, cell, and, tissue, specific, ##ity, is, provided, by, selective, cr, ##e, activity, (, fig, ., 2, ##b, ;, ata, ##so, ##y, et, al, ., 2008, ;, so, ##hal, et, al, ., 2009, ), ., an, alternative, to, viral, injection, ##s, is, the, use, of, trans, ##genic, animals, ,, where, r, ##ho, ##do, ##ps, ##in, expression, occurs, early, in, development, ., several, trans, ##genic, mouse, lines, exist, ,, expressing, channel, ##rh, ##od, ##ops, ##in, or, hr, under, the, pan, ##ne, ##uron, ##al, thy, -, 1, promoter, (, aren, ##kie, ##l, et, al, ., 2007, ;, wang, et, al, ., 2007, ;, zhao, et, al, ., 2008, ), or, the, g, ##lu, ##tama, ##ter, ##gic, v, ##gl, ##ut, ##2, promoter, (, fig, ., 2, ##c, ;, ha, ##gg, ##lund, et, al, ., 2010, ), ., in, analogy, to, the, above, -, mentioned, cr, ##e, -, dependent, conditional, approach, utilizing, viral, gene, delivery, systems, ,, a, cell, type, -, specific, expression, could, be, achieved, by, using, a, strong, pan, ##ne, ##uron, ##al, promoter, such, as, e, ##f, ##1, ##α, or, ca, ##g, in, combination, with, the, cr, ##e, -, lo, ##x, ##p, system, ., breeding, to, selective, cr, ##e, driver, mice, will, result, in, expression, of, ch, ##r, ##2, or, np, ##hr, driven, by, the, pan, ##ne, ##ural, promoter, ,, whereas, the, temporal, and, spatial, expression, will, depend, on, the, used, cr, ##e, driver, line, (, fig, ., 2d, ), ., for, in, vivo, cell, type, -, specific, ops, ##in, expression, in, ut, ##ero, electro, ##por, ##ation, has, been, used, ., lacking, construct, size, limitations, even, large, cell, type, -, specific, promoters, can, be, used, to, drive, expression, ., depending, on, the, day, of, embryo, ##nic, development, various, brain, areas, and, cell, types, can, efficiently, be, targeted, (, sai, ##to, 2006, ;, gr, ##adi, ##nar, ##u, et, al, ., 2007, ;, navarro, -, qui, ##ro, ##ga, et, al, ., 2007, ;, pet, ##rea, ##nu, et, al, ., 2007, ), ., besides, cell, type, -, specific, control, in, different, brain, areas, ,, circuit, -, specific, targeting, may, be, desirable, to, distinguish, more, precisely, between, neurons, ,, which, ,, although, carrying, the, same, cell, -, specific, set, of, genetic, markers, ,, are, het, ##ero, ##gen, ##eous, regarding, their, af, ##fer, ##ent, or, e, ##ffer, ##ent, influences, ., by, fu, ##sing, cr, ##e, rec, ##om, ##bina, ##se, to, ax, ##onal, ##ly, transported, proteins, such, as, wheat, ge, ##rm, ag, ##gl, ##uti, ##nin, (, w, ##ga, ), and, te, ##tan, ##us, toxin, fragment, c, (, tt, ##c, ), or, using, id, ##ios, ##yn, ##cratic, ant, ##ero, -, /, retro, ##grade, viral, ax, ##onal, delivery, ,, circuit, connectivity, can, be, analyzed, by, opt, ##ogen, ##etic, ##s, in, a, trans, ##ne, ##uron, ##al, fashion, ., this, trans, ##cellular, approach, in, combination, with, conditional, cr, ##e, -, dependent, expression, vectors, represents, a, versatile, tool, for, circuit, mapping, independent, of, the, use, of, cr, ##e, animals, ,, extending, the, cell, type, -, specific, opt, ##ogen, ##etic, approach, to, animals, such, as, rats, and, primate, ##s, ,, which, have, not, been, am, ##ena, ##ble, to, large, -, scale, genetic, manipulation, (, gr, ##adi, ##nar, ##u, et, al, ., 2010, ), ., fig, ., 2, ##tar, ##get, ##ed, delivery, of, ops, ##ins, to, the, mouse, brain, based, on, aden, ##o, -, associated, viruses, (, aa, ##v, ), or, trans, ##genic, approaches, ., a, ops, ##ins, can, be, expressed, in, specific, types, of, neurons, or, g, ##lia, using, gene, -, specific, promoter, elements, (, e, ., g, ., ,, cam, ##ki, ##i, ##α, ), ., aa, ##v, -, based, expression, vectors, integrating, such, promoter, elements, are, delivered, via, stereo, ##ta, ##ctic, injection, into, desired, brain, areas, ., b, stereo, ##ta, ##ctic, injection, of, aa, ##v, vectors, ,, which, combine, a, strong, ubiquitous, promoter, (, e, ., g, ., ,, e, ##f, ##1, ##α, or, ca, ##g, ), either, with, a, “, stop, ”, cassette, (, top, ), or, with, an, aa, ##v, -, flex, /, aa, ##v, -, di, ##o, system, (, bottom, ), ,, into, specific, cr, ##e, mouse, lines, will, result, in, a, strong, ops, ##in, expression, selective, ##ly, in, neurons, expressing, the, cr, ##e, rec, ##om, ##bina, ##se, ., c, classical, trans, ##genesis, via, pro, ##nu, ##cle, ##us, injection, using, a, gene, -, specific, promoter, (, top, ), or, targeted, knock, -, in, strategies, in, embryo, ##nic, stem, cells, (, bottom, ), will, result, in, a, ne, ##uron, -, or, g, ##lia, -, specific, ops, ##in, expression, in, trans, ##genic, mice, ., d, alternatively, ,, the, combination, of, a, ubiquitous, promoter, with, a, “, stop, ”, cassette, (, top, ), or, with, an, aa, ##v, -, flex, /, aa, ##v, -, di, ##o, system, (, bottom, ), can, be, applied, also, in, a, trans, ##genic, approach, either, in, a, random, or, targeted, fashion, ,, e, ., g, ., ,, to, the, ubiquitous, ##ly, expressed, rosa, ##26, locus, ., only, after, breeding, to, desired, cr, ##e, driver, lines, a, brain, region, -, or, cell, type, -, specific, expression, of, ops, ##ins, will, be, activated, ., mice, expressing, ops, ##ins, can, be, recognized, by, the, highlighted, brain, and, an, ins, ##et, in, the, background, showing, hip, ##po, ##camp, ##al, neurons, expressing, ops, ##in, -, g, ##fp, fusion, protein, ., aa, ##v, aden, ##o, -, associated, virus, ,, b, ##gh, ##pa, bo, ##vine, growth, hormone, poly, a, signal, ,, go, ##i, gene, of, interest, ,, gs, ##p, gene, -, specific, promoter, ,, ir, ##es, internal, rib, ##osomal, entry, side, ,, it, ##r, inverted, terminal, repeat, ,, stop, transcription, ##al, term, ##inator, ,, u, ##b, ##p, :, ubiquitous, promoter, ,, w, ##pre, wood, ##chu, ##ck, hepatitis, virus, post, ##tra, ##ns, ##cript, ##ional, regulatory, element'},\n", - " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", - " 'section_name': 'Optogenetics is compatible with a plethora of functional readouts',\n", - " 'text': 'The major advantage of optogenetics, besides genetic targeting, is stimulation with light, as it offers the possibility of simultaneous on-site electrical measurement. Depending on the desired resolution, optogenetics can be combined with a variety of readouts. For in vitro proof-of-concept experiments the most widely used methods are whole-cell patch clamp and field potential recordings in combination with optical illumination in brain slices (for example Nagel et al. 2003; Boyden et al. 2005; Deisseroth et al. 2006; Zhang et al. 2007a, b). To study neural activity beyond single cells on a network level calcium imaging can be used as a multisite indirect measurement of action potential activity in a full optical approach (Knopfel et al. 2006). The first example of postsynaptic calcium imaging following light-induced action potentials in ChR2-targeted presynaptic axons was demonstrated by Zhang and Oertner (2007) to study plasticity at single-synapse level. By using a spectrally compatible dye (Fluo-5F) and two-photon excitation at 810 nm in rat hippocampal slice cultures targeted with ChR2-tdimer2, synaptic contacts between labeled cells could be identified by imaging optically induced spinal calcium release. In addition, long-term potentiation of prevalent synaptic connections was induced (Zhang and Oertner 2007). An all-optical approach was also applied in the initial description of bidirectional optical control of neural circuits. After lentiviral transduction of murine acute cortical slices with CaMKIIα::ChR2-mCherry and EF1α::NpHR-EYFP Fura-2 calcium imaging was used to measure the effects of optical excitation and inhibition (Zhang et al. 2007a). Because of its UV-shifted spectral properties (excitation maximum at 340 nm) Fura-2 has been successfully used in concert with ChR2 (excitation maximum at 470 nm), NpHR (excitation maximum at 590 nm) and the OptoXRs (excitation maximum at 500 nm; Airan et al. 2009). Yet, although spectrally overlapping, genetically encoded calcium sensors such as G-CaMP can be applied in concert with ChR2. In a technically elegant study Guo et al. (2009) combined in vivo optical stimulation of ChR2 wavelength with simultaneous calcium imaging at 488 nm for functional connectivity mapping in C. elegans neurons. By separating an epifluorescent high-power stimulation path for ChR2 activation from a low-intensity laser light imaging path for G-CaMP fluorescence, unspecific ChR2 activation during imaging at 488 nm could be avoided although ChR2 has its peak activation at 470 nm (Guo et al. 2009, see also Fig. 1). Laser scanning photostimulation (LSPS) has previously also been used in combination with glutamate uncaging and whole-cell recordings to analyze synaptic connectivity in brain slices (Katz and Dalva 1994; Shepherd and Svoboda 2005; Svoboda and Yasuda 2006). By exchanging glutamate uncaging against light activation through targeted axonal photosensitivity via ChR2, the group of Svoboda developed ChR2-assisted circuit mapping (CRACM; Petreanu et al. 2007). Using in utero electroporation in mice layer, 2/3 cortical neurons were targeted with ChR2-venus and photostimulation was performed throughout a grid covering the entire depth of the cortex. Whole-cell current clamp recordings of fluorescent ChR2 positive cells revealed their depolarization and detected action potentials after perisomatic and axonal LSPS. Mapping postsynaptic targets of L2/3 neurons in several cortical layers in the ipsi- and contralateral hemisphere indicated laminar specificity of local and long-range cortical projections (Petreanu et al. 2007). A modified approach (sCRACM) was used to study the subcellular organization of excitatory pyramidal neurons. Local glutamate release was measured after LSPS in conditions blocking action potentials. EPSPs as a measure of light-induced activation were detected only in the case of overlap between the recorded cell and ChR2-targeted presynaptic axons. Interestingly, subcellular mapping of neural circuitry by sCRACM revealed that the structural connectivity of neurons, as indicated by overlap of axons and dendrites, is not always reflected by their connection on a functional level (Petreanu et al. 2009). To study whole circuit properties voltage-sensitive dyes (VSD) can be applied in brain slices for an all-optical approach. As VSDs change their light emission properties in a voltage-dependent and most notably in a millisecond time scale they are potentially well suited to match the high temporal resolution achieved by optogenetics (Grinvald and Hildesheim 2004). Although compatibility can be achieved with spectrally separated infrared dyes such as RH-155 and VSD imaging following optical stimulation has been established successfully, it has rarely been used experimentally up to now, most probably due to a less favorable signal-to-noise ratio in comparison to calcium imaging (Airan et al. 2007; Zhang et al. 2010). Another example for the study of macrocircuits and global in vivo mapping is optical stimulation in combination with high-resolution fMRI. Lee and colleagues showed in a first publication that blood oxygenation level-dependent (BOLD) signals similar to classical stimulus-evoked BOLD fMRI responses could be elicited optically. This effect was seen not only locally at the expression site of ChR2 in M1 CaMKIIα positive excitatory neurons, but also in distinct thalamic neurons defined by the corticofugal axonal projections (Lee et al. 2010). In a reverse approach optical stimulation of ChR2 expressing cortico-thalamic projection fibers at the level of the thalamus was sufficient to drive not only local thalamic BOLD signals, but also cortical signals, most probably in an antidromic axosomatic manner. “Opto-fMRI” or “ofMRI” has also been used to identify downstream targets of the primary sensory cortex (SI). Optical stimulation of a ChR2-targeted subpopulation of SI pyramidal cells evoked local BOLD signals and also in functionally connected network regions, with differences in awake compared to anesthetized mice (Desai et al. 2011). Even though widely hypothesized before, these experiments indicate a most likely causal link between local neuronal excitation and positive hemodynamic responses, although the generation of BOLD signals may have a more complex nature. However, functional mapping using optogenetics in combination with fMRI not only integrates cell type specificity and anatomical conjunction, but can also be used to functionally dissect brain circuitries based on their connection topology (Leopold 2010). For global measurements of brain activity in living animals, electroencephalography (EEG) has been combined with optogenetic stimulation. In a first experiment Adamantidis et al. (2007, 2010) identified the effect of hypocretin-producing neurons in the lateral hypothalamus on sleep to wake transition by analyzing sleep recordings of mice with chronically implanted EEG electrodes. In a bidirectional in vivo approach using eNpHR and ChR2 the same group studied the effect of locus coeruleus neurons on wakefulness by applying EEG and in vivo microdialysis as a functional readout (Carter et al. 2010). For in vivo extracellular recording upon targeted optical stimulation, a device called “optrode” was created fusing a stimulating fiberoptic with a recording electrode (Gradinaru et al. 2007, 2009). Constant technical development even allows simultaneous recordings at multiple sites in the living animal (Zhang et al. 2009; Royer et al. 2010). The foundation for using optogenetics in freely moving rodents was set by Aravanis et al. (2007). Via a lightweight, flexible optical fiber called optical neural interface (ONI) excitatory motor cortex neurons could selectively be activated in rats and mice as measured by their whisker movement. Several successive studies focused on more complex behavioral paradigms as readouts for optogenetical manipulation such as motor behavior in animal models of Parkinson’s disease (Gradinaru et al. 2009; Kravitz et al. 2010), reward motivated behavior and addiction (Airan et al. 2009; Tsai et al. 2009; Witten et al. 2010; Stuber et al. 2011), fear conditioning and anxiety (Ciocchi et al. 2010; Johansen et al. 2010; Tye et al. 2011) and other \\ncerebral targets such as prefrontal cortex or hypothalamus for the study of psychiatric diseases and aggressive behavior (Covington et al. 2010; Lin et al. 2011; Yizhar et al. 2011a, b).',\n", - " 'paragraph_id': 6,\n", - " 'tokenizer': 'the, major, advantage, of, opt, ##ogen, ##etic, ##s, ,, besides, genetic, targeting, ,, is, stimulation, with, light, ,, as, it, offers, the, possibility, of, simultaneous, on, -, site, electrical, measurement, ., depending, on, the, desired, resolution, ,, opt, ##ogen, ##etic, ##s, can, be, combined, with, a, variety, of, read, ##outs, ., for, in, vitro, proof, -, of, -, concept, experiments, the, most, widely, used, methods, are, whole, -, cell, patch, cl, ##amp, and, field, potential, recordings, in, combination, with, optical, illumination, in, brain, slices, (, for, example, na, ##gel, et, al, ., 2003, ;, boyd, ##en, et, al, ., 2005, ;, dei, ##sser, ##oth, et, al, ., 2006, ;, zhang, et, al, ., 2007, ##a, ,, b, ), ., to, study, neural, activity, beyond, single, cells, on, a, network, level, calcium, imaging, can, be, used, as, a, multi, ##sit, ##e, indirect, measurement, of, action, potential, activity, in, a, full, optical, approach, (, kn, ##op, ##fe, ##l, et, al, ., 2006, ), ., the, first, example, of, posts, ##yna, ##ptic, calcium, imaging, following, light, -, induced, action, potential, ##s, in, ch, ##r, ##2, -, targeted, pre, ##sy, ##na, ##ptic, ax, ##ons, was, demonstrated, by, zhang, and, o, ##ert, ##ner, (, 2007, ), to, study, plastic, ##ity, at, single, -, syn, ##ap, ##se, level, ., by, using, a, spectral, ##ly, compatible, dye, (, flu, ##o, -, 5, ##f, ), and, two, -, photon, ex, ##cit, ##ation, at, 81, ##0, nm, in, rat, hip, ##po, ##camp, ##al, slice, cultures, targeted, with, ch, ##r, ##2, -, td, ##ime, ##r, ##2, ,, syn, ##ap, ##tic, contacts, between, labeled, cells, could, be, identified, by, imaging, optical, ##ly, induced, spinal, calcium, release, ., in, addition, ,, long, -, term, potent, ##iation, of, prevalent, syn, ##ap, ##tic, connections, was, induced, (, zhang, and, o, ##ert, ##ner, 2007, ), ., an, all, -, optical, approach, was, also, applied, in, the, initial, description, of, bid, ##ire, ##ction, ##al, optical, control, of, neural, circuits, ., after, lent, ##iv, ##ira, ##l, trans, ##duction, of, mu, ##rine, acute, co, ##rti, ##cal, slices, with, cam, ##ki, ##i, ##α, :, :, ch, ##r, ##2, -, mc, ##her, ##ry, and, e, ##f, ##1, ##α, :, :, np, ##hr, -, e, ##y, ##fp, fur, ##a, -, 2, calcium, imaging, was, used, to, measure, the, effects, of, optical, ex, ##cit, ##ation, and, inhibition, (, zhang, et, al, ., 2007, ##a, ), ., because, of, its, uv, -, shifted, spectral, properties, (, ex, ##cit, ##ation, maximum, at, 340, nm, ), fur, ##a, -, 2, has, been, successfully, used, in, concert, with, ch, ##r, ##2, (, ex, ##cit, ##ation, maximum, at, 470, nm, ), ,, np, ##hr, (, ex, ##cit, ##ation, maximum, at, 590, nm, ), and, the, opt, ##ox, ##rs, (, ex, ##cit, ##ation, maximum, at, 500, nm, ;, air, ##an, et, al, ., 2009, ), ., yet, ,, although, spectral, ##ly, overlapping, ,, genetically, encoded, calcium, sensors, such, as, g, -, camp, can, be, applied, in, concert, with, ch, ##r, ##2, ., in, a, technically, elegant, study, guo, et, al, ., (, 2009, ), combined, in, vivo, optical, stimulation, of, ch, ##r, ##2, wavelength, with, simultaneous, calcium, imaging, at, 48, ##8, nm, for, functional, connectivity, mapping, in, c, ., el, ##egan, ##s, neurons, ., by, separating, an, ep, ##if, ##lu, ##ores, ##cent, high, -, power, stimulation, path, for, ch, ##r, ##2, activation, from, a, low, -, intensity, laser, light, imaging, path, for, g, -, camp, flu, ##orescence, ,, un, ##sp, ##ec, ##ific, ch, ##r, ##2, activation, during, imaging, at, 48, ##8, nm, could, be, avoided, although, ch, ##r, ##2, has, its, peak, activation, at, 470, nm, (, guo, et, al, ., 2009, ,, see, also, fig, ., 1, ), ., laser, scanning, photos, ##ti, ##mu, ##lation, (, l, ##sp, ##s, ), has, previously, also, been, used, in, combination, with, g, ##lu, ##tama, ##te, un, ##ca, ##ging, and, whole, -, cell, recordings, to, analyze, syn, ##ap, ##tic, connectivity, in, brain, slices, (, katz, and, dal, ##va, 1994, ;, shepherd, and, sv, ##ob, ##oda, 2005, ;, sv, ##ob, ##oda, and, ya, ##su, ##da, 2006, ), ., by, exchanging, g, ##lu, ##tama, ##te, un, ##ca, ##ging, against, light, activation, through, targeted, ax, ##onal, photos, ##ens, ##iti, ##vity, via, ch, ##r, ##2, ,, the, group, of, sv, ##ob, ##oda, developed, ch, ##r, ##2, -, assisted, circuit, mapping, (, cr, ##ac, ##m, ;, pet, ##rea, ##nu, et, al, ., 2007, ), ., using, in, ut, ##ero, electro, ##por, ##ation, in, mice, layer, ,, 2, /, 3, co, ##rti, ##cal, neurons, were, targeted, with, ch, ##r, ##2, -, venus, and, photos, ##ti, ##mu, ##lation, was, performed, throughout, a, grid, covering, the, entire, depth, of, the, cortex, ., whole, -, cell, current, cl, ##amp, recordings, of, fluorescent, ch, ##r, ##2, positive, cells, revealed, their, de, ##pol, ##ari, ##zation, and, detected, action, potential, ##s, after, per, ##iso, ##matic, and, ax, ##onal, l, ##sp, ##s, ., mapping, posts, ##yna, ##ptic, targets, of, l, ##2, /, 3, neurons, in, several, co, ##rti, ##cal, layers, in, the, ip, ##si, -, and, contra, ##lateral, hemisphere, indicated, lam, ##ina, ##r, specific, ##ity, of, local, and, long, -, range, co, ##rti, ##cal, projections, (, pet, ##rea, ##nu, et, al, ., 2007, ), ., a, modified, approach, (, sc, ##rac, ##m, ), was, used, to, study, the, sub, ##cellular, organization, of, ex, ##cit, ##atory, pyramid, ##al, neurons, ., local, g, ##lu, ##tama, ##te, release, was, measured, after, l, ##sp, ##s, in, conditions, blocking, action, potential, ##s, ., eps, ##ps, as, a, measure, of, light, -, induced, activation, were, detected, only, in, the, case, of, overlap, between, the, recorded, cell, and, ch, ##r, ##2, -, targeted, pre, ##sy, ##na, ##ptic, ax, ##ons, ., interesting, ##ly, ,, sub, ##cellular, mapping, of, neural, circuit, ##ry, by, sc, ##rac, ##m, revealed, that, the, structural, connectivity, of, neurons, ,, as, indicated, by, overlap, of, ax, ##ons, and, den, ##dr, ##ites, ,, is, not, always, reflected, by, their, connection, on, a, functional, level, (, pet, ##rea, ##nu, et, al, ., 2009, ), ., to, study, whole, circuit, properties, voltage, -, sensitive, dye, ##s, (, vs, ##d, ), can, be, applied, in, brain, slices, for, an, all, -, optical, approach, ., as, vs, ##ds, change, their, light, emission, properties, in, a, voltage, -, dependent, and, most, notably, in, a, mill, ##ise, ##con, ##d, time, scale, they, are, potentially, well, suited, to, match, the, high, temporal, resolution, achieved, by, opt, ##ogen, ##etic, ##s, (, grin, ##val, ##d, and, hi, ##lde, ##sh, ##eim, 2004, ), ., although, compatibility, can, be, achieved, with, spectral, ##ly, separated, infrared, dye, ##s, such, as, r, ##h, -, 155, and, vs, ##d, imaging, following, optical, stimulation, has, been, established, successfully, ,, it, has, rarely, been, used, experimental, ##ly, up, to, now, ,, most, probably, due, to, a, less, favorable, signal, -, to, -, noise, ratio, in, comparison, to, calcium, imaging, (, air, ##an, et, al, ., 2007, ;, zhang, et, al, ., 2010, ), ., another, example, for, the, study, of, macro, ##ci, ##rc, ##uit, ##s, and, global, in, vivo, mapping, is, optical, stimulation, in, combination, with, high, -, resolution, fm, ##ri, ., lee, and, colleagues, showed, in, a, first, publication, that, blood, oxygen, ##ation, level, -, dependent, (, bold, ), signals, similar, to, classical, stimulus, -, ev, ##oked, bold, fm, ##ri, responses, could, be, eli, ##cite, ##d, optical, ##ly, ., this, effect, was, seen, not, only, locally, at, the, expression, site, of, ch, ##r, ##2, in, m1, cam, ##ki, ##i, ##α, positive, ex, ##cit, ##atory, neurons, ,, but, also, in, distinct, tha, ##lam, ##ic, neurons, defined, by, the, co, ##rti, ##co, ##fu, ##gal, ax, ##onal, projections, (, lee, et, al, ., 2010, ), ., in, a, reverse, approach, optical, stimulation, of, ch, ##r, ##2, expressing, co, ##rti, ##co, -, tha, ##lam, ##ic, projection, fibers, at, the, level, of, the, tha, ##lam, ##us, was, sufficient, to, drive, not, only, local, tha, ##lam, ##ic, bold, signals, ,, but, also, co, ##rti, ##cal, signals, ,, most, probably, in, an, anti, ##dro, ##mic, ax, ##oso, ##matic, manner, ., “, opt, ##o, -, fm, ##ri, ”, or, “, of, ##m, ##ri, ”, has, also, been, used, to, identify, downstream, targets, of, the, primary, sensory, cortex, (, si, ), ., optical, stimulation, of, a, ch, ##r, ##2, -, targeted, sub, ##pop, ##ulation, of, si, pyramid, ##al, cells, ev, ##oked, local, bold, signals, and, also, in, functional, ##ly, connected, network, regions, ,, with, differences, in, awake, compared, to, an, ##est, ##het, ##ized, mice, (, des, ##ai, et, al, ., 2011, ), ., even, though, widely, h, ##yp, ##oth, ##es, ##ized, before, ,, these, experiments, indicate, a, most, likely, causal, link, between, local, ne, ##uron, ##al, ex, ##cit, ##ation, and, positive, hem, ##od, ##yna, ##mic, responses, ,, although, the, generation, of, bold, signals, may, have, a, more, complex, nature, ., however, ,, functional, mapping, using, opt, ##ogen, ##etic, ##s, in, combination, with, fm, ##ri, not, only, integrate, ##s, cell, type, specific, ##ity, and, anatomical, conjunction, ,, but, can, also, be, used, to, functional, ##ly, di, ##sse, ##ct, brain, circuit, ##ries, based, on, their, connection, topology, (, leopold, 2010, ), ., for, global, measurements, of, brain, activity, in, living, animals, ,, electro, ##ence, ##pha, ##log, ##raphy, (, ee, ##g, ), has, been, combined, with, opt, ##ogen, ##etic, stimulation, ., in, a, first, experiment, adamant, ##idi, ##s, et, al, ., (, 2007, ,, 2010, ), identified, the, effect, of, h, ##yp, ##oc, ##ret, ##in, -, producing, neurons, in, the, lateral, h, ##yp, ##oth, ##ala, ##mus, on, sleep, to, wake, transition, by, analyzing, sleep, recordings, of, mice, with, chronic, ##ally, implant, ##ed, ee, ##g, electrode, ##s, ., in, a, bid, ##ire, ##ction, ##al, in, vivo, approach, using, en, ##ph, ##r, and, ch, ##r, ##2, the, same, group, studied, the, effect, of, locus, coe, ##ru, ##le, ##us, neurons, on, wake, ##fulness, by, applying, ee, ##g, and, in, vivo, micro, ##dial, ##ysis, as, a, functional, read, ##out, (, carter, et, al, ., 2010, ), ., for, in, vivo, extra, ##cellular, recording, upon, targeted, optical, stimulation, ,, a, device, called, “, opt, ##rod, ##e, ”, was, created, fu, ##sing, a, stimulating, fiber, ##op, ##tic, with, a, recording, electrode, (, gr, ##adi, ##nar, ##u, et, al, ., 2007, ,, 2009, ), ., constant, technical, development, even, allows, simultaneous, recordings, at, multiple, sites, in, the, living, animal, (, zhang, et, al, ., 2009, ;, roy, ##er, et, al, ., 2010, ), ., the, foundation, for, using, opt, ##ogen, ##etic, ##s, in, freely, moving, rodents, was, set, by, ara, ##vani, ##s, et, al, ., (, 2007, ), ., via, a, lightweight, ,, flexible, optical, fiber, called, optical, neural, interface, (, on, ##i, ), ex, ##cit, ##atory, motor, cortex, neurons, could, selective, ##ly, be, activated, in, rats, and, mice, as, measured, by, their, w, ##his, ##ker, movement, ., several, successive, studies, focused, on, more, complex, behavioral, paradigm, ##s, as, read, ##outs, for, opt, ##ogen, ##etic, ##al, manipulation, such, as, motor, behavior, in, animal, models, of, parkinson, ’, s, disease, (, gr, ##adi, ##nar, ##u, et, al, ., 2009, ;, k, ##ra, ##vi, ##tz, et, al, ., 2010, ), ,, reward, motivated, behavior, and, addiction, (, air, ##an, et, al, ., 2009, ;, ts, ##ai, et, al, ., 2009, ;, wit, ##ten, et, al, ., 2010, ;, stu, ##ber, et, al, ., 2011, ), ,, fear, conditioning, and, anxiety, (, ci, ##oc, ##chi, et, al, ., 2010, ;, johan, ##sen, et, al, ., 2010, ;, ty, ##e, et, al, ., 2011, ), and, other, cerebral, targets, such, as, pre, ##front, ##al, cortex, or, h, ##yp, ##oth, ##ala, ##mus, for, the, study, of, psychiatric, diseases, and, aggressive, behavior, (, co, ##vington, et, al, ., 2010, ;, lin, et, al, ., 2011, ;, yi, ##zh, ##ar, et, al, ., 2011, ##a, ,, b, ), .'},\n", - " {'article_id': '6b7e3704a9abf4729f6585fa4cd6d6c0',\n", - " 'section_name': 'From microbes to model organisms and beyond',\n", - " 'text': 'Optogenetics is applicable to diverse species and animal models. For the initial functional characterization of ChR1 and ChR2 a host model was applied that had previously been successfully used for different rhodopsins. Expression of ChR1 and ChR2 in oocytes from Xenopus laevis in the presence of all-trans retinal was the first example of functional heterologous channelrhodopsin expression outside of algae (Nagel et al. 2002, 2003). At that moment the equation was: CHOP 1 or 2 + retinal = ChR1 or ChR2, as the photoreceptor system from Chlamydomonas reinhardtii was thought to be composed of channelopsin (from a cDNA originally named CHOP1 and CHOP2 but also termed Chlamyopsin, Cop3 or Cop4) and all-trans retinal (Nagel et al. 2003). Deisseroth and colleagues redid the math and prove that “CHOP2” successfully worked in rat hippocampal primary neurons after lentiviral transduction without adding all-trans retinal at all (although the culture media contained little amounts of the precursor retinyl acetate). By this, ChR2 was established as a new one-component functional tool for neuroscience in mammals neither requiring the substitution of any synthetic chemical substrate nor genetic orthogonality between the rhodopsin and the targeted host organism, even more important as there is no mammalian analog of the algal gene CHOP2 (Boyden et al. 2005). The first in vivo applications in living animals were put into practice in parallel by Li et al. (2005) and Nagel et al. (2005). Transgenic expression of ChR2 specifically in cholinergic motorneurons of C. elegans allowed to elicit behavioral responses via muscular contractions by blue light illumination (Nagel et al. 2005). Bidirectional, both inhibitory and excitatory in vivo control of spontaneous chick spinal cord activity was performed in chicken embryos after in ovo electroporating and transient expression of ChR2 and vertebrate Ro4, respectively (Li et al. 2005). Another example of bidirectional in vivo control of C. elegans locomotion was achieved after simultaneous expression of ChR2 and NpHR using the muscle-specific myosin promoter Pmyo-3 (Zhang et al. 2007a). As mentioned above C.\\nelegans has also been used for an in vivo all-optical interrogation of neural circuits using ChR2 and G-CaMP (Guo et al. 2009). The first use of optogenetics in zebrafish revealed that activation of zebrafish trigeminal neurons by ChR2 induces escape behavior even upon single spikes, as published by Douglass et al. (2008). By using Gal4 enhancer trapping in zebrafish, transgenic animals can be generated in a feasible way (Scott et al. 2007). The Bayer lab efficiently used the GAL4/UAS system to selectively express ChR2 and NpHR in specific neuronal subpopulations of zebrafish larvae. Owing to the transparent nature of the animal in vivo functional mapping at a single neuron resolution was performed dissecting neuronal populations involved in swim behavior, saccade generation as well cardiac development and function (Arrenberg et al. 2009, 2010; Schoonheim et al. 2010). GAL4/UAS was also used to introduce ChR2 into specific subsets of neuronal populations (painless) in Drosophila melanogaster by crossing transgenic UAS-ChR2 flies with neuronspecific Gal4 transgenic lines (Zhang et al. 2007c). Optical stimulation of nociceptive neurons in transgenic larvae by ChR2 induced behavioral responses. However, it has to be taken into account that D. melanogaster and zebrafish contain hydroxyretinal which does not enter the ChR or HR binding sites making a substitution of all-trans retinal necessary (for example by food supplement). Moreover, interpretation of behavioral data in D. melanogaster can be conflicting as the animal has an innate behavioral light response (Pulver et al. 2009). The species most widely investigated with optogenetic technologies is the mouse. This is largely owing to the vast availability of transgenic cre driver lines, which can readily be combined with cre-dependent viral vectors in order to facilitate strong cell-/tissue-specific rhodopsin expression (Fig. 2). As mentioned above, in mice also classical transgenic approaches have been applied to express ChR2 and NpHR under the control of the Thy-1 promoter. Arenkiel et al. (2007) showed strong and functional, regionally restricted, channelrhodopsin expression in Thy1::ChR2-EYFP mouse strains. By presynaptic optical manipulation of targeted cells in the bulbar-cortical circuit of the olfactory system they highlighted the potential of optogenetics for complex circuit analysis in brain slices and in vivo. Wang et al. (2007) used transgenic Thy1-ChR2-YFP mice for the mapping of functional connectivity in the neural circuitry of cortical layer VI neurons. In order to study the role of fast spiking parvalbumin interneurons in the generation of gamma oscillations, Thy1::ChR2-EYFP mice were analyzed in combination with a cre-dependent approach (Sohal et al. 2009). This animal model in combination with a cell type-specific lentiviral approach was also successfully used in the systematic dissection of circuits and deciphering of potential targets related to deep brain stimulation in a Parkinson mouse model (Gradinaru et al. 2009). Hagglund and colleagues used BAC transgenesis to express ChR2-EYFP under the control of the vesicular glutamate receptor two promoter. These transgenic mice express ChR2 in glutamatergic neurons of the hindbrain and spinal cord. By optical stimulation of the lumbar region of the spinal cord and also the caudal hindbrain rhythm generation was observed, suggesting a role of glutamatergic neurons in central pattern generators of locomotion (Hagglund et al. 2010). Various examples in nematodes, mice and rats have demonstrated a direct effect of in vivo optogenetic stimulation on neuronal activity and behavioral responses (Nagel et al. 2005; Gradinaru et al. 2009; Tsai et al. 2009; Lee et al. 2010). Yet optical control of cortical circuits in higher organisms might be more complex: the first optogenetic approach in primates was performed in the rhesus macaque. Boyden and colleagues targeted specifically excitatory neurons of the frontal cortex by stereotactic lentiviral gene delivery of ChR2-GFP driven by the CamKIIα promoter and recorded neuronal activity after simultaneous optical stimulation via an optrode (Han et al. 2009). Besides showing the feasibility and safety of optogenetics in primates and thereby implementing a potential clinical translation for the use in humans, the experiments showed a slightly discouraging, but seminal, result. Although ChR2 was targeted specifically to excitatory neurons a significant proportion of recorded cells showed decreased activity. This finding was previously also observed in transgenic Thy1-ChR2 mice and is comparable to heterogeneous tissue activation in the case of electrical stimulation. Thus, targeting cortical circuits in a cell type-specific manner cannot precisely predict a specific psychological response, respectively, behavioral or clinical outcome. The impact of optogenetic manipulation on cortical circuitries seems to be heavily dependent on the neural network, in which the target cells are embedded. Nevertheless, the results indicate important aspects for therapeutic options and suggest lentiviral rhodopsin delivery as a well immuno-tolerated method for a putative application in humans.',\n", - " 'paragraph_id': 7,\n", - " 'tokenizer': 'opt, ##ogen, ##etic, ##s, is, applicable, to, diverse, species, and, animal, models, ., for, the, initial, functional, characterization, of, ch, ##r, ##1, and, ch, ##r, ##2, a, host, model, was, applied, that, had, previously, been, successfully, used, for, different, r, ##ho, ##do, ##ps, ##ins, ., expression, of, ch, ##r, ##1, and, ch, ##r, ##2, in, o, ##ocytes, from, x, ##eno, ##pus, la, ##ev, ##is, in, the, presence, of, all, -, trans, re, ##tina, ##l, was, the, first, example, of, functional, het, ##ero, ##log, ##ous, channel, ##rh, ##od, ##ops, ##in, expression, outside, of, algae, (, na, ##gel, et, al, ., 2002, ,, 2003, ), ., at, that, moment, the, equation, was, :, chop, 1, or, 2, +, re, ##tina, ##l, =, ch, ##r, ##1, or, ch, ##r, ##2, ,, as, the, photo, ##re, ##ce, ##pt, ##or, system, from, ch, ##lam, ##yd, ##omo, ##nas, rein, ##hardt, ##ii, was, thought, to, be, composed, of, channel, ##ops, ##in, (, from, a, cd, ##na, originally, named, chop, ##1, and, chop, ##2, but, also, termed, ch, ##lam, ##yo, ##ps, ##in, ,, cop, ##3, or, cop, ##4, ), and, all, -, trans, re, ##tina, ##l, (, na, ##gel, et, al, ., 2003, ), ., dei, ##sser, ##oth, and, colleagues, red, ##id, the, math, and, prove, that, “, chop, ##2, ”, successfully, worked, in, rat, hip, ##po, ##camp, ##al, primary, neurons, after, lent, ##iv, ##ira, ##l, trans, ##duction, without, adding, all, -, trans, re, ##tina, ##l, at, all, (, although, the, culture, media, contained, little, amounts, of, the, precursor, re, ##tin, ##yl, ace, ##tate, ), ., by, this, ,, ch, ##r, ##2, was, established, as, a, new, one, -, component, functional, tool, for, neuroscience, in, mammals, neither, requiring, the, substitution, of, any, synthetic, chemical, substrate, nor, genetic, orthogonal, ##ity, between, the, r, ##ho, ##do, ##ps, ##in, and, the, targeted, host, organism, ,, even, more, important, as, there, is, no, mammalian, analog, of, the, al, ##gal, gene, chop, ##2, (, boyd, ##en, et, al, ., 2005, ), ., the, first, in, vivo, applications, in, living, animals, were, put, into, practice, in, parallel, by, li, et, al, ., (, 2005, ), and, na, ##gel, et, al, ., (, 2005, ), ., trans, ##genic, expression, of, ch, ##r, ##2, specifically, in, cho, ##liner, ##gic, motor, ##ne, ##uron, ##s, of, c, ., el, ##egan, ##s, allowed, to, eli, ##cit, behavioral, responses, via, muscular, contraction, ##s, by, blue, light, illumination, (, na, ##gel, et, al, ., 2005, ), ., bid, ##ire, ##ction, ##al, ,, both, inhibitor, ##y, and, ex, ##cit, ##atory, in, vivo, control, of, spontaneous, chick, spinal, cord, activity, was, performed, in, chicken, embryo, ##s, after, in, o, ##vo, electro, ##por, ##ating, and, transient, expression, of, ch, ##r, ##2, and, ve, ##rte, ##brate, ro, ##4, ,, respectively, (, li, et, al, ., 2005, ), ., another, example, of, bid, ##ire, ##ction, ##al, in, vivo, control, of, c, ., el, ##egan, ##s, loco, ##mot, ##ion, was, achieved, after, simultaneous, expression, of, ch, ##r, ##2, and, np, ##hr, using, the, muscle, -, specific, my, ##osi, ##n, promoter, pm, ##yo, -, 3, (, zhang, et, al, ., 2007, ##a, ), ., as, mentioned, above, c, ., el, ##egan, ##s, has, also, been, used, for, an, in, vivo, all, -, optical, interrogation, of, neural, circuits, using, ch, ##r, ##2, and, g, -, camp, (, guo, et, al, ., 2009, ), ., the, first, use, of, opt, ##ogen, ##etic, ##s, in, zebra, ##fish, revealed, that, activation, of, zebra, ##fish, tri, ##ge, ##mina, ##l, neurons, by, ch, ##r, ##2, induce, ##s, escape, behavior, even, upon, single, spikes, ,, as, published, by, douglass, et, al, ., (, 2008, ), ., by, using, gal, ##4, enhance, ##r, trapping, in, zebra, ##fish, ,, trans, ##genic, animals, can, be, generated, in, a, feasible, way, (, scott, et, al, ., 2007, ), ., the, bayer, lab, efficiently, used, the, gal, ##4, /, ua, ##s, system, to, selective, ##ly, express, ch, ##r, ##2, and, np, ##hr, in, specific, ne, ##uron, ##al, sub, ##pop, ##ulation, ##s, of, zebra, ##fish, larvae, ., owing, to, the, transparent, nature, of, the, animal, in, vivo, functional, mapping, at, a, single, ne, ##uron, resolution, was, performed, di, ##sse, ##cting, ne, ##uron, ##al, populations, involved, in, swim, behavior, ,, sac, ##cade, generation, as, well, cardiac, development, and, function, (, ar, ##ren, ##berg, et, al, ., 2009, ,, 2010, ;, sc, ##ho, ##on, ##heim, et, al, ., 2010, ), ., gal, ##4, /, ua, ##s, was, also, used, to, introduce, ch, ##r, ##2, into, specific, subset, ##s, of, ne, ##uron, ##al, populations, (, pain, ##less, ), in, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, by, crossing, trans, ##genic, ua, ##s, -, ch, ##r, ##2, flies, with, neurons, ##pe, ##ci, ##fi, ##c, gal, ##4, trans, ##genic, lines, (, zhang, et, al, ., 2007, ##c, ), ., optical, stimulation, of, no, ##cic, ##eptive, neurons, in, trans, ##genic, larvae, by, ch, ##r, ##2, induced, behavioral, responses, ., however, ,, it, has, to, be, taken, into, account, that, d, ., mel, ##ano, ##gas, ##ter, and, zebra, ##fish, contain, hydro, ##xy, ##ret, ##inal, which, does, not, enter, the, ch, ##r, or, hr, binding, sites, making, a, substitution, of, all, -, trans, re, ##tina, ##l, necessary, (, for, example, by, food, supplement, ), ., moreover, ,, interpretation, of, behavioral, data, in, d, ., mel, ##ano, ##gas, ##ter, can, be, conflicting, as, the, animal, has, an, innate, behavioral, light, response, (, pu, ##lver, et, al, ., 2009, ), ., the, species, most, widely, investigated, with, opt, ##ogen, ##etic, technologies, is, the, mouse, ., this, is, largely, owing, to, the, vast, availability, of, trans, ##genic, cr, ##e, driver, lines, ,, which, can, readily, be, combined, with, cr, ##e, -, dependent, viral, vectors, in, order, to, facilitate, strong, cell, -, /, tissue, -, specific, r, ##ho, ##do, ##ps, ##in, expression, (, fig, ., 2, ), ., as, mentioned, above, ,, in, mice, also, classical, trans, ##genic, approaches, have, been, applied, to, express, ch, ##r, ##2, and, np, ##hr, under, the, control, of, the, thy, -, 1, promoter, ., aren, ##kie, ##l, et, al, ., (, 2007, ), showed, strong, and, functional, ,, regional, ##ly, restricted, ,, channel, ##rh, ##od, ##ops, ##in, expression, in, thy, ##1, :, :, ch, ##r, ##2, -, e, ##y, ##fp, mouse, strains, ., by, pre, ##sy, ##na, ##ptic, optical, manipulation, of, targeted, cells, in, the, bulb, ##ar, -, co, ##rti, ##cal, circuit, of, the, ol, ##factory, system, they, highlighted, the, potential, of, opt, ##ogen, ##etic, ##s, for, complex, circuit, analysis, in, brain, slices, and, in, vivo, ., wang, et, al, ., (, 2007, ), used, trans, ##genic, thy, ##1, -, ch, ##r, ##2, -, y, ##fp, mice, for, the, mapping, of, functional, connectivity, in, the, neural, circuit, ##ry, of, co, ##rti, ##cal, layer, vi, neurons, ., in, order, to, study, the, role, of, fast, sp, ##iki, ##ng, par, ##val, ##bu, ##min, intern, ##eur, ##ons, in, the, generation, of, gamma, os, ##ci, ##llation, ##s, ,, thy, ##1, :, :, ch, ##r, ##2, -, e, ##y, ##fp, mice, were, analyzed, in, combination, with, a, cr, ##e, -, dependent, approach, (, so, ##hal, et, al, ., 2009, ), ., this, animal, model, in, combination, with, a, cell, type, -, specific, lent, ##iv, ##ira, ##l, approach, was, also, successfully, used, in, the, systematic, di, ##sse, ##ction, of, circuits, and, dec, ##ip, ##hering, of, potential, targets, related, to, deep, brain, stimulation, in, a, parkinson, mouse, model, (, gr, ##adi, ##nar, ##u, et, al, ., 2009, ), ., ha, ##gg, ##lund, and, colleagues, used, ba, ##c, trans, ##genesis, to, express, ch, ##r, ##2, -, e, ##y, ##fp, under, the, control, of, the, ve, ##sic, ##ular, g, ##lu, ##tama, ##te, receptor, two, promoter, ., these, trans, ##genic, mice, express, ch, ##r, ##2, in, g, ##lu, ##tama, ##ter, ##gic, neurons, of, the, hind, ##bra, ##in, and, spinal, cord, ., by, optical, stimulation, of, the, lu, ##mba, ##r, region, of, the, spinal, cord, and, also, the, ca, ##uda, ##l, hind, ##bra, ##in, rhythm, generation, was, observed, ,, suggesting, a, role, of, g, ##lu, ##tama, ##ter, ##gic, neurons, in, central, pattern, generators, of, loco, ##mot, ##ion, (, ha, ##gg, ##lund, et, al, ., 2010, ), ., various, examples, in, ne, ##mat, ##odes, ,, mice, and, rats, have, demonstrated, a, direct, effect, of, in, vivo, opt, ##ogen, ##etic, stimulation, on, ne, ##uron, ##al, activity, and, behavioral, responses, (, na, ##gel, et, al, ., 2005, ;, gr, ##adi, ##nar, ##u, et, al, ., 2009, ;, ts, ##ai, et, al, ., 2009, ;, lee, et, al, ., 2010, ), ., yet, optical, control, of, co, ##rti, ##cal, circuits, in, higher, organisms, might, be, more, complex, :, the, first, opt, ##ogen, ##etic, approach, in, primate, ##s, was, performed, in, the, r, ##hes, ##us, mac, ##aq, ##ue, ., boyd, ##en, and, colleagues, targeted, specifically, ex, ##cit, ##atory, neurons, of, the, frontal, cortex, by, stereo, ##ta, ##ctic, lent, ##iv, ##ira, ##l, gene, delivery, of, ch, ##r, ##2, -, g, ##fp, driven, by, the, cam, ##ki, ##i, ##α, promoter, and, recorded, ne, ##uron, ##al, activity, after, simultaneous, optical, stimulation, via, an, opt, ##rod, ##e, (, han, et, al, ., 2009, ), ., besides, showing, the, feasibility, and, safety, of, opt, ##ogen, ##etic, ##s, in, primate, ##s, and, thereby, implementing, a, potential, clinical, translation, for, the, use, in, humans, ,, the, experiments, showed, a, slightly, disco, ##ura, ##ging, ,, but, seminal, ,, result, ., although, ch, ##r, ##2, was, targeted, specifically, to, ex, ##cit, ##atory, neurons, a, significant, proportion, of, recorded, cells, showed, decreased, activity, ., this, finding, was, previously, also, observed, in, trans, ##genic, thy, ##1, -, ch, ##r, ##2, mice, and, is, comparable, to, het, ##ero, ##gen, ##eous, tissue, activation, in, the, case, of, electrical, stimulation, ., thus, ,, targeting, co, ##rti, ##cal, circuits, in, a, cell, type, -, specific, manner, cannot, precisely, predict, a, specific, psychological, response, ,, respectively, ,, behavioral, or, clinical, outcome, ., the, impact, of, opt, ##ogen, ##etic, manipulation, on, co, ##rti, ##cal, circuit, ##ries, seems, to, be, heavily, dependent, on, the, neural, network, ,, in, which, the, target, cells, are, embedded, ., nevertheless, ,, the, results, indicate, important, aspects, for, therapeutic, options, and, suggest, lent, ##iv, ##ira, ##l, r, ##ho, ##do, ##ps, ##in, delivery, as, a, well, im, ##mun, ##o, -, tolerated, method, for, a, put, ##ative, application, in, humans, .'},\n", - " {'article_id': '8809b39645cfee8416366a91cc615729',\n", - " 'section_name': 'Habituation, familiarization, and test delays',\n", - " 'text': 'The NOR test consists of the habituation phase, the familiarization phase, and finally the test phase. The time that animal spent during each of these phases as well as the delay between them can differ from study to study (for details, see Table 2).Table 2Habituation, familiarization, and test phase in the NOR paradigmHabituation phase1 day, with different duration and number of sessionsOne session: 3 min (Aubele et al. 2008), 5 min (Goulart et al. 2010; Oliveira et al. 2010; Walf et al. 2009), 6 min (Silvers et al. 2007), 10 min (Bevins et al. 2002; Botton et al. 2010; Gaskin et al. 2010; Hale and Good 2005; Wang et al. 2009); two sessions: 10 min (Taglialatela et al. 2009), four sessions: ~20–30 min (Piterkin et al. 2008)2–5 consecutive days with different duration2 days: 5 min (Albasser et al. 2009; Hammond et al. 2004), 10 min (Bevins et al., Gaskin et al. 2010; Burke et al. 2010), 3 days: 5, 10 or 30 min (Benice and Raber 2006; Herring et al. 2008; Reger et al. 2009; Sarkisyan and Hedlund 2009), 4 days, 20 min (Clarke et al. 2010), 10 min (Williams et al. 2007), 5 days, 5 min (Clark et al. 2000; Oliveira et al. 2010)Familiarization phase1 day, with different duration and number of sessions3 or 5 min (Ennaceur and Delacour 1988), 3 min (Aubele et al. 2008; Ennaceur and Delacour 1988; Reger et al. 2009; Nanfaro et al. 2010; Walf et al. 2009), 4 min (Burke et al. 2010), 5 min (Clarke et al. 2010; Ennaceur and Delacour 1988; Reger et al. 2009), 10 min (Botton et al. 2010; Frumberg et al. 2007; Hale and Good 2005; Taglialatela et al. 2009; Wang et al. 2007), 15 min (Nanfaro et al. 2010), three consecutive 10-min trials (Benice and Raber 2008)2–5 consecutive days with different duration2 days (Ennaceur 2010, Silvers et al. 2007), 3 days (Benice et al. 2006—5 min; Sarkisyan and Hedlund 2009—5 min; Schindler et al. 2010—6 min), 5 days (Weible et al. 2009—10 min)Time of contact with an object20 s (Ennaceur and Delacour 1988; Stemmelin et al. 2008), 30 s (Buckmaster et al. 2004; Clark et al. 2010, Herring et al. 2008; Goulart et al. 2010; Williams et al. 2007), 38 s (Hammond et al. 2004), 5 min (Stemmelin et al. 2008), 10 min (Hammond et al. 2004; Williams et al. 2007), 20 min (Goulart et al. 2010)Delay between the familiarization and the test phase10 s (Clark et al. 2000), 1 min (Ennaceur 2010; Ennaceur and Delacour 1988), 2 min (Hale and Good 2005; Taglialatela et al. 2009), 5 min (Hammond et al. 2004), 15 min (Gaskin et al. 2010; Reger et al. 2009; Piterkin et al. 2008), 10 min (Clark et al. 2000), 30 min (Hale and Good 2005), 1 h (Clark et al. 2000; Piterkin et al. 2008; Reger et al. 2009; Stemmelin et al. 2008; Williams et al. 2007), 3 h (Gaskin et al. 2010), 4 h (Aubele et al. 2008; Frumberg et al. 2007; Taglialatela et al. 2009; Walf et al. 2009), 24 h (Albasser et al. 2009; Bevins et al. 2002; Botton et al. 2010; Burke et al. 2010; Clark et al. 2000; Clarke et al. 2010; Ennaceur and Delacour 1988; Gaskin et al. 2010; Goulart et al. 2010; Hale and Good 2005; Herring et al. 2008; Nanfaro et al. 2010; Reger et al. 2009; Wang et al. 2007), 48 h (Ennaceur and Delacour 1988)Test phase1 day, with different duration and number of sessions3 min (Aubele et al. 2008; Clarke et al. 2010; Ennaceur 2010; Ennaceur and Delacour 1988; Reger et al. 2009; Nanfaro et al. 2010; Stemmelin et al. 2008), 4 min (Burke et al. 2010), 5 min (Clarke et al. 2010; Frumberg et al. 2007; Gaskin et al. 2010; Goulart et al. 2010; Mumby et al. 2002), 6 min (Silvers et al. 2007; Schindler et al. 2010), 10 min (Bevins et al. 2002; Hale and Good 2005; Taglialatela et al. 2009; Wang et al. 2007), 15 min (Oliveira et al. 2010), two consecutive 10-min trials (Benice and Raber 2008, Benice et al. 2006)2–6 consecutive days with different duration2 days: 3 or 5 min (Ennaceur and Delacour 1988; Sarkisyan and Hedlund 2009), 6 days: 5 min (Weible et al. 2009)',\n", - " 'paragraph_id': 24,\n", - " 'tokenizer': 'the, nor, test, consists, of, the, habit, ##uation, phase, ,, the, familiar, ##ization, phase, ,, and, finally, the, test, phase, ., the, time, that, animal, spent, during, each, of, these, phases, as, well, as, the, delay, between, them, can, differ, from, study, to, study, (, for, details, ,, see, table, 2, ), ., table, 2, ##hab, ##it, ##uation, ,, familiar, ##ization, ,, and, test, phase, in, the, nor, paradigm, ##hab, ##it, ##uation, phase, ##1, day, ,, with, different, duration, and, number, of, sessions, ##one, session, :, 3, min, (, au, ##bel, ##e, et, al, ., 2008, ), ,, 5, min, (, go, ##ular, ##t, et, al, ., 2010, ;, oliveira, et, al, ., 2010, ;, wal, ##f, et, al, ., 2009, ), ,, 6, min, (, silver, ##s, et, al, ., 2007, ), ,, 10, min, (, be, ##vin, ##s, et, al, ., 2002, ;, bot, ##ton, et, al, ., 2010, ;, gas, ##kin, et, al, ., 2010, ;, hale, and, good, 2005, ;, wang, et, al, ., 2009, ), ;, two, sessions, :, 10, min, (, tag, ##lia, ##late, ##la, et, al, ., 2009, ), ,, four, sessions, :, ~, 20, –, 30, min, (, pit, ##er, ##kin, et, al, ., 2008, ), 2, –, 5, consecutive, days, with, different, duration, ##2, days, :, 5, min, (, alba, ##sser, et, al, ., 2009, ;, hammond, et, al, ., 2004, ), ,, 10, min, (, be, ##vin, ##s, et, al, ., ,, gas, ##kin, et, al, ., 2010, ;, burke, et, al, ., 2010, ), ,, 3, days, :, 5, ,, 10, or, 30, min, (, ben, ##ice, and, ra, ##ber, 2006, ;, herring, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, ), ,, 4, days, ,, 20, min, (, clarke, et, al, ., 2010, ), ,, 10, min, (, williams, et, al, ., 2007, ), ,, 5, days, ,, 5, min, (, clark, et, al, ., 2000, ;, oliveira, et, al, ., 2010, ), familiar, ##ization, phase, ##1, day, ,, with, different, duration, and, number, of, sessions, ##3, or, 5, min, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ), ,, 3, min, (, au, ##bel, ##e, et, al, ., 2008, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, reg, ##er, et, al, ., 2009, ;, nan, ##far, ##o, et, al, ., 2010, ;, wal, ##f, et, al, ., 2009, ), ,, 4, min, (, burke, et, al, ., 2010, ), ,, 5, min, (, clarke, et, al, ., 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, reg, ##er, et, al, ., 2009, ), ,, 10, min, (, bot, ##ton, et, al, ., 2010, ;, fr, ##umber, ##g, et, al, ., 2007, ;, hale, and, good, 2005, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ;, wang, et, al, ., 2007, ), ,, 15, min, (, nan, ##far, ##o, et, al, ., 2010, ), ,, three, consecutive, 10, -, min, trials, (, ben, ##ice, and, ra, ##ber, 2008, ), 2, –, 5, consecutive, days, with, different, duration, ##2, days, (, en, ##nac, ##eur, 2010, ,, silver, ##s, et, al, ., 2007, ), ,, 3, days, (, ben, ##ice, et, al, ., 2006, —, 5, min, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, —, 5, min, ;, sc, ##hin, ##dler, et, al, ., 2010, —, 6, min, ), ,, 5, days, (, wei, ##ble, et, al, ., 2009, —, 10, min, ), time, of, contact, with, an, object, ##20, s, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, stem, ##mel, ##in, et, al, ., 2008, ), ,, 30, s, (, buck, ##master, et, al, ., 2004, ;, clark, et, al, ., 2010, ,, herring, et, al, ., 2008, ;, go, ##ular, ##t, et, al, ., 2010, ;, williams, et, al, ., 2007, ), ,, 38, s, (, hammond, et, al, ., 2004, ), ,, 5, min, (, stem, ##mel, ##in, et, al, ., 2008, ), ,, 10, min, (, hammond, et, al, ., 2004, ;, williams, et, al, ., 2007, ), ,, 20, min, (, go, ##ular, ##t, et, al, ., 2010, ), delay, between, the, familiar, ##ization, and, the, test, phase, ##10, s, (, clark, et, al, ., 2000, ), ,, 1, min, (, en, ##nac, ##eur, 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ), ,, 2, min, (, hale, and, good, 2005, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ), ,, 5, min, (, hammond, et, al, ., 2004, ), ,, 15, min, (, gas, ##kin, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ;, pit, ##er, ##kin, et, al, ., 2008, ), ,, 10, min, (, clark, et, al, ., 2000, ), ,, 30, min, (, hale, and, good, 2005, ), ,, 1, h, (, clark, et, al, ., 2000, ;, pit, ##er, ##kin, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, stem, ##mel, ##in, et, al, ., 2008, ;, williams, et, al, ., 2007, ), ,, 3, h, (, gas, ##kin, et, al, ., 2010, ), ,, 4, h, (, au, ##bel, ##e, et, al, ., 2008, ;, fr, ##umber, ##g, et, al, ., 2007, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ;, wal, ##f, et, al, ., 2009, ), ,, 24, h, (, alba, ##sser, et, al, ., 2009, ;, be, ##vin, ##s, et, al, ., 2002, ;, bot, ##ton, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, clarke, et, al, ., 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, hale, and, good, 2005, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ;, wang, et, al, ., 2007, ), ,, 48, h, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ), test, phase, ##1, day, ,, with, different, duration, and, number, of, sessions, ##3, min, (, au, ##bel, ##e, et, al, ., 2008, ;, clarke, et, al, ., 2010, ;, en, ##nac, ##eur, 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, reg, ##er, et, al, ., 2009, ;, nan, ##far, ##o, et, al, ., 2010, ;, stem, ##mel, ##in, et, al, ., 2008, ), ,, 4, min, (, burke, et, al, ., 2010, ), ,, 5, min, (, clarke, et, al, ., 2010, ;, fr, ##umber, ##g, et, al, ., 2007, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, mum, ##by, et, al, ., 2002, ), ,, 6, min, (, silver, ##s, et, al, ., 2007, ;, sc, ##hin, ##dler, et, al, ., 2010, ), ,, 10, min, (, be, ##vin, ##s, et, al, ., 2002, ;, hale, and, good, 2005, ;, tag, ##lia, ##late, ##la, et, al, ., 2009, ;, wang, et, al, ., 2007, ), ,, 15, min, (, oliveira, et, al, ., 2010, ), ,, two, consecutive, 10, -, min, trials, (, ben, ##ice, and, ra, ##ber, 2008, ,, ben, ##ice, et, al, ., 2006, ), 2, –, 6, consecutive, days, with, different, duration, ##2, days, :, 3, or, 5, min, (, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, ), ,, 6, days, :, 5, min, (, wei, ##ble, et, al, ., 2009, )'},\n", - " {'article_id': '8809b39645cfee8416366a91cc615729',\n", - " 'section_name': 'Animals',\n", - " 'text': 'The NOR test is widely used to evaluate object recognition memory in rodents and lead itself well cross-species generalization (Gaskin et al. 2010; Reger et al. 2009). Thus, it is important to understand what kind of animals has been used in the NOR test and which are their features (details presented in Table 1). Sometimes animals’ models with specific modifications were necessary. In Taglialatela et al.’s study (2009), transgenic animals to study Alzheimer’s disease (AD) have been used, since these mice suffer from progressive decline in several forms of declarative memory including fear conditioning and novel object recognition. For the same purpose, this kind of mice was also used in Hale and Good research (2005), once they studied the effect of a human amyloid precursor protein mutation that results in an autosomal dominant familial form of AD on processes supporting recognition memory, including object location memory.Table 1Animals used in the NOR testGenderRatsAggleton et al. 2010; Albasser et al. 2009; Aubele et al. 2008; Bevins et al. 2002; Broadbent et al. 2010; Burke et al. 2010; Clark et al. 2000; Ennaceur and Delacour 1988; Frumberg et al. 2007; Gaskin et al. 2010; Goulart et al. 2010; Herring et al. 2008; Nanfaro et al. 2010; Piterkin et al. 2008; Reger et al. 2009; Silvers et al. 2007MiceBenice and Raber 2008; Benice et al. 2006; Bilsland et al. 2008; Botton et al. 2010; Clarke et al. 2010; Dere et al. 2005; Hale and Good 2005; Hammond et al. 2004; Oliveira et al. 2010; Schindler et al. 2010; Wang et al. 2007; Weible et al. 2009SexMalesAggleton et al. 2010; Aubele et al. 2008; Bevins et al. 2002; Botton et al. 2010; Burke et al. 2010; Clark et al. 2000; Dere et al. 2005; Ennaceur and Delacour 1988; Frumberg et al. 2007; Gaskin et al. 2010; Goulart et al. 2010; Hammond et al. 2004; Herring et al. 2008; Nanfaro et al. 2010; Oliveira et al. 2010; Piterkin et al. 2008; Reger et al. 2009; Silvers et al. 2007; Schindler et al. 2010; Wang et al. 2007Both males and femalesBilsland et al. 2008; Hale and Good 2005AgeAnimals 2–4 months oldClark et al. 2000; Clarke et al. 2010; Dere et al. 2005; Frumberg et al. 2007; Goulart et al. 2010; Hammond et al. 2004; Mumby et al. 2002; Oliveira et al. 2010; Nanfaro et al. 2010; Piterkin et al. 2008; Walf et al. 2009Immature, i.e., 20–23 days (weanling), 29–40 days (juvenile), and more than 50 days (young adulthood) oldReger et al. 2009Aged, i.e., 7–9 months and 24–25 months oldBurke et al. 2010HousingIndividual cageBroadbent et al. 2010; Burke et al. 2010; Ennaceur and Delacour 1988; Gaskin et al. 2010; Mumby et al. 2002; Oliveira et al. 2010; Piterkin et al. 2008In groups of 2–5/cageAggleton et al. 2010; Botton et al. 2010; Goulart et al. 2010; Herring et al. 2008; Nanfaro et al. 2010FeedingAd libitumAggleton et al. 2010; Albasser et al. 2009; Aubele et al. 2008; Bevins et al. 2002; Bilsland et al. 2008; Botton et al. 2010; Broadbent et al. 2010; Burke et al. 2010; Clark et al. 2000; Clarke et al. 2010; Goulart et al. 2010; Hammond et al. 2004; Herring et al. 2008; Nanfaro et al. 2010; Oliveira et al. 2010; Reger et al. 2009; Sarkisyan and Hedlund 2009; Silvers et al. 2007; Schindler et al. 2010; Wang et al. 2007Access restricted, 25–30 g/dayBenice et al. 2006; Gaskin et al. 2010; Piterkin et al. 2008 Mumby et al. 2002',\n", - " 'paragraph_id': 18,\n", - " 'tokenizer': 'the, nor, test, is, widely, used, to, evaluate, object, recognition, memory, in, rodents, and, lead, itself, well, cross, -, species, general, ##ization, (, gas, ##kin, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ), ., thus, ,, it, is, important, to, understand, what, kind, of, animals, has, been, used, in, the, nor, test, and, which, are, their, features, (, details, presented, in, table, 1, ), ., sometimes, animals, ’, models, with, specific, modifications, were, necessary, ., in, tag, ##lia, ##late, ##la, et, al, ., ’, s, study, (, 2009, ), ,, trans, ##genic, animals, to, study, alzheimer, ’, s, disease, (, ad, ), have, been, used, ,, since, these, mice, suffer, from, progressive, decline, in, several, forms, of, dec, ##lar, ##ative, memory, including, fear, conditioning, and, novel, object, recognition, ., for, the, same, purpose, ,, this, kind, of, mice, was, also, used, in, hale, and, good, research, (, 2005, ), ,, once, they, studied, the, effect, of, a, human, amy, ##loid, precursor, protein, mutation, that, results, in, an, auto, ##som, ##al, dominant, fa, ##mi, ##lia, ##l, form, of, ad, on, processes, supporting, recognition, memory, ,, including, object, location, memory, ., table, 1a, ##ni, ##mal, ##s, used, in, the, nor, test, ##gen, ##der, ##rat, ##sa, ##ggle, ##ton, et, al, ., 2010, ;, alba, ##sser, et, al, ., 2009, ;, au, ##bel, ##e, et, al, ., 2008, ;, be, ##vin, ##s, et, al, ., 2002, ;, broad, ##ben, ##t, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, fr, ##umber, ##g, et, al, ., 2007, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, silver, ##s, et, al, ., 2007, ##mic, ##eb, ##eni, ##ce, and, ra, ##ber, 2008, ;, ben, ##ice, et, al, ., 2006, ;, bi, ##ls, ##land, et, al, ., 2008, ;, bot, ##ton, et, al, ., 2010, ;, clarke, et, al, ., 2010, ;, der, ##e, et, al, ., 2005, ;, hale, and, good, 2005, ;, hammond, et, al, ., 2004, ;, oliveira, et, al, ., 2010, ;, sc, ##hin, ##dler, et, al, ., 2010, ;, wang, et, al, ., 2007, ;, wei, ##ble, et, al, ., 2009, ##se, ##x, ##mal, ##esa, ##ggle, ##ton, et, al, ., 2010, ;, au, ##bel, ##e, et, al, ., 2008, ;, be, ##vin, ##s, et, al, ., 2002, ;, bot, ##ton, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, der, ##e, et, al, ., 2005, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, fr, ##umber, ##g, et, al, ., 2007, ;, gas, ##kin, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, hammond, et, al, ., 2004, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, oliveira, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ;, reg, ##er, et, al, ., 2009, ;, silver, ##s, et, al, ., 2007, ;, sc, ##hin, ##dler, et, al, ., 2010, ;, wang, et, al, ., 2007, ##bot, ##h, males, and, females, ##bil, ##sl, ##and, et, al, ., 2008, ;, hale, and, good, 2005, ##age, ##ani, ##mal, ##s, 2, –, 4, months, old, ##cl, ##ark, et, al, ., 2000, ;, clarke, et, al, ., 2010, ;, der, ##e, et, al, ., 2005, ;, fr, ##umber, ##g, et, al, ., 2007, ;, go, ##ular, ##t, et, al, ., 2010, ;, hammond, et, al, ., 2004, ;, mum, ##by, et, al, ., 2002, ;, oliveira, et, al, ., 2010, ;, nan, ##far, ##o, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ;, wal, ##f, et, al, ., 2009, ##im, ##mat, ##ure, ,, i, ., e, ., ,, 20, –, 23, days, (, we, ##an, ##ling, ), ,, 29, –, 40, days, (, juvenile, ), ,, and, more, than, 50, days, (, young, adulthood, ), old, ##re, ##ger, et, al, ., 2009, ##aged, ,, i, ., e, ., ,, 7, –, 9, months, and, 24, –, 25, months, old, ##bu, ##rke, et, al, ., 2010, ##ho, ##using, ##ind, ##iv, ##id, ##ual, cage, ##bro, ##ad, ##ben, ##t, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, en, ##nac, ##eur, and, del, ##aco, ##ur, 1988, ;, gas, ##kin, et, al, ., 2010, ;, mum, ##by, et, al, ., 2002, ;, oliveira, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, ##in, groups, of, 2, –, 5, /, cage, ##ag, ##gle, ##ton, et, al, ., 2010, ;, bot, ##ton, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ##fe, ##eding, ##ad, li, ##bit, ##uma, ##ggle, ##ton, et, al, ., 2010, ;, alba, ##sser, et, al, ., 2009, ;, au, ##bel, ##e, et, al, ., 2008, ;, be, ##vin, ##s, et, al, ., 2002, ;, bi, ##ls, ##land, et, al, ., 2008, ;, bot, ##ton, et, al, ., 2010, ;, broad, ##ben, ##t, et, al, ., 2010, ;, burke, et, al, ., 2010, ;, clark, et, al, ., 2000, ;, clarke, et, al, ., 2010, ;, go, ##ular, ##t, et, al, ., 2010, ;, hammond, et, al, ., 2004, ;, herring, et, al, ., 2008, ;, nan, ##far, ##o, et, al, ., 2010, ;, oliveira, et, al, ., 2010, ;, reg, ##er, et, al, ., 2009, ;, sar, ##kis, ##yan, and, he, ##dl, ##und, 2009, ;, silver, ##s, et, al, ., 2007, ;, sc, ##hin, ##dler, et, al, ., 2010, ;, wang, et, al, ., 2007, ##ac, ##ces, ##s, restricted, ,, 25, –, 30, g, /, day, ##ben, ##ice, et, al, ., 2006, ;, gas, ##kin, et, al, ., 2010, ;, pit, ##er, ##kin, et, al, ., 2008, mum, ##by, et, al, ., 2002'},\n", - " {'article_id': 'ac288501c74bcc85673f9b4b8e2a8432',\n", - " 'section_name': '3 RESULTS',\n", - " 'text': 'To evaluate the precision of the predicted connections, we manually reviewed a random subset of 2000 abstracts. Each pair was evaluated by two curators, yielding an interannotator agreement rate of 85%. Conflicts were resolved by a third curator or by consensus after discussion. Overall, the SLK predictions were 55.3% precise. Errors from the automated steps of named entity recognition and abbreviation expansion were 11% and 4%, respectively. These rates suggest a lesser impact of named entity recognition errors when compared with assessments in the protein–protein interaction domain (Kabiljo et al., 2009). Table 2 presents the five most and least confident connectivity relations for the rat brain. Classification confidence is approximated with the SLK prediction score (distance to classifying hyperplane), with highest values representing the cases closest to positive training examples. Two of the most confident predictions are extracted from an article title and have the same form (ranks 1 and 5). The sentences containing top predictions are shorter on average (192 characters) than the sentences with least confident predictions (282 characters), suggesting sentence complexity affects the prediction results. Of these 10 examples, only one is clearly a false-positive prediction (rank 9764), while several others point to errors in previous automated steps. The mentions of ‘internal capsule’ (rank 9766) and ‘Met-enkephalin’ (rank 4) are incorrectly predicted as brain region mentions (our definition of a brain region excludes fibre tracts like the internal capsule, while enkephalin is a peptide). We manually compared these 10 results with the BAMS system and found it surprisingly difficult to map the mentioned regions to those in BAMS. For example, ‘retrosplenial dysgranular cortex’ and ‘dorsal medullary reticular column’ were not found in BAMS. In the end, corresponding connections were found in BAMS for several of the relationships, but only between enclosing regions (ranks 9767 and 5).\\nTable 2.Top- and bottom-predicted relations from the 12 557 abstract set, ranked by SLK classification scoreRankSentenceScoreReference1Trigeminal projections to hypoglossal and facial motor nuclei in the rat.3.47Pinganaud, et al., 19992The cortical projections to retrosplenial dysgranular cortex (Rdg) originate primarily in the infraradiata, retrosplenial, postsubicular and areas 17 and 18b cortices.3.34van Groen and Wyss, 19923The thalamic projections to retrosplenial dysgranular cortex (Rdg) originate in the anterior (primarily the anteromedial), lateral (primarily the laterodorsal) and reuniens nuclei.3.33van Groen and Wyss, 19924Our results indicate that the centromedial amygdala receives Met-enkephalin afferents, as indicated by the presence of mu-opioid receptor, delta-opioid receptor and Met-enkephalin fibres in the CEA and MEA, originating primarily from the bed nucleus of the stria terminalis and from other amygdaloid nuclei.3.32Poulin, et al., 20065Thalamic projections to retrosplenial cortex in the rat.3.28Sripanidkulchai and Wyss, 1986...9757 relationships9763The sparse reciprocal connections to the other amygdaloid nuclei suggest that the CEA nucleus does not regulate the other amygdaloid regions, but rather executes the responses evoked by the other amygdaloid nuclei that innervate the CEA nucleus.5.46 × 10^−4Jolkkonen and Pitkanen, 19989764The majority of the endomorphin 1/fluoro-gold and endomorphin 2/fluoro-gold double-labelled neurons in the hypothalamus were distributed in the dorsomedial nucleus, areas between the dorsomedial and ventromedial nucleus and arcuate nucleus; a few were also seen in the ventromedial, periventricular and posterior nucleus.4.36 × 10^−4Chen, et al., 20089765Projections from the dorsal medullary reticular column are largely bilateral and are distributed preferentially to the ventral subdivision of the fifth cranial nerve motor nuclei in the rat (MoV), to the dorsal and intermediate subdivisions of VII and to both the dorsal and the ventral subdivision of XII.2.91 × 10^−4Cunningham and Sawchenko, 20009766Two additional large projections leave the MEA forebrain bundle in the hypothalamus; the ansa peduncularis–ventral amygdaloid bundle system turns laterally through the internal capsule into the striatal complex, amygdala and the external capsule to reach lateral and posterior cortex, and another system of fibers turns medially to innervate MEA hypothalamus and median eminence and forms a contralateral projection through the supraoptic commissures.2.87 × 10^−4Moore, et al., 19789767In animals with injected horseradish peroxidase confined within the main bulb, perikarya retrogradely labelled with the protein in the ipsilateral forebrain were observed in the anterior prepyriform cortex horizontal limb of the nucleus of the diagonal band, and far lateral preoptic and rostral lateral hypothalamic areas.3.36 × 10^−5Broadwell and Jacobowitz, 1976CEA, central; MEA, medial; MoV, the fifth cranial nerve motor nuclei in the rat.',\n", - " 'paragraph_id': 25,\n", - " 'tokenizer': 'to, evaluate, the, precision, of, the, predicted, connections, ,, we, manually, reviewed, a, random, subset, of, 2000, abstracts, ., each, pair, was, evaluated, by, two, curator, ##s, ,, yielding, an, inter, ##ann, ##ota, ##tor, agreement, rate, of, 85, %, ., conflicts, were, resolved, by, a, third, curator, or, by, consensus, after, discussion, ., overall, ,, the, sl, ##k, predictions, were, 55, ., 3, %, precise, ., errors, from, the, automated, steps, of, named, entity, recognition, and, abbreviation, expansion, were, 11, %, and, 4, %, ,, respectively, ., these, rates, suggest, a, lesser, impact, of, named, entity, recognition, errors, when, compared, with, assessments, in, the, protein, –, protein, interaction, domain, (, ka, ##bil, ##jo, et, al, ., ,, 2009, ), ., table, 2, presents, the, five, most, and, least, confident, connectivity, relations, for, the, rat, brain, ., classification, confidence, is, approximate, ##d, with, the, sl, ##k, prediction, score, (, distance, to, classify, ##ing, hyper, ##plane, ), ,, with, highest, values, representing, the, cases, closest, to, positive, training, examples, ., two, of, the, most, confident, predictions, are, extracted, from, an, article, title, and, have, the, same, form, (, ranks, 1, and, 5, ), ., the, sentences, containing, top, predictions, are, shorter, on, average, (, 192, characters, ), than, the, sentences, with, least, confident, predictions, (, 282, characters, ), ,, suggesting, sentence, complexity, affects, the, prediction, results, ., of, these, 10, examples, ,, only, one, is, clearly, a, false, -, positive, prediction, (, rank, 97, ##64, ), ,, while, several, others, point, to, errors, in, previous, automated, steps, ., the, mentions, of, ‘, internal, capsule, ’, (, rank, 97, ##66, ), and, ‘, met, -, en, ##ke, ##pha, ##lin, ’, (, rank, 4, ), are, incorrectly, predicted, as, brain, region, mentions, (, our, definition, of, a, brain, region, exclude, ##s, fibre, tracts, like, the, internal, capsule, ,, while, en, ##ke, ##pha, ##lin, is, a, peptide, ), ., we, manually, compared, these, 10, results, with, the, bam, ##s, system, and, found, it, surprisingly, difficult, to, map, the, mentioned, regions, to, those, in, bam, ##s, ., for, example, ,, ‘, retro, ##sp, ##len, ##ial, d, ##ys, ##gra, ##nu, ##lar, cortex, ’, and, ‘, dorsal, med, ##ulla, ##ry, re, ##tic, ##ular, column, ’, were, not, found, in, bam, ##s, ., in, the, end, ,, corresponding, connections, were, found, in, bam, ##s, for, several, of, the, relationships, ,, but, only, between, en, ##cl, ##osing, regions, (, ranks, 97, ##6, ##7, and, 5, ), ., table, 2, ., top, -, and, bottom, -, predicted, relations, from, the, 12, 55, ##7, abstract, set, ,, ranked, by, sl, ##k, classification, scorer, ##an, ##ks, ##ente, ##nce, ##sco, ##rer, ##efe, ##rence, ##1, ##tri, ##ge, ##mina, ##l, projections, to, h, ##yp, ##og, ##los, ##sal, and, facial, motor, nuclei, in, the, rat, ., 3, ., 47, ##ping, ##ana, ##ud, ,, et, al, ., ,, 1999, ##2, ##the, co, ##rti, ##cal, projections, to, retro, ##sp, ##len, ##ial, d, ##ys, ##gra, ##nu, ##lar, cortex, (, rd, ##g, ), originate, primarily, in, the, in, ##fra, ##rad, ##ia, ##ta, ,, retro, ##sp, ##len, ##ial, ,, posts, ##ub, ##icular, and, areas, 17, and, 18, ##b, co, ##rti, ##ces, ., 3, ., 34, ##van, gr, ##oe, ##n, and, w, ##ys, ##s, ,, 1992, ##3, ##the, tha, ##lam, ##ic, projections, to, retro, ##sp, ##len, ##ial, d, ##ys, ##gra, ##nu, ##lar, cortex, (, rd, ##g, ), originate, in, the, anterior, (, primarily, the, ant, ##ero, ##media, ##l, ), ,, lateral, (, primarily, the, later, ##od, ##ors, ##al, ), and, re, ##uni, ##ens, nuclei, ., 3, ., 33, ##van, gr, ##oe, ##n, and, w, ##ys, ##s, ,, 1992, ##4, ##our, results, indicate, that, the, centro, ##media, ##l, amy, ##g, ##dal, ##a, receives, met, -, en, ##ke, ##pha, ##lin, af, ##fer, ##ents, ,, as, indicated, by, the, presence, of, mu, -, op, ##io, ##id, receptor, ,, delta, -, op, ##io, ##id, receptor, and, met, -, en, ##ke, ##pha, ##lin, fibre, ##s, in, the, ce, ##a, and, me, ##a, ,, originating, primarily, from, the, bed, nucleus, of, the, st, ##ria, terminal, ##is, and, from, other, amy, ##g, ##dal, ##oid, nuclei, ., 3, ., 32, ##po, ##ulin, ,, et, al, ., ,, 2006, ##5, ##thal, ##ami, ##c, projections, to, retro, ##sp, ##len, ##ial, cortex, in, the, rat, ., 3, ., 28, ##sr, ##ip, ##ani, ##d, ##ku, ##lch, ##ai, and, w, ##ys, ##s, ,, 1986, ., ., ., 97, ##57, relationships, ##9, ##7, ##6, ##3, ##the, sparse, reciprocal, connections, to, the, other, amy, ##g, ##dal, ##oid, nuclei, suggest, that, the, ce, ##a, nucleus, does, not, regulate, the, other, amy, ##g, ##dal, ##oid, regions, ,, but, rather, execute, ##s, the, responses, ev, ##oked, by, the, other, amy, ##g, ##dal, ##oid, nuclei, that, inner, ##vate, the, ce, ##a, nucleus, ., 5, ., 46, ×, 10, ^, −, ##4, ##jo, ##lk, ##kon, ##en, and, pit, ##kan, ##en, ,, 1998, ##9, ##7, ##64, ##the, majority, of, the, end, ##omo, ##rp, ##hin, 1, /, flu, ##oro, -, gold, and, end, ##omo, ##rp, ##hin, 2, /, flu, ##oro, -, gold, double, -, labelled, neurons, in, the, h, ##yp, ##oth, ##ala, ##mus, were, distributed, in, the, do, ##rso, ##media, ##l, nucleus, ,, areas, between, the, do, ##rso, ##media, ##l, and, vent, ##rom, ##ed, ##ial, nucleus, and, arc, ##uate, nucleus, ;, a, few, were, also, seen, in, the, vent, ##rom, ##ed, ##ial, ,, per, ##ive, ##nt, ##ric, ##ular, and, posterior, nucleus, ., 4, ., 36, ×, 10, ^, −, ##4, ##chen, ,, et, al, ., ,, 2008, ##9, ##7, ##65, ##pro, ##ject, ##ions, from, the, dorsal, med, ##ulla, ##ry, re, ##tic, ##ular, column, are, largely, bilateral, and, are, distributed, prefer, ##ential, ##ly, to, the, ventral, subdivision, of, the, fifth, cr, ##anial, nerve, motor, nuclei, in, the, rat, (, mo, ##v, ), ,, to, the, dorsal, and, intermediate, subdivisions, of, vii, and, to, both, the, dorsal, and, the, ventral, subdivision, of, xii, ., 2, ., 91, ×, 10, ^, −, ##4, ##cu, ##nni, ##ng, ##ham, and, saw, ##chenko, ,, 2000, ##9, ##7, ##66, ##t, ##wo, additional, large, projections, leave, the, me, ##a, fore, ##bra, ##in, bundle, in, the, h, ##yp, ##oth, ##ala, ##mus, ;, the, an, ##sa, pe, ##dun, ##cular, ##is, –, ventral, amy, ##g, ##dal, ##oid, bundle, system, turns, lateral, ##ly, through, the, internal, capsule, into, the, st, ##ria, ##tal, complex, ,, amy, ##g, ##dal, ##a, and, the, external, capsule, to, reach, lateral, and, posterior, cortex, ,, and, another, system, of, fibers, turns, medial, ##ly, to, inner, ##vate, me, ##a, h, ##yp, ##oth, ##ala, ##mus, and, median, emi, ##nen, ##ce, and, forms, a, contra, ##lateral, projection, through, the, su, ##pr, ##ao, ##ptic, com, ##mis, ##sure, ##s, ., 2, ., 87, ×, 10, ^, −, ##4, ##moor, ##e, ,, et, al, ., ,, 1978, ##9, ##7, ##6, ##7, ##in, animals, with, injected, horse, ##rad, ##ish, per, ##ox, ##ida, ##se, confined, within, the, main, bulb, ,, per, ##ika, ##rya, retro, ##grade, ##ly, labelled, with, the, protein, in, the, ip, ##sil, ##ater, ##al, fore, ##bra, ##in, were, observed, in, the, anterior, prep, ##yr, ##iform, cortex, horizontal, limb, of, the, nucleus, of, the, diagonal, band, ,, and, far, lateral, pre, ##op, ##tic, and, ro, ##stra, ##l, lateral, h, ##yp, ##oth, ##ala, ##mic, areas, ., 3, ., 36, ×, 10, ^, −, ##5, ##bro, ##ad, ##well, and, jacob, ##ow, ##itz, ,, 1976, ##cea, ,, central, ;, me, ##a, ,, medial, ;, mo, ##v, ,, the, fifth, cr, ##anial, nerve, motor, nuclei, in, the, rat, .'},\n", - " {'article_id': '001fd76c438a28e34b3f7360a0031cbb',\n", - " 'section_name': 'Available data on CSF–ECF relationships',\n", - " 'text': 'With the introduction of microdialysis techniques, the possibility of making a direct comparison of CSF and brain ECF concentrations in animals became available. Also, intrabrain distribution aspects of drugs could be determined. Sawchuk’s group at the University in Minnesota was the first to do so. In rats, zidovudine and stavudine concentration–time profiles were obtained in CSF and Brain ECF, and challenged by inhibition of active transport processes [50–52]. Shen et al. [27] provided an extensive overview on CSF and brain ECF concentrations for drugs from many therapeutic classes with a wide spectrum in physico-chemical properties. Appending data of more recent studies, Table 2 presents CSF -brain ECF relationships for a broad set of drugs, including the methodology of assessment. These values have resulted from microdialysis to obtain brain ECF as well as CSF concentrations, CSF sampling for assessing CSF concentrations, as well as he brain slice method to obtain brain ECF concentrations. The brain slice method estimates brain ECF concentrations by determining total brain concentrations after drug administration, and to correct for the free fraction as obtained in brain slices after bathing the slice in a buffer solution containing the drug(s) of interest [53, 54].Table 2Drugs and their Kpuu, CSF and Kpuu, brain values obtained in animals (rats, sheep, rabbits, rhesus monkeys, and nonhuman primates) on the basis of steady state (SS) values, AUC values, continuous infusion (cont inf)CompoundSpeciesTimeKpuu, CSFKpuu, brainReference9-OH-RisperidoneRat6 h cont inf0,06840,0143[61]AcetaminophenRatAUC (partial)0,31,2[25]AlovudineRatSS0,40,16[72]AntipyrineRat2 h cont inf0,990,708[56]AtomoxetineRatSS1,70,7[64]BaclofenRatPseudo SS0,0280,035[73]BenzylpenicillinRat2 h cont inf0,01340,0264[56]BuspironeRat2 h cont inf0,5580,612[56]CaffeineRat2 h cont inf1,030,584[56]CarbamazepineRat2 h cont inf0,5350,771[56]CarbamazepineRat6 h cont inf0,1670,232[61]CarboplatinNonhuman primateAUC0,050,05[74]CefodizimeRatSpecific time0,020,22[75]CeftazidimeRatSS0,0390,022[76]CeftriaxoneRatSS0,710,8[76]CephalexinRat2 h cont inf0,02250,016[56]CimetidineRat2 h cont inf0,02110,00981[56]CisplatinNonhuman primateAUC0,050,05[74]CitalopramRat2 h cont inf0,6670,494[56]CitalopramRat6 h cont inf0,50,559[61]CP-615,003RatSS0,010,0014[77]DaidzeinRat2 h cont inf0,1890,0667[56]DantroleneRat2 h cont inf0,08380,0297[56]DiazepamRat2 h cont inf0,8470,805[56]DiphenylhydramineSheepSS (adults)3,43,4[78]DiphenylhydramineSheepSS (30 d lambs)4,96,6[78]DiphenylhydramineSheepSS (10 d lambs)5,66,6[78]EAB515Rat15 h0,180,08[51]FlavopiridolRat2 h cont inf0,2160,0525[56]FleroxacinRat2 h cont inf0,2830,25[56]FleroxacinRatSS0,420,15[79]GanciclovirRat6 h cont inf0,06470,0711[61]GenisteinRat2 h cont inf0,5890,181[56]LamotrigineRatSS1,51[62]LoperamideRat2 h cont inf0,03760,00886[56]MetoclopramideRat6 h cont inf0,1690,235[61]MidazolamRat2 h cont inf1,352,19[56]MorphineRatAUC0,1970,51[80]M6GRatAUC0,0290,56[80]N-desmethylclozapineRat6 h cont inf0,01510,01[61]NorfloxacinRatSS0,0330,034[79]OfloxacinRatSS0,230,12[79]OxaliplatinNonhuman primateAUC0,655,3[74]PerfloxacinRat2 h cont inf0,3890,199[56]PerfloxacinRatSS0,370,15[79]PhenytoinRat2 h cont inf0,3960,447[56]PhenytoinRatAUC0,20,85[81]ProbenecidRatSS0,60,2[82]QuinidineRat2 h cont inf0,09110,026[56]QuinidineRat6 h cont inf0,09690,0459[61]RisperidoneRat2 h cont inf0,1240,0787[56]RisperidoneRat6 h cont inf0,09130,0422[61]SalicylateRatSS0,50,1[82]SDZ EAA 494RatAUC0,170,11[83]SertralineRat2 h cont inf0,8321,85[56]StavudineRatSS0,50,3[84]StavudineRatSS0,60,6[52]SulpirideRat2 h cont inf0,04990,0219[56]ThiopentalRat2 h cont inf0,5990,911[56]ThiopentalRat6 h cont inf0,06630,0663[61]TiagabineRatAUC0,0110,011[85]VerapamilRat2 h cont inf0,3330,0786[56]YM992RatSS1,71,4[86]ZidovudinRabbitAUC0,170,08[50]ZidovudinRabbitSS0,290,19[87]ZidovudinRhesus MonkeySS0,270,15[88]Zidovudin + probenecidRabbitAUC0,190,1[50]ZolpidemRat2 h cont inf0,4750,447[56]',\n", - " 'paragraph_id': 17,\n", - " 'tokenizer': 'with, the, introduction, of, micro, ##dial, ##ysis, techniques, ,, the, possibility, of, making, a, direct, comparison, of, cs, ##f, and, brain, ec, ##f, concentrations, in, animals, became, available, ., also, ,, intra, ##bra, ##in, distribution, aspects, of, drugs, could, be, determined, ., saw, ##chuk, ’, s, group, at, the, university, in, minnesota, was, the, first, to, do, so, ., in, rats, ,, z, ##ido, ##vu, ##dine, and, st, ##av, ##udi, ##ne, concentration, –, time, profiles, were, obtained, in, cs, ##f, and, brain, ec, ##f, ,, and, challenged, by, inhibition, of, active, transport, processes, [, 50, –, 52, ], ., shen, et, al, ., [, 27, ], provided, an, extensive, overview, on, cs, ##f, and, brain, ec, ##f, concentrations, for, drugs, from, many, therapeutic, classes, with, a, wide, spectrum, in, ph, ##ys, ##ico, -, chemical, properties, ., app, ##ending, data, of, more, recent, studies, ,, table, 2, presents, cs, ##f, -, brain, ec, ##f, relationships, for, a, broad, set, of, drugs, ,, including, the, methodology, of, assessment, ., these, values, have, resulted, from, micro, ##dial, ##ysis, to, obtain, brain, ec, ##f, as, well, as, cs, ##f, concentrations, ,, cs, ##f, sampling, for, assessing, cs, ##f, concentrations, ,, as, well, as, he, brain, slice, method, to, obtain, brain, ec, ##f, concentrations, ., the, brain, slice, method, estimates, brain, ec, ##f, concentrations, by, determining, total, brain, concentrations, after, drug, administration, ,, and, to, correct, for, the, free, fraction, as, obtained, in, brain, slices, after, bathing, the, slice, in, a, buffer, solution, containing, the, drug, (, s, ), of, interest, [, 53, ,, 54, ], ., table, 2d, ##rug, ##s, and, their, k, ##pu, ##u, ,, cs, ##f, and, k, ##pu, ##u, ,, brain, values, obtained, in, animals, (, rats, ,, sheep, ,, rabbits, ,, r, ##hes, ##us, monkeys, ,, and, non, ##hum, ##an, primate, ##s, ), on, the, basis, of, steady, state, (, ss, ), values, ,, au, ##c, values, ,, continuous, in, ##fusion, (, con, ##t, in, ##f, ), compounds, ##pe, ##cies, ##time, ##k, ##pu, ##u, ,, cs, ##fk, ##pu, ##u, ,, brain, ##re, ##ference, ##9, -, oh, -, ri, ##sper, ##idon, ##era, ##t, ##6, h, con, ##t, in, ##f, ##0, ,, 06, ##8, ##40, ,, 01, ##43, [, 61, ], ace, ##tam, ##ino, ##ph, ##en, ##rata, ##uc, (, partial, ), 0, ,, 31, ,, 2, [, 25, ], al, ##ov, ##udi, ##ner, ##ats, ##s, ##0, ,, 40, ,, 16, [, 72, ], anti, ##py, ##rine, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 99, ##0, ,, 70, ##8, [, 56, ], atom, ##ox, ##eti, ##ner, ##ats, ##s, ##1, ,, 70, ,, 7, [, 64, ], ba, ##cl, ##of, ##en, ##rat, ##pse, ##ud, ##o, ss, ##0, ,, 02, ##80, ,, 03, ##5, [, 73, ], benz, ##yl, ##pen, ##ici, ##llin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 01, ##34, ##0, ,, 02, ##64, [, 56, ], bus, ##pi, ##rone, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 55, ##80, ,, 61, ##2, [, 56, ], caf, ##fe, ##iner, ##at, ##2, h, con, ##t, in, ##f, ##1, ,, 03, ##0, ,, 58, ##4, [, 56, ], car, ##ba, ##ma, ##ze, ##pine, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 53, ##50, ,, 77, ##1, [, 56, ], car, ##ba, ##ma, ##ze, ##pine, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 1670, ,, 232, [, 61, ], car, ##bo, ##pl, ##atin, ##non, ##hum, ##an, primate, ##au, ##c, ##0, ,, 050, ,, 05, [, 74, ], ce, ##fo, ##di, ##zi, ##mer, ##ats, ##pe, ##ci, ##fi, ##c, time, ##0, ,, 02, ##0, ,, 22, [, 75, ], ce, ##ft, ##azi, ##dim, ##era, ##ts, ##s, ##0, ,, 03, ##90, ,, 02, ##2, [, 76, ], ce, ##ft, ##ria, ##xon, ##era, ##ts, ##s, ##0, ,, 710, ,, 8, [, 76, ], ce, ##pha, ##le, ##xin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 02, ##25, ##0, ,, 01, ##6, [, 56, ], ci, ##met, ##idi, ##ner, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 02, ##11, ##0, ,, 00, ##9, ##8, ##1, [, 56, ], cis, ##pl, ##atin, ##non, ##hum, ##an, primate, ##au, ##c, ##0, ,, 050, ,, 05, [, 74, ], ci, ##tal, ##op, ##ram, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 66, ##70, ,, 49, ##4, [, 56, ], ci, ##tal, ##op, ##ram, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 50, ,, 55, ##9, [, 61, ], cp, -, 61, ##5, ,, 00, ##3, ##rat, ##ss, ##0, ,, 01, ##0, ,, 001, ##4, [, 77, ], dai, ##d, ##ze, ##in, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 1890, ,, 06, ##6, ##7, [, 56, ], dan, ##tro, ##lene, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 08, ##38, ##0, ,, 02, ##9, ##7, [, 56, ], diaz, ##ep, ##am, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 84, ##70, ,, 80, ##5, [, 56, ], dip, ##hen, ##yl, ##hy, ##dra, ##mine, ##sh, ##ee, ##ps, ##s, (, adults, ), 3, ,, 43, ,, 4, [, 78, ], dip, ##hen, ##yl, ##hy, ##dra, ##mine, ##sh, ##ee, ##ps, ##s, (, 30, d, lamb, ##s, ), 4, ,, 96, ,, 6, [, 78, ], dip, ##hen, ##yl, ##hy, ##dra, ##mine, ##sh, ##ee, ##ps, ##s, (, 10, d, lamb, ##s, ), 5, ,, 66, ,, 6, [, 78, ], ea, ##b, ##51, ##5, ##rat, ##15, h, ##0, ,, 180, ,, 08, [, 51, ], fl, ##av, ##op, ##iri, ##do, ##lr, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 216, ##0, ,, 05, ##25, [, 56, ], fl, ##ero, ##xa, ##cin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 283, ##0, ,, 25, [, 56, ], fl, ##ero, ##xa, ##cin, ##rat, ##ss, ##0, ,, 420, ,, 15, [, 79, ], gan, ##cic, ##lov, ##ir, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 06, ##47, ##0, ,, 07, ##11, [, 61, ], gen, ##iste, ##in, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 58, ##90, ,, 181, [, 56, ], lam, ##ot, ##ri, ##gin, ##era, ##ts, ##s, ##1, ,, 51, [, 62, ], lo, ##per, ##ami, ##der, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 03, ##7, ##60, ,, 00, ##8, ##86, [, 56, ], met, ##oc, ##lo, ##pr, ##ami, ##der, ##at, ##6, h, con, ##t, in, ##f, ##0, ,, 1690, ,, 235, [, 61, ], mid, ##az, ##ola, ##m, ##rat, ##2, h, con, ##t, in, ##f, ##1, ,, 352, ,, 19, [, 56, ], mor, ##phine, ##rata, ##uc, ##0, ,, 1970, ,, 51, [, 80, ], m, ##6, ##gra, ##ta, ##uc, ##0, ,, 02, ##90, ,, 56, [, 80, ], n, -, des, ##met, ##hyl, ##cl, ##oza, ##pine, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 01, ##51, ##0, ,, 01, [, 61, ], nor, ##fl, ##ox, ##ac, ##in, ##rat, ##ss, ##0, ,, 03, ##30, ,, 03, ##4, [, 79, ], of, ##lo, ##xa, ##cin, ##rat, ##ss, ##0, ,, 230, ,, 12, [, 79, ], ox, ##ali, ##pl, ##atin, ##non, ##hum, ##an, primate, ##au, ##c, ##0, ,, 65, ##5, ,, 3, [, 74, ], per, ##fl, ##ox, ##ac, ##in, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 38, ##90, ,, 199, [, 56, ], per, ##fl, ##ox, ##ac, ##in, ##rat, ##ss, ##0, ,, 370, ,, 15, [, 79, ], ph, ##en, ##yt, ##oin, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 39, ##60, ,, 44, ##7, [, 56, ], ph, ##en, ##yt, ##oin, ##rata, ##uc, ##0, ,, 20, ,, 85, [, 81, ], probe, ##ne, ##ci, ##dra, ##ts, ##s, ##0, ,, 60, ,, 2, [, 82, ], qui, ##ni, ##dine, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 09, ##11, ##0, ,, 02, ##6, [, 56, ], qui, ##ni, ##dine, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 09, ##6, ##90, ,, 04, ##59, [, 61, ], ri, ##sper, ##idon, ##era, ##t, ##2, h, con, ##t, in, ##f, ##0, ,, 124, ##0, ,, 07, ##8, ##7, [, 56, ], ri, ##sper, ##idon, ##era, ##t, ##6, h, con, ##t, in, ##f, ##0, ,, 09, ##13, ##0, ,, 04, ##22, [, 61, ], sal, ##ic, ##yla, ##tera, ##ts, ##s, ##0, ,, 50, ,, 1, [, 82, ], sd, ##z, ea, ##a, 49, ##4, ##rata, ##uc, ##0, ,, 170, ,, 11, [, 83, ], ser, ##tral, ##iner, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 83, ##21, ,, 85, [, 56, ], st, ##av, ##udi, ##ner, ##ats, ##s, ##0, ,, 50, ,, 3, [, 84, ], st, ##av, ##udi, ##ner, ##ats, ##s, ##0, ,, 60, ,, 6, [, 52, ], sul, ##pi, ##ride, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 04, ##9, ##90, ,, 02, ##19, [, 56, ], th, ##io, ##pen, ##tal, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 59, ##90, ,, 911, [, 56, ], th, ##io, ##pen, ##tal, ##rat, ##6, h, con, ##t, in, ##f, ##0, ,, 06, ##6, ##30, ,, 06, ##6, ##3, [, 61, ], tia, ##ga, ##bine, ##rata, ##uc, ##0, ,, 01, ##10, ,, 01, ##1, [, 85, ], vera, ##pa, ##mi, ##lr, ##at, ##2, h, con, ##t, in, ##f, ##0, ,, 333, ##0, ,, 07, ##86, [, 56, ], y, ##m, ##9, ##9, ##2, ##rat, ##ss, ##1, ,, 71, ,, 4, [, 86, ], z, ##ido, ##vu, ##din, ##ra, ##bb, ##ita, ##uc, ##0, ,, 170, ,, 08, [, 50, ], z, ##ido, ##vu, ##din, ##ra, ##bb, ##its, ##s, ##0, ,, 290, ,, 19, [, 87, ], z, ##ido, ##vu, ##din, ##rh, ##es, ##us, monkeys, ##s, ##0, ,, 270, ,, 15, [, 88, ], z, ##ido, ##vu, ##din, +, probe, ##ne, ##ci, ##dra, ##bb, ##ita, ##uc, ##0, ,, 190, ,, 1, [, 50, ], z, ##ol, ##pid, ##em, ##rat, ##2, h, con, ##t, in, ##f, ##0, ,, 475, ##0, ,, 44, ##7, [, 56, ]'},\n", - " {'article_id': '4e21f87d13094948d3982be834e803c6',\n", - " 'section_name': 'The Key Role of Dopamine and Neuromodulation',\n", - " 'text': \"It is remarkable that the finding of dopamine's importance to the primate dlPFC was published in 1979, years before parallel cognitive studies were performed in rodents (Bubser and Schmidt 1990). The dopamine innervation of the rat cortex was first mapped in the 1970's, showing a selective projection of dopamine fibers to the PFC but not other cortical areas (Berger et al. 1976). Pat and Roger Brown were the first to measure monoamine concentrations in the primate cortex, and found that dopamine levels and synthesis were very high in the primate PFC, but that unlike the rodent, dopamine was also prevalent in other cortical areas as well (Brown et al. 1979). Working with Brozoski, they examined the functional contribution of dopamine to the primate dlPFC by infusing the catecholamine neurotoxin, 6-OHDA, into the dlPFC, with or without desmethylimipramine (DMI), supposed to protect noradrenergic fibers. DMI was not very effective in protecting norepinephrine, but it did facilitate uptake into dopaminergic fibers to enhance depletion. Thus, they created lesions with very large dopaminergic (and large noradrenergic) depletions restricted to the dlPFC. These lesions markedly impaired spatial working memory performance, similar to that seen with dlPFC ablations. Performance was improved by catecholaminergic drugs: The catecholamine precursor l-3,4-dihydroxyphenylalanine, the dopamine D2 receptor agonist, apomorphine, and (in a footnote), the α2 noradrenergic agonist, clonidine. Since noradrenergic depletion with minimal dopamine depletion had little effect on working memory performance, the authors concluded that dopamine was the key factor. However, it is now known that both dopamine and norepinephrine are critical for dlPFC function, and it is likely that one can substitute for the other in long-term lesion studies such as the one performed by Brozoski et al. Indeed, that footnote on clonidine led to studies showing that noradrenergic stimulation of postsynaptic, α2 adrenergic receptors is essential to dlPFC function (Arnsten and Goldman-Rakic 1985) via functional strengthening of pyramidal cell circuits (Wang et al. 2007), and α2A receptor agonists such as guanfacine are now in widespread clinical use to treat PFC cognitive disorders (Hunt et al. 1995; Scahill et al. 2001,2006; Biederman et al. 2008; McAllister et al. 2011; Connor et al. 2013). Goldman-Rakic also began to explore other modulatory influences on dlPFC, including serotonin (e.g. Lidow et al. 1989; Williams et al. 2002); and acetylcholine (e.g. Mrzljak et al. 1993). But her primary focus remained on dopamine. She worked with Mark Williams to identify the midbrain source of dopamine to the PFC (Williams and Goldman-Rakic 1998), and to map the dopaminergic fibers innervating the frontal lobe (Williams and Goldman-Rakic 1993). The dopamine-containing fibers in the dlPFC are actually rather sparse (Fig. 8A), emphasizing that quantity does not always correlate with efficacy.\\nFigure 8.The key role of dopamine in the primate dlPFC. (A) The dopaminergic innervation of the primate PFC, including the dlPFC area 46, as visualized using an antibody directed against dopamine. Note the relatively sparse labeling in the dlPFC, a region that critically depends on dopamine actions. (From Williams and Goldman-Rakic 1993.) (B) A schematic illustration of the dopamine D1 receptor inverted-U influence on the pattern of Delay cell firing in the dlPFC. The memory fields of dlPFC neurons are shown under conditions of increasing levels of D1 receptor stimulation. Either very low or very high levels of D1 receptor stimulation markedly reduce delay-related firing. Low levels of D1 receptor stimulation are associated with noisy neuronal representations of visual space, while optimal levels reduce noise and enhance spatial tuning. The high levels of D1 receptor stimulation during stress exposure would reduce delay-related firing for all directions. Brighter colors indicate higher firing rates during the delay period. This figure is a schematic illustration of the physiological data presented in Williams and Goldman-Rakic (1995); Vijayraghavan et al. (2007); and Arnsten et al. (2009) and is consistent with the behavioral data from Arnsten et al. (1994); Murphy et al. (1996); Zahrt et al. (1997); and Arnsten and Goldman-Rakic (1998).\",\n", - " 'paragraph_id': 16,\n", - " 'tokenizer': \"it, is, remarkable, that, the, finding, of, do, ##pa, ##mine, ', s, importance, to, the, primate, dl, ##pf, ##c, was, published, in, 1979, ,, years, before, parallel, cognitive, studies, were, performed, in, rodents, (, bu, ##bs, ##er, and, schmidt, 1990, ), ., the, do, ##pa, ##mine, inner, ##vation, of, the, rat, cortex, was, first, mapped, in, the, 1970, ', s, ,, showing, a, selective, projection, of, do, ##pa, ##mine, fibers, to, the, p, ##fc, but, not, other, co, ##rti, ##cal, areas, (, berger, et, al, ., 1976, ), ., pat, and, roger, brown, were, the, first, to, measure, mono, ##amine, concentrations, in, the, primate, cortex, ,, and, found, that, do, ##pa, ##mine, levels, and, synthesis, were, very, high, in, the, primate, p, ##fc, ,, but, that, unlike, the, rode, ##nt, ,, do, ##pa, ##mine, was, also, prevalent, in, other, co, ##rti, ##cal, areas, as, well, (, brown, et, al, ., 1979, ), ., working, with, bro, ##zos, ##ki, ,, they, examined, the, functional, contribution, of, do, ##pa, ##mine, to, the, primate, dl, ##pf, ##c, by, in, ##fus, ##ing, the, cat, ##ech, ##ola, ##mine, ne, ##uro, ##to, ##xin, ,, 6, -, oh, ##da, ,, into, the, dl, ##pf, ##c, ,, with, or, without, des, ##met, ##hyl, ##imi, ##pr, ##amine, (, d, ##mi, ), ,, supposed, to, protect, nora, ##dre, ##ner, ##gic, fibers, ., d, ##mi, was, not, very, effective, in, protecting, nor, ##ep, ##ine, ##ph, ##rine, ,, but, it, did, facilitate, up, ##take, into, do, ##pa, ##mine, ##rg, ##ic, fibers, to, enhance, de, ##ple, ##tion, ., thus, ,, they, created, lesions, with, very, large, do, ##pa, ##mine, ##rg, ##ic, (, and, large, nora, ##dre, ##ner, ##gic, ), de, ##ple, ##tions, restricted, to, the, dl, ##pf, ##c, ., these, lesions, markedly, impaired, spatial, working, memory, performance, ,, similar, to, that, seen, with, dl, ##pf, ##c, ab, ##lation, ##s, ., performance, was, improved, by, cat, ##ech, ##ola, ##mine, ##rg, ##ic, drugs, :, the, cat, ##ech, ##ola, ##mine, precursor, l, -, 3, ,, 4, -, di, ##hy, ##dro, ##xy, ##ph, ##en, ##yla, ##lani, ##ne, ,, the, do, ##pa, ##mine, d, ##2, receptor, ago, ##nist, ,, ap, ##omo, ##rp, ##hine, ,, and, (, in, a, foot, ##note, ), ,, the, α, ##2, nora, ##dre, ##ner, ##gic, ago, ##nist, ,, cl, ##oni, ##dine, ., since, nora, ##dre, ##ner, ##gic, de, ##ple, ##tion, with, minimal, do, ##pa, ##mine, de, ##ple, ##tion, had, little, effect, on, working, memory, performance, ,, the, authors, concluded, that, do, ##pa, ##mine, was, the, key, factor, ., however, ,, it, is, now, known, that, both, do, ##pa, ##mine, and, nor, ##ep, ##ine, ##ph, ##rine, are, critical, for, dl, ##pf, ##c, function, ,, and, it, is, likely, that, one, can, substitute, for, the, other, in, long, -, term, les, ##ion, studies, such, as, the, one, performed, by, bro, ##zos, ##ki, et, al, ., indeed, ,, that, foot, ##note, on, cl, ##oni, ##dine, led, to, studies, showing, that, nora, ##dre, ##ner, ##gic, stimulation, of, posts, ##yna, ##ptic, ,, α, ##2, ad, ##ren, ##er, ##gic, receptors, is, essential, to, dl, ##pf, ##c, function, (, ar, ##nst, ##en, and, goldman, -, ra, ##kic, 1985, ), via, functional, strengthening, of, pyramid, ##al, cell, circuits, (, wang, et, al, ., 2007, ), ,, and, α, ##2, ##a, receptor, ago, ##nist, ##s, such, as, gu, ##an, ##fa, ##cine, are, now, in, widespread, clinical, use, to, treat, p, ##fc, cognitive, disorders, (, hunt, et, al, ., 1995, ;, sc, ##ah, ##ill, et, al, ., 2001, ,, 2006, ;, bi, ##ede, ##rman, et, al, ., 2008, ;, mca, ##llis, ##ter, et, al, ., 2011, ;, connor, et, al, ., 2013, ), ., goldman, -, ra, ##kic, also, began, to, explore, other, mod, ##ulator, ##y, influences, on, dl, ##pf, ##c, ,, including, ser, ##oton, ##in, (, e, ., g, ., lid, ##ow, et, al, ., 1989, ;, williams, et, al, ., 2002, ), ;, and, ace, ##ty, ##lch, ##olin, ##e, (, e, ., g, ., mr, ##z, ##l, ##jak, et, al, ., 1993, ), ., but, her, primary, focus, remained, on, do, ##pa, ##mine, ., she, worked, with, mark, williams, to, identify, the, mid, ##bra, ##in, source, of, do, ##pa, ##mine, to, the, p, ##fc, (, williams, and, goldman, -, ra, ##kic, 1998, ), ,, and, to, map, the, do, ##pa, ##mine, ##rg, ##ic, fibers, inner, ##vating, the, frontal, lobe, (, williams, and, goldman, -, ra, ##kic, 1993, ), ., the, do, ##pa, ##mine, -, containing, fibers, in, the, dl, ##pf, ##c, are, actually, rather, sparse, (, fig, ., 8, ##a, ), ,, emphasizing, that, quantity, does, not, always, co, ##rre, ##late, with, efficacy, ., figure, 8, ., the, key, role, of, do, ##pa, ##mine, in, the, primate, dl, ##pf, ##c, ., (, a, ), the, do, ##pa, ##mine, ##rg, ##ic, inner, ##vation, of, the, primate, p, ##fc, ,, including, the, dl, ##pf, ##c, area, 46, ,, as, visual, ##ized, using, an, antibody, directed, against, do, ##pa, ##mine, ., note, the, relatively, sparse, labeling, in, the, dl, ##pf, ##c, ,, a, region, that, critically, depends, on, do, ##pa, ##mine, actions, ., (, from, williams, and, goldman, -, ra, ##kic, 1993, ., ), (, b, ), a, sc, ##hema, ##tic, illustration, of, the, do, ##pa, ##mine, d, ##1, receptor, inverted, -, u, influence, on, the, pattern, of, delay, cell, firing, in, the, dl, ##pf, ##c, ., the, memory, fields, of, dl, ##pf, ##c, neurons, are, shown, under, conditions, of, increasing, levels, of, d, ##1, receptor, stimulation, ., either, very, low, or, very, high, levels, of, d, ##1, receptor, stimulation, markedly, reduce, delay, -, related, firing, ., low, levels, of, d, ##1, receptor, stimulation, are, associated, with, noisy, ne, ##uron, ##al, representations, of, visual, space, ,, while, optimal, levels, reduce, noise, and, enhance, spatial, tuning, ., the, high, levels, of, d, ##1, receptor, stimulation, during, stress, exposure, would, reduce, delay, -, related, firing, for, all, directions, ., brighter, colors, indicate, higher, firing, rates, during, the, delay, period, ., this, figure, is, a, sc, ##hema, ##tic, illustration, of, the, physiological, data, presented, in, williams, and, goldman, -, ra, ##kic, (, 1995, ), ;, vijay, ##rag, ##havan, et, al, ., (, 2007, ), ;, and, ar, ##nst, ##en, et, al, ., (, 2009, ), and, is, consistent, with, the, behavioral, data, from, ar, ##nst, ##en, et, al, ., (, 1994, ), ;, murphy, et, al, ., (, 1996, ), ;, za, ##hr, ##t, et, al, ., (, 1997, ), ;, and, ar, ##nst, ##en, and, goldman, -, ra, ##kic, (, 1998, ), .\"},\n", - " {'article_id': '1d823fbe87e8134938706f1f3e242b1e',\n", - " 'section_name': 'Characterization of the mixed brain culture',\n", - " 'text': 'In order to elucidate the molecular identity of our mixed culture, we used western blotting (Figures 5 and 6), confocal imaging (Figure 7), calcium imaging (Figure 8) and fluorescence activated cell sorter (FACS) (Figure 9). The human primary neuronal culture described here can serve as a relevant, rational and suitable tissue culture model for research on neurodegenerative disorders like AD, PD and other brain disorders. This culture contains measurable levels of synaptic (PSD-95, SNAP-25); glial (GFAP) and neuronal specific (NSE) proteins as evaluated by western blotting (Figure 5). Deposition of Aβ peptides and hyperphosphorylation of microtubule associated protein tau is the major hallmarks of AD. We have observed that this culture system produces significant amounts of Aβ (1–40) and Aβ (1–42), as assessed by a sensitive, human-specific ELISA. We have also measured AB at other time points [19]. At DIV 18, the amounts of Aβ (1–40) and Aβ (1–42) were measured to be 806.76 ± 212.02 pg/mL and 352.43 ± 95.95 pg/mL, respectively. We have also measured total and phospho-tau levels in the cell lysate samples by Western immunoblotting using specific antibodies. Total and phospho-tau levels were detected throughout the time points of the culture with highest peaks from DIV 28 onwards (Ray & Lahiri Unpublished data). The presence of tyrosine hydroxylase-positive neurons (Figure 6b) also makes this neuron culture appropriate for research related to PD. Serotonergic neurons and GABAergic neurons are also detectable, (Figure 6a and b) enabling this model to be employed in a wide variety of studies requiring these particular neuronal subtypes. Furthermore, the neurons present in the culture are suitable for electrophysiological study because of the expression of voltage-gated calcium channels (VGCC) as measured by Fura-2 AM experiments (Figure 8). The cells respond to depolarization by 70 mM KCl by allowing an influx of calcium, suggesting the presence of active VGCCs. We observed KCl-evoked Calcium influx at all three time points studied – DIV 4, DIV 16 and DIV 28 (Figure 8). The experiments show that these cells have a resting intracellular calcium level of 40 nM (data not shown). The slightly lower than expected intracellular calcium may be a consequence of the mixed cell culture that contains both mature and immature neurons.Figure 5Western immunoblotting of the cell lysates from cultures at different DIV shows presence of neuronal, glial and synaptic proteins (both pre-synaptic and post-synaptic proteins) at different time points of the culture. Band densities of different proteins were scanned, quantified and normalized with β-actin bands. Levels of neuron specific enolase (NSE), a marker for neurons, and glial fibrillary acidic protein (GFAP), a glial marker, increase time-dependently in the culture. These may suggest a continual process of neuro- and gliogenesis in the culture. This finding is in accordance with the presence of NPCs (nestin positive cells) observed at all the time points of the culture. Notably, presence of synaptic markers (SNAP-25 and PSD-95) even at the later time points indicates non-degenerating nature of the culture.Figure 6Serotonergic and dopaminergic characterization of human mixed brain culture. a Cells at DIV24 were fixed and ICC with 5-HT antibody revealed presence of serotonergic cells in the culture. The arrows indicate representative cells positive for 5-HT staining. The inset is an area magnified to better visualize 5-HT positive staining. b Western immunoblotting of the cell lysates indicates presence of GABAergic neurons (detected by glutamate decarboxylase antibody) in the culture. Number of GABAergic neurons gradually increase as the culture progresses. In contrast, dopaminergic neurons (detected by tyrosine hydroxylase antibody) are abundant in the initial time points of the culture and gradually decrease as the culture progresses.Figure 7Confocal imaging of Human mixed brain culture containing neurons, glia and neural progenitor cells. At each time point, cells were fixed using 4% Paraformaldehyde and dual-labeled with FITC-conjugated Neuronal antibody cocktail (Pan-N, 1:1000) and a Cy3-conjugate of either a glial marker (GFAP, 1:5000) or a neuronal progenitor (Nestin, 1:500). Results at DIV 12, and DIV 32 are shown. Antibodies against Pan-N and or Pan-N and GFAP were used with appropriate secondary antibodies (donkey-anti mouse; 1:500 or Goat-anti rabbit, 1:2000). Confocal fluorescence microscopy was performed on an inverted IX81microscope fitted with a FV1000-MPE and laser launch with confocal excitation with three diode lasers (405, 559 and 635 nm) and an Argon laser (458, 488, 514 nm), controlled by Fluoview v3.0 (Olympus). All imaging was performed with a 60x 1.2 NA water immersion objective. The scale bar is in the bottom right panel, and is applicable to all images.Figure 8Functional response of brain culture. Cells were cultured on PDL-coated glass coverslips. Approximately 100 regions of interest (ROI) s were selected indiscriminately. The coverslips are loaded with Fura-2 dye and placed in standard extracellular solution (see methods). After depolarization with 70 mM KCl, another wash with standard extracellular solution is utilized to eliminate dead cells. The trace shown represents an average (3 experiments) of all cells that respond to KCl and the second wash. It is important to note that there were cells that did not respond to KCl which could be dead cells or non-neuronal cells. Fura emits at two wavelengths – 340 nm and 380 nm [26] and the ratio of these corresponds to the intracellular calcium. All three points show a calcium response after induced depolarization, suggesting that these are functionally active neurons.Figure 9An increase in neuronal population over time. Human fetal brain (HFB) cells were grown as stated. At each time point, cells were fixed using 4% Paraformaldehyde and dual-labeled with FITC-conjugated Neuronal antibody cocktail (Pan-N, 1:1000) and a Cy3-conjugate of either a glial marker (GFAP, 1:5000) or a neuronal progenitor (Nestin, 1:500). Appropriate secondary antibodies were used. The values at the corners of the boxes refer to percent total of the cells gated for selection that were positive for the appropriate fluorescent-conjugated antibody. LL – Unlabeled cells. UL-Cells positive for Cy3-conjugated marker for either GFAP or Nestin. LR – Cells labeled with Pan-N. UR – Cells positive for either Pan-N and GFAP or Pan-N and Nestin. This data suggests that the stem-ness of the culture reduces over time and the neuronal phenotype beings to emerge.',\n", - " 'paragraph_id': 4,\n", - " 'tokenizer': 'in, order, to, el, ##uc, ##ida, ##te, the, molecular, identity, of, our, mixed, culture, ,, we, used, western, b, ##lot, ##ting, (, figures, 5, and, 6, ), ,, con, ##fo, ##cal, imaging, (, figure, 7, ), ,, calcium, imaging, (, figure, 8, ), and, flu, ##orescence, activated, cell, sort, ##er, (, fa, ##cs, ), (, figure, 9, ), ., the, human, primary, ne, ##uron, ##al, culture, described, here, can, serve, as, a, relevant, ,, rational, and, suitable, tissue, culture, model, for, research, on, ne, ##uro, ##de, ##gen, ##erative, disorders, like, ad, ,, pd, and, other, brain, disorders, ., this, culture, contains, me, ##asurable, levels, of, syn, ##ap, ##tic, (, ps, ##d, -, 95, ,, snap, -, 25, ), ;, g, ##lia, ##l, (, g, ##fa, ##p, ), and, ne, ##uron, ##al, specific, (, ns, ##e, ), proteins, as, evaluated, by, western, b, ##lot, ##ting, (, figure, 5, ), ., deposition, of, a, ##β, peptide, ##s, and, hyper, ##ph, ##os, ##ph, ##ory, ##lation, of, micro, ##tub, ##ule, associated, protein, tau, is, the, major, hallmark, ##s, of, ad, ., we, have, observed, that, this, culture, system, produces, significant, amounts, of, a, ##β, (, 1, –, 40, ), and, a, ##β, (, 1, –, 42, ), ,, as, assessed, by, a, sensitive, ,, human, -, specific, elisa, ., we, have, also, measured, ab, at, other, time, points, [, 19, ], ., at, di, ##v, 18, ,, the, amounts, of, a, ##β, (, 1, –, 40, ), and, a, ##β, (, 1, –, 42, ), were, measured, to, be, 80, ##6, ., 76, ±, 212, ., 02, pg, /, ml, and, 352, ., 43, ±, 95, ., 95, pg, /, ml, ,, respectively, ., we, have, also, measured, total, and, ph, ##os, ##ph, ##o, -, tau, levels, in, the, cell, l, ##ys, ##ate, samples, by, western, im, ##mun, ##ob, ##lot, ##ting, using, specific, antibodies, ., total, and, ph, ##os, ##ph, ##o, -, tau, levels, were, detected, throughout, the, time, points, of, the, culture, with, highest, peaks, from, di, ##v, 28, onwards, (, ray, &, la, ##hir, ##i, unpublished, data, ), ., the, presence, of, ty, ##ros, ##ine, hydro, ##xy, ##lase, -, positive, neurons, (, figure, 6, ##b, ), also, makes, this, ne, ##uron, culture, appropriate, for, research, related, to, pd, ., ser, ##oton, ##er, ##gic, neurons, and, ga, ##ba, ##er, ##gic, neurons, are, also, detect, ##able, ,, (, figure, 6, ##a, and, b, ), enabling, this, model, to, be, employed, in, a, wide, variety, of, studies, requiring, these, particular, ne, ##uron, ##al, sub, ##type, ##s, ., furthermore, ,, the, neurons, present, in, the, culture, are, suitable, for, electro, ##phy, ##sio, ##logical, study, because, of, the, expression, of, voltage, -, gate, ##d, calcium, channels, (, v, ##gc, ##c, ), as, measured, by, fur, ##a, -, 2, am, experiments, (, figure, 8, ), ., the, cells, respond, to, de, ##pol, ##ari, ##zation, by, 70, mm, kc, ##l, by, allowing, an, influx, of, calcium, ,, suggesting, the, presence, of, active, v, ##gc, ##cs, ., we, observed, kc, ##l, -, ev, ##oked, calcium, influx, at, all, three, time, points, studied, –, di, ##v, 4, ,, di, ##v, 16, and, di, ##v, 28, (, figure, 8, ), ., the, experiments, show, that, these, cells, have, a, resting, intra, ##cellular, calcium, level, of, 40, nm, (, data, not, shown, ), ., the, slightly, lower, than, expected, intra, ##cellular, calcium, may, be, a, consequence, of, the, mixed, cell, culture, that, contains, both, mature, and, immature, neurons, ., figure, 5, ##west, ##ern, im, ##mun, ##ob, ##lot, ##ting, of, the, cell, l, ##ys, ##ates, from, cultures, at, different, di, ##v, shows, presence, of, ne, ##uron, ##al, ,, g, ##lia, ##l, and, syn, ##ap, ##tic, proteins, (, both, pre, -, syn, ##ap, ##tic, and, post, -, syn, ##ap, ##tic, proteins, ), at, different, time, points, of, the, culture, ., band, den, ##sities, of, different, proteins, were, scanned, ,, quan, ##ti, ##fied, and, normal, ##ized, with, β, -, act, ##in, bands, ., levels, of, ne, ##uron, specific, en, ##ola, ##se, (, ns, ##e, ), ,, a, marker, for, neurons, ,, and, g, ##lia, ##l, fi, ##bri, ##llary, acidic, protein, (, g, ##fa, ##p, ), ,, a, g, ##lia, ##l, marker, ,, increase, time, -, dependent, ##ly, in, the, culture, ., these, may, suggest, a, continual, process, of, ne, ##uro, -, and, g, ##lio, ##genesis, in, the, culture, ., this, finding, is, in, accordance, with, the, presence, of, np, ##cs, (, nest, ##in, positive, cells, ), observed, at, all, the, time, points, of, the, culture, ., notably, ,, presence, of, syn, ##ap, ##tic, markers, (, snap, -, 25, and, ps, ##d, -, 95, ), even, at, the, later, time, points, indicates, non, -, de, ##gen, ##era, ##ting, nature, of, the, culture, ., figure, 6, ##ser, ##oton, ##er, ##gic, and, do, ##pa, ##mine, ##rg, ##ic, characterization, of, human, mixed, brain, culture, ., a, cells, at, di, ##v, ##24, were, fixed, and, icc, with, 5, -, h, ##t, antibody, revealed, presence, of, ser, ##oton, ##er, ##gic, cells, in, the, culture, ., the, arrows, indicate, representative, cells, positive, for, 5, -, h, ##t, stain, ##ing, ., the, ins, ##et, is, an, area, mag, ##nified, to, better, visual, ##ize, 5, -, h, ##t, positive, stain, ##ing, ., b, western, im, ##mun, ##ob, ##lot, ##ting, of, the, cell, l, ##ys, ##ates, indicates, presence, of, ga, ##ba, ##er, ##gic, neurons, (, detected, by, g, ##lu, ##tama, ##te, dec, ##ar, ##box, ##yla, ##se, antibody, ), in, the, culture, ., number, of, ga, ##ba, ##er, ##gic, neurons, gradually, increase, as, the, culture, progresses, ., in, contrast, ,, do, ##pa, ##mine, ##rg, ##ic, neurons, (, detected, by, ty, ##ros, ##ine, hydro, ##xy, ##lase, antibody, ), are, abundant, in, the, initial, time, points, of, the, culture, and, gradually, decrease, as, the, culture, progresses, ., figure, 7, ##con, ##fo, ##cal, imaging, of, human, mixed, brain, culture, containing, neurons, ,, g, ##lia, and, neural, pro, ##gen, ##itor, cells, ., at, each, time, point, ,, cells, were, fixed, using, 4, %, para, ##form, ##ald, ##eh, ##yde, and, dual, -, labeled, with, fit, ##c, -, con, ##ju, ##gated, ne, ##uron, ##al, antibody, cocktail, (, pan, -, n, ,, 1, :, 1000, ), and, a, cy, ##3, -, con, ##ju, ##gate, of, either, a, g, ##lia, ##l, marker, (, g, ##fa, ##p, ,, 1, :, 5000, ), or, a, ne, ##uron, ##al, pro, ##gen, ##itor, (, nest, ##in, ,, 1, :, 500, ), ., results, at, di, ##v, 12, ,, and, di, ##v, 32, are, shown, ., antibodies, against, pan, -, n, and, or, pan, -, n, and, g, ##fa, ##p, were, used, with, appropriate, secondary, antibodies, (, donkey, -, anti, mouse, ;, 1, :, 500, or, goat, -, anti, rabbit, ,, 1, :, 2000, ), ., con, ##fo, ##cal, flu, ##orescence, microscopy, was, performed, on, an, inverted, ix, ##8, ##1, ##mic, ##ros, ##cope, fitted, with, a, f, ##v, ##100, ##0, -, mp, ##e, and, laser, launch, with, con, ##fo, ##cal, ex, ##cit, ##ation, with, three, di, ##ode, lasers, (, 405, ,, 55, ##9, and, 63, ##5, nm, ), and, an, ar, ##gon, laser, (, 45, ##8, ,, 48, ##8, ,, 51, ##4, nm, ), ,, controlled, by, flu, ##ov, ##ie, ##w, v, ##3, ., 0, (, olympus, ), ., all, imaging, was, performed, with, a, 60, ##x, 1, ., 2, na, water, immersion, objective, ., the, scale, bar, is, in, the, bottom, right, panel, ,, and, is, applicable, to, all, images, ., figure, 8, ##fu, ##nction, ##al, response, of, brain, culture, ., cells, were, culture, ##d, on, pd, ##l, -, coated, glass, covers, ##lip, ##s, ., approximately, 100, regions, of, interest, (, roi, ), s, were, selected, ind, ##is, ##cr, ##imi, ##nate, ##ly, ., the, covers, ##lip, ##s, are, loaded, with, fur, ##a, -, 2, dye, and, placed, in, standard, extra, ##cellular, solution, (, see, methods, ), ., after, de, ##pol, ##ari, ##zation, with, 70, mm, kc, ##l, ,, another, wash, with, standard, extra, ##cellular, solution, is, utilized, to, eliminate, dead, cells, ., the, trace, shown, represents, an, average, (, 3, experiments, ), of, all, cells, that, respond, to, kc, ##l, and, the, second, wash, ., it, is, important, to, note, that, there, were, cells, that, did, not, respond, to, kc, ##l, which, could, be, dead, cells, or, non, -, ne, ##uron, ##al, cells, ., fur, ##a, emi, ##ts, at, two, wavelengths, –, 340, nm, and, 380, nm, [, 26, ], and, the, ratio, of, these, corresponds, to, the, intra, ##cellular, calcium, ., all, three, points, show, a, calcium, response, after, induced, de, ##pol, ##ari, ##zation, ,, suggesting, that, these, are, functional, ##ly, active, neurons, ., figure, 9, ##an, increase, in, ne, ##uron, ##al, population, over, time, ., human, fetal, brain, (, h, ##fb, ), cells, were, grown, as, stated, ., at, each, time, point, ,, cells, were, fixed, using, 4, %, para, ##form, ##ald, ##eh, ##yde, and, dual, -, labeled, with, fit, ##c, -, con, ##ju, ##gated, ne, ##uron, ##al, antibody, cocktail, (, pan, -, n, ,, 1, :, 1000, ), and, a, cy, ##3, -, con, ##ju, ##gate, of, either, a, g, ##lia, ##l, marker, (, g, ##fa, ##p, ,, 1, :, 5000, ), or, a, ne, ##uron, ##al, pro, ##gen, ##itor, (, nest, ##in, ,, 1, :, 500, ), ., appropriate, secondary, antibodies, were, used, ., the, values, at, the, corners, of, the, boxes, refer, to, percent, total, of, the, cells, gate, ##d, for, selection, that, were, positive, for, the, appropriate, fluorescent, -, con, ##ju, ##gated, antibody, ., ll, –, un, ##lab, ##ele, ##d, cells, ., ul, -, cells, positive, for, cy, ##3, -, con, ##ju, ##gated, marker, for, either, g, ##fa, ##p, or, nest, ##in, ., l, ##r, –, cells, labeled, with, pan, -, n, ., ur, –, cells, positive, for, either, pan, -, n, and, g, ##fa, ##p, or, pan, -, n, and, nest, ##in, ., this, data, suggests, that, the, stem, -, ness, of, the, culture, reduces, over, time, and, the, ne, ##uron, ##al, ph, ##eno, ##type, beings, to, emerge, .'},\n", - " {'article_id': '6cf6ba2467593b4237f6d3ac86313799',\n", - " 'section_name': 'TDP-43 cytoplasmic inclusion detected in ALS-TES derived skin',\n", - " 'text': 'In order to determine if cytoplasmic TDP-43 aggregates can be detected in ALS-TES, 7-μm thick tissue sections were prepared and stained with commercial TDP-43 polyclonal antibody. Interestingly, TDP-43 cytoplasmic aggregates, characteristic of ALS pathology, were detected in SALS-derived skins by indirect immunofluorescence and standard microscopy (Figure 2). These results were also further confirmed by confocal microscopy, using 25-um thick sections (Additional file 5: Figure S3). To our knowledge, it is the first time that cytoplasmic TDP-43 aggregates are detected outside of the nervous system and in non-neuronal cells in any model so far. In contrast, no TDP-43 abnormal cytoplasmic accumulation was observed in control-derived reconstructed skin. To further confirm our results and determine if cytoplasmic TDP-43 can also be detected in non-symptomatic patients, we have generated C9orf72 FALS-derived TES. Five out of six generated C9orf72-TES were derived from non-symptomatic patients carrying the GGGGCC DNA repeat expansion (Additional file 2: Figure S1; Table 1). Remarkably, cytoplasmic TDP-43 inclusions were detected by standard immunofluorescence analysis in both symptomatic and yet non-symptomatic C9orf72-linked ALS patients carrying the expansion (Figure 2). Actually, around 30% of the fibroblasts within the C9orf72- and SALS-derived skins presented cytoplasmic TDP-43 positive inclusions while only 4% of the fibroblasts in the control-derived skins demonstrated TDP-43 cytoplasmic inclusions (Figure 3A). Validation of these results were done by Western blotting after proper fractionation of the cytoplasmic and nulear fractions (Figure 3B; Additional file 6: Figure S4). Interestingly, cytoplasmic TDP-43 inclusions were only detected in our three dimensional (3D) ALS-TES model and were not detected in patient’s fibroblasts alone standard two dimensional (2D) cell culture indicating that our 3D skin model is necessary to observe the described phenotype (Figure 4). Western immunoblots, detected with nuclear (anti-nuclei antibody, clone 235-1, Millipore: cat# MAB1281) and cytoplasmic (anti-GAPDH antibody, AbD Serotec: cat# AHP1628) markers, revealed that our cytoplasmic fraction was completely free of nuclear protein indicating that the detected cytolasmic TDP-43 signal was not due to a contamination of the fraction with nuclear proteins (Additional file 6: Figure S4).Figure 2Cytoplasmic TDP-43 accumulation detected in SALS- and C9orf72 FALS-derived tissue-engineered skins. Indirect immunofluorescence analysis using anti-TDP43 antibody (green) counterstained with DAPI (blue) revealed cytoplasmic TDP-43 accumulation in SALS-derived as well as in C9orf72 FALS-derived tissue-engineered skins. Note that representative pictures of 7-um thick tissue-sections were stained and visualized using a standard epifluorescent microscope. Each picture was taken using the same microscope, camera and exposure settings. Scale bar (white): 10 μm.Figure 3Cellular counts and Western blots quantification of TDP-43 cytoplasmic accumulation. a) Percentage of cell with positive cytoplasmic TDP-43 inclusions. 200 nuclei were counted for each of the generated tissue-engineered skins. *correspond to a P value < 0.01. b) Subcellular fractionation (cytoplasmic fraction vs nuclear fraction) of total protein extracted from ALS-fibroblast (2D culture), control-derived TES, C9ORF72-derived TES and SALS-derived TES (n = 5 for each group) was performed and loaded on a regular SDS-PAGE. TDP-43 expression in each fractionated sample was quantified using ImageJ after normalization against actin. Equal amount of proteins was used as shown on western blots after. *correspond to a P value < 0.05.Figure 4Nuclear TDP-43 expression in\\nC9orf72\\nfibroblasts cultured cells. Indirect immunofluorescence using anti-TDP43 commercial antibody (green) conterstained with DAPI (nucleus) revealed no cytoplasmic TDP-43 accumulation in C9orf72 cultured fibroblasts collected from symptomatic and non-symptomatic C9orf72 FALS patients. These results indicate that the described 3D tissue-engineered skin model, allowing for cell-to-cell and cell-to-matrix interactions, is necessary to observe the pathological cytoplasmic accumulation of TDP-43. Scale bar (white): 10 μm.',\n", - " 'paragraph_id': 14,\n", - " 'tokenizer': 'in, order, to, determine, if, cy, ##top, ##las, ##mic, td, ##p, -, 43, aggregate, ##s, can, be, detected, in, als, -, te, ##s, ,, 7, -, μ, ##m, thick, tissue, sections, were, prepared, and, stained, with, commercial, td, ##p, -, 43, poly, ##cl, ##onal, antibody, ., interesting, ##ly, ,, td, ##p, -, 43, cy, ##top, ##las, ##mic, aggregate, ##s, ,, characteristic, of, als, pathology, ,, were, detected, in, sal, ##s, -, derived, skins, by, indirect, im, ##mun, ##of, ##lu, ##orescence, and, standard, microscopy, (, figure, 2, ), ., these, results, were, also, further, confirmed, by, con, ##fo, ##cal, microscopy, ,, using, 25, -, um, thick, sections, (, additional, file, 5, :, figure, s, ##3, ), ., to, our, knowledge, ,, it, is, the, first, time, that, cy, ##top, ##las, ##mic, td, ##p, -, 43, aggregate, ##s, are, detected, outside, of, the, nervous, system, and, in, non, -, ne, ##uron, ##al, cells, in, any, model, so, far, ., in, contrast, ,, no, td, ##p, -, 43, abnormal, cy, ##top, ##las, ##mic, accumulation, was, observed, in, control, -, derived, reconstructed, skin, ., to, further, confirm, our, results, and, determine, if, cy, ##top, ##las, ##mic, td, ##p, -, 43, can, also, be, detected, in, non, -, sy, ##mpt, ##oma, ##tic, patients, ,, we, have, generated, c, ##9, ##orf, ##7, ##2, fa, ##ls, -, derived, te, ##s, ., five, out, of, six, generated, c, ##9, ##orf, ##7, ##2, -, te, ##s, were, derived, from, non, -, sy, ##mpt, ##oma, ##tic, patients, carrying, the, g, ##gg, ##gc, ##c, dna, repeat, expansion, (, additional, file, 2, :, figure, s, ##1, ;, table, 1, ), ., remarkably, ,, cy, ##top, ##las, ##mic, td, ##p, -, 43, inclusion, ##s, were, detected, by, standard, im, ##mun, ##of, ##lu, ##orescence, analysis, in, both, sy, ##mpt, ##oma, ##tic, and, yet, non, -, sy, ##mpt, ##oma, ##tic, c, ##9, ##orf, ##7, ##2, -, linked, als, patients, carrying, the, expansion, (, figure, 2, ), ., actually, ,, around, 30, %, of, the, fi, ##bro, ##bla, ##sts, within, the, c, ##9, ##orf, ##7, ##2, -, and, sal, ##s, -, derived, skins, presented, cy, ##top, ##las, ##mic, td, ##p, -, 43, positive, inclusion, ##s, while, only, 4, %, of, the, fi, ##bro, ##bla, ##sts, in, the, control, -, derived, skins, demonstrated, td, ##p, -, 43, cy, ##top, ##las, ##mic, inclusion, ##s, (, figure, 3a, ), ., validation, of, these, results, were, done, by, western, b, ##lot, ##ting, after, proper, fraction, ##ation, of, the, cy, ##top, ##las, ##mic, and, nu, ##lea, ##r, fraction, ##s, (, figure, 3, ##b, ;, additional, file, 6, :, figure, s, ##4, ), ., interesting, ##ly, ,, cy, ##top, ##las, ##mic, td, ##p, -, 43, inclusion, ##s, were, only, detected, in, our, three, dimensional, (, 3d, ), als, -, te, ##s, model, and, were, not, detected, in, patient, ’, s, fi, ##bro, ##bla, ##sts, alone, standard, two, dimensional, (, 2d, ), cell, culture, indicating, that, our, 3d, skin, model, is, necessary, to, observe, the, described, ph, ##eno, ##type, (, figure, 4, ), ., western, im, ##mun, ##ob, ##lot, ##s, ,, detected, with, nuclear, (, anti, -, nuclei, antibody, ,, clone, 235, -, 1, ,, mill, ##ip, ##ore, :, cat, #, mab, ##12, ##8, ##1, ), and, cy, ##top, ##las, ##mic, (, anti, -, gap, ##dh, antibody, ,, abd, ser, ##ote, ##c, :, cat, #, ah, ##p, ##16, ##28, ), markers, ,, revealed, that, our, cy, ##top, ##las, ##mic, fraction, was, completely, free, of, nuclear, protein, indicating, that, the, detected, cy, ##to, ##las, ##mic, td, ##p, -, 43, signal, was, not, due, to, a, contamination, of, the, fraction, with, nuclear, proteins, (, additional, file, 6, :, figure, s, ##4, ), ., figure, 2, ##cy, ##top, ##las, ##mic, td, ##p, -, 43, accumulation, detected, in, sal, ##s, -, and, c, ##9, ##orf, ##7, ##2, fa, ##ls, -, derived, tissue, -, engineered, skins, ., indirect, im, ##mun, ##of, ##lu, ##orescence, analysis, using, anti, -, td, ##p, ##43, antibody, (, green, ), counters, ##tained, with, da, ##pi, (, blue, ), revealed, cy, ##top, ##las, ##mic, td, ##p, -, 43, accumulation, in, sal, ##s, -, derived, as, well, as, in, c, ##9, ##orf, ##7, ##2, fa, ##ls, -, derived, tissue, -, engineered, skins, ., note, that, representative, pictures, of, 7, -, um, thick, tissue, -, sections, were, stained, and, visual, ##ized, using, a, standard, ep, ##if, ##lu, ##ores, ##cent, microscope, ., each, picture, was, taken, using, the, same, microscope, ,, camera, and, exposure, settings, ., scale, bar, (, white, ), :, 10, μ, ##m, ., figure, 3, ##cellular, counts, and, western, b, ##lot, ##s, quan, ##ti, ##fication, of, td, ##p, -, 43, cy, ##top, ##las, ##mic, accumulation, ., a, ), percentage, of, cell, with, positive, cy, ##top, ##las, ##mic, td, ##p, -, 43, inclusion, ##s, ., 200, nuclei, were, counted, for, each, of, the, generated, tissue, -, engineered, skins, ., *, correspond, to, a, p, value, <, 0, ., 01, ., b, ), sub, ##cellular, fraction, ##ation, (, cy, ##top, ##las, ##mic, fraction, vs, nuclear, fraction, ), of, total, protein, extracted, from, als, -, fi, ##bro, ##bla, ##st, (, 2d, culture, ), ,, control, -, derived, te, ##s, ,, c, ##9, ##orf, ##7, ##2, -, derived, te, ##s, and, sal, ##s, -, derived, te, ##s, (, n, =, 5, for, each, group, ), was, performed, and, loaded, on, a, regular, sd, ##s, -, page, ., td, ##p, -, 43, expression, in, each, fraction, ##ated, sample, was, quan, ##ti, ##fied, using, image, ##j, after, normal, ##ization, against, act, ##in, ., equal, amount, of, proteins, was, used, as, shown, on, western, b, ##lot, ##s, after, ., *, correspond, to, a, p, value, <, 0, ., 05, ., figure, 4, ##nu, ##cle, ##ar, td, ##p, -, 43, expression, in, c, ##9, ##orf, ##7, ##2, fi, ##bro, ##bla, ##sts, culture, ##d, cells, ., indirect, im, ##mun, ##of, ##lu, ##orescence, using, anti, -, td, ##p, ##43, commercial, antibody, (, green, ), con, ##ters, ##tained, with, da, ##pi, (, nucleus, ), revealed, no, cy, ##top, ##las, ##mic, td, ##p, -, 43, accumulation, in, c, ##9, ##orf, ##7, ##2, culture, ##d, fi, ##bro, ##bla, ##sts, collected, from, sy, ##mpt, ##oma, ##tic, and, non, -, sy, ##mpt, ##oma, ##tic, c, ##9, ##orf, ##7, ##2, fa, ##ls, patients, ., these, results, indicate, that, the, described, 3d, tissue, -, engineered, skin, model, ,, allowing, for, cell, -, to, -, cell, and, cell, -, to, -, matrix, interactions, ,, is, necessary, to, observe, the, path, ##ological, cy, ##top, ##las, ##mic, accumulation, of, td, ##p, -, 43, ., scale, bar, (, white, ), :, 10, μ, ##m, .'},\n", - " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", - " 'section_name': 'Red protein calcium indicators in mouse V1',\n", - " 'text': 'The measured jRGECO1a and jRCaMP1a responses in the visual cortex were smaller than expected based on measurements in cultured neurons (Figure 2a, Figure 4c) and lower than those produced by GCaMP6s (Chen et al., 2013b). High-resolution microscopy of fixed brain tissue sections revealed bright fluorescent punctae in neurons labeled with jRGECO1a but not with jRCaMP1a/b. jRGECO1a punctae co-localized with LAMP-1, a marker of lysosomes (Figure 4—figure supplement 1a) (Katayama et al., 2008). Similar punctae were also found in cultured neurons, but were less numerous (Wilcoxon rank sum test, p<0.001, Figure 4—figure supplement 1b). When imaged in vivo, ROIs containing punctae had higher baseline fluorescence by 90% but lower peak ΔF/F_0 by 20% compared to their surrounding soma (10 cells and 39 punctae, Figure 4—figure supplement 1c). This implies that accumulation of fluorescent, non-responsive jRGECO1a in lysosomes reduces the signal-to-noise ratio for in vivo imaging.10.7554/eLife.12727.014Figure 4.Combined imaging and electrophysiology in the mouse visual cortex.(a) Simultaneous fluorescence dynamics and spikes measured from jRGECO1a (top, blue) and jRCaMP1a (bottom, black) expressing neurons. The number of spikes for each burst is indicated below the trace (single spikes are indicated by asterisks). Left inset, a jRCaMP1a expressing neuron with the recording pipette (green). (b) Zoomed-in view of bursts of action potentials (corresponding to boxes in a). Top, jRGECO1a; bottom, jRCaMP1a. (c) jRGECO1a fluorescence changes in response to 1 AP (top, 199 spikes from 11 cells, n=6 mice), and jRCaMP1a fluorescence changes in response to 2 APs (bottom, 65 spikes from 10 cells, n=5 mice). Blue (top) and black (bottom) lines are the median traces. (d) Distribution of peak fluorescence change as a function of number of action potentials in a time bin (jRGECO1a, blue boxes: 199 1AP events; 2 APs: 70 events within a 100 ms time bin; 3 APs: 29, 125 ms; 4 APs: 34, 150 ms; 5 APs: 35, 175 ms; 6 APs: 22, 200 ms; 7 APs:14, 225 ms; 8 APs: 21, 250 ms. jRCaMP1a, black boxes: 135 1 AP events; 2 APs: 65, 150 ms; 3 APs: 71, 200 ms; 4 APs: 52, 250 ms; 5 APs: 33, 300 ms; 6 APs: 20, 350 ms; 7 APs: 14, 350 ms; 8 APs: 11, 350 ms). Each box corresponds to the 25th to 75^th percentile of the distribution (q_1 and q_3 respectively), whisker length is up to the extreme data point or 1.5_l (q3 - q1). (e) Receiver operating characteristic (ROC) curve for classifying 1 and 2 APs for jRGECO1a and jRCaMP1a (jRGECO1a: 320 events of no AP firing within a 4 s bin, jRCaMP1a: 274 events of no AP firing within a 5 s bin, 1 AP and 2 APs data same as in d). (f) Detection sensitivity index (d’) as a function of number of spikes in a time bin (same parameters as in d–e). (g) Comparison of mean half rise (left) and decay (right) times of jRGECO1a and jRCaMP1a for 2 AP response. Error bars correspond to s.e.m.DOI:10.7554/eLife.12727.015Figure 4—figure supplement 1.jRGECO1a accumulates in lysosomes.(a) Red GECI expression (top, red) and LAMP-1 immunostaining (bottom, green) of fixed tissue sections from mouse V1. (b) Distribution of the fraction of somatic area covered by protein aggregates for neurons expressing jRGECO1a. Neurons in V1 (fixed tissue) show more frequent jRGECO1a aggregates than cultured neurons (Wilcoxon rank sum test, p<0.001; n=10 cultured cells; 14, fixed tissue cells; 8, fixed tissue LAMP-1 immunostained cells). (c) Example traces from V1 L2/3 cell showing ΔF/F_0 changes of somatic regions overlapping with protein aggregates (red, black) and regions excluding aggregates (blue). Inset, image of the cell, with aggregates indicated by circles.DOI:10.7554/eLife.12727.016Figure 4—figure supplement 2.Red GECIs lack functional response at 900nm excitation.Functional responses of three example cells (jRGECO1a, expressed in L4 V1 neurons) at 1040 nm excitation (left) and 900 nm (25 vs. 1 cells were detected as responsive out of 50 cells in FOV; drifting grating stimuli, Materials and methods).DOI:10.7554/eLife.12727.017Figure 4—figure supplement 3.Complex spectral and functional characteristics of the red GECIs after long-term expression in vivo.(a) Images of jRGECO1a (left) and jRCaMP1a (right) L2/3 neurons in vivo excited by 1040 nm (top) and 900 nm light (bottom). Note the punctate fluorescence image in the bottom images. (b) Emission spectra from fixed tissue cells of jRGEC1a (top) and jRCaMP1b (bottom) when illuminated with 900 nm and 1000 nm laser reveal a greenish emission band. (c) Effect of long-term expression on accumulation of greenish species. Scatter plot of the ratio between jRGECO1a somatic signal detected at 900 nm excitation (red and green channel summed) and baseline fluorescence detected at 1040 nm excitation, and the peak somatic ΔF/F_0 for drifting grating stimuli. Measurements were done 16 (left) and 132 (right) days after AAV injection. Red solid line shows the linear regression model, red dashed lines are 95% confidence interval; R^2=0.09 for both datasets and slope of -9.2 and -10 respectively (n=98 cells, left panel; n=274 cells, right panel; linear regression model, F test, p<0.005). (d) Distribution of the somatic fluorescence ratio between 900 nm and 1040 nm excitation (same data as in c) show an increase in both the ratio median and its range with longer expression time. Each box corresponds to the 25th to 75^th percentile of the distribution (q_1 and q_3 respectively), whisker length is up to the extreme data point or 1.5 (q3 - q_1).DOI:',\n", - " 'paragraph_id': 13,\n", - " 'tokenizer': 'the, measured, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, responses, in, the, visual, cortex, were, smaller, than, expected, based, on, measurements, in, culture, ##d, neurons, (, figure, 2a, ,, figure, 4, ##c, ), and, lower, than, those, produced, by, g, ##camp, ##6, ##s, (, chen, et, al, ., ,, 2013, ##b, ), ., high, -, resolution, microscopy, of, fixed, brain, tissue, sections, revealed, bright, fluorescent, pun, ##cta, ##e, in, neurons, labeled, with, jr, ##ge, ##co, ##1, ##a, but, not, with, jr, ##camp, ##1, ##a, /, b, ., jr, ##ge, ##co, ##1, ##a, pun, ##cta, ##e, co, -, localized, with, lamp, -, 1, ,, a, marker, of, l, ##ys, ##oso, ##mes, (, figure, 4, —, figure, supplement, 1a, ), (, kata, ##yama, et, al, ., ,, 2008, ), ., similar, pun, ##cta, ##e, were, also, found, in, culture, ##d, neurons, ,, but, were, less, numerous, (, wilcox, ##on, rank, sum, test, ,, p, <, 0, ., 001, ,, figure, 4, —, figure, supplement, 1b, ), ., when, image, ##d, in, vivo, ,, roi, ##s, containing, pun, ##cta, ##e, had, higher, baseline, flu, ##orescence, by, 90, %, but, lower, peak, δ, ##f, /, f, _, 0, by, 20, %, compared, to, their, surrounding, so, ##ma, (, 10, cells, and, 39, pun, ##cta, ##e, ,, figure, 4, —, figure, supplement, 1, ##c, ), ., this, implies, that, accumulation, of, fluorescent, ,, non, -, responsive, jr, ##ge, ##co, ##1, ##a, in, l, ##ys, ##oso, ##mes, reduces, the, signal, -, to, -, noise, ratio, for, in, vivo, imaging, ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##4, ##fi, ##gur, ##e, 4, ., combined, imaging, and, electro, ##phy, ##sio, ##logy, in, the, mouse, visual, cortex, ., (, a, ), simultaneous, flu, ##orescence, dynamics, and, spikes, measured, from, jr, ##ge, ##co, ##1, ##a, (, top, ,, blue, ), and, jr, ##camp, ##1, ##a, (, bottom, ,, black, ), expressing, neurons, ., the, number, of, spikes, for, each, burst, is, indicated, below, the, trace, (, single, spikes, are, indicated, by, as, ##ter, ##isk, ##s, ), ., left, ins, ##et, ,, a, jr, ##camp, ##1, ##a, expressing, ne, ##uron, with, the, recording, pipe, ##tte, (, green, ), ., (, b, ), zoom, ##ed, -, in, view, of, bursts, of, action, potential, ##s, (, corresponding, to, boxes, in, a, ), ., top, ,, jr, ##ge, ##co, ##1, ##a, ;, bottom, ,, jr, ##camp, ##1, ##a, ., (, c, ), jr, ##ge, ##co, ##1, ##a, flu, ##orescence, changes, in, response, to, 1, ap, (, top, ,, 199, spikes, from, 11, cells, ,, n, =, 6, mice, ), ,, and, jr, ##camp, ##1, ##a, flu, ##orescence, changes, in, response, to, 2, ap, ##s, (, bottom, ,, 65, spikes, from, 10, cells, ,, n, =, 5, mice, ), ., blue, (, top, ), and, black, (, bottom, ), lines, are, the, median, traces, ., (, d, ), distribution, of, peak, flu, ##orescence, change, as, a, function, of, number, of, action, potential, ##s, in, a, time, bin, (, jr, ##ge, ##co, ##1, ##a, ,, blue, boxes, :, 199, 1a, ##p, events, ;, 2, ap, ##s, :, 70, events, within, a, 100, ms, time, bin, ;, 3, ap, ##s, :, 29, ,, 125, ms, ;, 4, ap, ##s, :, 34, ,, 150, ms, ;, 5, ap, ##s, :, 35, ,, 175, ms, ;, 6, ap, ##s, :, 22, ,, 200, ms, ;, 7, ap, ##s, :, 14, ,, 225, ms, ;, 8, ap, ##s, :, 21, ,, 250, ms, ., jr, ##camp, ##1, ##a, ,, black, boxes, :, 135, 1, ap, events, ;, 2, ap, ##s, :, 65, ,, 150, ms, ;, 3, ap, ##s, :, 71, ,, 200, ms, ;, 4, ap, ##s, :, 52, ,, 250, ms, ;, 5, ap, ##s, :, 33, ,, 300, ms, ;, 6, ap, ##s, :, 20, ,, 350, ms, ;, 7, ap, ##s, :, 14, ,, 350, ms, ;, 8, ap, ##s, :, 11, ,, 350, ms, ), ., each, box, corresponds, to, the, 25th, to, 75, ^, th, percent, ##ile, of, the, distribution, (, q, _, 1, and, q, _, 3, respectively, ), ,, w, ##his, ##ker, length, is, up, to, the, extreme, data, point, or, 1, ., 5, _, l, (, q, ##3, -, q, ##1, ), ., (, e, ), receiver, operating, characteristic, (, roc, ), curve, for, classify, ##ing, 1, and, 2, ap, ##s, for, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, (, jr, ##ge, ##co, ##1, ##a, :, 320, events, of, no, ap, firing, within, a, 4, s, bin, ,, jr, ##camp, ##1, ##a, :, 274, events, of, no, ap, firing, within, a, 5, s, bin, ,, 1, ap, and, 2, ap, ##s, data, same, as, in, d, ), ., (, f, ), detection, sensitivity, index, (, d, ’, ), as, a, function, of, number, of, spikes, in, a, time, bin, (, same, parameters, as, in, d, –, e, ), ., (, g, ), comparison, of, mean, half, rise, (, left, ), and, decay, (, right, ), times, of, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, for, 2, ap, response, ., error, bars, correspond, to, s, ., e, ., m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##5, ##fi, ##gur, ##e, 4, —, figure, supplement, 1, ., jr, ##ge, ##co, ##1, ##a, accumulate, ##s, in, l, ##ys, ##oso, ##mes, ., (, a, ), red, ge, ##ci, expression, (, top, ,, red, ), and, lamp, -, 1, im, ##mun, ##osta, ##ining, (, bottom, ,, green, ), of, fixed, tissue, sections, from, mouse, v, ##1, ., (, b, ), distribution, of, the, fraction, of, so, ##matic, area, covered, by, protein, aggregate, ##s, for, neurons, expressing, jr, ##ge, ##co, ##1, ##a, ., neurons, in, v, ##1, (, fixed, tissue, ), show, more, frequent, jr, ##ge, ##co, ##1, ##a, aggregate, ##s, than, culture, ##d, neurons, (, wilcox, ##on, rank, sum, test, ,, p, <, 0, ., 001, ;, n, =, 10, culture, ##d, cells, ;, 14, ,, fixed, tissue, cells, ;, 8, ,, fixed, tissue, lamp, -, 1, im, ##mun, ##osta, ##ined, cells, ), ., (, c, ), example, traces, from, v, ##1, l, ##2, /, 3, cell, showing, δ, ##f, /, f, _, 0, changes, of, so, ##matic, regions, overlapping, with, protein, aggregate, ##s, (, red, ,, black, ), and, regions, excluding, aggregate, ##s, (, blue, ), ., ins, ##et, ,, image, of, the, cell, ,, with, aggregate, ##s, indicated, by, circles, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##6, ##fi, ##gur, ##e, 4, —, figure, supplement, 2, ., red, ge, ##cis, lack, functional, response, at, 900, ##n, ##m, ex, ##cit, ##ation, ., functional, responses, of, three, example, cells, (, jr, ##ge, ##co, ##1, ##a, ,, expressed, in, l, ##4, v, ##1, neurons, ), at, 104, ##0, nm, ex, ##cit, ##ation, (, left, ), and, 900, nm, (, 25, vs, ., 1, cells, were, detected, as, responsive, out, of, 50, cells, in, f, ##ov, ;, drifting, gr, ##ating, stimuli, ,, materials, and, methods, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##7, ##fi, ##gur, ##e, 4, —, figure, supplement, 3, ., complex, spectral, and, functional, characteristics, of, the, red, ge, ##cis, after, long, -, term, expression, in, vivo, ., (, a, ), images, of, jr, ##ge, ##co, ##1, ##a, (, left, ), and, jr, ##camp, ##1, ##a, (, right, ), l, ##2, /, 3, neurons, in, vivo, excited, by, 104, ##0, nm, (, top, ), and, 900, nm, light, (, bottom, ), ., note, the, pun, ##cta, ##te, flu, ##orescence, image, in, the, bottom, images, ., (, b, ), emission, spectra, from, fixed, tissue, cells, of, jr, ##ge, ##c, ##1, ##a, (, top, ), and, jr, ##camp, ##1, ##b, (, bottom, ), when, illuminated, with, 900, nm, and, 1000, nm, laser, reveal, a, greenish, emission, band, ., (, c, ), effect, of, long, -, term, expression, on, accumulation, of, greenish, species, ., sc, ##atter, plot, of, the, ratio, between, jr, ##ge, ##co, ##1, ##a, so, ##matic, signal, detected, at, 900, nm, ex, ##cit, ##ation, (, red, and, green, channel, sum, ##med, ), and, baseline, flu, ##orescence, detected, at, 104, ##0, nm, ex, ##cit, ##ation, ,, and, the, peak, so, ##matic, δ, ##f, /, f, _, 0, for, drifting, gr, ##ating, stimuli, ., measurements, were, done, 16, (, left, ), and, 132, (, right, ), days, after, aa, ##v, injection, ., red, solid, line, shows, the, linear, regression, model, ,, red, dashed, lines, are, 95, %, confidence, interval, ;, r, ^, 2, =, 0, ., 09, for, both, data, ##set, ##s, and, slope, of, -, 9, ., 2, and, -, 10, respectively, (, n, =, 98, cells, ,, left, panel, ;, n, =, 274, cells, ,, right, panel, ;, linear, regression, model, ,, f, test, ,, p, <, 0, ., 00, ##5, ), ., (, d, ), distribution, of, the, so, ##matic, flu, ##orescence, ratio, between, 900, nm, and, 104, ##0, nm, ex, ##cit, ##ation, (, same, data, as, in, c, ), show, an, increase, in, both, the, ratio, median, and, its, range, with, longer, expression, time, ., each, box, corresponds, to, the, 25th, to, 75, ^, th, percent, ##ile, of, the, distribution, (, q, _, 1, and, q, _, 3, respectively, ), ,, w, ##his, ##ker, length, is, up, to, the, extreme, data, point, or, 1, ., 5, (, q, ##3, -, q, _, 1, ), ., doi, :'},\n", - " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", - " 'section_name': 'Red protein calcium indicators in Drosophila, zebrafish, and C. elegans',\n", - " 'text': 'We next tested red GECIs in flies, zebrafish and worms. Red GECIs were expressed pan-neuronally in transgenic flies (R57C10-Gal4). Boutons were imaged in the larval neuromuscular junction (NMJ) after electrical stimulation (Figure 7a,b; Materials and methods) (Hendel et al., 2008). Consistent with cultured neuron data, we saw a significant boost of single AP sensitivity in jRGECO1a, jRCaMP1a, and jRCaMP1b variants compared to their parent indicators (p<0.008 for all comparisons; Wilcoxon rank sum test; Figure 7c, Figure 7—figure supplement 1–2, Figure 7—source data 1–2). Peak response amplitudes of jRGECO1a and jRCaMP1a outperform GCaMP6s in the 1–5 Hz stimulation range (single AP ΔF/F_0 amplitude 11.6 ± 0.9%, 8.6 ± 0.5%, and 4.5 ± 0.3% respectively, mean ± s.e.m; Figure 7c, Figure 7—figure supplement 3, Figure 7—source data 3; 12 FOVs for jRGECO1a; 11, jRCaMP1a; 12, GCaMP6f; n=7 flies for all constructs). The decay kinetics of jRGECO1a (half decay time at 160 Hz: 0.42 ± 0.02 s, mean ± s.e.m) was similar to GCaMP6f (0.43 ± 0.01 s; Figure 7d, Figure 7—figure supplement 3, Figure 7—source data 3). The combination of high sensitivity and fast kinetics for jRGECO1a allows detection of individual spikes on top of the response envelope for stimuli up to 10 Hz (Figure 7b, Figure 7—figure supplement 1).10.7554/eLife.12727.021Figure 7.Imaging activity in Drosophila larval NMJ boutouns with red GECIs.(a) Schematic representation of Drosophila larval neuromuscular junction (NMJ) assay. Segmented motor nerve is electrically stimulated while optically imaging calcium responses in presynaptic boutons (green arrows). (b) Response transients (mean ± s.e.m.) to 5 Hz stimulation (2 s duration) for several red and green GECIs. Response amplitudes were 4-fold and 60% higher for jRGECO1a than GCaMP6f and GCaMP6s respectively (p<10–4 and p=0.01, Wilcoxon rank sum test), jRCaMP1a response amplitude was 3-fold higher than GCaMP6f (p=10–4) and similar to GCaMP6s (12 FOVs for jRGECO1a; 11, jRCaMP1a; 13, jRCaMP1b; 12, GCaMP6s; 12, GCaMP6f; n=7 flies for all constructs) (c) Comparison of frequency tuned responses (peak ΔF/F_0, mean ± s.e.m.) of red and green GECIs for 1, 5, 10, 20, 40, 80 and 160 Hz stimulation (2 s duration). jRGECO1a and jRCaMP1a response amplitudes were 2–3 fold higher than GCaMP6s and GCaMP6f for 1 Hz stimulus (p<0.001, Wilcoxon rank sum test), but lower for stimulus frequencies of 20 Hz and higher (12 FOVs for jRGECO1a; 10, R-GECO1; 11, jRCaMP1a; 13, jRCaMP1b; 10, RCaMP1h; 12, GCaMP6s; 12, GCaMP6f; n=5 flies for R-GECO1, n=7 flies for all other constructs) (d) Half decay time (mean ± s.e.m.) of red and green GECIs at 160 Hz stimulation (same FOVs and flies as in c; ***, p<0.001, Wilcoxon rank sum test).DOI:10.7554/eLife.12727.022Figure 7—source data 1.Summary of results shown in Figure 7—figure supplement 1.Wilcoxon rank sum test is used for p-value.DOI:10.7554/eLife.12727.023Figure 7—source data 2.Summary of results shown in Figure 7—figure supplement 2.Wilcoxon rank sum test is used for p-value.DOI:10.7554/eLife.12727.024Figure 7—source data 3.Summary of results shown in Figure 7—figure supplement 3.Wilcoxon rank sum test is used for p-value.DOI:10.7554/eLife.12727.025Figure 7—figure supplement 1.Imaging activity in Drosophila larval NMJ boutons with jRGECO1a.(a) Schematic of experimental setup. Epifluorescence and high magnification △F/F_0 images of Type 1b boutons (green arrowheads) from muscle 13 (segments A3-A5), with image segmentation ROIs superimposed (Materials and methods). (b) Single trial and averaged fluorescence transients after 1 Hz stimulus for 2 s for R-GECO1, jRGECO1a and jRGECO1b (R-GECO1: 10 FOVs in 5 flies, 40 boutons; jRGECO1a: 12 FOVs in 7 flies, 48 boutons; jRGECO1b: 9 FOVs in 6 flies, 36 boutons. Same data set used for all other analyses). jRGECO1a performance was superior to jRGECO1b in the Drosophila NMJ and zebrafish trigeminal neuron; therefore jRGECO1b was not fully tested in other animal models. (c–d) Fourier spectra normalized to 0 Hz of fluorescence signals acquired during 5 Hz (c) and 10 Hz (d) stimulation. (e–f) △F/F_0 (e) and SNR (f) traces (mean ± s.e.m.) recorded with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation for 2 s (indicated by red curves at the bottom, amplitude not to scale). (g–h) △F/F_0 (g) and SNR (h) traces (mean ± s.e.m.) recorded with 1 and 5 Hz stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (i–j) Comparison of △F/F_0 traces (mean ± s.e.m.) of R-GECO1 and jRGECO1 variants with 1, 5, 10 Hz (i) and 20, 40, 80 Hz (j) stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (k–l) Comparison of frequency tuned averaged peak △F/F_0 (k) and peak SNR (l) (mean ± s.e.m.) of GCaMP6 variants, R-GECO1 and jRGECO1 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation. Note that vertical axes are log scale. (m) Comparison of kinetics of GCaMP6 variants, R-GECO1 and jRGECO1 variants with 40 Hz stimulation. Horizontal axes are half rise time and vertical axes are half decay time.DOI:10.7554/eLife.12727.026Figure 7—figure supplement 2.Imaging activity in Drosophila larval NMJ boutons with jRCaMP1 constructs.(a) Schematic of experimental setup. Epifluorescence and high magnification △F/F_0 images of Type 1b boutons (green arrowheads) from muscle 13 (segments A3-A5), with image segmentation ROIs superimposed (Materials and methods). (b) Single trial and averaged fluorescence transients after 1 Hz stimulus for 2 s for R-GECO1, jRCaMP1a and jRCaMP1b (RCaMP1h: 10 FOVs in 7 flies, 40 boutons; jRCaMP1a: 11 FOVs in 7 flies, 44 boutons; jRCaMP1b: 13 FOVs in 7 flies, 52 boutons. Same data set used for all other analyses). (c-d) △F/F_0 (c) and SNR (d) traces (mean ± s.e.m.) recorded with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (e–f) △F/F_0 (e) and SNR (f) traces (mean ± s.e.m.) recorded with 1 and 5 Hz stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (g–h), Comparison of △F/F_0 traces (mean ± s.e.m.) of R-GECO1 and jRCaMP1 variants with 1, 5, 10 Hz (g) and 20, 40, 80 Hz (h) stimulation for 2 s (shown by red curves at the bottom, amplitude not to scale). (i–j) Comparison of frequency tuned averaged peak △F/F_0 (i) and peak SNR (j) (mean ± s.e.m.) of RCaMP1h and jRCaMP1 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation. Note that vertical axes are log scale. (k) Comparison of kinetics of RCaMP1h and jRCaMP1 variants with 40 Hz stimulation. Horizontal axes are half rise time and vertical axes are half decay time.DOI:10.7554/eLife.12727.027Figure 7—figure supplement 3.Comparing red and green GECI activity in Drosophila larval NMJ boutons.(a–b) Single trial and averaged fluorescence transients after 1 Hz (a) and 5 Hz (b) stimulus for 2 s for jRGECO1a, jRCaMP1a, jRCaMP1b, GCaMP6s and GCaMP6f (jRGECO1a: 12 FOVs in 7 flies, 48 boutons; jRCaMP1a: 11 FOVs in 7 flies, 44 boutons; jRCaMP1b: 13 FOVs in 7 flies, 52 boutons; GCaMP6s: 12 FOVs in 7 flies, 48 boutons; GCaMP6f: 12 FOVs in 7 flies. Same data set used for all other analyses). (c) Comparison of frequency tuned averaged peak △F/F_0 (mean ± s.e.m.) of jRGECO1a, jRCaMP1 variants and GCaMP6 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation. Note that vertical axes are log scale. (d–e) Comparison of frequency tuned averaged half decay (d) and half rise (e) (mean ± s.e.m.) of jRGECO1a, jRCaMP1 variants and GCaMP6 variants, with 1, 5, 10, 20, 40, 80 and 160 Hz stimulation.DOI:',\n", - " 'paragraph_id': 19,\n", - " 'tokenizer': 'we, next, tested, red, ge, ##cis, in, flies, ,, zebra, ##fish, and, worms, ., red, ge, ##cis, were, expressed, pan, -, ne, ##uron, ##ally, in, trans, ##genic, flies, (, r, ##57, ##c, ##10, -, gal, ##4, ), ., bout, ##ons, were, image, ##d, in, the, la, ##rval, ne, ##uro, ##mus, ##cular, junction, (, nm, ##j, ), after, electrical, stimulation, (, figure, 7, ##a, ,, b, ;, materials, and, methods, ), (, hen, ##del, et, al, ., ,, 2008, ), ., consistent, with, culture, ##d, ne, ##uron, data, ,, we, saw, a, significant, boost, of, single, ap, sensitivity, in, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, and, jr, ##camp, ##1, ##b, variants, compared, to, their, parent, indicators, (, p, <, 0, ., 00, ##8, for, all, comparisons, ;, wilcox, ##on, rank, sum, test, ;, figure, 7, ##c, ,, figure, 7, —, figure, supplement, 1, –, 2, ,, figure, 7, —, source, data, 1, –, 2, ), ., peak, response, amplitude, ##s, of, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, out, ##per, ##form, g, ##camp, ##6, ##s, in, the, 1, –, 5, hz, stimulation, range, (, single, ap, δ, ##f, /, f, _, 0, amplitude, 11, ., 6, ±, 0, ., 9, %, ,, 8, ., 6, ±, 0, ., 5, %, ,, and, 4, ., 5, ±, 0, ., 3, %, respectively, ,, mean, ±, s, ., e, ., m, ;, figure, 7, ##c, ,, figure, 7, —, figure, supplement, 3, ,, figure, 7, —, source, data, 3, ;, 12, f, ##ov, ##s, for, jr, ##ge, ##co, ##1, ##a, ;, 11, ,, jr, ##camp, ##1, ##a, ;, 12, ,, g, ##camp, ##6, ##f, ;, n, =, 7, flies, for, all, construct, ##s, ), ., the, decay, kinetic, ##s, of, jr, ##ge, ##co, ##1, ##a, (, half, decay, time, at, 160, hz, :, 0, ., 42, ±, 0, ., 02, s, ,, mean, ±, s, ., e, ., m, ), was, similar, to, g, ##camp, ##6, ##f, (, 0, ., 43, ±, 0, ., 01, s, ;, figure, 7, ##d, ,, figure, 7, —, figure, supplement, 3, ,, figure, 7, —, source, data, 3, ), ., the, combination, of, high, sensitivity, and, fast, kinetic, ##s, for, jr, ##ge, ##co, ##1, ##a, allows, detection, of, individual, spikes, on, top, of, the, response, envelope, for, stimuli, up, to, 10, hz, (, figure, 7, ##b, ,, figure, 7, —, figure, supplement, 1, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##1, ##fi, ##gur, ##e, 7, ., imaging, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##oun, ##s, with, red, ge, ##cis, ., (, a, ), sc, ##hema, ##tic, representation, of, dr, ##oso, ##phila, la, ##rval, ne, ##uro, ##mus, ##cular, junction, (, nm, ##j, ), ass, ##ay, ., segment, ##ed, motor, nerve, is, electrically, stimulated, while, optical, ##ly, imaging, calcium, responses, in, pre, ##sy, ##na, ##ptic, bout, ##ons, (, green, arrows, ), ., (, b, ), response, transient, ##s, (, mean, ±, s, ., e, ., m, ., ), to, 5, hz, stimulation, (, 2, s, duration, ), for, several, red, and, green, ge, ##cis, ., response, amplitude, ##s, were, 4, -, fold, and, 60, %, higher, for, jr, ##ge, ##co, ##1, ##a, than, g, ##camp, ##6, ##f, and, g, ##camp, ##6, ##s, respectively, (, p, <, 10, –, 4, and, p, =, 0, ., 01, ,, wilcox, ##on, rank, sum, test, ), ,, jr, ##camp, ##1, ##a, response, amplitude, was, 3, -, fold, higher, than, g, ##camp, ##6, ##f, (, p, =, 10, –, 4, ), and, similar, to, g, ##camp, ##6, ##s, (, 12, f, ##ov, ##s, for, jr, ##ge, ##co, ##1, ##a, ;, 11, ,, jr, ##camp, ##1, ##a, ;, 13, ,, jr, ##camp, ##1, ##b, ;, 12, ,, g, ##camp, ##6, ##s, ;, 12, ,, g, ##camp, ##6, ##f, ;, n, =, 7, flies, for, all, construct, ##s, ), (, c, ), comparison, of, frequency, tuned, responses, (, peak, δ, ##f, /, f, _, 0, ,, mean, ±, s, ., e, ., m, ., ), of, red, and, green, ge, ##cis, for, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, (, 2, s, duration, ), ., jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, response, amplitude, ##s, were, 2, –, 3, fold, higher, than, g, ##camp, ##6, ##s, and, g, ##camp, ##6, ##f, for, 1, hz, stimulus, (, p, <, 0, ., 001, ,, wilcox, ##on, rank, sum, test, ), ,, but, lower, for, stimulus, frequencies, of, 20, hz, and, higher, (, 12, f, ##ov, ##s, for, jr, ##ge, ##co, ##1, ##a, ;, 10, ,, r, -, ge, ##co, ##1, ;, 11, ,, jr, ##camp, ##1, ##a, ;, 13, ,, jr, ##camp, ##1, ##b, ;, 10, ,, rca, ##mp, ##1, ##h, ;, 12, ,, g, ##camp, ##6, ##s, ;, 12, ,, g, ##camp, ##6, ##f, ;, n, =, 5, flies, for, r, -, ge, ##co, ##1, ,, n, =, 7, flies, for, all, other, construct, ##s, ), (, d, ), half, decay, time, (, mean, ±, s, ., e, ., m, ., ), of, red, and, green, ge, ##cis, at, 160, hz, stimulation, (, same, f, ##ov, ##s, and, flies, as, in, c, ;, *, *, *, ,, p, <, 0, ., 001, ,, wilcox, ##on, rank, sum, test, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##2, ##fi, ##gur, ##e, 7, —, source, data, 1, ., summary, of, results, shown, in, figure, 7, —, figure, supplement, 1, ., wilcox, ##on, rank, sum, test, is, used, for, p, -, value, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##3, ##fi, ##gur, ##e, 7, —, source, data, 2, ., summary, of, results, shown, in, figure, 7, —, figure, supplement, 2, ., wilcox, ##on, rank, sum, test, is, used, for, p, -, value, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##4, ##fi, ##gur, ##e, 7, —, source, data, 3, ., summary, of, results, shown, in, figure, 7, —, figure, supplement, 3, ., wilcox, ##on, rank, sum, test, is, used, for, p, -, value, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##5, ##fi, ##gur, ##e, 7, —, figure, supplement, 1, ., imaging, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##ons, with, jr, ##ge, ##co, ##1, ##a, ., (, a, ), sc, ##hema, ##tic, of, experimental, setup, ., ep, ##if, ##lu, ##orescence, and, high, mag, ##ni, ##fication, [UNK], /, f, _, 0, images, of, type, 1b, bout, ##ons, (, green, arrow, ##heads, ), from, muscle, 13, (, segments, a, ##3, -, a, ##5, ), ,, with, image, segment, ##ation, roi, ##s, super, ##im, ##posed, (, materials, and, methods, ), ., (, b, ), single, trial, and, averaged, flu, ##orescence, transient, ##s, after, 1, hz, stimulus, for, 2, s, for, r, -, ge, ##co, ##1, ,, jr, ##ge, ##co, ##1, ##a, and, jr, ##ge, ##co, ##1, ##b, (, r, -, ge, ##co, ##1, :, 10, f, ##ov, ##s, in, 5, flies, ,, 40, bout, ##ons, ;, jr, ##ge, ##co, ##1, ##a, :, 12, f, ##ov, ##s, in, 7, flies, ,, 48, bout, ##ons, ;, jr, ##ge, ##co, ##1, ##b, :, 9, f, ##ov, ##s, in, 6, flies, ,, 36, bout, ##ons, ., same, data, set, used, for, all, other, analyses, ), ., jr, ##ge, ##co, ##1, ##a, performance, was, superior, to, jr, ##ge, ##co, ##1, ##b, in, the, dr, ##oso, ##phila, nm, ##j, and, zebra, ##fish, tri, ##ge, ##mina, ##l, ne, ##uron, ;, therefore, jr, ##ge, ##co, ##1, ##b, was, not, fully, tested, in, other, animal, models, ., (, c, –, d, ), fourier, spectra, normal, ##ized, to, 0, hz, of, flu, ##orescence, signals, acquired, during, 5, hz, (, c, ), and, 10, hz, (, d, ), stimulation, ., (, e, –, f, ), [UNK], /, f, _, 0, (, e, ), and, s, ##nr, (, f, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, for, 2, s, (, indicated, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, g, –, h, ), [UNK], /, f, _, 0, (, g, ), and, s, ##nr, (, h, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, and, 5, hz, stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, i, –, j, ), comparison, of, [UNK], /, f, _, 0, traces, (, mean, ±, s, ., e, ., m, ., ), of, r, -, ge, ##co, ##1, and, jr, ##ge, ##co, ##1, variants, with, 1, ,, 5, ,, 10, hz, (, i, ), and, 20, ,, 40, ,, 80, hz, (, j, ), stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, k, –, l, ), comparison, of, frequency, tuned, averaged, peak, [UNK], /, f, _, 0, (, k, ), and, peak, s, ##nr, (, l, ), (, mean, ±, s, ., e, ., m, ., ), of, g, ##camp, ##6, variants, ,, r, -, ge, ##co, ##1, and, jr, ##ge, ##co, ##1, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., note, that, vertical, axes, are, log, scale, ., (, m, ), comparison, of, kinetic, ##s, of, g, ##camp, ##6, variants, ,, r, -, ge, ##co, ##1, and, jr, ##ge, ##co, ##1, variants, with, 40, hz, stimulation, ., horizontal, axes, are, half, rise, time, and, vertical, axes, are, half, decay, time, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##6, ##fi, ##gur, ##e, 7, —, figure, supplement, 2, ., imaging, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##ons, with, jr, ##camp, ##1, construct, ##s, ., (, a, ), sc, ##hema, ##tic, of, experimental, setup, ., ep, ##if, ##lu, ##orescence, and, high, mag, ##ni, ##fication, [UNK], /, f, _, 0, images, of, type, 1b, bout, ##ons, (, green, arrow, ##heads, ), from, muscle, 13, (, segments, a, ##3, -, a, ##5, ), ,, with, image, segment, ##ation, roi, ##s, super, ##im, ##posed, (, materials, and, methods, ), ., (, b, ), single, trial, and, averaged, flu, ##orescence, transient, ##s, after, 1, hz, stimulus, for, 2, s, for, r, -, ge, ##co, ##1, ,, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, (, rca, ##mp, ##1, ##h, :, 10, f, ##ov, ##s, in, 7, flies, ,, 40, bout, ##ons, ;, jr, ##camp, ##1, ##a, :, 11, f, ##ov, ##s, in, 7, flies, ,, 44, bout, ##ons, ;, jr, ##camp, ##1, ##b, :, 13, f, ##ov, ##s, in, 7, flies, ,, 52, bout, ##ons, ., same, data, set, used, for, all, other, analyses, ), ., (, c, -, d, ), [UNK], /, f, _, 0, (, c, ), and, s, ##nr, (, d, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, e, –, f, ), [UNK], /, f, _, 0, (, e, ), and, s, ##nr, (, f, ), traces, (, mean, ±, s, ., e, ., m, ., ), recorded, with, 1, and, 5, hz, stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, g, –, h, ), ,, comparison, of, [UNK], /, f, _, 0, traces, (, mean, ±, s, ., e, ., m, ., ), of, r, -, ge, ##co, ##1, and, jr, ##camp, ##1, variants, with, 1, ,, 5, ,, 10, hz, (, g, ), and, 20, ,, 40, ,, 80, hz, (, h, ), stimulation, for, 2, s, (, shown, by, red, curves, at, the, bottom, ,, amplitude, not, to, scale, ), ., (, i, –, j, ), comparison, of, frequency, tuned, averaged, peak, [UNK], /, f, _, 0, (, i, ), and, peak, s, ##nr, (, j, ), (, mean, ±, s, ., e, ., m, ., ), of, rca, ##mp, ##1, ##h, and, jr, ##camp, ##1, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., note, that, vertical, axes, are, log, scale, ., (, k, ), comparison, of, kinetic, ##s, of, rca, ##mp, ##1, ##h, and, jr, ##camp, ##1, variants, with, 40, hz, stimulation, ., horizontal, axes, are, half, rise, time, and, vertical, axes, are, half, decay, time, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 02, ##7, ##fi, ##gur, ##e, 7, —, figure, supplement, 3, ., comparing, red, and, green, ge, ##ci, activity, in, dr, ##oso, ##phila, la, ##rval, nm, ##j, bout, ##ons, ., (, a, –, b, ), single, trial, and, averaged, flu, ##orescence, transient, ##s, after, 1, hz, (, a, ), and, 5, hz, (, b, ), stimulus, for, 2, s, for, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, jr, ##camp, ##1, ##b, ,, g, ##camp, ##6, ##s, and, g, ##camp, ##6, ##f, (, jr, ##ge, ##co, ##1, ##a, :, 12, f, ##ov, ##s, in, 7, flies, ,, 48, bout, ##ons, ;, jr, ##camp, ##1, ##a, :, 11, f, ##ov, ##s, in, 7, flies, ,, 44, bout, ##ons, ;, jr, ##camp, ##1, ##b, :, 13, f, ##ov, ##s, in, 7, flies, ,, 52, bout, ##ons, ;, g, ##camp, ##6, ##s, :, 12, f, ##ov, ##s, in, 7, flies, ,, 48, bout, ##ons, ;, g, ##camp, ##6, ##f, :, 12, f, ##ov, ##s, in, 7, flies, ., same, data, set, used, for, all, other, analyses, ), ., (, c, ), comparison, of, frequency, tuned, averaged, peak, [UNK], /, f, _, 0, (, mean, ±, s, ., e, ., m, ., ), of, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, variants, and, g, ##camp, ##6, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., note, that, vertical, axes, are, log, scale, ., (, d, –, e, ), comparison, of, frequency, tuned, averaged, half, decay, (, d, ), and, half, rise, (, e, ), (, mean, ±, s, ., e, ., m, ., ), of, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, variants, and, g, ##camp, ##6, variants, ,, with, 1, ,, 5, ,, 10, ,, 20, ,, 40, ,, 80, and, 160, hz, stimulation, ., doi, :'},\n", - " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", - " 'section_name': 'Protein engineering',\n", - " 'text': 'Beneficial mutations were combined in a second round of mutagenesis (136 RCaMP1h and 166 R-GECO1 variants) (Figure 1c,d). Based on criteria similar to those outlined above, two new mRuby-based sensors, jRCaMP1a and jRCaMP1b, and one mApple-based sensor, jRGECO1a, were selected for in-depth analysis (red bars in the histograms of Figure 1c,d). These sensors have similar absorption and emission spectra to each other and their parent constructs but they differ in sensitivity for detecting neural activity, kinetics, and other biophysical properties (−Figure 2, Figure 2—figure supplement 1–2, Figure 2—source data 1).10.7554/eLife.12727.004Figure 2.jRGECO1 and jRCaMP1 performance in dissociated neurons.(a) Average responses in response to one action potential (AP) for RCaMP1h (9479 neurons, 605 wells), R-GECO1 (8988 neurons, 539 wells), R-CaMP2 (265 neurons, 22 wells), jRGECO1a (383 neurons, 26 wells), jRCaMP1a (599 neurons, 38 wells), and jRCaMP1b (641 neurons, 31 wells). (b) Same for 10 APs response. (c–f) Comparison of jRGECO1 and jRCaMP1 sensors and other red GECIs, as a function of number of APs (color code as in a). (c) Response amplitude, ΔF/F_0. (d) Signal-to-noise ratio, SNR, defined as the fluorescence signal peak above baseline, divided by the signal standard deviation before the stimulation is given. (e) Half decay time. (f) Half rise time. Error bars correspond to s.e.m (n=605 wells for RCaMP1h; 539, R-GECO1; 22, R-CaMP2; 38, jRCaMP1a; 31, jRCaMP1b; 26, jRGECO1a).DOI:10.7554/eLife.12727.005Figure 2—source data 1.Biophysical properties of purified jRGECO1 and jRCaMP1 sensors.Summary of red GECI biophysical properties, mean ± s.d., where indicated, for independently purified protein samples (Materials and methods).DOI:10.7554/eLife.12727.006Figure 2—figure supplement 1.Absorption and emission spectra of red GECIs.(a) One-photon excitation (dashed lines) and emission (solid lines) spectra for jRGECO1a (left panel), jRCaMP1a (middle), and jRCaMP1b (right) in Ca-free (blue lines) and Ca-saturated (red lines) states. (b) Two-photon excitation spectra for jRGECO1a, jRCaMP1a, and jRCaMP1b, in Ca-free (blue) and Ca- saturated (red) states. Dashed green lines show the ratio between these two states.DOI:10.7554/eLife.12727.007Figure 2—figure supplement 2.Biophysical properties.(a) Fluorescence quantum yield of red GECIs and red FPs (all at 1070 nm), and GCaMP6s (940 nm). (b) Peak two-photon molecular brightness (Ca-bound state for GECIs) of red GECIs, red FPs, and GCaMP6s (note the different wavelengths used). mApple data in a and b is taken from Akerboom et al., 2013. Measurements were done in a purified protein assay (Materials and methods). (c–d) One-photon bleaching curves of jRGECO1a (blue), jRCaMP1a (black), and jRCaMP1b (red) in Ca-free (c) and Ca-saturated (d) states. Note that Ca-free jRGECO1a bleaching is negligible, while ~40% of the Ca-saturated jRGECO1a molecules photobleach within few seconds. e–g, Two-photon bleaching curves of jRCaMP1a (e), jRGECO1a (f), and GCaMP6s (g) in Ca-free and Ca-saturated states. h–i, Two-photon bleaching profile of Ca-saturated jRCaMP1a (h) and jRGECO1a (i) when excited with 2 different wavelengths while maintaining an identical SNR.DOI:10.7554/eLife.12727.008Figure 2—figure supplement 3.Photoswitching in purified protein assay.Fluorescence traces of purified Ca^2+-free protein droplets (red traces) of jRCaMP1a (left panel), jRGECO1a (middle), and R-CaMP2 (right) constantly illuminated with 561 nm excitation light (40 mW/mm^2), and with 488 nm light pulses (3.2 mW/mm^2 peak power, 50 ms duration, 0.2 Hz, 1 Hz, and 1.8 Hz in upper, middle, and lower rows respectively). For the mApple-based GECIs, jRGECO1a and R-CaMP2, blue illumination induced a transient, calcium-independent increase in fluorescence intensity indicative of photoswitching, while jRCaMP1a does not photoswitch, but photobleaches.DOI:10.7554/eLife.12727.009Figure 2—figure supplement 4.jRCaMP1a is more compatible than jRGECO1a for simultaneous use with ChR2.(a) Fluorescence signal from cultured rat hippocampal neurons transfected with either jRGECO1a alone (gray) or jRGECO1a+ChR2-Venus (blue) following stimulation with blue light (33 mW, 10 ms pulses, 83 Hz, 200 μm X 200 μm FOV; Materials and methods) stimulus pulses (light blue bars). Inset, merged image of neuron expressing both jRGECO1a (red) and ChR2-Venus (green). (b) Same experiment as in a with cultured neurons expressing jRCaMP1a alone (gray) or jRCaMP1a+ChR2-Venus (black). (c) Peak ΔF/F_0 values for 5 neurons expressing jRGECO1a+ChR2-Venus (blue) and 5 neurons expressing jRGECO1a alone (gray) as a function of blue stimulus light power. (d) Peak ΔF/F_0 for 5 neurons expressing jRCaMP1a+ChR2-Venus (black) and 5 neurons expressing jRCaMP1a alone (gray) as function of blue stimulus light power.DOI:',\n", - " 'paragraph_id': 7,\n", - " 'tokenizer': 'beneficial, mutations, were, combined, in, a, second, round, of, mu, ##tage, ##nes, ##is, (, 136, rca, ##mp, ##1, ##h, and, 166, r, -, ge, ##co, ##1, variants, ), (, figure, 1, ##c, ,, d, ), ., based, on, criteria, similar, to, those, outlined, above, ,, two, new, mr, ##ub, ##y, -, based, sensors, ,, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, ,, and, one, map, ##ple, -, based, sensor, ,, jr, ##ge, ##co, ##1, ##a, ,, were, selected, for, in, -, depth, analysis, (, red, bars, in, the, his, ##to, ##gram, ##s, of, figure, 1, ##c, ,, d, ), ., these, sensors, have, similar, absorption, and, emission, spectra, to, each, other, and, their, parent, construct, ##s, but, they, differ, in, sensitivity, for, detecting, neural, activity, ,, kinetic, ##s, ,, and, other, bio, ##physical, properties, (, −, ##fi, ##gur, ##e, 2, ,, figure, 2, —, figure, supplement, 1, –, 2, ,, figure, 2, —, source, data, 1, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##4, ##fi, ##gur, ##e, 2, ., jr, ##ge, ##co, ##1, and, jr, ##camp, ##1, performance, in, di, ##sso, ##cia, ##ted, neurons, ., (, a, ), average, responses, in, response, to, one, action, potential, (, ap, ), for, rca, ##mp, ##1, ##h, (, 94, ##7, ##9, neurons, ,, 60, ##5, wells, ), ,, r, -, ge, ##co, ##1, (, 89, ##8, ##8, neurons, ,, 53, ##9, wells, ), ,, r, -, camp, ##2, (, 265, neurons, ,, 22, wells, ), ,, jr, ##ge, ##co, ##1, ##a, (, 38, ##3, neurons, ,, 26, wells, ), ,, jr, ##camp, ##1, ##a, (, 59, ##9, neurons, ,, 38, wells, ), ,, and, jr, ##camp, ##1, ##b, (, 64, ##1, neurons, ,, 31, wells, ), ., (, b, ), same, for, 10, ap, ##s, response, ., (, c, –, f, ), comparison, of, jr, ##ge, ##co, ##1, and, jr, ##camp, ##1, sensors, and, other, red, ge, ##cis, ,, as, a, function, of, number, of, ap, ##s, (, color, code, as, in, a, ), ., (, c, ), response, amplitude, ,, δ, ##f, /, f, _, 0, ., (, d, ), signal, -, to, -, noise, ratio, ,, s, ##nr, ,, defined, as, the, flu, ##orescence, signal, peak, above, baseline, ,, divided, by, the, signal, standard, deviation, before, the, stimulation, is, given, ., (, e, ), half, decay, time, ., (, f, ), half, rise, time, ., error, bars, correspond, to, s, ., e, ., m, (, n, =, 60, ##5, wells, for, rca, ##mp, ##1, ##h, ;, 53, ##9, ,, r, -, ge, ##co, ##1, ;, 22, ,, r, -, camp, ##2, ;, 38, ,, jr, ##camp, ##1, ##a, ;, 31, ,, jr, ##camp, ##1, ##b, ;, 26, ,, jr, ##ge, ##co, ##1, ##a, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##5, ##fi, ##gur, ##e, 2, —, source, data, 1, ., bio, ##physical, properties, of, pu, ##rified, jr, ##ge, ##co, ##1, and, jr, ##camp, ##1, sensors, ., summary, of, red, ge, ##ci, bio, ##physical, properties, ,, mean, ±, s, ., d, ., ,, where, indicated, ,, for, independently, pu, ##rified, protein, samples, (, materials, and, methods, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##6, ##fi, ##gur, ##e, 2, —, figure, supplement, 1, ., absorption, and, emission, spectra, of, red, ge, ##cis, ., (, a, ), one, -, photon, ex, ##cit, ##ation, (, dashed, lines, ), and, emission, (, solid, lines, ), spectra, for, jr, ##ge, ##co, ##1, ##a, (, left, panel, ), ,, jr, ##camp, ##1, ##a, (, middle, ), ,, and, jr, ##camp, ##1, ##b, (, right, ), in, ca, -, free, (, blue, lines, ), and, ca, -, saturated, (, red, lines, ), states, ., (, b, ), two, -, photon, ex, ##cit, ##ation, spectra, for, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, and, jr, ##camp, ##1, ##b, ,, in, ca, -, free, (, blue, ), and, ca, -, saturated, (, red, ), states, ., dashed, green, lines, show, the, ratio, between, these, two, states, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##7, ##fi, ##gur, ##e, 2, —, figure, supplement, 2, ., bio, ##physical, properties, ., (, a, ), flu, ##orescence, quantum, yield, of, red, ge, ##cis, and, red, f, ##ps, (, all, at, 107, ##0, nm, ), ,, and, g, ##camp, ##6, ##s, (, 94, ##0, nm, ), ., (, b, ), peak, two, -, photon, molecular, brightness, (, ca, -, bound, state, for, ge, ##cis, ), of, red, ge, ##cis, ,, red, f, ##ps, ,, and, g, ##camp, ##6, ##s, (, note, the, different, wavelengths, used, ), ., map, ##ple, data, in, a, and, b, is, taken, from, ak, ##er, ##bo, ##om, et, al, ., ,, 2013, ., measurements, were, done, in, a, pu, ##rified, protein, ass, ##ay, (, materials, and, methods, ), ., (, c, –, d, ), one, -, photon, b, ##lea, ##ching, curves, of, jr, ##ge, ##co, ##1, ##a, (, blue, ), ,, jr, ##camp, ##1, ##a, (, black, ), ,, and, jr, ##camp, ##1, ##b, (, red, ), in, ca, -, free, (, c, ), and, ca, -, saturated, (, d, ), states, ., note, that, ca, -, free, jr, ##ge, ##co, ##1, ##a, b, ##lea, ##ching, is, ne, ##gli, ##gible, ,, while, ~, 40, %, of, the, ca, -, saturated, jr, ##ge, ##co, ##1, ##a, molecules, photo, ##ble, ##ach, within, few, seconds, ., e, –, g, ,, two, -, photon, b, ##lea, ##ching, curves, of, jr, ##camp, ##1, ##a, (, e, ), ,, jr, ##ge, ##co, ##1, ##a, (, f, ), ,, and, g, ##camp, ##6, ##s, (, g, ), in, ca, -, free, and, ca, -, saturated, states, ., h, –, i, ,, two, -, photon, b, ##lea, ##ching, profile, of, ca, -, saturated, jr, ##camp, ##1, ##a, (, h, ), and, jr, ##ge, ##co, ##1, ##a, (, i, ), when, excited, with, 2, different, wavelengths, while, maintaining, an, identical, s, ##nr, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##8, ##fi, ##gur, ##e, 2, —, figure, supplement, 3, ., photos, ##wi, ##tch, ##ing, in, pu, ##rified, protein, ass, ##ay, ., flu, ##orescence, traces, of, pu, ##rified, ca, ^, 2, +, -, free, protein, droplets, (, red, traces, ), of, jr, ##camp, ##1, ##a, (, left, panel, ), ,, jr, ##ge, ##co, ##1, ##a, (, middle, ), ,, and, r, -, camp, ##2, (, right, ), constantly, illuminated, with, 56, ##1, nm, ex, ##cit, ##ation, light, (, 40, mw, /, mm, ^, 2, ), ,, and, with, 48, ##8, nm, light, pulses, (, 3, ., 2, mw, /, mm, ^, 2, peak, power, ,, 50, ms, duration, ,, 0, ., 2, hz, ,, 1, hz, ,, and, 1, ., 8, hz, in, upper, ,, middle, ,, and, lower, rows, respectively, ), ., for, the, map, ##ple, -, based, ge, ##cis, ,, jr, ##ge, ##co, ##1, ##a, and, r, -, camp, ##2, ,, blue, illumination, induced, a, transient, ,, calcium, -, independent, increase, in, flu, ##orescence, intensity, indicative, of, photos, ##wi, ##tch, ##ing, ,, while, jr, ##camp, ##1, ##a, does, not, photos, ##wi, ##tch, ,, but, photo, ##ble, ##ache, ##s, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 00, ##9, ##fi, ##gur, ##e, 2, —, figure, supplement, 4, ., jr, ##camp, ##1, ##a, is, more, compatible, than, jr, ##ge, ##co, ##1, ##a, for, simultaneous, use, with, ch, ##r, ##2, ., (, a, ), flu, ##orescence, signal, from, culture, ##d, rat, hip, ##po, ##camp, ##al, neurons, trans, ##fect, ##ed, with, either, jr, ##ge, ##co, ##1, ##a, alone, (, gray, ), or, jr, ##ge, ##co, ##1, ##a, +, ch, ##r, ##2, -, venus, (, blue, ), following, stimulation, with, blue, light, (, 33, mw, ,, 10, ms, pulses, ,, 83, hz, ,, 200, μ, ##m, x, 200, μ, ##m, f, ##ov, ;, materials, and, methods, ), stimulus, pulses, (, light, blue, bars, ), ., ins, ##et, ,, merged, image, of, ne, ##uron, expressing, both, jr, ##ge, ##co, ##1, ##a, (, red, ), and, ch, ##r, ##2, -, venus, (, green, ), ., (, b, ), same, experiment, as, in, a, with, culture, ##d, neurons, expressing, jr, ##camp, ##1, ##a, alone, (, gray, ), or, jr, ##camp, ##1, ##a, +, ch, ##r, ##2, -, venus, (, black, ), ., (, c, ), peak, δ, ##f, /, f, _, 0, values, for, 5, neurons, expressing, jr, ##ge, ##co, ##1, ##a, +, ch, ##r, ##2, -, venus, (, blue, ), and, 5, neurons, expressing, jr, ##ge, ##co, ##1, ##a, alone, (, gray, ), as, a, function, of, blue, stimulus, light, power, ., (, d, ), peak, δ, ##f, /, f, _, 0, for, 5, neurons, expressing, jr, ##camp, ##1, ##a, +, ch, ##r, ##2, -, venus, (, black, ), and, 5, neurons, expressing, jr, ##camp, ##1, ##a, alone, (, gray, ), as, function, of, blue, stimulus, light, power, ., doi, :'},\n", - " {'article_id': 'f77b17a6d78c949b30ad68164a1027b8',\n", - " 'section_name': 'Red protein calcium indicators in mouse V1',\n", - " 'text': 'We tested jRGECO1a, jRCaMP1a, jRCaMP1b, their parent indicators, and R-CaMP2 (Inoue et al., 2015) in the mouse primary visual cortex (V1) in vivo (Chen et al., 2013b) (Figure 3a, Video 1). The majority of V1 neurons can be driven to fire action potentials in response to drifting gratings (Mrsic-Flogel et al., 2007; Niell and Stryker, 2008). V1 neurons were infected with adeno-associated virus (AAV) expressing one of the red GECI variants under the human synapsin1 promoter (AAV-SYN1-red GECI variant) and imaged 16–180 days later. Two-photon excitation was performed with a tunable ultrafast laser (Insight DS+; Spectra-Physics) running at 1040 nm or 1100 nm. L2/3 neurons showed red fluorescence in the neuronal cytoplasm. Visual stimuli consisted of moving gratings presented in eight directions to the contralateral eye (Akerboom et al., 2012; Chen et al., 2013b). Regions of interest corresponding to single neurons revealed visual stimulus-evoked fluorescence transients that were stable across trials and tuned to stimulus orientation (Figure 3b). Orientation tuning was similar for all constructs tested (Figure 3—figure supplement 1). Fluorescence transients tracked the dynamics of the sensory stimuli (Figure 3b–d, Video 1). mApple-based indicators tracked more faithfully than mRuby-based indicators because of their faster kinetics (signal half-decay time after end of stimulus was 300 ± 22 ms for R-GECO1, 175 cells; 390 ± 20 ms, jRGECO1a, 395 cells; 330 ± 16 ms, R-CaMP2, 310 cells; 640 ± 30 ms, jRCaMP1a, 347 cells; 500 ± 45 ms, jRCaMP1b, 95 cells; activity of RCaMP1h expressing cells was to weak to be reliably characterized, mean ± s.e.m., Materials and methods).10.7554/eLife.12727.010Figure 3.jRGECO1a and jRCaMP1a and jRCaMP1b performance in the mouse primary visual cortex.(a) Top, schematic of the experiment. Bottom, image of V1 L2/3 cells expressing jRGECO1a (left), and the same field of view color-coded according to the neurons’ preferred orientation (hue) and response amplitude (brightness). (b) Example traces from three L2/3 neurons expressing jRGECO1a (left) and jRCaMP1a (right). Single trials (gray) and averages of 5 trials (blue and black for jRGECO1a and jRCaMP1a respectively) are overlaid. Eight grating motion directions are indicated by arrows and shown above traces. The preferred stimulus is the direction evoking the largest response. jRGECO1a traces correspond to the cells indicated in panel a (see also Video 1). (c) Average response of neurons to their preferred stimulus (175 cells, R-GECO1; 310, R-CaMP2; 395, jRGECO1a; 347, jRCaMP1a; 95, jRCaMP1b. n=4 mice for jRGECO1a and jRCaMP1a, n=3 mice for all other constructs. Panels c-f are based on the same data set. (d) Fourier spectra normalized to the amplitude at 0 Hz for neurons driven with 1 Hz drifting gratings, transduced with RCaMP1h, R-GECO1, R-CaMP2, jRGECaMP1a, jRCaMP1b, and jRGECO1a. Inset, zoomed-in view of 1 Hz response amplitudes. (e) Fraction of cells detected as responding to visual stimulus (ANOVA test, p<0.01) when expressing different calcium indicators. This fraction was 8- and 6-fold higher for jRCaMP1a and jRCaMP1b compared to RCaMP1h, respectively, and 60% higher for jRGECO1a compared to R-GECO1 (Wilcoxon rank sum test; *, p<0.05; **, p<0.01; ***, p<0.001). Error bars correspond to s.e.m (26 fields-of-view, RCaMP1h; 45, jRCaMP1a; 31, jRCaMP1b; 30, R-GECO1; 40, jRGECO1a; 33, R-CaMP2; 23, GCaMP6s; 29, GCaMP6f) (f) Distribution of ΔF/F amplitude for the preferred stimulus. A right-shifted curve, such as jRGECO1a vs. R-GECO1 or jRCaMP1a/b vs. jRCaMP1h, indicates enhancement of response amplitude (75 percentile values of 0.36 and 0.27 vs. 0.18 for jRCaMP1a and jRCaMP1b vs. RCaMP1h, and 0.66 vs. 0.38 for jRGECO1a vs. GCaMP6f, respectively). (1210 cells, R-GECO1; 861, RCaMP1h; 1733, R-CaMP2; 1605, jRGECO1a; 1981, jRCaMP1a; 971, jRCaMP1b; 907, GCaMP6f; 672, GCaMP6s), same colors as in e.DOI:10.7554/eLife.12727.011Figure 3—figure supplement 1.Comparison of orientation tuning in V1 neurons measured with different red GECIs.Distribution of orientation selectivity index (OSI, 3 upper rows) for all cells detected as responsive, measured using different GECIs. Bottom panel, mean ± s.d for all constructs show similar tuning properties (n=238 cells, R-GECO1; 308, jRGECO1a; 386, R-CaMP2; 277, jRCaMP1a; 141, jRCaMP1b; 337, GCaMP6s; 203, GCaMP6f).DOI:10.7554/eLife.12727.012Figure 3—figure supplement 2.Long-term expression of red GECIs in mouse V1.(a) Example images of V1 L2/3 neurons after long term expression of red GECIs. (b) Comparison of the proportion of responsive cells, orientation-tuned cells, and the ratio between them. Each time point corresponds to a different mouse. (c) Distributions of peak ΔF/F_0 for different animals imaged after different times of expression of the red GECI. No strong effect of expression time on peak response was detected. (d) Half decay times of the fluorescence response for different animals with different expression time of the red GECI. No strong effect of expression time on the decay kinetics was seen. jRCaMP1a data for 16 days of expression is not shown because the number of cells eligible for this analysis was too small (Materials and methods).DOI:Video 1.jRGECO1a L2/3 functional imaging in the mouse V1.The mouse was anesthetized and presented with moving gratings in eight directions to the contralateral eye. Gratings were presented for 4 s (indicated by appearance of an arrowhead in the grating propagation direction) followed by a 4 s of blank display. Field of view size was 250x250 μm^2, acquired at 15 Hz and filtered with a 5 frame moving average.DOI:10.7554/eLife.12727.013',\n", - " 'paragraph_id': 10,\n", - " 'tokenizer': 'we, tested, jr, ##ge, ##co, ##1, ##a, ,, jr, ##camp, ##1, ##a, ,, jr, ##camp, ##1, ##b, ,, their, parent, indicators, ,, and, r, -, camp, ##2, (, in, ##oue, et, al, ., ,, 2015, ), in, the, mouse, primary, visual, cortex, (, v, ##1, ), in, vivo, (, chen, et, al, ., ,, 2013, ##b, ), (, figure, 3a, ,, video, 1, ), ., the, majority, of, v, ##1, neurons, can, be, driven, to, fire, action, potential, ##s, in, response, to, drifting, gr, ##ating, ##s, (, mrs, ##ic, -, fl, ##oge, ##l, et, al, ., ,, 2007, ;, ni, ##ell, and, stryker, ,, 2008, ), ., v, ##1, neurons, were, infected, with, aden, ##o, -, associated, virus, (, aa, ##v, ), expressing, one, of, the, red, ge, ##ci, variants, under, the, human, syn, ##ap, ##sin, ##1, promoter, (, aa, ##v, -, syn, ##1, -, red, ge, ##ci, variant, ), and, image, ##d, 16, –, 180, days, later, ., two, -, photon, ex, ##cit, ##ation, was, performed, with, a, tuna, ##ble, ultra, ##fast, laser, (, insight, ds, +, ;, spectra, -, physics, ), running, at, 104, ##0, nm, or, 1100, nm, ., l, ##2, /, 3, neurons, showed, red, flu, ##orescence, in, the, ne, ##uron, ##al, cy, ##top, ##las, ##m, ., visual, stimuli, consisted, of, moving, gr, ##ating, ##s, presented, in, eight, directions, to, the, contra, ##lateral, eye, (, ak, ##er, ##bo, ##om, et, al, ., ,, 2012, ;, chen, et, al, ., ,, 2013, ##b, ), ., regions, of, interest, corresponding, to, single, neurons, revealed, visual, stimulus, -, ev, ##oked, flu, ##orescence, transient, ##s, that, were, stable, across, trials, and, tuned, to, stimulus, orientation, (, figure, 3, ##b, ), ., orientation, tuning, was, similar, for, all, construct, ##s, tested, (, figure, 3, —, figure, supplement, 1, ), ., flu, ##orescence, transient, ##s, tracked, the, dynamics, of, the, sensory, stimuli, (, figure, 3, ##b, –, d, ,, video, 1, ), ., map, ##ple, -, based, indicators, tracked, more, faithful, ##ly, than, mr, ##ub, ##y, -, based, indicators, because, of, their, faster, kinetic, ##s, (, signal, half, -, decay, time, after, end, of, stimulus, was, 300, ±, 22, ms, for, r, -, ge, ##co, ##1, ,, 175, cells, ;, 390, ±, 20, ms, ,, jr, ##ge, ##co, ##1, ##a, ,, 395, cells, ;, 330, ±, 16, ms, ,, r, -, camp, ##2, ,, 310, cells, ;, 640, ±, 30, ms, ,, jr, ##camp, ##1, ##a, ,, 34, ##7, cells, ;, 500, ±, 45, ms, ,, jr, ##camp, ##1, ##b, ,, 95, cells, ;, activity, of, rca, ##mp, ##1, ##h, expressing, cells, was, to, weak, to, be, re, ##lia, ##bly, characterized, ,, mean, ±, s, ., e, ., m, ., ,, materials, and, methods, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##0, ##fi, ##gur, ##e, 3, ., jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, performance, in, the, mouse, primary, visual, cortex, ., (, a, ), top, ,, sc, ##hema, ##tic, of, the, experiment, ., bottom, ,, image, of, v, ##1, l, ##2, /, 3, cells, expressing, jr, ##ge, ##co, ##1, ##a, (, left, ), ,, and, the, same, field, of, view, color, -, coded, according, to, the, neurons, ’, preferred, orientation, (, hue, ), and, response, amplitude, (, brightness, ), ., (, b, ), example, traces, from, three, l, ##2, /, 3, neurons, expressing, jr, ##ge, ##co, ##1, ##a, (, left, ), and, jr, ##camp, ##1, ##a, (, right, ), ., single, trials, (, gray, ), and, averages, of, 5, trials, (, blue, and, black, for, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, respectively, ), are, over, ##laid, ., eight, gr, ##ating, motion, directions, are, indicated, by, arrows, and, shown, above, traces, ., the, preferred, stimulus, is, the, direction, ev, ##oki, ##ng, the, largest, response, ., jr, ##ge, ##co, ##1, ##a, traces, correspond, to, the, cells, indicated, in, panel, a, (, see, also, video, 1, ), ., (, c, ), average, response, of, neurons, to, their, preferred, stimulus, (, 175, cells, ,, r, -, ge, ##co, ##1, ;, 310, ,, r, -, camp, ##2, ;, 395, ,, jr, ##ge, ##co, ##1, ##a, ;, 34, ##7, ,, jr, ##camp, ##1, ##a, ;, 95, ,, jr, ##camp, ##1, ##b, ., n, =, 4, mice, for, jr, ##ge, ##co, ##1, ##a, and, jr, ##camp, ##1, ##a, ,, n, =, 3, mice, for, all, other, construct, ##s, ., panels, c, -, f, are, based, on, the, same, data, set, ., (, d, ), fourier, spectra, normal, ##ized, to, the, amplitude, at, 0, hz, for, neurons, driven, with, 1, hz, drifting, gr, ##ating, ##s, ,, trans, ##duced, with, rca, ##mp, ##1, ##h, ,, r, -, ge, ##co, ##1, ,, r, -, camp, ##2, ,, jr, ##ge, ##camp, ##1, ##a, ,, jr, ##camp, ##1, ##b, ,, and, jr, ##ge, ##co, ##1, ##a, ., ins, ##et, ,, zoom, ##ed, -, in, view, of, 1, hz, response, amplitude, ##s, ., (, e, ), fraction, of, cells, detected, as, responding, to, visual, stimulus, (, an, ##ova, test, ,, p, <, 0, ., 01, ), when, expressing, different, calcium, indicators, ., this, fraction, was, 8, -, and, 6, -, fold, higher, for, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, compared, to, rca, ##mp, ##1, ##h, ,, respectively, ,, and, 60, %, higher, for, jr, ##ge, ##co, ##1, ##a, compared, to, r, -, ge, ##co, ##1, (, wilcox, ##on, rank, sum, test, ;, *, ,, p, <, 0, ., 05, ;, *, *, ,, p, <, 0, ., 01, ;, *, *, *, ,, p, <, 0, ., 001, ), ., error, bars, correspond, to, s, ., e, ., m, (, 26, fields, -, of, -, view, ,, rca, ##mp, ##1, ##h, ;, 45, ,, jr, ##camp, ##1, ##a, ;, 31, ,, jr, ##camp, ##1, ##b, ;, 30, ,, r, -, ge, ##co, ##1, ;, 40, ,, jr, ##ge, ##co, ##1, ##a, ;, 33, ,, r, -, camp, ##2, ;, 23, ,, g, ##camp, ##6, ##s, ;, 29, ,, g, ##camp, ##6, ##f, ), (, f, ), distribution, of, δ, ##f, /, f, amplitude, for, the, preferred, stimulus, ., a, right, -, shifted, curve, ,, such, as, jr, ##ge, ##co, ##1, ##a, vs, ., r, -, ge, ##co, ##1, or, jr, ##camp, ##1, ##a, /, b, vs, ., jr, ##camp, ##1, ##h, ,, indicates, enhancement, of, response, amplitude, (, 75, percent, ##ile, values, of, 0, ., 36, and, 0, ., 27, vs, ., 0, ., 18, for, jr, ##camp, ##1, ##a, and, jr, ##camp, ##1, ##b, vs, ., rca, ##mp, ##1, ##h, ,, and, 0, ., 66, vs, ., 0, ., 38, for, jr, ##ge, ##co, ##1, ##a, vs, ., g, ##camp, ##6, ##f, ,, respectively, ), ., (, 121, ##0, cells, ,, r, -, ge, ##co, ##1, ;, 86, ##1, ,, rca, ##mp, ##1, ##h, ;, 1733, ,, r, -, camp, ##2, ;, 1605, ,, jr, ##ge, ##co, ##1, ##a, ;, 1981, ,, jr, ##camp, ##1, ##a, ;, 97, ##1, ,, jr, ##camp, ##1, ##b, ;, 90, ##7, ,, g, ##camp, ##6, ##f, ;, 67, ##2, ,, g, ##camp, ##6, ##s, ), ,, same, colors, as, in, e, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##1, ##fi, ##gur, ##e, 3, —, figure, supplement, 1, ., comparison, of, orientation, tuning, in, v, ##1, neurons, measured, with, different, red, ge, ##cis, ., distribution, of, orientation, select, ##ivity, index, (, os, ##i, ,, 3, upper, rows, ), for, all, cells, detected, as, responsive, ,, measured, using, different, ge, ##cis, ., bottom, panel, ,, mean, ±, s, ., d, for, all, construct, ##s, show, similar, tuning, properties, (, n, =, 238, cells, ,, r, -, ge, ##co, ##1, ;, 308, ,, jr, ##ge, ##co, ##1, ##a, ;, 38, ##6, ,, r, -, camp, ##2, ;, 277, ,, jr, ##camp, ##1, ##a, ;, 141, ,, jr, ##camp, ##1, ##b, ;, 337, ,, g, ##camp, ##6, ##s, ;, 203, ,, g, ##camp, ##6, ##f, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##2, ##fi, ##gur, ##e, 3, —, figure, supplement, 2, ., long, -, term, expression, of, red, ge, ##cis, in, mouse, v, ##1, ., (, a, ), example, images, of, v, ##1, l, ##2, /, 3, neurons, after, long, term, expression, of, red, ge, ##cis, ., (, b, ), comparison, of, the, proportion, of, responsive, cells, ,, orientation, -, tuned, cells, ,, and, the, ratio, between, them, ., each, time, point, corresponds, to, a, different, mouse, ., (, c, ), distributions, of, peak, δ, ##f, /, f, _, 0, for, different, animals, image, ##d, after, different, times, of, expression, of, the, red, ge, ##ci, ., no, strong, effect, of, expression, time, on, peak, response, was, detected, ., (, d, ), half, decay, times, of, the, flu, ##orescence, response, for, different, animals, with, different, expression, time, of, the, red, ge, ##ci, ., no, strong, effect, of, expression, time, on, the, decay, kinetic, ##s, was, seen, ., jr, ##camp, ##1, ##a, data, for, 16, days, of, expression, is, not, shown, because, the, number, of, cells, eligible, for, this, analysis, was, too, small, (, materials, and, methods, ), ., doi, :, video, 1, ., jr, ##ge, ##co, ##1, ##a, l, ##2, /, 3, functional, imaging, in, the, mouse, v, ##1, ., the, mouse, was, an, ##est, ##het, ##ized, and, presented, with, moving, gr, ##ating, ##s, in, eight, directions, to, the, contra, ##lateral, eye, ., gr, ##ating, ##s, were, presented, for, 4, s, (, indicated, by, appearance, of, an, arrow, ##head, in, the, gr, ##ating, propagation, direction, ), followed, by, a, 4, s, of, blank, display, ., field, of, view, size, was, 250, ##x, ##25, ##0, μ, ##m, ^, 2, ,, acquired, at, 15, hz, and, filtered, with, a, 5, frame, moving, average, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 127, ##27, ., 01, ##3'},\n", - " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", - " 'section_name': 'PB line expression patterns',\n", - " 'text': \"The rate of obtaining lines with brain expression in the PB screen (78.5% ) was more than twice that obtained with lentiviral transgenesis (Table 1). Lines generated by local hop of PB (within ~100 Kb) had similar expression patterns to that of the original line (Figure 2—figure supplement 1), probably because shared local enhancers regulated expression of the reporter. In most of lines, we did not find clear resemblance between reporter expression patterns and those of genes near insertion sites (see supplemental note). Some lines had dominant expression in a single anatomical structure, such as deep entorhinal cortex (P038, Figure 2A), subiculum (P141, Figure 2B), retrosplenial cortex (P099, Figure 2C), or dorsal hindbrain (P108, Figure 2D). Many lines had expression in multiple regions but with unique cell types in each area. For example, P008 has broad expression in striatum (Figure 2E1) but has restricted expression in the most medial part of the hippocampus (fasciola cinereum, Figure 2E2). P057 had cortical layer 5 expression and restricted expression in anterior-lateral caudate putamen (CP; Figure 2H). Interestingly, the mCitrine-positive CP cells appeared to be part of the direct pathway; the cells projected axons to a limited area in substantia nigra pars reticulata (Figure 2H2 inset) but not to the globus pallidus (Figure 2H1 arrow; compare the GP projection of P008 in Figure 2E1). Lines with broad expression, (Figure 2J), those labeling few cells, and those closely resembling existing lines were terminated (48 lines). Most lines with 'broad expression' had strong mCitrine expression restricted to forebrain and founders carrying multiple PB copies also had strong forebrain expression.10.7554/eLife.13503.011Figure 2.Example PiggyBac lines.(A–D) Examples of lines that appear to label a single cell type. (d) P038 has expression in entorhinal cortex medial part (ENTm) layer 6 neurons (A1: sagittal) that send axons to lateral dorsal nucleus of thalamus (LD in A2: coronal). (B) P141 has expression in a restricted area in subiculum (SUB, B1: sagittal, B2: coronal). (C) Retrosplenial cortex (RSP) expression in P099 (C1: sagittal, C2: coronal). (D) Dorsal hindbrain expression in P108 (D1: sagittal, D2: coronal at hindbrain). (E–H) Examples of lines with regionally distinctive cell type labeling. (E) P008 has expression in striatum (STR) broadly (E1: sagittal) but its hippocampal expression is restricted to the most medial part (fasciola cinereum: FC, E2 inset) (F) P122 has scattered expression in hippocampus and strong expression in cortical amygdalar area. F1: sagittal, F2: coronal sections. (G) P134 has broad expression in cortical interneurons and cerebellar Lugaro cells (G1: sagittal). Its expression in midbrain is restricted to subnuclei (G2, superior olivary complex: SOC and presumably pedunculopontine nucleus: PPN). (H) P057 (H1:coronal, H2, sagittal section) has expression in layer 5 pyramidal cells in the cortex. Expression in caudate putamen (CP) is restricted to lateral-most areas (arrows in H1). H2 inset: coronal section at the level of the dotted line. The striatal neurons project to a small area in the reticular part of the substantia nigra, reticular part (SNr, dotted area in H2 inset) but not to globus pallidus (H2 arrow). (J) Lines with broad expressions. Scale bar: 500 μm.DOI:10.7554/eLife.13503.012Figure 2—source data 1.Viral reporter expression counting data One or two animals per line were injected with TRE3G –myristorylsted mCherry HA.The numbers of cells (mCitirne+, mCherry+, mCitrine+;mCherry+, and mCitrine-:mCherry+) infection rate (mCitrine+;mCherry+/ mCitirne +) were counted from confocal image stacks from sections near injection sites (5 - 9 sections/line). Infection rates (mCherry+;mCitrine+ /mCitrine) and 'off-target' expression rate (mCherry+;mCitirne-/mCherry+) are shown in average ± SEM.DOI:10.7554/eLife.13503.013Figure 2—figure supplement 1.Similar expression patterns in lines with nearby insertions.Insertion sites and expression patterns of a founder PBAS and lines generated from PBAS by local hop are shown. Lines inserted near original PBAS site have scattered expression in Purkinje cells in cerebellum. Many lines have axonal projections in dentate gyrus from entorhinal cortex. P103 and P136 have insertion sites more than 300 kb away from the origin and their expression patterns are quite different from PBAS.DOI:10.7554/eLife.13503.014Figure 2—figure supplement 2.Developmental dynamics in P162 expression patterns.(A and B) sections from P10 (A) and mature (B) animals. Parafascicular nucleus of thalamus had expression at P10 but not in mature animal (arrowheads). (C and D) P10 (C) animal expressed reporter in pontine gray (arrowhead) but matured animal (D) did not. (E and F) Subiculum expression was not seen at P10 (E) but was present in mature (F) animals (arrowheads). (G) Higher magnification of parafascicular nucleus in A. Asterisk: fasciculus retroflexus. (H) Higher magnification of pontine gray. (I) Cerebellum receives axons from pontine gray. (J) High magnification of cerebellum. Mossy terminals were labeled.DOI:10.7554/eLife.13503.015Figure 2—figure supplement 3.Examples of virus injection.AAV–TRE3G- myristoylated mCherry-HA was injected to the brain. Wide field images (1) and confocal images (2, rectangle areas in 1) of injection sites. Note that myristoylated mCherry strongly labels axons and dendrites. (A–C) Injection to retrosplenial cortex. P160 labels layer 2/3 (A), P136 in layer 5 (B), and P160 in layer 6 (C). In P160, virus spread to entire cortex (see infected cells in deep layer (arrows in A2) but viral reporter expression is restricted to mCtirine positive cells. (D) Hippocampal CA1 injection to P160. (E–F) Examples of 'off-target' expression. Primary somatosensory cortex injection in P057 (E) and subiculum injection in P113 (F). Arrowheads: cells with viral reporter without visible mCitrine expression. Blue: DAPI, Green: anti-GFP, Red: anti-HA.DOI:10.7554/eLife.13503.016Figure 2—figure supplement 4.tet reporter expression in cultured cell lines.(A–I) Induction of tet reporter constructs was tested with 293T cells. Cells were transfected without (A–I, first panels) or with (A–I, second panels) CMV-tTA plasmid. Some constructs had strong tTA-independent 'leak' expression (ex. A1, E1, and F1). GBP-split Cre had the strongest expression of Cre reporter in the presence of GFP (I3) but could activate the reporter expression without GFP expression (I2). See Supplemental note for further details.DOI:10.7554/eLife.13503.017Figure 2—figure supplement 5.Specificity of tet reporter expression in vivo.(A) AAV–TREtight-myrmCherry expression in 56L. mCherry expression was restricted to mCitrine positive cells (mCitrine+ cells/ mCherry+ cells: 152/152). (A2) higher magnification of injection site. (B) Co-infection of AAV–TRE3G–Cre and AAV–CAG–Flex-myrmCherry HAnsulator sequence from. There was strong non-specific mCherry expression near injection site (B2). (C) TRE3G–Split Cre had specific expression of reporter without apparent leak. (D) TRE3G–Flpe had non-specific expression in a few cells (D2, arrows) (E) TRE3G split Cre had non-specific expression from Ai14 reporter allele in P113 subiculum. (F) TRE3G-nanobody Split Cre had specific expression (mCitrine+ cells/mCherry + cells: 64/64). (F2) higher magnification of the injection site. (G) Specific expression of AAV Cre repoter by TRE3G-nanobody split Cre in 56L.DOI:\",\n", - " 'paragraph_id': 13,\n", - " 'tokenizer': \"the, rate, of, obtaining, lines, with, brain, expression, in, the, p, ##b, screen, (, 78, ., 5, %, ), was, more, than, twice, that, obtained, with, lent, ##iv, ##ira, ##l, trans, ##genesis, (, table, 1, ), ., lines, generated, by, local, hop, of, p, ##b, (, within, ~, 100, kb, ), had, similar, expression, patterns, to, that, of, the, original, line, (, figure, 2, —, figure, supplement, 1, ), ,, probably, because, shared, local, enhance, ##rs, regulated, expression, of, the, reporter, ., in, most, of, lines, ,, we, did, not, find, clear, resemblance, between, reporter, expression, patterns, and, those, of, genes, near, insertion, sites, (, see, supplemental, note, ), ., some, lines, had, dominant, expression, in, a, single, anatomical, structure, ,, such, as, deep, en, ##tor, ##hin, ##al, cortex, (, p, ##0, ##38, ,, figure, 2a, ), ,, sub, ##ic, ##ulum, (, p, ##14, ##1, ,, figure, 2, ##b, ), ,, retro, ##sp, ##len, ##ial, cortex, (, p, ##0, ##9, ##9, ,, figure, 2, ##c, ), ,, or, dorsal, hind, ##bra, ##in, (, p, ##10, ##8, ,, figure, 2d, ), ., many, lines, had, expression, in, multiple, regions, but, with, unique, cell, types, in, each, area, ., for, example, ,, p, ##00, ##8, has, broad, expression, in, st, ##ria, ##tum, (, figure, 2, ##e, ##1, ), but, has, restricted, expression, in, the, most, medial, part, of, the, hip, ##po, ##camp, ##us, (, fa, ##sc, ##iol, ##a, ci, ##ner, ##eum, ,, figure, 2, ##e, ##2, ), ., p, ##0, ##57, had, co, ##rti, ##cal, layer, 5, expression, and, restricted, expression, in, anterior, -, lateral, ca, ##uda, ##te, put, ##amen, (, cp, ;, figure, 2, ##h, ), ., interesting, ##ly, ,, the, mc, ##it, ##rine, -, positive, cp, cells, appeared, to, be, part, of, the, direct, pathway, ;, the, cells, projected, ax, ##ons, to, a, limited, area, in, sub, ##stan, ##tia, ni, ##gra, par, ##s, re, ##tic, ##ulata, (, figure, 2, ##h, ##2, ins, ##et, ), but, not, to, the, g, ##lo, ##bus, pal, ##lid, ##us, (, figure, 2, ##h, ##1, arrow, ;, compare, the, gp, projection, of, p, ##00, ##8, in, figure, 2, ##e, ##1, ), ., lines, with, broad, expression, ,, (, figure, 2, ##j, ), ,, those, labeling, few, cells, ,, and, those, closely, resembling, existing, lines, were, terminated, (, 48, lines, ), ., most, lines, with, ', broad, expression, ', had, strong, mc, ##it, ##rine, expression, restricted, to, fore, ##bra, ##in, and, founders, carrying, multiple, p, ##b, copies, also, had, strong, fore, ##bra, ##in, expression, ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##1, ##fi, ##gur, ##e, 2, ., example, pig, ##gy, ##ba, ##c, lines, ., (, a, –, d, ), examples, of, lines, that, appear, to, label, a, single, cell, type, ., (, d, ), p, ##0, ##38, has, expression, in, en, ##tor, ##hin, ##al, cortex, medial, part, (, en, ##tm, ), layer, 6, neurons, (, a1, :, sa, ##git, ##tal, ), that, send, ax, ##ons, to, lateral, dorsal, nucleus, of, tha, ##lam, ##us, (, ld, in, a2, :, corona, ##l, ), ., (, b, ), p, ##14, ##1, has, expression, in, a, restricted, area, in, sub, ##ic, ##ulum, (, sub, ,, b1, :, sa, ##git, ##tal, ,, b, ##2, :, corona, ##l, ), ., (, c, ), retro, ##sp, ##len, ##ial, cortex, (, rs, ##p, ), expression, in, p, ##0, ##9, ##9, (, c1, :, sa, ##git, ##tal, ,, c2, :, corona, ##l, ), ., (, d, ), dorsal, hind, ##bra, ##in, expression, in, p, ##10, ##8, (, d, ##1, :, sa, ##git, ##tal, ,, d, ##2, :, corona, ##l, at, hind, ##bra, ##in, ), ., (, e, –, h, ), examples, of, lines, with, regional, ##ly, distinctive, cell, type, labeling, ., (, e, ), p, ##00, ##8, has, expression, in, st, ##ria, ##tum, (, st, ##r, ), broadly, (, e, ##1, :, sa, ##git, ##tal, ), but, its, hip, ##po, ##camp, ##al, expression, is, restricted, to, the, most, medial, part, (, fa, ##sc, ##iol, ##a, ci, ##ner, ##eum, :, fc, ,, e, ##2, ins, ##et, ), (, f, ), p, ##12, ##2, has, scattered, expression, in, hip, ##po, ##camp, ##us, and, strong, expression, in, co, ##rti, ##cal, amy, ##g, ##dal, ##ar, area, ., f1, :, sa, ##git, ##tal, ,, f, ##2, :, corona, ##l, sections, ., (, g, ), p, ##13, ##4, has, broad, expression, in, co, ##rti, ##cal, intern, ##eur, ##ons, and, ce, ##re, ##bella, ##r, lu, ##gar, ##o, cells, (, g, ##1, :, sa, ##git, ##tal, ), ., its, expression, in, mid, ##bra, ##in, is, restricted, to, sub, ##nu, ##cle, ##i, (, g, ##2, ,, superior, ol, ##ivar, ##y, complex, :, soc, and, presumably, pe, ##dun, ##cu, ##lo, ##pon, ##tine, nucleus, :, pp, ##n, ), ., (, h, ), p, ##0, ##57, (, h, ##1, :, corona, ##l, ,, h, ##2, ,, sa, ##git, ##tal, section, ), has, expression, in, layer, 5, pyramid, ##al, cells, in, the, cortex, ., expression, in, ca, ##uda, ##te, put, ##amen, (, cp, ), is, restricted, to, lateral, -, most, areas, (, arrows, in, h, ##1, ), ., h, ##2, ins, ##et, :, corona, ##l, section, at, the, level, of, the, dotted, line, ., the, st, ##ria, ##tal, neurons, project, to, a, small, area, in, the, re, ##tic, ##ular, part, of, the, sub, ##stan, ##tia, ni, ##gra, ,, re, ##tic, ##ular, part, (, s, ##nr, ,, dotted, area, in, h, ##2, ins, ##et, ), but, not, to, g, ##lo, ##bus, pal, ##lid, ##us, (, h, ##2, arrow, ), ., (, j, ), lines, with, broad, expressions, ., scale, bar, :, 500, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##2, ##fi, ##gur, ##e, 2, —, source, data, 1, ., viral, reporter, expression, counting, data, one, or, two, animals, per, line, were, injected, with, tre, ##3, ##g, –, my, ##rist, ##ory, ##ls, ##ted, mc, ##her, ##ry, ha, ., the, numbers, of, cells, (, mc, ##iti, ##rne, +, ,, mc, ##her, ##ry, +, ,, mc, ##it, ##rine, +, ;, mc, ##her, ##ry, +, ,, and, mc, ##it, ##rine, -, :, mc, ##her, ##ry, +, ), infection, rate, (, mc, ##it, ##rine, +, ;, mc, ##her, ##ry, +, /, mc, ##iti, ##rne, +, ), were, counted, from, con, ##fo, ##cal, image, stacks, from, sections, near, injection, sites, (, 5, -, 9, sections, /, line, ), ., infection, rates, (, mc, ##her, ##ry, +, ;, mc, ##it, ##rine, +, /, mc, ##it, ##rine, ), and, ', off, -, target, ', expression, rate, (, mc, ##her, ##ry, +, ;, mc, ##iti, ##rne, -, /, mc, ##her, ##ry, +, ), are, shown, in, average, ±, se, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##3, ##fi, ##gur, ##e, 2, —, figure, supplement, 1, ., similar, expression, patterns, in, lines, with, nearby, insertion, ##s, ., insertion, sites, and, expression, patterns, of, a, founder, pba, ##s, and, lines, generated, from, pba, ##s, by, local, hop, are, shown, ., lines, inserted, near, original, pba, ##s, site, have, scattered, expression, in, pu, ##rkin, ##je, cells, in, ce, ##re, ##bell, ##um, ., many, lines, have, ax, ##onal, projections, in, dent, ##ate, g, ##yr, ##us, from, en, ##tor, ##hin, ##al, cortex, ., p, ##10, ##3, and, p, ##13, ##6, have, insertion, sites, more, than, 300, kb, away, from, the, origin, and, their, expression, patterns, are, quite, different, from, pba, ##s, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##4, ##fi, ##gur, ##e, 2, —, figure, supplement, 2, ., developmental, dynamics, in, p, ##16, ##2, expression, patterns, ., (, a, and, b, ), sections, from, p, ##10, (, a, ), and, mature, (, b, ), animals, ., para, ##fa, ##sc, ##icular, nucleus, of, tha, ##lam, ##us, had, expression, at, p, ##10, but, not, in, mature, animal, (, arrow, ##heads, ), ., (, c, and, d, ), p, ##10, (, c, ), animal, expressed, reporter, in, pont, ##ine, gray, (, arrow, ##head, ), but, mature, ##d, animal, (, d, ), did, not, ., (, e, and, f, ), sub, ##ic, ##ulum, expression, was, not, seen, at, p, ##10, (, e, ), but, was, present, in, mature, (, f, ), animals, (, arrow, ##heads, ), ., (, g, ), higher, mag, ##ni, ##fication, of, para, ##fa, ##sc, ##icular, nucleus, in, a, ., as, ##ter, ##isk, :, fa, ##sc, ##ic, ##ulus, retro, ##fle, ##x, ##us, ., (, h, ), higher, mag, ##ni, ##fication, of, pont, ##ine, gray, ., (, i, ), ce, ##re, ##bell, ##um, receives, ax, ##ons, from, pont, ##ine, gray, ., (, j, ), high, mag, ##ni, ##fication, of, ce, ##re, ##bell, ##um, ., moss, ##y, terminals, were, labeled, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##5, ##fi, ##gur, ##e, 2, —, figure, supplement, 3, ., examples, of, virus, injection, ., aa, ##v, –, tre, ##3, ##g, -, my, ##rist, ##oy, ##lated, mc, ##her, ##ry, -, ha, was, injected, to, the, brain, ., wide, field, images, (, 1, ), and, con, ##fo, ##cal, images, (, 2, ,, rec, ##tangle, areas, in, 1, ), of, injection, sites, ., note, that, my, ##rist, ##oy, ##lated, mc, ##her, ##ry, strongly, labels, ax, ##ons, and, den, ##dr, ##ites, ., (, a, –, c, ), injection, to, retro, ##sp, ##len, ##ial, cortex, ., p, ##16, ##0, labels, layer, 2, /, 3, (, a, ), ,, p, ##13, ##6, in, layer, 5, (, b, ), ,, and, p, ##16, ##0, in, layer, 6, (, c, ), ., in, p, ##16, ##0, ,, virus, spread, to, entire, cortex, (, see, infected, cells, in, deep, layer, (, arrows, in, a2, ), but, viral, reporter, expression, is, restricted, to, mc, ##ti, ##rine, positive, cells, ., (, d, ), hip, ##po, ##camp, ##al, ca, ##1, injection, to, p, ##16, ##0, ., (, e, –, f, ), examples, of, ', off, -, target, ', expression, ., primary, so, ##mat, ##ose, ##nsor, ##y, cortex, injection, in, p, ##0, ##57, (, e, ), and, sub, ##ic, ##ulum, injection, in, p, ##11, ##3, (, f, ), ., arrow, ##heads, :, cells, with, viral, reporter, without, visible, mc, ##it, ##rine, expression, ., blue, :, da, ##pi, ,, green, :, anti, -, g, ##fp, ,, red, :, anti, -, ha, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##6, ##fi, ##gur, ##e, 2, —, figure, supplement, 4, ., te, ##t, reporter, expression, in, culture, ##d, cell, lines, ., (, a, –, i, ), induction, of, te, ##t, reporter, construct, ##s, was, tested, with, 293, ##t, cells, ., cells, were, trans, ##fect, ##ed, without, (, a, –, i, ,, first, panels, ), or, with, (, a, –, i, ,, second, panels, ), cm, ##v, -, tt, ##a, pl, ##as, ##mi, ##d, ., some, construct, ##s, had, strong, tt, ##a, -, independent, ', leak, ', expression, (, ex, ., a1, ,, e, ##1, ,, and, f1, ), ., gb, ##p, -, split, cr, ##e, had, the, strongest, expression, of, cr, ##e, reporter, in, the, presence, of, g, ##fp, (, i, ##3, ), but, could, activate, the, reporter, expression, without, g, ##fp, expression, (, i, ##2, ), ., see, supplemental, note, for, further, details, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 01, ##7, ##fi, ##gur, ##e, 2, —, figure, supplement, 5, ., specific, ##ity, of, te, ##t, reporter, expression, in, vivo, ., (, a, ), aa, ##v, –, tre, ##tight, -, my, ##rm, ##cher, ##ry, expression, in, 56, ##l, ., mc, ##her, ##ry, expression, was, restricted, to, mc, ##it, ##rine, positive, cells, (, mc, ##it, ##rine, +, cells, /, mc, ##her, ##ry, +, cells, :, 152, /, 152, ), ., (, a2, ), higher, mag, ##ni, ##fication, of, injection, site, ., (, b, ), co, -, infection, of, aa, ##v, –, tre, ##3, ##g, –, cr, ##e, and, aa, ##v, –, ca, ##g, –, flex, -, my, ##rm, ##cher, ##ry, hans, ##ulator, sequence, from, ., there, was, strong, non, -, specific, mc, ##her, ##ry, expression, near, injection, site, (, b, ##2, ), ., (, c, ), tre, ##3, ##g, –, split, cr, ##e, had, specific, expression, of, reporter, without, apparent, leak, ., (, d, ), tre, ##3, ##g, –, fl, ##pe, had, non, -, specific, expression, in, a, few, cells, (, d, ##2, ,, arrows, ), (, e, ), tre, ##3, ##g, split, cr, ##e, had, non, -, specific, expression, from, ai, ##14, reporter, all, ##ele, in, p, ##11, ##3, sub, ##ic, ##ulum, ., (, f, ), tre, ##3, ##g, -, nano, ##body, split, cr, ##e, had, specific, expression, (, mc, ##it, ##rine, +, cells, /, mc, ##her, ##ry, +, cells, :, 64, /, 64, ), ., (, f, ##2, ), higher, mag, ##ni, ##fication, of, the, injection, site, ., (, g, ), specific, expression, of, aa, ##v, cr, ##e, rep, ##ote, ##r, by, tre, ##3, ##g, -, nano, ##body, split, cr, ##e, in, 56, ##l, ., doi, :\"},\n", - " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", - " 'section_name': 'Hippocampal formation',\n", - " 'text': 'The entorhinal cortex, hippocampus, and subiculum are interconnected by complex loops with reciprocal connections (Ding, 2013; Witter et al., 2014). Many (92) lines have expression in subregions of the hippocampal formation. CA1 is one of major input source of the subiculum, which sends axons to the entorhinal cortex through the presubiculum (PRE) and parasubiculum (PAR). Labeled cells proximal to CA1 in three lines, P162 (Figure 6A), P139 (Figure 6B), and P141 (Figure 6C), do not project to PRE but the distal subiculum population labeled in P157 (Figure 6D) does. P066, which has expression in the whole subiculum, also has PRE projections (Figure 6E). P162, P139, and P141 have expression in adjacent positions (cells in P162 and P139 are in nearly the same positions and P141 cells are located posterior to them, (see distal ends of CA1 marked by arrowheads in Figure 6A–C) but have different axonal projections. P162 has dense mCitrine-positive axons in the reuniens nucleus (RE) and dorsal and ventral submedial nucleus (SMT) but there are few axons in the corresponding areas in P139 and P141 (Figure 6—figure supplement 1A–F). Injection of tet –dependent virus (AAV-Tre3G-myristylated mCherry-HA) into the subiculum in P162 confirmed that axons in RE and SMT were coming from the subiculum (Figure 6—figure supplement 1G–I). P160 has expression in PRE and PAR and dense axonal projections to entorhinal cortex, medial part (ENTm, Figure 6E). P149 has expression in ENTm layer 5 (Figure 6H). P084 also has expression in the same region, but the expression is restricted to the most medial part of ENTm (Figure 6G). 56L had broad expression in deep layer 6 of neocortex, but its expression in ENTm was observed in upper layer 6 (Figure 6J). P038 occupied ENTm deep layer 6 (Figure 6I). We also obtained lines with ENTm layer 2/3 (PBAS, Figure 6K) and entorhinal cortex, lateral part (ENTl) layer 2/3 (P126, Figure 6L).10.7554/eLife.13503.023Figure 6.Lines with expression in the hippocampal formation.Horizontal sections through the hippocampal formation. (A–B) Expression closer to CA1 (P162, A) and to subiculum (P139, B) at the region of their border. CA1: Ammon’s horn, field CA1, SUB: subiculum, PRE: presubiculum, PAR: parasubiculum, ENTm: entorhinal cortex, medial part, ENTl: entorhinal cortex, lateral part. Arrowheads in (A–C) distal end of CA1 pyramidal layer. (C–E) Subiculum expression in P141(C), P157 (D) and P066 (E). (F) Presubiculum expression in P160. (G and H) Expression in medial entorhinal cortex layer 5 in P084 (G) and P149 (H). (I and J) medial entorhinal cortex layer6 expression in P038 (I) and 56L (J). (K and L) medial entorhinal (PBAS, K) and lateral entorhinal (P126, L).layer 2 expression. Scale bar: 500 μm.DOI:10.7554/eLife.13503.024Figure 6—figure supplement 1.P162 subiculum neurons project to thalamus.(A–F) Axonal projection in nucleus of reunions (RE), dorsal (dSMT), and ventral (vSMT) submedial nuclei are prominent in P162 (A–B) but are weak or absent in p139 (C–D) and P141 (E–F). B, D, and F magnified images of areas shown A, C, and E, respectively. (G–I) TRE3G-myrmCherryHA injection to P162. (G) the injection site. (H) axons in RE. (I) axons in RE and vSMT.DOI:',\n", - " 'paragraph_id': 24,\n", - " 'tokenizer': 'the, en, ##tor, ##hin, ##al, cortex, ,, hip, ##po, ##camp, ##us, ,, and, sub, ##ic, ##ulum, are, inter, ##connected, by, complex, loops, with, reciprocal, connections, (, ding, ,, 2013, ;, wit, ##ter, et, al, ., ,, 2014, ), ., many, (, 92, ), lines, have, expression, in, sub, ##region, ##s, of, the, hip, ##po, ##camp, ##al, formation, ., ca, ##1, is, one, of, major, input, source, of, the, sub, ##ic, ##ulum, ,, which, sends, ax, ##ons, to, the, en, ##tor, ##hin, ##al, cortex, through, the, pre, ##su, ##bic, ##ulum, (, pre, ), and, para, ##su, ##bic, ##ulum, (, par, ), ., labeled, cells, pro, ##xi, ##mal, to, ca, ##1, in, three, lines, ,, p, ##16, ##2, (, figure, 6, ##a, ), ,, p, ##13, ##9, (, figure, 6, ##b, ), ,, and, p, ##14, ##1, (, figure, 6, ##c, ), ,, do, not, project, to, pre, but, the, distal, sub, ##ic, ##ulum, population, labeled, in, p, ##15, ##7, (, figure, 6, ##d, ), does, ., p, ##0, ##66, ,, which, has, expression, in, the, whole, sub, ##ic, ##ulum, ,, also, has, pre, projections, (, figure, 6, ##e, ), ., p, ##16, ##2, ,, p, ##13, ##9, ,, and, p, ##14, ##1, have, expression, in, adjacent, positions, (, cells, in, p, ##16, ##2, and, p, ##13, ##9, are, in, nearly, the, same, positions, and, p, ##14, ##1, cells, are, located, posterior, to, them, ,, (, see, distal, ends, of, ca, ##1, marked, by, arrow, ##heads, in, figure, 6, ##a, –, c, ), but, have, different, ax, ##onal, projections, ., p, ##16, ##2, has, dense, mc, ##it, ##rine, -, positive, ax, ##ons, in, the, re, ##uni, ##ens, nucleus, (, re, ), and, dorsal, and, ventral, sub, ##media, ##l, nucleus, (, sm, ##t, ), but, there, are, few, ax, ##ons, in, the, corresponding, areas, in, p, ##13, ##9, and, p, ##14, ##1, (, figure, 6, —, figure, supplement, 1a, –, f, ), ., injection, of, te, ##t, –, dependent, virus, (, aa, ##v, -, tre, ##3, ##g, -, my, ##rist, ##yla, ##ted, mc, ##her, ##ry, -, ha, ), into, the, sub, ##ic, ##ulum, in, p, ##16, ##2, confirmed, that, ax, ##ons, in, re, and, sm, ##t, were, coming, from, the, sub, ##ic, ##ulum, (, figure, 6, —, figure, supplement, 1, ##g, –, i, ), ., p, ##16, ##0, has, expression, in, pre, and, par, and, dense, ax, ##onal, projections, to, en, ##tor, ##hin, ##al, cortex, ,, medial, part, (, en, ##tm, ,, figure, 6, ##e, ), ., p, ##14, ##9, has, expression, in, en, ##tm, layer, 5, (, figure, 6, ##h, ), ., p, ##0, ##8, ##4, also, has, expression, in, the, same, region, ,, but, the, expression, is, restricted, to, the, most, medial, part, of, en, ##tm, (, figure, 6, ##g, ), ., 56, ##l, had, broad, expression, in, deep, layer, 6, of, neo, ##cor, ##te, ##x, ,, but, its, expression, in, en, ##tm, was, observed, in, upper, layer, 6, (, figure, 6, ##j, ), ., p, ##0, ##38, occupied, en, ##tm, deep, layer, 6, (, figure, 6, ##i, ), ., we, also, obtained, lines, with, en, ##tm, layer, 2, /, 3, (, pba, ##s, ,, figure, 6, ##k, ), and, en, ##tor, ##hin, ##al, cortex, ,, lateral, part, (, en, ##tl, ), layer, 2, /, 3, (, p, ##12, ##6, ,, figure, 6, ##l, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##3, ##fi, ##gur, ##e, 6, ., lines, with, expression, in, the, hip, ##po, ##camp, ##al, formation, ., horizontal, sections, through, the, hip, ##po, ##camp, ##al, formation, ., (, a, –, b, ), expression, closer, to, ca, ##1, (, p, ##16, ##2, ,, a, ), and, to, sub, ##ic, ##ulum, (, p, ##13, ##9, ,, b, ), at, the, region, of, their, border, ., ca, ##1, :, am, ##mon, ’, s, horn, ,, field, ca, ##1, ,, sub, :, sub, ##ic, ##ulum, ,, pre, :, pre, ##su, ##bic, ##ulum, ,, par, :, para, ##su, ##bic, ##ulum, ,, en, ##tm, :, en, ##tor, ##hin, ##al, cortex, ,, medial, part, ,, en, ##tl, :, en, ##tor, ##hin, ##al, cortex, ,, lateral, part, ., arrow, ##heads, in, (, a, –, c, ), distal, end, of, ca, ##1, pyramid, ##al, layer, ., (, c, –, e, ), sub, ##ic, ##ulum, expression, in, p, ##14, ##1, (, c, ), ,, p, ##15, ##7, (, d, ), and, p, ##0, ##66, (, e, ), ., (, f, ), pre, ##su, ##bic, ##ulum, expression, in, p, ##16, ##0, ., (, g, and, h, ), expression, in, medial, en, ##tor, ##hin, ##al, cortex, layer, 5, in, p, ##0, ##8, ##4, (, g, ), and, p, ##14, ##9, (, h, ), ., (, i, and, j, ), medial, en, ##tor, ##hin, ##al, cortex, layer, ##6, expression, in, p, ##0, ##38, (, i, ), and, 56, ##l, (, j, ), ., (, k, and, l, ), medial, en, ##tor, ##hin, ##al, (, pba, ##s, ,, k, ), and, lateral, en, ##tor, ##hin, ##al, (, p, ##12, ##6, ,, l, ), ., layer, 2, expression, ., scale, bar, :, 500, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##4, ##fi, ##gur, ##e, 6, —, figure, supplement, 1, ., p, ##16, ##2, sub, ##ic, ##ulum, neurons, project, to, tha, ##lam, ##us, ., (, a, –, f, ), ax, ##onal, projection, in, nucleus, of, reunion, ##s, (, re, ), ,, dorsal, (, ds, ##mt, ), ,, and, ventral, (, vs, ##mt, ), sub, ##media, ##l, nuclei, are, prominent, in, p, ##16, ##2, (, a, –, b, ), but, are, weak, or, absent, in, p, ##13, ##9, (, c, –, d, ), and, p, ##14, ##1, (, e, –, f, ), ., b, ,, d, ,, and, f, mag, ##nified, images, of, areas, shown, a, ,, c, ,, and, e, ,, respectively, ., (, g, –, i, ), tre, ##3, ##g, -, my, ##rm, ##cher, ##ry, ##ha, injection, to, p, ##16, ##2, ., (, g, ), the, injection, site, ., (, h, ), ax, ##ons, in, re, ., (, i, ), ax, ##ons, in, re, and, vs, ##mt, ., doi, :'},\n", - " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", - " 'section_name': 'An altered classification of layer 6 cortico-thalamic pyramidal neurons',\n", - " 'text': 'We obtained three lines with expression in layer 6 cortical pyramidal neurons (Figure 10). P162 has mCitrine-positive cells in primary somatosensory area (SSp), primary visual area (VISp), and retrosplenical cortex and axonal projection in VPm and LGd (Figure 10G–J). P139 has expression in lateral cortex including supplemental somatosensory area (SSs) and gustatory cortex and projection in Po (Figure 10M–P). There are topological projection patterns in RTN; dorsally located P162 cells project to dorsal RTN and laterally located P139 cells project to ventral RTN (Figure 10—figure supplement 1B and C). The third line, 56L, has broad expression across neocortex (Figure 10A–D). 56L neurons have projection to both primary and secondary nuclei but not to RTN (Figure 10—figure supplement 1A).10.7554/eLife.13503.028Figure 10.Projections of layer 6 corticothalamic (CT) neurons.(A–D) Coronal images from 56L. (E and F) confocal images from SSp (E) and VISp (F) from 56L. (G–J) Coronal sections from P162. (K and L) Confocal images from SSp (K) and VISp (L) from P162. (M–P) Coronal images from P139. (Q) Confocal image from P139 SSs. Sections were taken from 0.7 mm (A, G, and M), 1.7 mm (B, D, H, J, N, and P), 2.3 mm (C, I, and O) caudal from bregma. (R–W) tet-reporter virus injection into 56L SSp (R), 56L SSs (T), P162 SSp (V), and P139 SSs (X) and their projection to thalamus (S, U, W, and Y, respectively). (Z) Schematic view of projections in layer 6 lines. ILM: interlaminar nucleus, Po: posterior complex, VPM: ventral posteomedial nucleus. Scale bars: 500 μm.DOI:10.7554/eLife.13503.029Figure 10—figure supplement 1.Projections to the reticular nucleus of the thalamus (RT) (A–C) DAPI (blue), anti-GFP (green), and anti-Parvalbumin (PV, red) staining for thalamus of 56L (A), P162 (B), and P139 (C).Few or no mCitrine-positive axons from 56L (A) project to the PV-positive RT. P162 (B) axons project only to the dorsal (d) part of RT, whereas the ventral (v) part receives axons from P139 (C).DOI:10.7554/eLife.13503.030Figure 10—figure supplement 2.Sublaminar location and intrinsic physiology of layer 6 neurons.(A and B) Positions of mCitrine-positive cell bodies in Layer 5–6 are plotted. (A) P162 (green) and 56L (blue) in SSp. (B) P139 (green) and 56L (blue) in SSs. Dotted lines: averaged borders between layers 5 and 6. (C) Current clamp responses of P162, 56L SSp, P139, 56L SSs to 100 pA current injections. Input resistance (D) whole cell capacitance (E) of layer 6 cells. Asterisks: p<0.05 with Turkey-Kremer’s post hoc test. (F and G) Current clamp responses of labeled (F) and nearby non-labeled (G) neurons in 56L layer 6 during current injection. (H) Firing frequency – current injection plot for labeled and non-labeled neurons in 56L layer 6. n = 16–20.DOI:10.7554/eLife.13503.031Figure 10—figure supplement 3.56L axonal projection from VISp to thalamus.(A) Injection site. (B) High magnification of injection site. (C) Axonal projections to thalamus avoid the dorsal leteral geniculate nuceus (LGd).DOI:10.7554/eLife.13503.032Figure 10—figure supplement 4.Long lateral projections in 56L and P139 AAV–TRE3GmCherryHA was injected to 56L.(A–C) and P139 (D–F). B and C high magnification of designated area in A. E and F high magnification of designated area in D. 56L had callosal projections (arrowhead in A) but these were not seen in P139 (arrowhead in C). Red: anti-HA, Green: anti-GFP, Blue: DAPI. Images in D–F and Figure 10X were taken from the same section.DOI:',\n", - " 'paragraph_id': 33,\n", - " 'tokenizer': 'we, obtained, three, lines, with, expression, in, layer, 6, co, ##rti, ##cal, pyramid, ##al, neurons, (, figure, 10, ), ., p, ##16, ##2, has, mc, ##it, ##rine, -, positive, cells, in, primary, so, ##mat, ##ose, ##nsor, ##y, area, (, ss, ##p, ), ,, primary, visual, area, (, vis, ##p, ), ,, and, retro, ##sp, ##len, ##ical, cortex, and, ax, ##onal, projection, in, vp, ##m, and, l, ##g, ##d, (, figure, 10, ##g, –, j, ), ., p, ##13, ##9, has, expression, in, lateral, cortex, including, supplemental, so, ##mat, ##ose, ##nsor, ##y, area, (, ss, ##s, ), and, gust, ##atory, cortex, and, projection, in, po, (, figure, 10, ##m, –, p, ), ., there, are, topological, projection, patterns, in, rt, ##n, ;, dorsal, ##ly, located, p, ##16, ##2, cells, project, to, dorsal, rt, ##n, and, lateral, ##ly, located, p, ##13, ##9, cells, project, to, ventral, rt, ##n, (, figure, 10, —, figure, supplement, 1b, and, c, ), ., the, third, line, ,, 56, ##l, ,, has, broad, expression, across, neo, ##cor, ##te, ##x, (, figure, 10, ##a, –, d, ), ., 56, ##l, neurons, have, projection, to, both, primary, and, secondary, nuclei, but, not, to, rt, ##n, (, figure, 10, —, figure, supplement, 1a, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##8, ##fi, ##gur, ##e, 10, ., projections, of, layer, 6, co, ##rti, ##cot, ##hala, ##mic, (, ct, ), neurons, ., (, a, –, d, ), corona, ##l, images, from, 56, ##l, ., (, e, and, f, ), con, ##fo, ##cal, images, from, ss, ##p, (, e, ), and, vis, ##p, (, f, ), from, 56, ##l, ., (, g, –, j, ), corona, ##l, sections, from, p, ##16, ##2, ., (, k, and, l, ), con, ##fo, ##cal, images, from, ss, ##p, (, k, ), and, vis, ##p, (, l, ), from, p, ##16, ##2, ., (, m, –, p, ), corona, ##l, images, from, p, ##13, ##9, ., (, q, ), con, ##fo, ##cal, image, from, p, ##13, ##9, ss, ##s, ., sections, were, taken, from, 0, ., 7, mm, (, a, ,, g, ,, and, m, ), ,, 1, ., 7, mm, (, b, ,, d, ,, h, ,, j, ,, n, ,, and, p, ), ,, 2, ., 3, mm, (, c, ,, i, ,, and, o, ), ca, ##uda, ##l, from, br, ##eg, ##ma, ., (, r, –, w, ), te, ##t, -, reporter, virus, injection, into, 56, ##l, ss, ##p, (, r, ), ,, 56, ##l, ss, ##s, (, t, ), ,, p, ##16, ##2, ss, ##p, (, v, ), ,, and, p, ##13, ##9, ss, ##s, (, x, ), and, their, projection, to, tha, ##lam, ##us, (, s, ,, u, ,, w, ,, and, y, ,, respectively, ), ., (, z, ), sc, ##hema, ##tic, view, of, projections, in, layer, 6, lines, ., il, ##m, :, inter, ##lam, ##ina, ##r, nucleus, ,, po, :, posterior, complex, ,, vp, ##m, :, ventral, post, ##eo, ##media, ##l, nucleus, ., scale, bars, :, 500, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 02, ##9, ##fi, ##gur, ##e, 10, —, figure, supplement, 1, ., projections, to, the, re, ##tic, ##ular, nucleus, of, the, tha, ##lam, ##us, (, rt, ), (, a, –, c, ), da, ##pi, (, blue, ), ,, anti, -, g, ##fp, (, green, ), ,, and, anti, -, par, ##val, ##bu, ##min, (, pv, ,, red, ), stain, ##ing, for, tha, ##lam, ##us, of, 56, ##l, (, a, ), ,, p, ##16, ##2, (, b, ), ,, and, p, ##13, ##9, (, c, ), ., few, or, no, mc, ##it, ##rine, -, positive, ax, ##ons, from, 56, ##l, (, a, ), project, to, the, pv, -, positive, rt, ., p, ##16, ##2, (, b, ), ax, ##ons, project, only, to, the, dorsal, (, d, ), part, of, rt, ,, whereas, the, ventral, (, v, ), part, receives, ax, ##ons, from, p, ##13, ##9, (, c, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##0, ##fi, ##gur, ##e, 10, —, figure, supplement, 2, ., sub, ##lam, ##ina, ##r, location, and, intrinsic, physiology, of, layer, 6, neurons, ., (, a, and, b, ), positions, of, mc, ##it, ##rine, -, positive, cell, bodies, in, layer, 5, –, 6, are, plotted, ., (, a, ), p, ##16, ##2, (, green, ), and, 56, ##l, (, blue, ), in, ss, ##p, ., (, b, ), p, ##13, ##9, (, green, ), and, 56, ##l, (, blue, ), in, ss, ##s, ., dotted, lines, :, averaged, borders, between, layers, 5, and, 6, ., (, c, ), current, cl, ##amp, responses, of, p, ##16, ##2, ,, 56, ##l, ss, ##p, ,, p, ##13, ##9, ,, 56, ##l, ss, ##s, to, 100, pa, current, injection, ##s, ., input, resistance, (, d, ), whole, cell, cap, ##ac, ##itan, ##ce, (, e, ), of, layer, 6, cells, ., as, ##ter, ##isk, ##s, :, p, <, 0, ., 05, with, turkey, -, k, ##rem, ##er, ’, s, post, hoc, test, ., (, f, and, g, ), current, cl, ##amp, responses, of, labeled, (, f, ), and, nearby, non, -, labeled, (, g, ), neurons, in, 56, ##l, layer, 6, during, current, injection, ., (, h, ), firing, frequency, –, current, injection, plot, for, labeled, and, non, -, labeled, neurons, in, 56, ##l, layer, 6, ., n, =, 16, –, 20, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##1, ##fi, ##gur, ##e, 10, —, figure, supplement, 3, ., 56, ##l, ax, ##onal, projection, from, vis, ##p, to, tha, ##lam, ##us, ., (, a, ), injection, site, ., (, b, ), high, mag, ##ni, ##fication, of, injection, site, ., (, c, ), ax, ##onal, projections, to, tha, ##lam, ##us, avoid, the, dorsal, let, ##eral, gen, ##iculate, nu, ##ce, ##us, (, l, ##g, ##d, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##2, ##fi, ##gur, ##e, 10, —, figure, supplement, 4, ., long, lateral, projections, in, 56, ##l, and, p, ##13, ##9, aa, ##v, –, tre, ##3, ##gm, ##cher, ##ry, ##ha, was, injected, to, 56, ##l, ., (, a, –, c, ), and, p, ##13, ##9, (, d, –, f, ), ., b, and, c, high, mag, ##ni, ##fication, of, designated, area, in, a, ., e, and, f, high, mag, ##ni, ##fication, of, designated, area, in, d, ., 56, ##l, had, call, ##osa, ##l, projections, (, arrow, ##head, in, a, ), but, these, were, not, seen, in, p, ##13, ##9, (, arrow, ##head, in, c, ), ., red, :, anti, -, ha, ,, green, :, anti, -, g, ##fp, ,, blue, :, da, ##pi, ., images, in, d, –, f, and, figure, 10, ##x, were, taken, from, the, same, section, ., doi, :'},\n", - " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", - " 'section_name': 'Lentivirus transgenesis',\n", - " 'text': 'Although only a minority of lentiviral tet lines had reporter expression, the majority of lines with brain expression had highly restricted expression patterns. Some lines had expression only in restricted cell types, including medial prefrontal cortex layer 5 neurons (Figure 1A), retinal ganglion cells projecting axons to superior colliculus (Figure 1B), and Cajal-Retzius cells in cerebral cortex and dentate gyrus (Figure 1C). We had two lines with distinctive expression in cortical layer 4 neurons; TCGS in primary sensory cortices (including primary visual, somatosensory and auditory cortices; Figure 1D) and TCFQ which was devoid of expression in primary sensory cortices but expressed in associative cortices (Figure 1E). We also obtained lines labeling specific cell types, such as thalamocortical projection neurons in the dorsal part of the lateral geniculate complex (LGd; Figure 1F), anatomically clustered subsets of cerebellar granule cells, semilunar cells and a subset of superficial pyramidal neurons in piriform cortex, and a subtype of cortico-thalamic pyramidal neurons in layer 6 of neocortex (see below). Tet reporter expression could be turned off and on by administration of doxycycline (Figure 1—figure supplement 3). For a summary of expression patterns in all lines, see Supplementary file 1.10.7554/eLife.13503.004Figure 1.Example Lentiviral lines.(A) 48L has expression in limbic cortex (A1, coronal section) layer 5 pyramidal cells (A2, magnified image in limbic cortex). (B) Superior colliculus (SC) of TCBV has columnar axons from retina. B1: sagittal section, B2: magnified image of superior colliculus. (C) 52L has expression in piriform cortex (see Figure 9) and Cajal-Retzius cells in dentate gyrus (DG, C2) and cerebral cortex (C3, inset: magnified image of a Cajal-Retzius cell). (D) TCGS has expression in layer 4 neurons of primary sensory cortices (primary somatosensory area: SSp and primary visual area:VISp in D3). (E) TCFQ has nearly complimentary layer 4 expression excluding primary sensory cortices. D1 and E1: sagittal sections, D2 and E2: confocal images of cortex, D3 and E3: dorsal view of whole brains. (F) TCJD has expression in dorsal part of lateral geniculate nucleus (LGd, F1), which projects to primary visual cortex (VISp). F1: sagittal section, F2: higher magnification of LGd, F3: higher magnification of axons in layers 1, 4, and 6 of VISp. Scale bars are 50 μm in A2, B2, C2, F2 and 500 μm in others.DOI:10.7554/eLife.13503.005Figure 1—figure supplement 1.Transgenesis.(A) Lentiviral transgenesis. Lentivirus encoding an enhancer probe is injected into the perivitelline space between the single cell embryo and the zona pellucida. Infected embryos are transferred to foster mothers. Founders are genotyped by PCR and transgene copy number is estimated by southern blot or quantitative PCR and additional rounds of breeding and quantitative genotyping are carried out (not shown) to produce single copy founders. (B) PiggyBac (PB) transgenesis. Plasmid DNA for a PB enhancer probe and PB transposase (PBase) mRNA are injected into the cytosol of single cell embryos. Copy numbers of PB probes are examined as for lentiviral founders. Animals with single copy PB are selected as seed lines for PB transgenesis. Seed lines (P) are crossed with PBase animals, and their children (F1) carrying both PB and PBase are mated with wild-type (WT) animals. PB hops only in F1 PB;PBase mice, and animals with new PB insertion sites are generated in the following generation (F2). Among F2 animals, animals with hopped PB but without PBase are founders of new transgenic lines. PB; prm-PBase females can also be founders since prm-PBase will not be expressed in the female germ line.DOI:10.7554/eLife.13503.006Figure 1—figure supplement 2.Constructs for transgenesis.(A) Lentiviral constructs. Viral sequences were inserted into the lentiviral backbone plasmid. The five variants listed are described in the text. (B) PiggyBac constructs containing tTA or tTA and Cre. Except for hsp-tet3, transcripts from lentiviral constructs use 3’ long terminal repeat (△U3-R–U5 in the backbone plasmid) as poly adenylation signal. In all constructs, tTA and mCitrine share poly adenylation signal sequences. HSPmp: minimal promoter from Hspa1a, tTA: tet transactivator, TRE: tet response element, WPRE: woodchuck hepatitis virus post-transcriptional regulatory element, 2A: FMDV-2A sequence, BGHpA: poly-adenylation signal from bovine growth hormone, HS4ins: insulator sequence from DNase hyper sensitive site in the chicken β-globin gene, PB- 5’ITR and PB-3’ITR: PiggyBac inverted terminal repeat.DOI:10.7554/eLife.13503.007Figure 1—figure supplement 3.Transgene regulation by Doxycycline (Dox).Pregnant 48L females received water with Dox (0.2 mg/ml) or regular water (control) (A–B) P21 (A) and P42 (B) images from 48L animals receiving water lacking Dox. (C–I) Images from 48L animals receiving Dox. Regular water (D–F, second row) and doxycycline water (G–I, third row) were used for 3 weeks from when pups were weaned at P21. Siblings are dissected at P21 (C), P28 (D and G), P35 (E and H) and P42 (F and I).DOI:',\n", - " 'paragraph_id': 6,\n", - " 'tokenizer': 'although, only, a, minority, of, lent, ##iv, ##ira, ##l, te, ##t, lines, had, reporter, expression, ,, the, majority, of, lines, with, brain, expression, had, highly, restricted, expression, patterns, ., some, lines, had, expression, only, in, restricted, cell, types, ,, including, medial, pre, ##front, ##al, cortex, layer, 5, neurons, (, figure, 1a, ), ,, re, ##tina, ##l, gang, ##lion, cells, projecting, ax, ##ons, to, superior, col, ##lic, ##ulus, (, figure, 1b, ), ,, and, ca, ##jal, -, re, ##tz, ##ius, cells, in, cerebral, cortex, and, dent, ##ate, g, ##yr, ##us, (, figure, 1, ##c, ), ., we, had, two, lines, with, distinctive, expression, in, co, ##rti, ##cal, layer, 4, neurons, ;, tc, ##gs, in, primary, sensory, co, ##rti, ##ces, (, including, primary, visual, ,, so, ##mat, ##ose, ##nsor, ##y, and, auditory, co, ##rti, ##ces, ;, figure, 1, ##d, ), and, tc, ##f, ##q, which, was, devoid, of, expression, in, primary, sensory, co, ##rti, ##ces, but, expressed, in, ass, ##oc, ##ia, ##tive, co, ##rti, ##ces, (, figure, 1, ##e, ), ., we, also, obtained, lines, labeling, specific, cell, types, ,, such, as, tha, ##lam, ##oco, ##rti, ##cal, projection, neurons, in, the, dorsal, part, of, the, lateral, gen, ##iculate, complex, (, l, ##g, ##d, ;, figure, 1, ##f, ), ,, anatomical, ##ly, clustered, subset, ##s, of, ce, ##re, ##bella, ##r, gran, ##ule, cells, ,, semi, ##lun, ##ar, cells, and, a, subset, of, superficial, pyramid, ##al, neurons, in, pi, ##ri, ##form, cortex, ,, and, a, sub, ##type, of, co, ##rti, ##co, -, tha, ##lam, ##ic, pyramid, ##al, neurons, in, layer, 6, of, neo, ##cor, ##te, ##x, (, see, below, ), ., te, ##t, reporter, expression, could, be, turned, off, and, on, by, administration, of, do, ##xy, ##cy, ##cl, ##ine, (, figure, 1, —, figure, supplement, 3, ), ., for, a, summary, of, expression, patterns, in, all, lines, ,, see, supplementary, file, 1, ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##4, ##fi, ##gur, ##e, 1, ., example, lent, ##iv, ##ira, ##l, lines, ., (, a, ), 48, ##l, has, expression, in, limb, ##ic, cortex, (, a1, ,, corona, ##l, section, ), layer, 5, pyramid, ##al, cells, (, a2, ,, mag, ##nified, image, in, limb, ##ic, cortex, ), ., (, b, ), superior, col, ##lic, ##ulus, (, sc, ), of, tc, ##b, ##v, has, column, ##ar, ax, ##ons, from, re, ##tina, ., b1, :, sa, ##git, ##tal, section, ,, b, ##2, :, mag, ##nified, image, of, superior, col, ##lic, ##ulus, ., (, c, ), 52, ##l, has, expression, in, pi, ##ri, ##form, cortex, (, see, figure, 9, ), and, ca, ##jal, -, re, ##tz, ##ius, cells, in, dent, ##ate, g, ##yr, ##us, (, d, ##g, ,, c2, ), and, cerebral, cortex, (, c, ##3, ,, ins, ##et, :, mag, ##nified, image, of, a, ca, ##jal, -, re, ##tz, ##ius, cell, ), ., (, d, ), tc, ##gs, has, expression, in, layer, 4, neurons, of, primary, sensory, co, ##rti, ##ces, (, primary, so, ##mat, ##ose, ##nsor, ##y, area, :, ss, ##p, and, primary, visual, area, :, vis, ##p, in, d, ##3, ), ., (, e, ), tc, ##f, ##q, has, nearly, compliment, ##ary, layer, 4, expression, excluding, primary, sensory, co, ##rti, ##ces, ., d, ##1, and, e, ##1, :, sa, ##git, ##tal, sections, ,, d, ##2, and, e, ##2, :, con, ##fo, ##cal, images, of, cortex, ,, d, ##3, and, e, ##3, :, dorsal, view, of, whole, brains, ., (, f, ), tc, ##j, ##d, has, expression, in, dorsal, part, of, lateral, gen, ##iculate, nucleus, (, l, ##g, ##d, ,, f1, ), ,, which, projects, to, primary, visual, cortex, (, vis, ##p, ), ., f1, :, sa, ##git, ##tal, section, ,, f, ##2, :, higher, mag, ##ni, ##fication, of, l, ##g, ##d, ,, f, ##3, :, higher, mag, ##ni, ##fication, of, ax, ##ons, in, layers, 1, ,, 4, ,, and, 6, of, vis, ##p, ., scale, bars, are, 50, μ, ##m, in, a2, ,, b, ##2, ,, c2, ,, f, ##2, and, 500, μ, ##m, in, others, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##5, ##fi, ##gur, ##e, 1, —, figure, supplement, 1, ., trans, ##genesis, ., (, a, ), lent, ##iv, ##ira, ##l, trans, ##genesis, ., lent, ##iv, ##irus, encoding, an, enhance, ##r, probe, is, injected, into, the, per, ##iv, ##ite, ##llin, ##e, space, between, the, single, cell, embryo, and, the, z, ##ona, pe, ##ll, ##uc, ##ida, ., infected, embryo, ##s, are, transferred, to, foster, mothers, ., founders, are, gen, ##otype, ##d, by, pc, ##r, and, trans, ##gen, ##e, copy, number, is, estimated, by, southern, b, ##lot, or, quantitative, pc, ##r, and, additional, rounds, of, breeding, and, quantitative, gen, ##ot, ##yp, ##ing, are, carried, out, (, not, shown, ), to, produce, single, copy, founders, ., (, b, ), pig, ##gy, ##ba, ##c, (, p, ##b, ), trans, ##genesis, ., pl, ##as, ##mi, ##d, dna, for, a, p, ##b, enhance, ##r, probe, and, p, ##b, trans, ##po, ##sas, ##e, (, pba, ##se, ), mrna, are, injected, into, the, cy, ##tos, ##ol, of, single, cell, embryo, ##s, ., copy, numbers, of, p, ##b, probe, ##s, are, examined, as, for, lent, ##iv, ##ira, ##l, founders, ., animals, with, single, copy, p, ##b, are, selected, as, seed, lines, for, p, ##b, trans, ##genesis, ., seed, lines, (, p, ), are, crossed, with, pba, ##se, animals, ,, and, their, children, (, f1, ), carrying, both, p, ##b, and, pba, ##se, are, mated, with, wild, -, type, (, w, ##t, ), animals, ., p, ##b, hop, ##s, only, in, f1, p, ##b, ;, pba, ##se, mice, ,, and, animals, with, new, p, ##b, insertion, sites, are, generated, in, the, following, generation, (, f, ##2, ), ., among, f, ##2, animals, ,, animals, with, hopped, p, ##b, but, without, pba, ##se, are, founders, of, new, trans, ##genic, lines, ., p, ##b, ;, pr, ##m, -, pba, ##se, females, can, also, be, founders, since, pr, ##m, -, pba, ##se, will, not, be, expressed, in, the, female, ge, ##rm, line, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##6, ##fi, ##gur, ##e, 1, —, figure, supplement, 2, ., construct, ##s, for, trans, ##genesis, ., (, a, ), lent, ##iv, ##ira, ##l, construct, ##s, ., viral, sequences, were, inserted, into, the, lent, ##iv, ##ira, ##l, backbone, pl, ##as, ##mi, ##d, ., the, five, variants, listed, are, described, in, the, text, ., (, b, ), pig, ##gy, ##ba, ##c, construct, ##s, containing, tt, ##a, or, tt, ##a, and, cr, ##e, ., except, for, hs, ##p, -, te, ##t, ##3, ,, transcript, ##s, from, lent, ##iv, ##ira, ##l, construct, ##s, use, 3, ’, long, terminal, repeat, (, [UNK], -, r, –, u, ##5, in, the, backbone, pl, ##as, ##mi, ##d, ), as, poly, aden, ##yla, ##tion, signal, ., in, all, construct, ##s, ,, tt, ##a, and, mc, ##it, ##rine, share, poly, aden, ##yla, ##tion, signal, sequences, ., hs, ##pm, ##p, :, minimal, promoter, from, hs, ##pa, ##1, ##a, ,, tt, ##a, :, te, ##t, trans, ##act, ##iva, ##tor, ,, tre, :, te, ##t, response, element, ,, w, ##pre, :, wood, ##chu, ##ck, hepatitis, virus, post, -, transcription, ##al, regulatory, element, ,, 2a, :, fm, ##d, ##v, -, 2a, sequence, ,, b, ##gh, ##pa, :, poly, -, aden, ##yla, ##tion, signal, from, bo, ##vine, growth, hormone, ,, hs, ##4, ##ins, :, ins, ##ulator, sequence, from, dna, ##se, hyper, sensitive, site, in, the, chicken, β, -, g, ##lo, ##bin, gene, ,, p, ##b, -, 5, ’, it, ##r, and, p, ##b, -, 3, ’, it, ##r, :, pig, ##gy, ##ba, ##c, inverted, terminal, repeat, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 00, ##7, ##fi, ##gur, ##e, 1, —, figure, supplement, 3, ., trans, ##gen, ##e, regulation, by, do, ##xy, ##cy, ##cl, ##ine, (, do, ##x, ), ., pregnant, 48, ##l, females, received, water, with, do, ##x, (, 0, ., 2, mg, /, ml, ), or, regular, water, (, control, ), (, a, –, b, ), p, ##21, (, a, ), and, p, ##42, (, b, ), images, from, 48, ##l, animals, receiving, water, lacking, do, ##x, ., (, c, –, i, ), images, from, 48, ##l, animals, receiving, do, ##x, ., regular, water, (, d, –, f, ,, second, row, ), and, do, ##xy, ##cy, ##cl, ##ine, water, (, g, –, i, ,, third, row, ), were, used, for, 3, weeks, from, when, pup, ##s, were, we, ##ane, ##d, at, p, ##21, ., siblings, are, di, ##sse, ##cted, at, p, ##21, (, c, ), ,, p, ##28, (, d, and, g, ), ,, p, ##35, (, e, and, h, ), and, p, ##42, (, f, and, i, ), ., doi, :'},\n", - " {'article_id': '931457be4cb80a456fe566b0722649f5',\n", - " 'section_name': 'An altered classification of layer 6 cortico-thalamic pyramidal neurons',\n", - " 'text': 'In order to complement our phenotypic analyses of differences between subtypes of L6 corticothalamic neurons, we also analyzed their RNAseq profiles and compared them to VISp layer 6 pyramidal neurons from the Ntsr1-Cre line, which is also known to have layer 6 specific expression in the cortex (Gong et al., 2007). Ntsr1-Cre labels virtually all primary CT neurons in layer 6 and also has projection to RTN (Bortone et al., 2014; Kim et al., 2014; Olsen et al., 2012). Clustering samples by correlations between gene expression vectors revealed two main clusters: those from 56L and all others (Figure 11A). Samples from P162 and P139 are intermingled in the cluster, implying they have quite similar RNA expression profiles. Analysis of differentially expressed genes also showed clear differences between the two main groups. There were 1869 genes differentially expressed among all sample groups (false discovery rate (FDR) < 0.01), and most differentially expressed genes showed bimodal patterns; high expressions in one group and low expressions in the other (Figure 11B and C). We also examined the expression of previously identified layer 6 marker genes (Molyneaux et al., 2007; Zeisel et al., 2015) and of genes used to generate BAC-Cre lines having layer 6 expression (Harris et al., 2014). Most of these known layer 6 markers are expressed both in the Ntsr1-cre group and in 56L (including the Ntsr1 gene itself) or were present only in the Ntsr1-cre lines. None were reliable markers for the 56L population (see Figure 11—figure supplement 1 and supplemental Note). We also examined expression profile of entorhinal cortical layer 6 cells from P038 in addition to isocortical layer 6 cells. Based on RNAseq expression profiles, P038 cells belonged to the Ntsr1-cre group but expressed unique set of genes (see Figure 11—figure supplement 2).10.7554/eLife.13503.033Figure 11.Two main subtypes of L6 CT neurons distinguished by gene expression .(A) Clustering of L6 CT neuron samples based on correlations (color scale) between expression profiles. (B) Heat map of normalized gene expression (TPM) of 50 genes with lowest ANOVA p-values. Except for Plcxd2 (asterisk), the genes had dominant expression in either Ntsr1/P162/P139 or 56L. (C) Coverage histograms of differentially expressed genes. Examples of genes expressed in P162/P139 (Tle4 and Rgs4), 56L (Nptxr and Cacna1g), P139 (Atp1b2), and P162 (Ifitm2). Scale bars: 100 counts. (D–F) In situ hybridization for Tle4 (red) and Bmp3 (green) in wild type P10 animal SSp. (E) high-magnification image. (F) Proportion of cells expressing Tle4 and Bmp3 in SSp layer 6. (G–O) In situ hybridization for mCitrine and Tle4 (G, J, and M) or Bmp3 (H, K and N) in P162 SSp (G and H), P139 SSs (J and K) and P56 SSp (M and N). (I, L, O) Proportions of mCitrine^+ cells that expressTle4 or Bmp3 and converse proportions of cells expressing the dominant marker (Tle4 for I,L Bmp3 for O) that are mCitrine^+ from P162 (I), P139 (L) and 56L (O). Colors in bar graphs represent in situ signal patterns (Red: cells with marker gene but not mCitrine, Green: cells with mCitrine signal but not marker gene, and Yellow: cells with both marker and mCitrine signals). Scale bar in D: 500 μm, in E: 50 μm.DOI:10.7554/eLife.13503.034Figure 11—figure supplement 1.Expression of known L6 marker genes.(A) Expression levels of known layer 6 marker genes (Molyneaux et al., 2007). (B) Expression levels of genes used to make BAC transgenic lines with layer 6 expression (Harris et al., 2014). (C) Layer 6 marker genes found by single cell RNAseq (Zeisel et al., 2015).DOI:10.7554/eLife.13503.035Figure 11—figure supplement 2.P038 entorhinal cortex layer 6 neurons are a distinct population.(A) Sample clustering (B) Heat map for top 100 genes with lowest ANOVA p-values. Arrows: genes shown in C. (C) Example of genes uniquely expressed in P038 (Nr4a2 and Parm1), Ntsr1 group and 56L markers (Tle4 and Bmp3), and selectively not expressed in P038 (Pcdh7 and Mef2c). y-axes: TPM.DOI:',\n", - " 'paragraph_id': 37,\n", - " 'tokenizer': 'in, order, to, complement, our, ph, ##eno, ##typic, analyses, of, differences, between, sub, ##type, ##s, of, l, ##6, co, ##rti, ##cot, ##hala, ##mic, neurons, ,, we, also, analyzed, their, rna, ##se, ##q, profiles, and, compared, them, to, vis, ##p, layer, 6, pyramid, ##al, neurons, from, the, nt, ##sr, ##1, -, cr, ##e, line, ,, which, is, also, known, to, have, layer, 6, specific, expression, in, the, cortex, (, gong, et, al, ., ,, 2007, ), ., nt, ##sr, ##1, -, cr, ##e, labels, virtually, all, primary, ct, neurons, in, layer, 6, and, also, has, projection, to, rt, ##n, (, bo, ##rton, ##e, et, al, ., ,, 2014, ;, kim, et, al, ., ,, 2014, ;, olsen, et, al, ., ,, 2012, ), ., cluster, ##ing, samples, by, correlation, ##s, between, gene, expression, vectors, revealed, two, main, clusters, :, those, from, 56, ##l, and, all, others, (, figure, 11, ##a, ), ., samples, from, p, ##16, ##2, and, p, ##13, ##9, are, inter, ##ming, ##led, in, the, cluster, ,, implying, they, have, quite, similar, rna, expression, profiles, ., analysis, of, differential, ##ly, expressed, genes, also, showed, clear, differences, between, the, two, main, groups, ., there, were, 1869, genes, differential, ##ly, expressed, among, all, sample, groups, (, false, discovery, rate, (, f, ##dr, ), <, 0, ., 01, ), ,, and, most, differential, ##ly, expressed, genes, showed, bi, ##mo, ##dal, patterns, ;, high, expressions, in, one, group, and, low, expressions, in, the, other, (, figure, 11, ##b, and, c, ), ., we, also, examined, the, expression, of, previously, identified, layer, 6, marker, genes, (, mo, ##lyn, ##eaux, et, al, ., ,, 2007, ;, ze, ##ise, ##l, et, al, ., ,, 2015, ), and, of, genes, used, to, generate, ba, ##c, -, cr, ##e, lines, having, layer, 6, expression, (, harris, et, al, ., ,, 2014, ), ., most, of, these, known, layer, 6, markers, are, expressed, both, in, the, nt, ##sr, ##1, -, cr, ##e, group, and, in, 56, ##l, (, including, the, nt, ##sr, ##1, gene, itself, ), or, were, present, only, in, the, nt, ##sr, ##1, -, cr, ##e, lines, ., none, were, reliable, markers, for, the, 56, ##l, population, (, see, figure, 11, —, figure, supplement, 1, and, supplemental, note, ), ., we, also, examined, expression, profile, of, en, ##tor, ##hin, ##al, co, ##rti, ##cal, layer, 6, cells, from, p, ##0, ##38, in, addition, to, iso, ##cor, ##tical, layer, 6, cells, ., based, on, rna, ##se, ##q, expression, profiles, ,, p, ##0, ##38, cells, belonged, to, the, nt, ##sr, ##1, -, cr, ##e, group, but, expressed, unique, set, of, genes, (, see, figure, 11, —, figure, supplement, 2, ), ., 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##3, ##fi, ##gur, ##e, 11, ., two, main, sub, ##type, ##s, of, l, ##6, ct, neurons, distinguished, by, gene, expression, ., (, a, ), cluster, ##ing, of, l, ##6, ct, ne, ##uron, samples, based, on, correlation, ##s, (, color, scale, ), between, expression, profiles, ., (, b, ), heat, map, of, normal, ##ized, gene, expression, (, t, ##pm, ), of, 50, genes, with, lowest, an, ##ova, p, -, values, ., except, for, plc, ##x, ##d, ##2, (, as, ##ter, ##isk, ), ,, the, genes, had, dominant, expression, in, either, nt, ##sr, ##1, /, p, ##16, ##2, /, p, ##13, ##9, or, 56, ##l, ., (, c, ), coverage, his, ##to, ##gram, ##s, of, differential, ##ly, expressed, genes, ., examples, of, genes, expressed, in, p, ##16, ##2, /, p, ##13, ##9, (, t, ##le, ##4, and, r, ##gs, ##4, ), ,, 56, ##l, (, np, ##t, ##x, ##r, and, ca, ##c, ##na, ##1, ##g, ), ,, p, ##13, ##9, (, atp, ##1, ##b, ##2, ), ,, and, p, ##16, ##2, (, if, ##it, ##m, ##2, ), ., scale, bars, :, 100, counts, ., (, d, –, f, ), in, situ, hybrid, ##ization, for, t, ##le, ##4, (, red, ), and, b, ##mp, ##3, (, green, ), in, wild, type, p, ##10, animal, ss, ##p, ., (, e, ), high, -, mag, ##ni, ##fication, image, ., (, f, ), proportion, of, cells, expressing, t, ##le, ##4, and, b, ##mp, ##3, in, ss, ##p, layer, 6, ., (, g, –, o, ), in, situ, hybrid, ##ization, for, mc, ##it, ##rine, and, t, ##le, ##4, (, g, ,, j, ,, and, m, ), or, b, ##mp, ##3, (, h, ,, k, and, n, ), in, p, ##16, ##2, ss, ##p, (, g, and, h, ), ,, p, ##13, ##9, ss, ##s, (, j, and, k, ), and, p, ##56, ss, ##p, (, m, and, n, ), ., (, i, ,, l, ,, o, ), proportions, of, mc, ##it, ##rine, ^, +, cells, that, express, ##tle, ##4, or, b, ##mp, ##3, and, converse, proportions, of, cells, expressing, the, dominant, marker, (, t, ##le, ##4, for, i, ,, l, b, ##mp, ##3, for, o, ), that, are, mc, ##it, ##rine, ^, +, from, p, ##16, ##2, (, i, ), ,, p, ##13, ##9, (, l, ), and, 56, ##l, (, o, ), ., colors, in, bar, graphs, represent, in, situ, signal, patterns, (, red, :, cells, with, marker, gene, but, not, mc, ##it, ##rine, ,, green, :, cells, with, mc, ##it, ##rine, signal, but, not, marker, gene, ,, and, yellow, :, cells, with, both, marker, and, mc, ##it, ##rine, signals, ), ., scale, bar, in, d, :, 500, μ, ##m, ,, in, e, :, 50, μ, ##m, ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##4, ##fi, ##gur, ##e, 11, —, figure, supplement, 1, ., expression, of, known, l, ##6, marker, genes, ., (, a, ), expression, levels, of, known, layer, 6, marker, genes, (, mo, ##lyn, ##eaux, et, al, ., ,, 2007, ), ., (, b, ), expression, levels, of, genes, used, to, make, ba, ##c, trans, ##genic, lines, with, layer, 6, expression, (, harris, et, al, ., ,, 2014, ), ., (, c, ), layer, 6, marker, genes, found, by, single, cell, rna, ##se, ##q, (, ze, ##ise, ##l, et, al, ., ,, 2015, ), ., doi, :, 10, ., 75, ##54, /, eli, ##fe, ., 135, ##0, ##3, ., 03, ##5, ##fi, ##gur, ##e, 11, —, figure, supplement, 2, ., p, ##0, ##38, en, ##tor, ##hin, ##al, cortex, layer, 6, neurons, are, a, distinct, population, ., (, a, ), sample, cluster, ##ing, (, b, ), heat, map, for, top, 100, genes, with, lowest, an, ##ova, p, -, values, ., arrows, :, genes, shown, in, c, ., (, c, ), example, of, genes, uniquely, expressed, in, p, ##0, ##38, (, nr, ##4, ##a, ##2, and, par, ##m, ##1, ), ,, nt, ##sr, ##1, group, and, 56, ##l, markers, (, t, ##le, ##4, and, b, ##mp, ##3, ), ,, and, selective, ##ly, not, expressed, in, p, ##0, ##38, (, pc, ##dh, ##7, and, me, ##f, ##2, ##c, ), ., y, -, axes, :, t, ##pm, ., doi, :'},\n", - " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", - " 'section_name': 'Results',\n", - " 'text': \"Research general issues:Abi-Rached JM: The implications of the new brain sciences. 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., 105, ##7, /, bio, ##so, ##c, ., 2012, ., 21, ., wu, kc, :, soul, -, making, in, ne, ##uro, ##ima, ##ging, ?, am, j, bio, ##eth, 2008, ,, 8, (, 9, ), :, 21, -, 22, ., doi, :, 10, ., 108, ##0, /, 152, ##65, ##16, ##0, ##80, ##24, ##12, ##53, ##6, ., za, ##rz, ##ec, ##z, ##ny, a, ,, ca, ##ulf, ##ield, t, :, legal, liability, and, research, ethics, boards, :, the, case, of, ne, ##uro, ##ima, ##ging, and, incident, ##al, findings, ., int, j, law, psychiatry, 2012, ,, 35, (, 2, ), :, si, ##13, ##7, -, si, ##14, ##5, ., doi, :, 10, ., 1016, /, j, ., i, ##j, ##lp, ., 2011, ., 12, ., 00, ##5, .'},\n", - " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", - " 'section_name': 'Results',\n", - " 'text': 'Book Chapters:Arentshorst ME, Broerse JEW, Roelofsen A, de Cock Buning T: Towards responsible neuroimaging applications in health care: guiding visions of scientists and technology developers. In Responsible Innovation 1: Innovative Solutions for Global Issues. Edited by Jeroen van den Hoven. Dordrecht: Springer; 2014: 255-280.Canli T, Amin Z: Neuroimaging of emotion and personality: ethical considerations. In Neuroethics: An Introduction with Readings. Edited by Martha J. Farah. Cambridge, Mass.: MIT Press; 2010:147-154.Canli T: When genes and brains unite: ethical implications of genomic neuroimaging. In Neuroethics: Defining the Issues in Theory, Practice and Policy. Edited by Judith Illes. Oxford: Oxford University Press; 2006: 169-184.Farrah MJ, Gillihan SJ: Neuroimaging in clinical psychiatry. In Neuroethics in Practice. Edited by Anjan Chatterjee, Martha J. Farah. New York: Oxford University Press; 2013: 128-148.Frederico C, Lombera S, Illes J: Intersecting complexities in neuroimaging and neuroethics. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011: 377-387.Hadskis MR, Schmidt MH: Pediatric neuroimaging research. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011:389-404.Illes J et al.: Ethical and practical considerations in managing incidental findings in functional magnetic resonance imaging. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 104-114.Illes J, Racine E: Imaging or imagining? A neuroethics challenge informed by genetics. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 140-162.Illes J: Neuroethics in a new era of neuroimaging. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 99-103.Illes J, Rosen A, Greicius M, Racine E: Prospects for prediction: ethics analysis of neuroimaging in Alzheimer’s disease. In Imaging and the Aging Brain. Edited by Mony J. de Leon, Donald A. Snider, Howard Federoff. Boston: Blackwell; 2007: 278-295.Kahlaoui K et al.: Neurobiological and neuroethical perspectives on the contribution of functional neuroimaging to the study of aging in the brain. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011: 495-512.Karanasion IS, Biniaris CG, Marsh AJ: Ethical issues of brain functional imaging: reading your mind. In Medical and Care Compunetics 5. Edited by Lodewijk Bos. Amsterdam: IOS Press; 2008: 310-320.Koch T: Images of uncertainty: two cases of neuroimages and what they cannot show. In Neurotechnology: Premises, Potential, and Problems. Edited by James Giordano. Boca Raton: CRC Press; 2012: 47-57.Kulynych J: Legal and ethical issues in neuroimaging research: human subjects protection, medical privacy, and the public communication of research results. In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 115-133.Mamourian A: Incidental findings on research functional MR images: should we look? In Defining Right and Wrong in Brain Science: Essential Readings in Neuroethics. Edited by Walter Glannon. New York: Dana Press; 2007: 134-139.Owen AM: Functional magnetic resonance imaging, covert awareness, and brain injury. In The Oxford Handbook of Neuroethics. Edited by Judy Illes, Barbara J. Sahakian. Oxford: Oxford University Press; 2011:135-147.Phelps EA, Thomas LA: Race, behavior, and the brain: the role of neuroimaging in understanding complex social behaviors. In Neuroethics: An Introduction with Readings. Edited by Martha J. Farah. Cambridge, Mass.: MIT Press; 2010: 191-200.Racine E, Bell E, Illes J: Can we read minds? ethical challenges and responsibilities in the use of neuroimaging research. In Scientific and Philosophical Perspectives in Neuroethics. Edited by James J. Giordano, Bert Gordijn. Cambridge: Cambridge University Press; 2010: 244-270.Raschle N et al.: Pediatric neuroimaging in early childhood and infancy: challenges and practical guidelines. In The Neurosciences and Music IV: Learning and Memory. Edited by Katie Overy. Boston, Mass.: Blackwell; 2012: 43-50.Toole C, Zarzeczny A, Caulfield T: Research ethics challenges in neuroimaging research: a Canadian perspective. In International Neurolaw: A Comparative Analysis. Edited by Tade Matthias Spranger. Berlin: Springer; 2012: 89-101.Ulmer S et al.: Incidental findings in neuroimaging research: ethical considerations. In fMRI: Basics and Clinical Applications. Edited by Stephan Ulmer, Olav Jansen. Berlin: Springer; 2013: 311-318.Vanmeter J: Neuroimaging: thinking in pictures. In Scientific and Philosophical Perspectives in Neuroethics. Edited by James J. Giordano, Bert Gordijn. Cambridge: Cambridge University Press; 2010: 230-243.',\n", - " 'paragraph_id': 12,\n", - " 'tokenizer': 'book, chapters, :, aren, ##ts, ##hor, ##st, me, ,, bro, ##ers, ##e, jew, ,, roe, ##lo, ##fs, ##en, a, ,, de, cock, bun, ##ing, t, :, towards, responsible, ne, ##uro, ##ima, ##ging, applications, in, health, care, :, guiding, visions, of, scientists, and, technology, developers, ., in, responsible, innovation, 1, :, innovative, solutions, for, global, issues, ., edited, by, je, ##ro, ##en, van, den, hove, ##n, ., do, ##rd, ##recht, :, springer, ;, 2014, :, 255, -, 280, ., can, ##li, t, ,, amin, z, :, ne, ##uro, ##ima, ##ging, of, emotion, and, personality, :, ethical, considerations, ., in, ne, ##uro, ##eth, ##ics, :, an, introduction, with, readings, ., edited, by, martha, j, ., far, ##ah, ., cambridge, ,, mass, ., :, mit, press, ;, 2010, :, 147, -, 154, ., can, ##li, t, :, when, genes, and, brains, unite, :, ethical, implications, of, gen, ##omic, ne, ##uro, ##ima, ##ging, ., in, 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issues, of, brain, functional, imaging, :, reading, your, mind, ., in, medical, and, care, com, ##pu, ##net, ##ics, 5, ., edited, by, lo, ##de, ##wi, ##jk, bo, ##s, ., amsterdam, :, ios, press, ;, 2008, :, 310, -, 320, ., koch, t, :, images, of, uncertainty, :, two, cases, of, ne, ##uro, ##ima, ##ges, and, what, they, cannot, show, ., in, ne, ##uro, ##tech, ##nology, :, premises, ,, potential, ,, and, problems, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ;, 2012, :, 47, -, 57, ., ku, ##lyn, ##ych, j, :, legal, and, ethical, issues, in, ne, ##uro, ##ima, ##ging, research, :, human, subjects, protection, ,, medical, privacy, ,, and, the, public, communication, of, research, results, ., in, defining, right, and, wrong, in, brain, science, :, essential, readings, in, ne, ##uro, ##eth, ##ics, ., edited, by, walter, g, ##lan, ##non, ., new, york, :, dana, press, ;, 2007, :, 115, -, 133, ., ma, ##mour, ##ian, a, :, incident, ##al, findings, on, research, functional, mr, images, :, should, we, look, ?, in, defining, right, and, wrong, in, brain, science, :, essential, readings, in, ne, ##uro, ##eth, ##ics, ., edited, by, walter, g, ##lan, ##non, ., new, york, :, dana, press, ;, 2007, :, 134, -, 139, ., owen, am, :, functional, magnetic, resonance, imaging, ,, covert, awareness, ,, and, brain, injury, ., in, the, oxford, handbook, of, ne, ##uro, ##eth, ##ics, ., edited, by, judy, ill, ##es, ,, barbara, j, ., sa, ##hak, ##ian, ., oxford, :, oxford, university, press, ;, 2011, :, 135, -, 147, ., phelps, ea, ,, thomas, la, :, race, ,, behavior, ,, and, the, brain, :, the, role, of, ne, ##uro, ##ima, ##ging, in, understanding, complex, social, behaviors, ., in, ne, ##uro, ##eth, ##ics, :, an, introduction, with, readings, ., edited, by, martha, j, ., far, ##ah, ., cambridge, ,, mass, ., :, mit, press, ;, 2010, :, 191, -, 200, ., ra, ##cine, e, ,, bell, e, ,, ill, ##es, j, :, can, we, read, minds, ?, ethical, challenges, and, responsibilities, in, the, use, of, ne, ##uro, ##ima, ##ging, research, ., in, scientific, and, philosophical, perspectives, in, ne, ##uro, ##eth, ##ics, ., edited, by, james, j, ., gi, ##ord, ##ano, ,, bert, go, ##rdi, ##jn, ., cambridge, :, cambridge, university, press, ;, 2010, :, 244, -, 270, ., ras, ##ch, ##le, n, et, al, ., :, pediatric, ne, ##uro, ##ima, ##ging, in, early, childhood, and, infancy, :, challenges, and, practical, guidelines, ., in, the, neuroscience, ##s, and, music, iv, :, learning, and, memory, ., edited, by, katie, over, ##y, ., boston, ,, mass, ., :, blackwell, ;, 2012, :, 43, -, 50, ., tool, ##e, c, ,, za, ##rz, ##ec, ##z, ##ny, a, ,, ca, ##ulf, ##ield, t, :, research, ethics, challenges, in, ne, ##uro, ##ima, ##ging, research, :, a, canadian, perspective, ., in, international, ne, ##uro, ##law, :, a, comparative, analysis, ., edited, by, tad, ##e, matthias, sprang, ##er, ., berlin, :, springer, ;, 2012, :, 89, -, 101, ., ul, ##mer, s, et, al, ., :, incident, 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Law Psychol Rev 2003, 27:29-54.',\n", - " 'paragraph_id': 13,\n", - " 'tokenizer': 'ne, ##uro, ##gen, ##etic, ##s, :, choosing, deaf, ##ness, ., arch, di, ##s, child, 2003, ,, 88, (, 1, ), :, 24, ., ab, ##re, ##u, al, ##ves, fr, ,, qui, ##nta, ##ni, ##l, ##ha, rib, ##eiro, f, ##de, a, :, diagnosis, routine, and, approach, in, genetic, sensor, ##ine, ##ural, hearing, loss, ., bra, ##z, j, ot, ##or, ##hin, ##olar, ##yn, ##gol, 2007, ,, 73, (, 3, ), :, 412, -, 417, ., al, ##cala, ##y, rn, et, al, ., :, michael, j, ., fox, foundation, l, ##rr, ##k, ##2, consortium, :, geographical, differences, in, returning, genetic, research, data, to, study, participants, ., gene, ##t, med, 2014, ,, 16, (, 8, ), :, 64, ##4, -, 64, ##5, ., doi, :, 10, ., 103, ##8, /, gi, ##m, ., 2014, ., 55, ., alonso, me, et, al, ., :, homo, ##zy, ##gos, ##ity, in, huntington, \\', s, disease, :, new, ethical, dilemma, caused, by, molecular, diagnosis, ., cl, ##in, gene, ##t, 2002, ,, 61, (, 6, ), :, 43, ##7, -, 44, ##2, ., an, ##ido, a, ,, carlson, l, ##m, ,, sherman, sl, :, attitudes, toward, fragile, x, mutation, carrier, testing, from, women, identified, in, a, general, population, survey, ., j, gene, ##t, co, ##un, ##s, 2007, ,, 16, (, 1, ), :, 97, -, 104, ., doi, :, 10, ., 100, ##7, /, s, ##10, ##8, ##9, ##7, -, 00, ##6, -, 90, ##49, -, 0, ., ar, ##nos, ks, :, the, implications, of, genetic, testing, for, deaf, ##ness, ., ear, hear, 2003, ,, 24, (, 4, ), :, 324, -, 331, ., doi, :, 10, ., 109, ##7, /, 01, ., au, ##d, ., 000, ##00, ##7, ##9, ##80, ##0, ., 64, ##7, ##41, ., cf, ., ar, ##nos, ks, :, ethical, and, social, implications, of, genetic, testing, for, communication, disorders, ., j, com, ##mun, di, ##sor, ##d, 2008, ,, 41, (, 5, ), :, 44, ##4, -, 45, ##7, ., doi, :, 10, ., 1016, /, j, ., jc, ##om, ##dis, ., 2008, ., 03, ., 001, ., ass, ##cher, e, ,, ko, ##ops, b, ##j, :, the, right, not, to, know, and, pre, ##im, ##pl, ##anta, ##tion, genetic, diagnosis, for, huntington, \\', s, 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Alcohol Clin Exp Res 2013, 37(9):1451-1455. doi: 10.1111/acer.12115.\",\n", - " 'paragraph_id': 16,\n", - " 'tokenizer': \"ne, ##uro, ##bio, ##mark, ##ers, :, arias, jj, ,, karl, ##aw, ##ish, j, :, confidential, ##ity, in, pre, ##cl, ##ini, ##cal, alzheimer, disease, studies, :, when, research, and, medical, records, meet, ., ne, ##uro, ##logy, 2014, ,, 82, (, 8, ), :, 72, ##5, -, 72, ##9, ., doi, :, 10, ., 121, ##2, /, w, ##nl, ., 000, ##00, ##00, ##00, ##00, ##00, ##15, ##3, ., cho, ##ud, ##hur, ##y, s, ,, gold, i, ,, ki, ##rma, ##yer, l, ##j, :, from, brain, image, to, the, bush, doctrine, :, critical, neuroscience, and, the, political, uses, of, ne, ##uro, ##tech, ##nology, ., aj, ##ob, ne, ##uro, ##sc, ##i, 2010, ,, 1, (, 2, ), :, 17, -, 19, ., doi, :, 10, ., 108, ##0, /, 215, ##0, ##7, ##7, ##41, ##00, ##36, ##9, ##9, ##28, ##0, ., dani, ka, ,, mccormick, mt, ,, muir, kw, :, brain, les, ##ion, volume, and, capacity, for, consent, in, stroke, trials, :, potential, regulatory, 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113, ##6, /, med, ##eth, ##ics, -, 2013, -, 1016, ##15, ., far, ##ah, m, ##j, ,, gill, ##ih, ##an, s, ##j, :, the, puzzle, of, ne, ##uro, ##ima, ##ging, and, psychiatric, diagnosis, :, technology, and, nos, ##ology, in, an, evolving, discipline, ., aj, ##ob, ne, ##uro, ##sc, ##i, 2012, ,, 3, (, 4, ), :, 31, -, 41, ., doi, :, 10, ., 108, ##0, /, 215, ##0, ##7, ##7, ##40, ., 2012, ., 71, ##30, ##7, ##2, ., ga, ##uth, ##ier, s, ,, le, ##uz, ##y, a, ,, ra, ##cine, e, ,, rosa, -, net, ##o, p, :, diagnosis, and, management, of, alzheimer, ', s, disease, :, past, ,, present, and, future, ethical, issues, ., pro, ##g, ne, ##uro, ##bio, ##l, 2013, ,, 110, :, 102, -, 113, ., doi, :, 10, ., 1016, /, j, ., p, ##ne, ##uro, ##bio, ., 2013, ., 01, ., 00, ##3, ., gi, ##ord, ##ano, j, ,, abrams, ##on, k, ,, bo, ##swell, mv, :, pain, assessment, :, subject, ##ivity, ,, object, ##ivity, ,, and, the, use, of, ne, ##uro, ##tech, ##nology, ., pain, physician, 2010, ,, 13, (, 4, ), :, 305, -, 315, ., go, 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##3, ., doi, :, 10, ., 121, ##2, /, w, ##nl, ., 0, ##b, ##01, ##3, ##e, ##31, ##8, ##23, ##2, ##ac, ##1, ##a, ., klein, e, ,, karl, ##aw, ##ish, j, :, ethical, issues, in, the, ne, ##uro, ##logy, of, aging, and, cognitive, decline, ., hand, ##b, cl, ##in, ne, ##uro, ##l, 2013, ,, 118, :, 233, -, 242, ., doi, :, 10, ., 1016, /, b, ##9, ##7, ##8, -, 0, -, 44, ##4, -, 53, ##50, ##1, -, 6, ., 000, ##20, -, 2, ., la, ##khan, se, ,, vie, ##ira, k, ##f, ,, ham, ##lat, e, :, bio, ##mark, ##ers, in, psychiatry, :, draw, ##backs, and, potential, for, mis, ##use, ., int, arch, med, 2010, ,, 3, :, 1, ., doi, :, 10, ., 118, ##6, /, 1755, -, 76, ##8, ##2, -, 3, -, 1, ., le, ##hr, ##ner, a, ,, ye, ##hu, ##da, r, :, bio, ##mark, ##ers, of, pts, ##d, :, military, applications, and, considerations, ., eu, ##r, j, psycho, ##tra, ##uma, ##to, ##l, 2014, ,, 5, ., doi, :, 10, ., 340, ##2, /, e, ##j, ##pt, ., v, ##5, ., 237, ##9, ##7, ., matt, ##sson, n, ,, bra, ##x, d, ,, ze, ##tter, ##berg, h, :, to, know, 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{'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", - " 'section_name': 'Results',\n", - " 'text': \"Issues Concerning Pediatric Subjects/Patients:Altavilla A et al.: Activity of ethics committees in Europe on issues related to clinical trials in paediatrics: results of a survey. 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##nu, ., 2010, ., 07, ., 01, ##1, .\"},\n", - " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", - " 'section_name': 'Results',\n", - " 'text': 'Mood stabilizers/anti-depressants/antipsychotic and nootropic agents:Adam D, Kasper S, Moller HJ, Singer EA, 3rd European Expert Forum on Ethical Evaluation of Placebo-Controlled Studies in Depression: Placebo-controlled trials in major depression are necessary and ethically justifiable: how to improve the communication between researchers and ethical committees. 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PLoS One 2013, 8(5):e62609. doi:10.1371/journal.pone.0062609.',\n", - " 'paragraph_id': 22,\n", - " 'tokenizer': 'mood, stabilize, ##rs, /, anti, -, de, ##press, ##ants, /, anti, ##psy, ##cho, ##tic, and, no, ##ot, ##rop, ##ic, agents, :, adam, d, ,, ka, ##sper, s, ,, mo, ##ller, h, ##j, ,, singer, ea, ,, 3rd, european, expert, forum, on, ethical, evaluation, of, place, ##bo, -, controlled, studies, in, depression, :, place, ##bo, -, controlled, trials, in, major, depression, are, necessary, and, ethical, ##ly, just, ##if, ##iable, :, how, to, improve, the, communication, between, researchers, and, ethical, committees, ., eu, ##r, arch, psychiatry, cl, ##in, ne, ##uro, ##sc, ##i, 2005, ,, 255, (, 4, ), :, 258, -, 260, ., doi, :, 10, ., 100, ##7, /, s, ##00, ##40, ##6, -, 00, ##4, -, 05, ##55, -, 5, ., ag, ##ius, m, ,, bradley, v, ,, ryan, d, ,, za, ##man, r, :, the, ethics, of, identifying, and, treating, psycho, ##sis, early, ., ps, ##ych, ##ia, ##tr, dan, ##ub, 2008, ,, 20, (, 1, ), 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##8, ##9, ., doi, :, 10, ., 137, ##1, /, journal, ., p, ##bio, ., 100, ##12, ##8, ##9, ., vo, ##ari, ##no, n, :, rec, ##ons, ##ider, ##ing, the, concept, of, ‘, dual, -, use, ’, in, the, context, of, neuroscience, research, ., bio, ##eth, ##ique, ##on, ##line, 2014, ,, 3, /, 16, :, 1, -, 6, ., walsh, c, :, youth, justice, and, neuroscience, :, a, dual, -, use, dilemma, ., br, j, cr, ##imi, ##no, ##l, 2011, ,, 51, (, 1, ), :, 21, -, 29, ., doi, :, 10, ., 109, ##3, /, b, ##j, ##c, /, az, ##q, ##0, ##6, ##1, ., wheel, ##is, m, ,, dan, ##do, m, :, ne, ##uro, ##biology, :, a, case, study, on, the, imminent, mil, ##ita, ##rization, of, biology, ., revue, internationale, de, la, croix, -, rouge, /, international, review, of, the, red, cross, 2005, ,, 87, (, 85, ##9, ), :, 56, ##3, -, 57, ##1, ., doi, :, 10, ., 101, ##7, /, s, ##18, ##16, ##38, ##31, ##00, ##18, ##43, ##8, ##3, ., zimmerman, e, ,, ra, ##cine, e, ., ethical, issues, in, the, translation, of, social, neuroscience, :, a, policy, analysis, of, current, guidelines, for, public, dialogue, in, human, research, ., account, res, 2012, ,, 19, (, 1, ), :, 27, -, 46, ., doi, :, 10, ., 108, ##0, /, 08, ##9, ##8, ##9, ##6, ##21, ., 2012, ., 650, ##9, ##49, ., z, ##ona, ##na, h, :, physicians, must, honor, refusal, of, treatment, to, restore, compete, ##ncy, by, non, -, dangerous, inmates, on, death, row, ., j, law, med, ethics, 2010, ,, 38, (, 4, ), :, 76, ##4, -, 77, ##3, ., doi, :, 10, ., 111, ##1, /, j, ., 1748, -, 720, ##x, ., 2010, ., 00, ##53, ##0, ., x, .'},\n", - " {'article_id': '297f84eb1b3e8f31d8e500f76ba75f96',\n", - " 'section_name': 'Results',\n", - " 'text': 'Book chapters:Abney K, Lin P, Mehlman M: Military neuroenhancement and risk assessment. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 239-248.Balaban CD: Neurotechnology and operational medicine. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 65-78.Bartolucci V, Dando M: What does neuroethics have to say about the problem of dual use? In On the Dual Uses of Science and Ethics: Principles, Practices, and Prospects. Edited by Brian Rappert, Michael J. Selgelid. Canberra, Australia: ANU Press; 2013: 29-44.Bell C: Why neuroscientists should take the pledge: a collective approach to the misuse of neuroscience. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 227-238.Benanti P: Between neuroskepticism and neurogullibility: the key role of neuroethics in the regulation and mitigation of neurotechnology in national security and defense. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 217-225.Casebeer WD: Postscript: a neuroscience and national security normative framework for the twenty-first century. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 279-283.Dando M: Neuroscience advances and future warfare. In Handbook of Neuroethics. Edited by Jens Clausen, Neil Levy. Dordrecht: Springer; 2014, 2015: 1785-1800.Ganis G: Investigating deception and deception detection with brain stimulation methods. In Detecting Deception: Current Challenges and Cognitive Approaches. Edited by Pär Anders Granhag, Aldert Vrij, Bruno Verschuere. Hoboken, NJ: John Wiley & Sons; 2014, 2015: 253-268.Giordano J: Neurotechnology, global relations, and national security: shifting contexts and neuroethical demands. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 1-10.Farwell JP: Issues of law raised by developments and use of neuroscience and neurotechnology in national security and defense. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 133-165.Marchant GE, Gaudet LM: Neuroscience, national security, and the reverse dual-use dilemma. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 167-178.Marks JH: Neuroskepticism: rethinking the ethics of neuroscience and national security. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 179-198.McCreight R: Brain brinksmanship: devising neuroweapons looking at battlespace, doctrine, and strategy. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 115-132.Murray S, Yanagi MA: Transitioning brain research: from bench to battlefield. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 11-22.Nuffield Council on Bioethics. Non-therapeutic applications. In its Novel Neurotechnologies: Intervening in the Brain. London: Nuffield Council on Bioethics; 2013: 162-190.Oie KS, McDowell K: Neurocognitive engineering for systems’ development. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 33-50.Paulus MP et al.: Neural mechanisms as putative targets for warfighter resilience and optimal performance. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 51-63.Stanney KM et al.: Neural systems in intelligence and training applications. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James J. Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 23-32.Tabery J: Can (and should) we regulate neurosecurity? lessons from history. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 249-258.Thomsen K: Prison camp or “prison clinic?”: biopolitics, neuroethics, and national security. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 199-216.Tractenberg RE, FitzGerald KT, Giordano J: Engaging neuroethical issues generated by the use of neurotechnology in national security and defense: toward process, methods, and paradigm. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 259-277.Wurzman R, Giordano J: “NEURINT” and neuroweapons: neurotechnologies in national intelligence and defense. In Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical Concerns. Edited by James Giordano. Boca Raton: CRC Press, Taylor & Francis Group; 2014, 2015: 79-113.',\n", - " 'paragraph_id': 52,\n", - " 'tokenizer': 'book, chapters, :, ab, ##ney, k, ,, lin, p, ,, me, ##hl, ##man, m, :, military, ne, ##uro, ##en, ##han, ##ce, ##ment, and, risk, assessment, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 239, -, 248, ., bala, ##ban, cd, :, ne, ##uro, ##tech, ##nology, and, operational, medicine, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 65, -, 78, ., bart, ##ol, ##ucci, v, ,, dan, ##do, m, :, what, does, ne, ##uro, ##eth, ##ics, have, to, say, about, the, problem, of, dual, use, ?, in, on, the, dual, uses, of, science, and, ethics, :, principles, ,, practices, ,, and, prospects, ., edited, by, brian, rapper, ##t, ,, michael, j, ., se, ##lge, ##lid, ., canberra, ,, australia, :, an, ##u, press, ;, 2013, :, 29, -, 44, ., bell, c, :, why, ne, ##uro, ##sc, ##ient, ##ists, should, take, the, pledge, :, a, collective, approach, to, the, mis, ##use, of, neuroscience, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 227, -, 238, ., ben, ##ant, ##i, p, :, between, ne, ##uro, ##ske, ##ptic, ##ism, and, ne, ##uro, ##gul, ##lib, ##ility, :, the, key, role, of, ne, ##uro, ##eth, ##ics, in, the, regulation, and, mit, ##iga, ##tion, of, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 217, -, 225, ., case, ##bee, ##r, w, ##d, :, posts, ##cript, :, a, neuroscience, and, national, security, norma, ##tive, framework, for, the, twenty, -, first, century, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 279, -, 283, ., dan, ##do, m, :, neuroscience, advances, and, future, warfare, ., in, handbook, of, ne, ##uro, ##eth, ##ics, ., edited, by, jens, clause, ##n, ,, neil, levy, ., do, ##rd, ##recht, :, springer, ;, 2014, ,, 2015, :, 1785, -, 1800, ., gan, ##is, g, :, investigating, deception, and, deception, detection, with, brain, stimulation, methods, ., in, detecting, deception, :, current, challenges, and, cognitive, approaches, ., edited, by, par, anders, gran, ##ha, ##g, ,, al, ##der, ##t, vr, ##ij, ,, bruno, ve, ##rs, ##chu, ##ere, ., ho, ##bo, ##ken, ,, nj, :, john, wiley, &, sons, ;, 2014, ,, 2015, :, 253, -, 268, ., gi, ##ord, ##ano, j, :, ne, ##uro, ##tech, ##nology, ,, global, relations, ,, and, national, security, :, shifting, contexts, and, ne, ##uro, ##eth, ##ical, demands, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 1, -, 10, ., far, ##well, jp, :, issues, of, law, raised, by, developments, and, use, of, neuroscience, and, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 133, -, 165, ., march, ##ant, ge, ,, ga, ##ude, ##t, l, ##m, :, neuroscience, ,, national, security, ,, and, the, reverse, dual, -, use, dilemma, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, j, ., gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 167, -, 178, ., marks, j, ##h, :, ne, ##uro, ##ske, ##ptic, ##ism, :, re, ##thi, ##nk, ##ing, the, ethics, of, neuroscience, and, national, security, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, 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francis, group, ;, 2014, ,, 2015, :, 51, -, 63, ., stan, ##ney, km, et, al, ., :, neural, systems, in, intelligence, and, training, applications, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, j, ., gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 23, -, 32, ., tab, ##ery, j, :, can, (, and, should, ), we, regulate, ne, ##uro, ##se, ##cu, ##rity, ?, lessons, from, history, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 249, -, 258, ., thom, ##sen, k, :, prison, camp, or, “, prison, clinic, ?, ”, :, bio, ##pol, ##itic, ##s, ,, ne, ##uro, ##eth, ##ics, ,, and, national, security, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 199, -, 216, ., tract, ##enberg, re, ,, fitzgerald, k, ##t, ,, gi, ##ord, ##ano, j, :, engaging, ne, ##uro, ##eth, ##ical, issues, generated, by, the, use, of, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, toward, process, ,, methods, ,, and, paradigm, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 259, -, 277, ., wu, ##rz, ##man, r, ,, gi, ##ord, ##ano, j, :, “, ne, ##uri, ##nt, ”, and, ne, ##uro, ##we, ##ap, ##ons, :, ne, ##uro, ##tech, ##no, ##logies, in, national, intelligence, and, defense, ., in, ne, ##uro, ##tech, ##nology, in, national, security, and, defense, :, practical, considerations, ,, ne, ##uro, ##eth, ##ical, concerns, ., edited, by, james, gi, ##ord, ##ano, ., boca, rat, ##on, :, cr, ##c, press, ,, taylor, &, francis, group, ;, 2014, ,, 2015, :, 79, -, 113, .'},\n", - " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", - " 'section_name': 'Conditional Control on the Rabies Life Cycle',\n", - " 'text': 'We screened the suitability to viral production and TEVp dependence of six viral constructs, in which each viral protein was targeted to the proteasome alone or in combination (Figures 1C–1K; Table S1). To this aim, we generated a stable cell line expressing TEVp and the spike glycoprotein (Figures 1A and 1B). Surprisingly, the destabilization of the viral proteins M, P, N/P, and N/P/L led to a virus unable to efficiently spread even in presence of the protease. In contrast, the virus with proteasome-targeted L protein did amplify both in presence (Figure 1D) and absence (Figure 1J) of the TEV protease, indicating that the partial destabilization of the L protein by the degradation domain is insufficient to impair the viral replication machinery. The virus in which the N protein alone was destabilized showed the desired conditional control: failure to amplify in absence of TEVp and successful amplification in TEVp-expressing cells (at 18 days post transfection +TEVp 80% ± 4%, −TEVp 2% ± 0.2% of infected cells, p = 3 × 10^−3, two-tailed two-sample Student’s t test, Figure 1K). This indicates that N is the sole viral protein whose conditional destabilization, in our design, is sufficient to reversibly suppress the viral transcription-replication cycle. We confirmed that the conditional inactivation of the N-tagged ΔG-rabies is a proteasome-dependent process by amplifying the virus in absence of TEVp but in presence of the proteasome inhibitor MG-132 (Figure S1A). Indeed, the amplification rate of the N-tagged ΔG-rabies virus significantly increases, in a dose-dependent manner, following the administration of the proteasome inhibitor MG-132 (at 12 days post transfection 0 nM MG-132, 0.1% ± 0.1%; 250 nM MG-132, 13% ± 5% of infected cells, p = 0.04, two-tailed two-sample Student’s t test, Figure S1B). After a further round of improvement on the viral cassette design (Figures S2 and S3; STAR Methods), we were able to produce a SiR with the desired TEVp-dependent ON/OFF kinetics constituted by an NPEST-rabies-mCherry cassette containing a TEVp-cleavable linker between N and the PEST sequence.Figure S1Proteasome Inhibition Supports Attenuated Rabies Production, Related to Figure 1(A) Scheme of tested conditions for the production of N-tagged ΔG-Rabies^mCherry in HEK-GG (-TEV_P) cells in presence or absence of proteasome inhibitor (MG-132). (B) Percentage of infected cells at different concentrations of MG-132 administered after 3-12 days post-transfection (mean ± SEM, n = 3).Figure S2Rapamaycin-Induced SPLIT-TEVp Reconstitution and Cleavage of PEST Domain in HEK293T Cells, Related to Figure 1(A) Strategy for the pharmacological stabilization of tagged viral protein by rapamycin-induced dimerization of the SPLIT-TEVp. (B) SPLIT-TEVp rapamycin response in HEK293T cells transfected with a TEVp activity reporter increases at incremental concentration of rapamycin (0-10-50 nM). (C) The SPLIT-TEVp cassette was cloned into the glycoprotein locus in the Rabies genome. Rapamycin dependent TEVp activity in HEK293T 48 hr post transfection with TEVp activity reporter and infection with the SPLIT-TEVp expressing ΔG-Rabies.Figure S3Testing Cytotoxicity of ΔG-N^PESTRabies^SPLIT-TEVp-mCherry In Vitro and In Vivo, Related to Figure 1(A) hESCs derived neurons were infected with ΔG-N^PESTRabies^SPLIT-TEVp-mCherry and imaged longitudinally over 16 days. (B)-B”) ΔG-N^PESTRabies^SPLIT-TEVp-mCherry and B19 ΔG-Rabies control (C)-C”) infected hESCs derived neurons imaged at 4, 10 and 16 days post-infection (p.i.). (D) Percentage of infected cells after administration of control ΔG-Rabies or ΔG-N^PESTRabies^SPLIT-TEVp-mCherry in presence or absence of rapamycin after 4–10 and 16 days normalized to day 4 time-point (mean ± SEM). (E) mCherry signal intensity of ΔG-N^PESTRabies^SPLIT-TEVp-mCherry and ΔG-Rabies infected neurons normalized to day 4 time-point (mean ± SEM., scale as in (D). Scale bar: 50 μm. (F) Hippocampi of Rosa-LoxP-STOP-LoxP-YFP mice were injected bilaterally with ΔG-Rabies^GFP (cyan) and ΔG-N^PESTRabies^SPLIT-TEVp-CRE (magenta). Confocal images of ΔG-Rabies^GFP (G-G’) or ΔG-N^PESTRabies ^SPLIT-TEVp-CRE (H-H’) infected hippocampi at 1, 2 or 3 weeks p.i. Scale bar: 50 μm (I) Percentage of infected neurons at 1, 2 or 3 weeks p.i. of ΔG-Rabies^GFP (black) or ΔG-N^PESTRabies^SPLIT-TEVp-CRE (gray) in hippocampus normalized to 1 week time-point (mean ± SEM, n = 3 animals per time point).',\n", - " 'paragraph_id': 4,\n", - " 'tokenizer': 'we, screened, the, suit, ##ability, to, viral, production, and, te, ##v, ##p, dependence, of, six, viral, construct, ##s, ,, in, which, each, viral, protein, was, targeted, to, the, pro, ##tea, ##some, alone, or, in, combination, (, figures, 1, ##c, –, 1, ##k, ;, table, s, ##1, ), ., to, this, aim, ,, we, generated, a, stable, cell, line, expressing, te, ##v, ##p, and, the, spike, g, ##ly, ##co, ##pro, ##tein, (, figures, 1a, and, 1b, ), ., surprisingly, ,, the, des, ##ta, ##bil, ##ization, of, the, viral, proteins, m, ,, p, ,, n, /, p, ,, and, n, /, p, /, l, led, to, a, virus, unable, to, efficiently, spread, even, in, presence, of, the, pro, ##tea, ##se, ., in, contrast, ,, the, virus, with, pro, ##tea, ##some, -, targeted, l, protein, did, amp, ##li, ##fy, both, in, presence, (, figure, 1, ##d, ), and, absence, (, figure, 1, ##j, ), of, the, te, ##v, pro, ##tea, ##se, ,, indicating, that, the, partial, des, ##ta, ##bil, ##ization, of, the, l, protein, by, the, degradation, domain, is, insufficient, to, imp, ##air, the, viral, replication, machinery, ., the, virus, in, which, the, n, protein, alone, was, des, ##ta, ##bil, ##ized, showed, the, desired, conditional, control, :, failure, to, amp, ##li, ##fy, in, absence, of, te, ##v, ##p, and, successful, amp, ##li, ##fication, in, te, ##v, ##p, -, expressing, cells, (, at, 18, days, post, trans, ##fect, ##ion, +, te, ##v, ##p, 80, %, ±, 4, %, ,, −, ##te, ##v, ##p, 2, %, ±, 0, ., 2, %, of, infected, cells, ,, p, =, 3, ×, 10, ^, −, ##3, ,, two, -, tailed, two, -, sample, student, ’, s, t, test, ,, figure, 1, ##k, ), ., this, indicates, that, n, is, the, sole, viral, protein, whose, conditional, des, ##ta, ##bil, ##ization, ,, in, our, design, ,, is, sufficient, to, rev, ##ers, ##ibly, suppress, the, viral, transcription, -, replication, cycle, ., we, confirmed, that, the, conditional, ina, ##ct, ##ivation, of, the, n, -, tagged, δ, ##g, -, ra, ##bies, is, a, pro, ##tea, ##some, -, dependent, process, by, amp, ##li, ##fying, the, virus, in, absence, of, te, ##v, ##p, but, in, presence, of, the, pro, ##tea, ##some, inhibitor, mg, -, 132, (, figure, s, ##1, ##a, ), ., indeed, ,, the, amp, ##li, ##fication, rate, of, the, n, -, tagged, δ, ##g, -, ra, ##bies, virus, significantly, increases, ,, in, a, dose, -, dependent, manner, ,, following, the, administration, of, the, pro, ##tea, ##some, inhibitor, mg, -, 132, (, at, 12, days, post, trans, ##fect, ##ion, 0, nm, mg, -, 132, ,, 0, ., 1, %, ±, 0, ., 1, %, ;, 250, nm, mg, -, 132, ,, 13, %, ±, 5, %, of, infected, cells, ,, p, =, 0, ., 04, ,, two, -, tailed, two, -, sample, student, ’, s, t, test, ,, figure, s, ##1, ##b, ), ., after, a, further, round, of, improvement, on, the, viral, cassette, design, (, figures, s, ##2, and, s, ##3, ;, star, methods, ), ,, we, were, able, to, produce, a, sir, with, the, desired, te, ##v, ##p, -, dependent, on, /, off, kinetic, ##s, constituted, by, an, np, ##est, -, ra, ##bies, -, mc, ##her, ##ry, cassette, containing, a, te, ##v, ##p, -, cl, ##ea, ##vable, link, ##er, between, n, and, the, pest, sequence, ., figure, s, ##1, ##pro, ##tea, ##some, inhibition, supports, at, ##ten, ##uated, ra, ##bies, production, ,, related, to, figure, 1, (, a, ), scheme, of, tested, conditions, for, the, production, of, n, -, tagged, δ, ##g, -, ra, ##bies, ^, mc, ##her, ##ry, in, he, ##k, -, g, ##g, (, -, te, ##v, _, p, ), cells, in, presence, or, absence, of, pro, ##tea, ##some, inhibitor, (, mg, -, 132, ), ., (, b, ), percentage, of, infected, cells, at, different, concentrations, of, mg, -, 132, administered, after, 3, -, 12, days, post, -, trans, ##fect, ##ion, (, mean, ±, se, ##m, ,, n, =, 3, ), ., figure, s, ##2, ##ra, ##pa, ##may, ##cin, -, induced, split, -, te, ##v, ##p, rec, ##ons, ##ti, ##tu, ##tion, and, cleavage, of, pest, domain, in, he, ##k, ##29, ##3, ##t, cells, ,, related, to, figure, 1, (, a, ), strategy, for, the, ph, ##arm, ##aco, ##logical, stabilization, of, tagged, viral, protein, by, rap, ##amy, ##cin, -, induced, dime, ##rization, of, the, split, -, te, ##v, ##p, ., (, b, ), split, -, te, ##v, ##p, rap, ##amy, ##cin, response, in, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, a, te, ##v, ##p, activity, reporter, increases, at, inc, ##rem, ##ental, concentration, of, rap, ##amy, ##cin, (, 0, -, 10, -, 50, nm, ), ., (, c, ), the, split, -, te, ##v, ##p, cassette, was, clone, ##d, into, the, g, ##ly, ##co, ##pro, ##tein, locus, in, the, ra, ##bies, genome, ., rap, ##amy, ##cin, dependent, te, ##v, ##p, activity, in, he, ##k, ##29, ##3, ##t, 48, hr, post, trans, ##fect, ##ion, with, te, ##v, ##p, activity, reporter, and, infection, with, the, split, -, te, ##v, ##p, expressing, δ, ##g, -, ra, ##bies, ., figure, s, ##3, ##test, ##ing, cy, ##to, ##to, ##xi, ##city, of, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, in, vitro, and, in, vivo, ,, related, to, figure, 1, (, a, ), he, ##sc, ##s, derived, neurons, were, infected, with, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, and, image, ##d, longitudinal, ##ly, over, 16, days, ., (, b, ), -, b, ”, ), δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, and, b1, ##9, δ, ##g, -, ra, ##bies, control, (, c, ), -, c, ”, ), infected, he, ##sc, ##s, derived, neurons, image, ##d, at, 4, ,, 10, and, 16, days, post, -, infection, (, p, ., i, ., ), ., (, d, ), percentage, of, infected, cells, after, administration, of, control, δ, ##g, -, ra, ##bies, or, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, in, presence, or, absence, of, rap, ##amy, ##cin, after, 4, –, 10, and, 16, days, normal, ##ized, to, day, 4, time, -, point, (, mean, ±, se, ##m, ), ., (, e, ), mc, ##her, ##ry, signal, intensity, of, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, mc, ##her, ##ry, and, δ, ##g, -, ra, ##bies, infected, neurons, normal, ##ized, to, day, 4, time, -, point, (, mean, ±, se, ##m, ., ,, scale, as, in, (, d, ), ., scale, bar, :, 50, μ, ##m, ., (, f, ), hip, ##po, ##camp, ##i, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, were, injected, bilateral, ##ly, with, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, cy, ##an, ), and, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, cr, ##e, (, mage, ##nta, ), ., con, ##fo, ##cal, images, of, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, g, -, g, ’, ), or, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, cr, ##e, (, h, -, h, ’, ), infected, hip, ##po, ##camp, ##i, at, 1, ,, 2, or, 3, weeks, p, ., i, ., scale, bar, :, 50, μ, ##m, (, i, ), percentage, of, infected, neurons, at, 1, ,, 2, or, 3, weeks, p, ., i, ., of, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, black, ), or, δ, ##g, -, n, ^, pest, ##ra, ##bies, ^, split, -, te, ##v, ##p, -, cr, ##e, (, gray, ), in, hip, ##po, ##camp, ##us, normal, ##ized, to, 1, week, time, -, point, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), .'},\n", - " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", - " 'section_name': 'Permanent Genetic Access to Neural Circuits with SiR',\n", - " 'text': 'In order to experimentally assess the in vivo cytotoxicity of the newly generated SiR, we added a CRE recombinase and a destabilized mCherry (SiR^CRE-mCherry, Figure 2B) to the SiR genome. We then tested SiR transcription-replication kinetics and cytotoxicity in vivo by injecting SiR^CRE-mCherry in the CA1 pyramidal layer of Rosa-LoxP-STOP-LoxP-YFP mice (Figure 2B). The transient expression of the CRE recombinase driven by the SiR should be adequate to ensure a permanent recombination of the Rosa locus and consequent YFP expression even after a complete transcriptional shut down of the virus (Figure 2A). At the same time, the destabilized mCherry marks the presence of active virus with high temporal resolution. Indeed, while at 3 days post infection (p.i.) only the virally encoded mCherry can be detected (Figures S4C–S4C′′′ and S4F), by 6 days p.i. the virally encoded CRE has induced recombination of the conditional mouse reporter cassette, triggering the expression of YFP in all infected neurons (Figures S4D–S4D′′′ and S4F′). In order to exclude any SiR-induced cytotoxicity, we monitored the survival of SiR^CRE-mCherry-infected CA1 pyramidal neurons over a 6-month period. By 3 weeks p.i., the SiR had completely shut down (98% ± 2% YFP^ON mCherry^OFF, Figures 2D–2D′′′ and 2G) and, more importantly, no significant neuronal loss was observed during the 6-month period following SiR infection (one-way ANOVA, F = 0.12, p = 0.97, Figures 2F–2F′′′and 2G). This is in striking contrast with what is observed after canonical ΔG-rabies infection, in which the majority of infected neurons in the hippocampus die within 2 weeks from the primary infection (Figures S5A–S5C). We further confirmed the absence of SiR-induced cytotoxic effects in vivo by assessing the level of caspase-3 activation (cCaspase3) at 1 and 2 weeks following SiR infection and comparing it to that elicited in mock-injected controls. The results indicate no significant differences between SiR and mock-injected conditions in the levels of caspase-3 activation (one-way ANOVA, F = 0.11, p = 0.7, Figures S5F–S5G′′′ and S5H). Monitoring the in vivo viral RNA genomic titer during the course of the infection also shows that SiR completely disappears (at a genomic level) from the infected neurons by 2 weeks p.i. (Figure 2H). Overall, these results show that the SiR^CRE-mCherry transcription-replication kinetics provides enough time to generate an early CRE recombination event (Figures S4D–S4D′′′) before the virus disappears (Figures 2D–2D′′′). It thereby ensures permanent genetic (CRE-mediated) access to the infected neurons without affecting their survival (Figures 2G and 2H).Figure 2Absence of Cytotoxicity In Vivo(A) SiR life cycle scheme.(B) SiR expression cassette and experimental procedure.(C–F′′′) Confocal images of hippocampal sections of Rosa-LoxP-STOP-LoxP-YFP mice infected with SiR^CRE-mCherry and imaged at 1 week (C–C′′′), 3 weeks (D–D′′′), 2 months (E–E′′′), and 6 months (F–F′′′) p.i. Scale bar, 25 μm.(G) Number of YFP and mCherry positive neurons at 1–3 weeks, 2 months, and 6 months p.i. normalized to 1 week time point (mean ± SEM, n = 3 animals per time point).(H) Levels of viral RNA (magenta) and endogenous YFP expression (cyan) normalized to 1 week RNA level (mean ± SEM, n = 3 animals per time point).See also Figures S4 and S5.Figure S4Short-Term SiR^CRE-mCherry Kinetics In Vivo, Related to Figure 2(A) SiR^CRE-mCherry cassette design. (B) SiR^CRE-mCherry injection in CA1 of Rosa-LoxP-STOP-LoxP-YFP mice. (C-E”’) Confocal images of CA1 pyramidal neurons infected with SiR^CRE-mCherry at 3, 6 and 9 days p.i. Scale bar: 25 μm. (F-F’’) Percentage of YFP^ON, mCherry^ON and YFP^ONmCherry^ON neurons at 3, 6 and 9 days p.i.Figure S5ΔG-Rabies Induced Mortality in Cortex and Hippocampus, Related to Figure 2(A-A’’) Confocal images of cortical neurons and (B-B’’) CA1 pyramidal neurons infected with ΔG-Rabies^GFP at 1, 2 and 3 weeks p.i. Scale bar: 50 μm. (C) Percentage of ΔG-Rabies infected neurons at 1, 2 or 3 weeks p.i. in cortex (black) or hippocampus (gray) normalized to 1 week time-point (mean ± SEM,) (hippocampus, 92% ± 3% cell death at 2 weeks, n = 3 animals per time-point, one-way ANOVA, F = 101, p = 2.4x10^−5; cortex 85 % ± 2% cell death at 3 weeks, n = 3 animals per time-point, one-way ANOVA, F = 17, p = 3.2x10^−3). Confocal images of ΔG-Rabies^GFP (D-E’’’) or SiR^CRE (F-G’’’) infected hippocampi of Rosa-LoxP-STOP-LoxP-YFP mice at 1 and 2 weeks p.i. stained for cleaved caspase-3 (cCaspase3) (arrowheads point to ΔG-Rab-cCaspase3 double positive neurons). Scale bar: 25 μm (H) Percentage of positive cCaspase3 neurons every 1000 neurons at 1 and 2 weeks p.i. in PBS, ΔG-Rabies or SiR infected hippocampi (mean ± SEM, n = 3 animals per time-point).',\n", - " 'paragraph_id': 5,\n", - " 'tokenizer': 'in, order, to, experimental, ##ly, assess, the, in, vivo, cy, ##to, ##to, ##xi, ##city, of, the, newly, generated, sir, ,, we, added, a, cr, ##e, rec, ##om, ##bina, ##se, and, a, des, ##ta, ##bil, ##ized, mc, ##her, ##ry, (, sir, ^, cr, ##e, -, mc, ##her, ##ry, ,, figure, 2, ##b, ), to, the, sir, genome, ., we, then, tested, sir, transcription, -, replication, kinetic, ##s, and, cy, ##to, ##to, ##xi, ##city, in, vivo, by, in, ##ject, ##ing, sir, ^, cr, ##e, -, mc, ##her, ##ry, in, the, ca, ##1, pyramid, ##al, layer, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, (, figure, 2, ##b, ), ., the, transient, expression, of, the, cr, ##e, rec, ##om, ##bina, ##se, driven, by, the, sir, should, be, adequate, to, ensure, a, permanent, rec, ##om, ##bina, ##tion, of, the, rosa, locus, and, con, ##se, ##quent, y, ##fp, expression, even, after, a, complete, transcription, ##al, shut, down, of, the, virus, (, figure, 2a, ), ., at, the, same, time, ,, the, des, ##ta, ##bil, ##ized, mc, ##her, ##ry, marks, the, presence, of, active, virus, with, high, temporal, resolution, ., indeed, ,, while, at, 3, days, post, infection, (, p, ., i, ., ), only, the, viral, ##ly, encoded, mc, ##her, ##ry, can, be, detected, (, figures, s, ##4, ##c, –, s, ##4, ##c, ′, ′, ′, and, s, ##4, ##f, ), ,, by, 6, days, p, ., i, ., the, viral, ##ly, encoded, cr, ##e, has, induced, rec, ##om, ##bina, ##tion, of, the, conditional, mouse, reporter, cassette, ,, triggering, the, expression, of, y, ##fp, in, all, infected, neurons, (, figures, s, ##4, ##d, –, s, ##4, ##d, ′, ′, ′, and, s, ##4, ##f, ′, ), ., in, order, to, exclude, any, sir, -, induced, cy, ##to, ##to, ##xi, ##city, ,, we, monitored, the, survival, of, sir, ^, cr, ##e, -, mc, ##her, ##ry, -, infected, ca, ##1, pyramid, ##al, neurons, over, a, 6, -, month, period, ., by, 3, weeks, p, ., i, ., ,, the, sir, had, completely, shut, down, (, 98, %, ±, 2, %, y, ##fp, ^, on, mc, ##her, ##ry, ^, off, ,, figures, 2d, –, 2d, ′, ′, ′, and, 2, ##g, ), and, ,, more, importantly, ,, no, significant, ne, ##uron, ##al, loss, was, observed, during, the, 6, -, month, period, following, sir, infection, (, one, -, way, an, ##ova, ,, f, =, 0, ., 12, ,, p, =, 0, ., 97, ,, figures, 2, ##f, –, 2, ##f, ′, ′, ′, and, 2, ##g, ), ., this, is, in, striking, contrast, with, what, is, observed, after, canonical, δ, ##g, -, ra, ##bies, infection, ,, in, which, the, majority, of, infected, neurons, in, the, hip, ##po, ##camp, ##us, die, within, 2, weeks, from, the, primary, infection, (, figures, s, ##5, ##a, –, s, ##5, ##c, ), ., we, further, confirmed, the, absence, of, sir, -, induced, cy, ##to, ##to, ##xi, ##c, effects, in, vivo, by, assessing, the, level, of, cas, ##pas, ##e, -, 3, activation, (, cc, ##as, ##pas, ##e, ##3, ), at, 1, and, 2, weeks, following, sir, infection, and, comparing, it, to, that, eli, ##cite, ##d, in, mock, -, injected, controls, ., the, results, indicate, no, significant, differences, between, sir, and, mock, -, injected, conditions, in, the, levels, of, cas, ##pas, ##e, -, 3, activation, (, one, -, way, an, ##ova, ,, f, =, 0, ., 11, ,, p, =, 0, ., 7, ,, figures, s, ##5, ##f, –, s, ##5, ##g, ′, ′, ′, and, s, ##5, ##h, ), ., monitoring, the, in, vivo, viral, rna, gen, ##omic, ti, ##ter, during, the, course, of, the, infection, also, shows, that, sir, completely, disappears, (, at, a, gen, ##omic, level, ), from, the, infected, neurons, by, 2, weeks, p, ., i, ., (, figure, 2, ##h, ), ., overall, ,, these, results, show, that, the, sir, ^, cr, ##e, -, mc, ##her, ##ry, transcription, -, replication, kinetic, ##s, provides, enough, time, to, generate, an, early, cr, ##e, rec, ##om, ##bina, ##tion, event, (, figures, s, ##4, ##d, –, s, ##4, ##d, ′, ′, ′, ), before, the, virus, disappears, (, figures, 2d, –, 2d, ′, ′, ′, ), ., it, thereby, ensures, permanent, genetic, (, cr, ##e, -, mediated, ), access, to, the, infected, neurons, without, affecting, their, survival, (, figures, 2, ##g, and, 2, ##h, ), ., figure, 2a, ##bs, ##ence, of, cy, ##to, ##to, ##xi, ##city, in, vivo, (, a, ), sir, life, cycle, scheme, ., (, b, ), sir, expression, cassette, and, experimental, procedure, ., (, c, –, f, ′, ′, ′, ), con, ##fo, ##cal, images, of, hip, ##po, ##camp, ##al, sections, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, infected, with, sir, ^, cr, ##e, -, mc, ##her, ##ry, and, image, ##d, at, 1, week, (, c, –, c, ′, ′, ′, ), ,, 3, weeks, (, d, –, d, ′, ′, ′, ), ,, 2, months, (, e, –, e, ′, ′, ′, ), ,, and, 6, months, (, f, –, f, ′, ′, ′, ), p, ., i, ., scale, bar, ,, 25, μ, ##m, ., (, g, ), number, of, y, ##fp, and, mc, ##her, ##ry, positive, neurons, at, 1, –, 3, weeks, ,, 2, months, ,, and, 6, months, p, ., i, ., normal, ##ized, to, 1, week, time, point, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), ., (, h, ), levels, of, viral, rna, (, mage, ##nta, ), and, end, ##ogen, ##ous, y, ##fp, expression, (, cy, ##an, ), normal, ##ized, to, 1, week, rna, level, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), ., see, also, figures, s, ##4, and, s, ##5, ., figure, s, ##4, ##sho, ##rt, -, term, sir, ^, cr, ##e, -, mc, ##her, ##ry, kinetic, ##s, in, vivo, ,, related, to, figure, 2, (, a, ), sir, ^, cr, ##e, -, mc, ##her, ##ry, cassette, design, ., (, b, ), sir, ^, cr, ##e, -, mc, ##her, ##ry, injection, in, ca, ##1, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, ., (, c, -, e, ”, ’, ), con, ##fo, ##cal, images, of, ca, ##1, pyramid, ##al, neurons, infected, with, sir, ^, cr, ##e, -, mc, ##her, ##ry, at, 3, ,, 6, and, 9, days, p, ., i, ., scale, bar, :, 25, μ, ##m, ., (, f, -, f, ’, ’, ), percentage, of, y, ##fp, ^, on, ,, mc, ##her, ##ry, ^, on, and, y, ##fp, ^, on, ##mc, ##her, ##ry, ^, on, neurons, at, 3, ,, 6, and, 9, days, p, ., i, ., figure, s, ##5, ##δ, ##g, -, ra, ##bies, induced, mortality, in, cortex, and, hip, ##po, ##camp, ##us, ,, related, to, figure, 2, (, a, -, a, ’, ’, ), con, ##fo, ##cal, images, of, co, ##rti, ##cal, neurons, and, (, b, -, b, ’, ’, ), ca, ##1, pyramid, ##al, neurons, infected, with, δ, ##g, -, ra, ##bies, ^, g, ##fp, at, 1, ,, 2, and, 3, weeks, p, ., i, ., scale, bar, :, 50, μ, ##m, ., (, c, ), percentage, of, δ, ##g, -, ra, ##bies, infected, neurons, at, 1, ,, 2, or, 3, weeks, p, ., i, ., in, cortex, (, black, ), or, hip, ##po, ##camp, ##us, (, gray, ), normal, ##ized, to, 1, week, time, -, point, (, mean, ±, se, ##m, ,, ), (, hip, ##po, ##camp, ##us, ,, 92, %, ±, 3, %, cell, death, at, 2, weeks, ,, n, =, 3, animals, per, time, -, point, ,, one, -, way, an, ##ova, ,, f, =, 101, ,, p, =, 2, ., 4, ##x, ##10, ^, −, ##5, ;, cortex, 85, %, ±, 2, %, cell, death, at, 3, weeks, ,, n, =, 3, animals, per, time, -, point, ,, one, -, way, an, ##ova, ,, f, =, 17, ,, p, =, 3, ., 2, ##x, ##10, ^, −, ##3, ), ., con, ##fo, ##cal, images, of, δ, ##g, -, ra, ##bies, ^, g, ##fp, (, d, -, e, ’, ’, ’, ), or, sir, ^, cr, ##e, (, f, -, g, ’, ’, ’, ), infected, hip, ##po, ##camp, ##i, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, y, ##fp, mice, at, 1, and, 2, weeks, p, ., i, ., stained, for, cl, ##ea, ##ved, cas, ##pas, ##e, -, 3, (, cc, ##as, ##pas, ##e, ##3, ), (, arrow, ##heads, point, to, δ, ##g, -, ra, ##b, -, cc, ##as, ##pas, ##e, ##3, double, positive, neurons, ), ., scale, bar, :, 25, μ, ##m, (, h, ), percentage, of, positive, cc, ##as, ##pas, ##e, ##3, neurons, every, 1000, neurons, at, 1, and, 2, weeks, p, ., i, ., in, pbs, ,, δ, ##g, -, ra, ##bies, or, sir, infected, hip, ##po, ##camp, ##i, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, -, point, ), .'},\n", - " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", - " 'section_name': 'Key Resources Table',\n", - " 'text': 'REAGENT or RESOURCESOURCEIDENTIFIERAntibodiesChicken polyclonal anti-GFPThermo Fisher ScientificCat#A10262; RRID:Rabbit polyclonal anti-RFPRocklandCat#600-401-379; RRID:Mouse monoclonal anti-V5Sigma-AldrichCat#V8012; RRID:Rabbit polyclonal anti-cleaved caspase-3 (Asp175)NEBCat#9661; RRID:Donkey polyclonal anti-rabbit Cy3Jackson ImmunoResearchCat#711-165-152; RRID:Donkey polyclonal anti-chicken alexa 488Jackson ImmunoResearchCat#703-545-155; RRID:Goat polyclonal anti-Mouse IgG (H+L) HRPThermo Fisher ScientificCat#32430; RRID:Chemicals, Peptides, and Recombinant ProteinsRabiesΔG-mCherryThis paperN/ARabiesΔG-_N-terTAGs-mCherryThis paperN/ARabiesΔG-_N-terTAGs-N^PEST-mCherryThis paperN/ARabiesΔG-_N-terTAGs-M^PEST- mCherryThis paperN/ARabiesΔG-_N-terTAGs-P^PEST- mCherryThis paperN/ARabiesΔG-_N-terTAGs-L^PEST- mCherryThis paperN/ARabiesΔG-N^PEST-mCherry (SiR-mCherry)This paperN/ARabiesΔG-_N-terTAGs-(P+L)^PEST- mCherryThis paperN/ARabiesΔG-(P+L+N)^PEST- mCherryThis 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structures, such as the amygdala and hypothalamus, have been proposed to provide executive control and coordinate goal-driven social behaviors in humans (Insel and Fernald, 2004); however, only a few reports have suggested a link between PFC activity and abnormal social behaviors in rodents (Yizhar, 2012; Wang et al., 2014; Figure 1). Moreover, the computational representations by which the mPFC communicates and facilitates the selective coupling of relevant information in downstream subcortical areas have not been systematically investigated in rodents. On a more detailed level, evidence for a causal link between cell type-specific activity and synchronous brain activity in social behavior is generally lacking. Several transgenic mouse lines carrying mutations in genes associated with social neuropsychiatric diseases have been reported to exhibit altered synaptic transmission (Silverman et al., 2010). Yet, molecular, biochemical, and electrophysiological abnormalities in these transgenic mice are quite divergent and not restricted to the PFC alone (Silverman et al., 2010). Therefore, it remains unclear as to whether local alterations in the excitation/inhibition ratio (E/I) and functional desynchronization between different cell types in the mPFC directly causes abnormal social cognition (see Kim et al., 2016 for an alternative perspective). Nevertheless, a partial correlation between mPFC activity and a subset of social behavior-related neuropsychiatric disorders in humans has led to the hypothesis that E/I balance in mPFC circuits may be critical for normal social behavior (Yizhar, 2012; Bicks et al., 2015). For example, using a three-chamber behavioral paradigm that assesses social cognition in the form of general sociability and preference for social novelty, researchers showed that a subset of mPFC neurons exhibited elevated discharge rates while mice approached an unfamiliar mouse, but not when mice approached an inanimate object or empty chamber (Kaidanovich-Beilin et al., 2011); these observations are consistent with the idea that neural activity in the mPFC correlates with social-approach behavior in mice (Lee et al., 2016). mPFC neurons have also been reported to exhibit functional asymmetry between hemispheres in mice, such that the right mPFC was reported to control the acquisition of stress during hazardous experiences while the left mPFC was found to play a dominant role in translating stress into social behavior (Lee et al., 2016). Additionally, knockdown of phospholipase C-β1 in the mPFC impairs social interactions, whereas chronic deletion of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor in the mPFC increases social approach behavior without affecting social novelty preference in mice (Finlay et al., 2015; Kim S. W. et al., 2015). NMDA-NR1 dysfunction in the CA3 region of the hippocampus is also sufficient to impair social approach, suggesting that social interaction can be differentially modulated by distinct alterations in a relevant circuit (Finlay et al., 2015). Yet, the positive correlation between mPFC activity and social behavior is not robust to different manipulations of mPFC activity in rodents. Neuroligin-2 is an inhibitory synapse-specific cell-adhesion molecule that was recently implicated in synaptic inhibition in the mPFC. Conditional deletion of the Nlgn2 gene in mice produced a gradual deterioration in inhibitory synapse structure and transmission, suggesting that neuroligin-2 is essential for the long-term maintenance and reconfiguration of inhibitory synapses in the mPFC (Liang et al., 2015). Moreover, neuroligin-2-knockout (KO) mice exhibit behavioral abnormalities that are partially correlated with electrophysiological phenotypes at 6–7 weeks but not at 2–3 weeks after gene inactivation (Liang et al., 2015). As a possible explanation for this observation, the authors hypothesized that the behavioral phenotype was produced by dysfunction of a peculiarly plastic subpopulation of inhibitory synapses in neuroligin-2-KO mice (Liang et al., 2015). These studies illustrate the idea that various synaptic signaling and adhesion pathways operating in the mPFC contribute to the initiation, maintenance, and/or modulation of social behaviors. A general goal of future studies should be to establish how common social behavioral impairments in various transgenic mice are related on molecular and synaptic levels. In particular, the optogenetic manipulation of mPFC neurons using the recently engineered Stabilized Step-Function Opsins can help to identify the circuit and synaptic mechanisms that underpin mPFC interactions with specific, distant subcortical regions to regulate various social behaviors (Yizhar et al., 2011; Riga et al., 2014; Ferenczi et al., 2016).',\n", - " 'paragraph_id': 6,\n", - " 'tokenizer': 'top, -, down, p, ##fc, projections, to, sub, ##cor, ##tical, structures, ,, such, as, the, amy, ##g, ##dal, ##a, and, h, ##yp, ##oth, ##ala, ##mus, ,, have, been, proposed, to, provide, executive, control, and, coordinate, goal, -, driven, social, behaviors, in, humans, (, ins, ##el, and, fern, ##ald, ,, 2004, ), ;, however, ,, only, a, few, reports, have, suggested, a, link, between, p, ##fc, activity, and, abnormal, social, behaviors, in, rodents, (, yi, ##zh, ##ar, ,, 2012, ;, wang, et, al, ., ,, 2014, ;, figure, 1, ), ., moreover, ,, the, computational, representations, by, which, the, mp, ##fc, communicate, ##s, and, facilitates, the, selective, coupling, of, relevant, information, in, downstream, sub, ##cor, ##tical, areas, have, not, been, systematically, investigated, in, rodents, ., on, a, more, detailed, level, ,, evidence, for, a, causal, link, between, cell, type, -, specific, activity, and, sync, ##hr, ##ono, ##us, brain, activity, in, social, behavior, is, generally, lacking, ., several, trans, ##genic, mouse, lines, carrying, mutations, in, genes, associated, with, social, ne, ##uro, ##psy, ##chia, ##tric, diseases, have, been, reported, to, exhibit, altered, syn, ##ap, ##tic, transmission, (, silver, ##man, et, al, ., ,, 2010, ), ., yet, ,, molecular, ,, bio, ##chemical, ,, and, electro, ##phy, ##sio, ##logical, abnormalities, in, these, trans, ##genic, mice, are, quite, diver, ##gent, and, not, restricted, to, the, p, ##fc, alone, (, silver, ##man, et, al, ., ,, 2010, ), ., therefore, ,, it, remains, unclear, as, to, whether, local, alterations, in, the, ex, ##cit, ##ation, /, inhibition, ratio, (, e, /, i, ), and, functional, des, ##yn, ##ch, ##ron, ##ization, between, different, cell, types, in, the, mp, ##fc, directly, causes, abnormal, social, cognition, (, see, kim, et, al, ., ,, 2016, for, an, alternative, perspective, ), ., nevertheless, ,, a, partial, correlation, between, mp, ##fc, activity, and, a, subset, of, social, behavior, -, related, ne, ##uro, ##psy, ##chia, ##tric, disorders, in, humans, has, led, to, the, hypothesis, that, e, /, i, balance, in, mp, ##fc, circuits, may, be, critical, for, normal, social, behavior, (, yi, ##zh, ##ar, ,, 2012, ;, bi, ##cks, et, al, ., ,, 2015, ), ., for, example, ,, using, a, three, -, chamber, behavioral, paradigm, that, assess, ##es, social, cognition, in, the, form, of, general, soc, ##ia, ##bility, and, preference, for, social, novelty, ,, researchers, showed, that, a, subset, of, mp, ##fc, neurons, exhibited, elevated, discharge, rates, while, mice, approached, an, unfamiliar, mouse, ,, but, not, when, mice, approached, an, ina, ##ni, ##mate, object, or, empty, chamber, (, kai, ##dan, ##ovich, -, bei, ##lin, et, al, ., ,, 2011, ), ;, these, observations, are, consistent, with, the, idea, that, neural, activity, in, the, mp, ##fc, co, ##rre, ##lates, with, social, -, approach, behavior, in, mice, (, lee, et, al, ., ,, 2016, ), ., mp, ##fc, neurons, have, also, been, reported, to, exhibit, functional, as, ##ym, ##metry, between, hemisphere, ##s, in, mice, ,, such, that, the, right, mp, ##fc, was, reported, to, control, the, acquisition, of, stress, during, hazardous, experiences, while, the, left, mp, ##fc, was, found, to, play, a, dominant, role, in, translating, stress, into, social, behavior, (, lee, et, al, ., ,, 2016, ), ., additionally, ,, knock, ##down, of, ph, ##os, ##ph, ##oli, ##pas, ##e, c, -, β, ##1, in, the, mp, ##fc, imp, ##air, ##s, social, interactions, ,, whereas, chronic, del, ##eti, ##on, of, the, nr, ##1, subunit, of, the, n, -, methyl, -, d, -, as, ##par, ##tate, (, nm, ##da, ), receptor, in, the, mp, ##fc, increases, social, approach, behavior, without, affecting, social, novelty, preference, in, mice, (, fin, ##lay, et, al, ., ,, 2015, ;, kim, s, ., w, ., et, al, ., ,, 2015, ), ., nm, ##da, -, nr, ##1, dysfunction, in, the, ca, ##3, region, of, the, hip, ##po, ##camp, ##us, is, also, sufficient, to, imp, ##air, social, approach, ,, suggesting, that, social, interaction, can, be, differential, ##ly, mod, ##ulated, by, distinct, alterations, in, a, relevant, circuit, (, fin, ##lay, et, al, ., ,, 2015, ), ., yet, ,, the, positive, correlation, between, mp, ##fc, activity, and, social, behavior, is, not, robust, to, different, manipulation, ##s, of, mp, ##fc, activity, in, rodents, ., ne, ##uro, ##li, ##gin, -, 2, is, an, inhibitor, ##y, syn, ##ap, ##se, -, specific, cell, -, ad, ##hesion, molecule, that, was, recently, implicated, in, syn, ##ap, ##tic, inhibition, in, the, mp, ##fc, ., conditional, del, ##eti, ##on, of, the, nl, ##gn, ##2, gene, in, mice, produced, a, gradual, deterioration, in, inhibitor, ##y, syn, ##ap, ##se, structure, and, transmission, ,, suggesting, that, ne, ##uro, ##li, ##gin, -, 2, is, essential, for, the, long, -, term, maintenance, and, rec, ##on, ##fi, ##gur, ##ation, of, inhibitor, ##y, syn, ##ap, ##ses, in, the, mp, ##fc, (, liang, et, al, ., ,, 2015, ), ., moreover, ,, ne, ##uro, ##li, ##gin, -, 2, -, knockout, (, ko, ), mice, exhibit, behavioral, abnormalities, that, are, partially, correlated, with, electro, ##phy, ##sio, ##logical, ph, ##eno, ##type, ##s, at, 6, –, 7, weeks, but, not, at, 2, –, 3, weeks, after, gene, ina, ##ct, ##ivation, (, liang, et, al, ., ,, 2015, ), ., as, a, possible, explanation, for, this, observation, ,, the, authors, h, ##yp, ##oth, ##es, ##ized, that, the, behavioral, ph, ##eno, ##type, was, produced, by, dysfunction, of, a, peculiar, ##ly, plastic, sub, ##pop, ##ulation, of, inhibitor, ##y, syn, ##ap, ##ses, in, ne, ##uro, ##li, ##gin, -, 2, -, ko, mice, (, liang, et, al, ., ,, 2015, ), ., these, studies, illustrate, the, idea, that, various, syn, ##ap, ##tic, signaling, and, ad, ##hesion, pathways, operating, in, the, mp, ##fc, contribute, to, the, initiation, ,, maintenance, ,, and, /, or, modulation, of, social, behaviors, ., a, general, goal, of, future, studies, should, be, to, establish, how, common, social, behavioral, impairment, ##s, in, various, trans, ##genic, mice, are, related, on, molecular, and, syn, ##ap, ##tic, levels, ., in, particular, ,, the, opt, ##ogen, ##etic, manipulation, of, mp, ##fc, neurons, using, the, recently, engineered, stabilized, step, -, function, ops, ##ins, can, help, to, identify, the, circuit, and, syn, ##ap, ##tic, mechanisms, that, under, ##pin, mp, ##fc, interactions, with, specific, ,, distant, sub, ##cor, ##tical, regions, to, regulate, various, social, behaviors, (, yi, ##zh, ##ar, et, al, ., ,, 2011, ;, riga, et, al, ., ,, 2014, ;, fe, ##ren, ##cz, ##i, et, al, ., ,, 2016, ), .'},\n", - " {'article_id': '92c9d75c6098986f4d7327dbd4712b4d',\n", - " 'section_name': '4. Impairment of NGF/TrkA Signaling Triggers an Early Activation of “a Dying-Back” Process of Degeneration of Cholinergic Neurons',\n", - " 'text': 'Synaptic dysfunction is an early event in AD pathogenesis and is directly related to progressive cognitive impairment [89,90]. A large body of evidence indicates that neurons affected in AD follow a “dying-back pattern” of degeneration, where abnormalities in synaptic function and axonal connectivity long precede somatic cell death [91]. In fact, the early cognitive deficits occur during the AD progression in parallel with cortical synaptic loss [92,93,94,95] and are subsequently followed by death and/or atrophy of BFCN. The latter more directly accounts for the full-blown clinical symptoms of the disorder [38,96,97,98,99,100]. In view of the notion that, the synaptic density correlates more closely with memory/learning impairment than any other pathological lesion observable in the AD neuropathology [101] and that dysfunction of NGF/TkA signaling underlies the selective degeneration of cortical cholinergic projecting neurons in AD pathogenesis [29], septal primary cultures have been recently employed by our research group with the intent of analyzing the NGF activity and consequences, at the synaptic level, of its in vitro withdrawal. In order to sensitize primary neurons to the following removal of trophic factor, we have recently developed a novel culturing procedure whereby pretreatment (10 DIV) with NGF in the presence of low 0.2% B27 nutrients, selectively enriches (+36%) NGF-responsive forebrain cholinergic neurons at the expense of all other non-cholinergic resident populations, such as GABAergic (~38%) and glutamatergic (~56%) [102]. This simple, less expensive but valuable method allows a consistent and fully mature cholinergic population to be obtained, as demonstrated by biochemical, morphological, and electrophysiological approaches. In fact, this culturing procedure can actually represent an important achievement in the research of AD neuropathology since the yield in cholinergic neurons following the classical culture protocols is lower [103,104,105,106]. By taking advantage of this newly-established in vitro neuronal paradigm, we revealed that the NGF withdrawal induces a progressive deficit in the presynaptic excitatory neurotransmission which occurs in concomitance with a pronounced and time-dependent reduction in several distinct pre-synaptic markers, such as synapsin I, SNAP-25, and α-synuclein, and in the absence of any sign of neuronal death. This rapid presynaptic dysfunction: (i) is reversible in a time-dependent manner, being suppressed by de novo external administration of NGF within six hours from its initial withdrawal; (ii) is specific, since it is not accompanied by contextual changes in expression levels of non-synaptic proteins from other subcellular compartments including specific markers of endoplasmic reticulum and mitochondria such as calnexin, VDAC, and Tom20; (iii) is not secondary to axonal degeneration, because it precedes the post-translational modifications of tubulin subunits critically controlling the cytoskeleton dynamics and is insensible to pharmacological treatment with known microtubule-stabilizing drug such paclitaxel; (iv) involves TrkA-dependent mechanisms because the effects of NGF re-application are blocked by acute exposure to a specific and cell-permeable inhibitor of TrkA receptor. In addition, in line with previous findings reporting a modulatory effect of NGF signaling on APP expression [39,107], a significant upregulation in expression of three APP isoforms of ~110 kDa, ~120 kDa, and ~130 kDa along with marked increase in the immunoreactivity level of the carboxyl-terminal CTFβ fragment of 14 kDa, are detected in primary septal neurons upon 24–48 h of neurotrophin starvation, indicating that the APP metabolism is also greatly influenced following NGF withdrawal in this novel AD-like neuronal paradigm. These results clearly demonstrate that the combined modulatory actions of NGF on the expression of important pre-synaptic proteins and neurosecretory function(s) of in vitro cholinergic septal primary neurons are directly and causally linked via the stimulation of NGF/TrkA signaling. These findings point out the pathological relevance of the lack of NGF availability in the earliest synaptic deficits occurring at the onset of AD progression [102]. Taken together, these findings: (i) provide a valuable in vitro tool to better investigate the survival/disease changes of basal forebrain septo-hippocampal projecting neurons occurring during the prodromal stages of AD pathology caused by dysfunction in NGF/TrkA signaling; (ii) demonstrate that NGF withdrawal induces neurodegenerative changes initiated by early, selective, and reversible presynaptic dysfunction in cholinergic neurons, just resembling the synapses loss and retrograde “dying-back” axonal degeneration appearing at prodromal stages of AD pathology in correlation with incipient memory dysfunction [46,108,109,110]; (iii) have potential, important clinical implications in the field of therapeutical in vivo NGF delivery in humans, because it not only constitutes a molecular rationale for the existence of its limited therapeutic time window, but also offers a prime useful presynaptic-based target with the intent of extending its neuroprotective action in AD intervention.',\n", - " 'paragraph_id': 13,\n", - " 'tokenizer': 'syn, ##ap, ##tic, dysfunction, is, an, early, event, in, ad, pathogen, ##esis, and, is, directly, related, to, progressive, cognitive, impairment, [, 89, ,, 90, ], ., a, large, body, of, evidence, indicates, that, neurons, affected, in, ad, follow, a, “, dying, -, back, pattern, ”, of, de, ##gen, ##eration, ,, where, abnormalities, in, syn, ##ap, ##tic, function, and, ax, ##onal, connectivity, long, pre, ##cede, so, ##matic, cell, death, [, 91, ], ., in, fact, ,, the, early, cognitive, deficit, ##s, occur, during, the, ad, progression, in, parallel, with, co, ##rti, ##cal, syn, ##ap, ##tic, loss, [, 92, ,, 93, ,, 94, ,, 95, ], and, are, subsequently, followed, by, death, and, /, or, at, ##rop, ##hy, of, bf, ##c, ##n, ., the, latter, more, directly, accounts, for, the, full, -, blown, clinical, symptoms, of, the, disorder, [, 38, ,, 96, ,, 97, ,, 98, ,, 99, ,, 100, ], ., in, view, of, the, notion, that, ,, the, syn, ##ap, ##tic, density, co, ##rre, ##lates, more, closely, with, memory, /, learning, impairment, than, any, other, path, ##ological, les, ##ion, ob, ##ser, ##vable, in, the, ad, ne, ##uro, ##path, ##ology, [, 101, ], and, that, dysfunction, of, ng, ##f, /, t, ##ka, signaling, under, ##lies, the, selective, de, ##gen, ##eration, of, co, ##rti, ##cal, cho, ##liner, ##gic, projecting, neurons, in, ad, pathogen, ##esis, [, 29, ], ,, sept, ##al, primary, cultures, have, been, recently, employed, by, our, research, group, with, the, intent, of, analyzing, the, ng, ##f, activity, and, consequences, ,, at, the, syn, ##ap, ##tic, level, ,, of, its, in, vitro, withdrawal, ., in, order, to, sen, ##sit, ##ize, primary, neurons, to, the, following, removal, of, tr, ##op, ##hic, factor, ,, we, have, recently, developed, a, novel, cult, ##uring, procedure, whereby, pre, ##tre, ##at, ##ment, (, 10, di, ##v, ), with, ng, ##f, in, the, presence, of, low, 0, ., 2, %, b, ##27, nutrients, ,, selective, ##ly, en, ##rich, ##es, (, +, 36, %, ), ng, ##f, -, responsive, fore, ##bra, ##in, cho, ##liner, ##gic, neurons, at, the, expense, of, all, other, non, -, cho, ##liner, ##gic, resident, populations, ,, such, as, ga, ##ba, ##er, ##gic, (, ~, 38, %, ), and, g, ##lu, ##tama, ##ter, ##gic, (, ~, 56, %, ), [, 102, ], ., this, simple, ,, less, expensive, but, valuable, method, allows, a, consistent, and, fully, mature, cho, ##liner, ##gic, population, to, be, obtained, ,, as, demonstrated, by, bio, ##chemical, ,, morphological, ,, and, electro, ##phy, ##sio, ##logical, approaches, ., in, fact, ,, this, cult, ##uring, procedure, can, actually, represent, an, important, achievement, in, the, research, of, ad, ne, ##uro, ##path, ##ology, since, the, yield, in, cho, ##liner, ##gic, neurons, following, the, classical, culture, protocols, is, lower, [, 103, ,, 104, ,, 105, ,, 106, ], ., by, taking, advantage, of, this, newly, -, established, in, vitro, ne, ##uron, ##al, paradigm, ,, we, revealed, that, the, ng, ##f, withdrawal, induce, ##s, a, progressive, deficit, in, the, pre, ##sy, ##na, ##ptic, ex, ##cit, ##atory, ne, ##uro, ##tra, ##ns, ##mission, which, occurs, in, con, ##com, ##itan, ##ce, with, a, pronounced, and, time, -, dependent, reduction, in, several, distinct, pre, -, syn, ##ap, ##tic, markers, ,, such, as, syn, ##ap, ##sin, i, ,, snap, -, 25, ,, and, α, -, syn, ##uc, ##lein, ,, and, in, the, absence, of, any, sign, of, ne, ##uron, ##al, death, ., this, rapid, pre, ##sy, ##na, ##ptic, dysfunction, :, (, i, ), is, rev, ##ers, ##ible, in, a, time, -, dependent, manner, ,, being, suppressed, by, de, novo, external, administration, of, ng, ##f, within, six, hours, from, its, initial, withdrawal, ;, (, ii, ), is, specific, ,, since, it, is, not, accompanied, by, context, ##ual, changes, in, expression, levels, of, non, -, syn, ##ap, ##tic, proteins, from, other, sub, ##cellular, compartments, including, specific, markers, of, end, ##op, ##las, ##mic, re, ##tic, ##ulum, and, mit, ##och, ##ond, ##ria, such, as, cal, ##ne, ##xin, ,, v, ##da, ##c, ,, and, tom, ##20, ;, (, iii, ), is, not, secondary, to, ax, ##onal, de, ##gen, ##eration, ,, because, it, pre, ##cede, ##s, the, post, -, translation, ##al, modifications, of, tub, ##ulin, subunit, ##s, critically, controlling, the, cy, ##tos, ##kel, ##eto, ##n, dynamics, and, is, ins, ##ens, ##ible, to, ph, ##arm, ##aco, ##logical, treatment, with, known, micro, ##tub, ##ule, -, stab, ##ili, ##zing, drug, such, pac, ##lita, ##x, ##el, ;, (, iv, ), involves, tr, ##ka, -, dependent, mechanisms, because, the, effects, of, ng, ##f, re, -, application, are, blocked, by, acute, exposure, to, a, specific, and, cell, -, per, ##me, ##able, inhibitor, of, tr, ##ka, receptor, ., in, addition, ,, in, line, with, previous, findings, reporting, a, mod, ##ulator, ##y, effect, of, ng, ##f, signaling, on, app, expression, [, 39, ,, 107, ], ,, a, significant, up, ##re, ##gul, ##ation, in, expression, of, three, app, iso, ##forms, of, ~, 110, k, ##da, ,, ~, 120, k, ##da, ,, and, ~, 130, k, ##da, along, with, marked, increase, in, the, im, ##mun, ##ore, ##act, ##ivity, level, of, the, car, ##box, ##yl, -, terminal, ct, ##f, ##β, fragment, of, 14, k, ##da, ,, are, detected, in, primary, sept, ##al, neurons, upon, 24, –, 48, h, of, ne, ##uro, ##tro, ##phi, ##n, starvation, ,, indicating, that, the, app, metabolism, is, also, greatly, influenced, following, ng, ##f, withdrawal, in, this, novel, ad, -, like, ne, ##uron, ##al, paradigm, ., these, results, clearly, demonstrate, that, the, combined, mod, ##ulator, ##y, actions, of, ng, ##f, on, the, expression, of, important, pre, -, syn, ##ap, ##tic, proteins, and, ne, ##uro, ##se, ##cre, ##tory, function, (, s, ), of, in, vitro, cho, ##liner, ##gic, sept, ##al, primary, neurons, are, directly, and, causal, ##ly, linked, via, the, stimulation, of, ng, ##f, /, tr, ##ka, signaling, ., these, findings, point, out, the, path, ##ological, relevance, of, the, lack, of, ng, ##f, availability, in, the, earliest, syn, ##ap, ##tic, deficit, ##s, occurring, at, the, onset, of, ad, progression, [, 102, ], ., taken, together, ,, these, findings, :, (, i, ), provide, a, valuable, in, vitro, tool, to, better, investigate, the, survival, /, disease, changes, of, basal, fore, ##bra, ##in, sept, ##o, -, hip, ##po, ##camp, ##al, projecting, neurons, occurring, during, the, pro, ##dro, ##mal, stages, of, ad, pathology, caused, by, dysfunction, in, ng, ##f, /, tr, ##ka, signaling, ;, (, ii, ), demonstrate, that, ng, ##f, withdrawal, induce, ##s, ne, ##uro, ##de, ##gen, ##erative, changes, initiated, by, early, ,, selective, ,, and, rev, ##ers, ##ible, pre, ##sy, ##na, ##ptic, dysfunction, in, cho, ##liner, ##gic, neurons, ,, just, resembling, the, syn, ##ap, ##ses, loss, and, retro, ##grade, “, dying, -, back, ”, ax, ##onal, de, ##gen, ##eration, appearing, at, pro, ##dro, ##mal, stages, of, ad, pathology, in, correlation, with, inc, ##ip, ##ient, memory, dysfunction, [, 46, ,, 108, ,, 109, ,, 110, ], ;, (, iii, ), have, potential, ,, important, clinical, implications, in, the, field, of, therapeutic, ##al, in, vivo, ng, ##f, delivery, in, humans, ,, because, it, not, only, constitutes, a, molecular, rational, ##e, for, the, existence, of, its, limited, therapeutic, time, window, ,, but, also, offers, a, prime, useful, pre, ##sy, ##na, ##ptic, -, based, target, with, the, intent, of, extending, its, ne, ##uro, ##pro, ##tec, ##tive, action, in, ad, intervention, .'},\n", - " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", - " 'section_name': 'SiR Transsynaptic Spreading Capabilities',\n", - " 'text': 'For its use in long-term functional investigations of neural networks, it is key that the SiR retains the ability to spread transsynaptically. Therefore, we assessed the spreading capabilities of SiR and compared it to the canonical B19 ΔG-rabies in both cortical and subcortical circuits. In order to test this, we first injected the nucleus accumbens (NAc) bilaterally with an AAV expressing TVA and the newly developed optimized rabies glycoprotein (oG) (Figure 4A), which has been shown to enhance rabies virus spreading (Kim et al., 2016). The expression of TVA permits selective infection of the starting cells in the NAc by an EnvA pseudotyped SiR, while the expression of oG allows its transsynaptic retrograde spread (Kim et al., 2016, Wickersham et al., 2007b). Then, we re-targeted the NAc in the two hemispheres with either SiR or ΔG-rabies EnvA-pseudotyped viruses. In agreement with the known connectivity of this area (Russo and Nestler, 2013), we identified transsynaptically labeled neurons in various cortical and subcortical regions, including the basolateral amygdala (BLA) and ventral tegmental area (VTA). We focused on these two areas to quantify spreading efficiency. At 1 week p.i., we observed no significant difference in the spreading capabilities between SiR and the canonical B19 ΔG-rabies (Figures 4A, 4B, 4D, 4D′, 4F, 4F′, and 4I; one-way ANOVA, F = 0.03, p = 0.96), indicating that the self-inactivating nature of the SiR does not affect its ability to spread efficiently. Moreover, as expected, by 3 weeks p.i., we observed a decrease in the number of transsynaptically labeled neurons upon B19 ΔG-rabies infection due to neuronal loss, while no changes upon SiR infection were detected (Figures 4C, 4E, 4E′, and 4G–4H; B19 ΔG-rabies, one-way ANOVA, F = 43, p = 6 × 10^−5; SiR, one-way ANOVA, F = 0.03, p = 0.96).Figure 4SiR Transsynaptic and Intraneuronal Retrograde Spread(A) Diagram of the injection procedure for the transsynaptic spread from the nucleus accumbens (NAc).(B and C) Spreading at 1 week (B) and 3 weeks p.i. (C) of B19 ΔG-rabies (cyan) and SiR (magenta). Scale bar, 1,000 μm.(D–E′) Transsynaptically labeled neurons in basolateral amygdala (BLA) at 1 week (D and D′) and 3 weeks p.i. (E and E′) with SiR (D and E, magenta) and ΔG-rabies (D′ and E ′, cyan). Scale bar, 50 μm.(F–G′) Transsynaptically labeled neurons in ventral tegmental area (VTA) at 1 week (F and F′) and 3 weeks p.i. (G and G′) with SiR (D and E, magenta) and ΔG-rabies (D′ and E′, cyan).(H) Number of SiR or ΔG-rabies positive neurons at 1 and 3 weeks p.i. in BLA and VTA normalized to 1 week time points (mean ± SEM, n = 3 animals per time point).(I) Efficiency of spreading at 1 week p.i. as number of inputs normalized to number of starting cells, and of SiR and ΔG-rabies in BLA and VTA (SiR = 1, mean ± SEM, n = 3 animals).(J) Scheme of retrograde intraneuronal spreading from VTA.(K–M′′) Retrogradely labeled neurons with SiR and rAAV2-retro (SiR, magenta; rAAV2-retro, cyan) in medial prefrontal cortex (mPFC) (K–K′′), lateral hypothalamus (LH) (L–L′′), and NAc (M–M′′).(N) Number of SiR- and rAAV2-retro-infected neurons in NAc, LH, and PFC (mean ± SEM, n = 3 animals) Scale bars, 1,000 μm (K–M); 50 μm (K′, K′′, L′, L′′, M′, and M′′).See also Figure S6.',\n", - " 'paragraph_id': 8,\n", - " 'tokenizer': 'for, its, use, in, long, -, term, functional, investigations, of, neural, networks, ,, it, is, key, that, the, sir, retains, the, ability, to, spread, trans, ##sy, ##na, ##ptic, ##ally, ., therefore, ,, we, assessed, the, spreading, capabilities, of, sir, and, compared, it, to, the, canonical, b1, ##9, δ, ##g, -, ra, ##bies, in, both, co, ##rti, ##cal, and, sub, ##cor, ##tical, circuits, ., in, order, to, test, this, ,, we, first, injected, the, nucleus, acc, ##umb, ##ens, (, na, ##c, ), bilateral, ##ly, with, an, aa, ##v, expressing, tv, ##a, and, the, newly, developed, opt, ##imi, ##zed, ra, ##bies, g, ##ly, ##co, ##pro, ##tein, (, og, ), (, figure, 4a, ), ,, which, has, been, shown, to, enhance, ra, ##bies, virus, spreading, (, kim, et, al, ., ,, 2016, ), ., the, expression, of, tv, ##a, permits, selective, infection, of, the, starting, cells, in, the, na, ##c, by, an, en, ##va, pseudo, ##type, ##d, sir, ,, while, the, expression, of, og, allows, its, trans, ##sy, ##na, ##ptic, retro, ##grade, spread, (, kim, et, al, ., ,, 2016, ,, wi, ##cker, ##sham, et, al, ., ,, 2007, ##b, ), ., then, ,, we, re, -, targeted, the, na, ##c, in, the, two, hemisphere, ##s, with, either, sir, or, δ, ##g, -, ra, ##bies, en, ##va, -, pseudo, ##type, ##d, viruses, ., in, agreement, with, the, known, connectivity, of, this, area, (, russo, and, nest, ##ler, ,, 2013, ), ,, we, identified, trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, in, various, co, ##rti, ##cal, and, sub, ##cor, ##tical, regions, ,, including, the, bas, ##olate, ##ral, amy, ##g, ##dal, ##a, (, b, ##la, ), and, ventral, te, ##gm, ##ental, area, (, vt, ##a, ), ., we, focused, on, these, two, areas, to, quan, ##tify, spreading, efficiency, ., at, 1, week, p, ., i, ., ,, we, observed, no, significant, difference, in, the, spreading, capabilities, between, sir, and, the, canonical, b1, ##9, δ, ##g, -, ra, ##bies, (, figures, 4a, ,, 4, ##b, ,, 4, ##d, ,, 4, ##d, ′, ,, 4, ##f, ,, 4, ##f, ′, ,, and, 4, ##i, ;, one, -, way, an, ##ova, ,, f, =, 0, ., 03, ,, p, =, 0, ., 96, ), ,, indicating, that, the, self, -, ina, ##ct, ##ivating, nature, of, the, sir, does, not, affect, its, ability, to, spread, efficiently, ., moreover, ,, as, expected, ,, by, 3, weeks, p, ., i, ., ,, we, observed, a, decrease, in, the, number, of, trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, upon, b1, ##9, δ, ##g, -, ra, ##bies, infection, due, to, ne, ##uron, ##al, loss, ,, while, no, changes, upon, sir, infection, were, detected, (, figures, 4, ##c, ,, 4, ##e, ,, 4, ##e, ′, ,, and, 4, ##g, –, 4, ##h, ;, b1, ##9, δ, ##g, -, ra, ##bies, ,, one, -, way, an, ##ova, ,, f, =, 43, ,, p, =, 6, ×, 10, ^, −, ##5, ;, sir, ,, one, -, way, an, ##ova, ,, f, =, 0, ., 03, ,, p, =, 0, ., 96, ), ., figure, 4, ##sir, trans, ##sy, ##na, ##ptic, and, intra, ##ne, ##uron, ##al, retro, ##grade, spread, (, a, ), diagram, of, the, injection, procedure, for, the, trans, ##sy, ##na, ##ptic, spread, from, the, nucleus, acc, ##umb, ##ens, (, na, ##c, ), ., (, b, and, c, ), spreading, at, 1, week, (, b, ), and, 3, weeks, p, ., i, ., (, c, ), of, b1, ##9, δ, ##g, -, ra, ##bies, (, cy, ##an, ), and, sir, (, mage, ##nta, ), ., scale, bar, ,, 1, ,, 000, μ, ##m, ., (, d, –, e, ′, ), trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, in, bas, ##olate, ##ral, amy, ##g, ##dal, ##a, (, b, ##la, ), at, 1, week, (, d, and, d, ′, ), and, 3, weeks, p, ., i, ., (, e, and, e, ′, ), with, sir, (, d, and, e, ,, mage, ##nta, ), and, δ, ##g, -, ra, ##bies, (, d, ′, and, e, ′, ,, cy, ##an, ), ., scale, bar, ,, 50, μ, ##m, ., (, f, –, g, ′, ), trans, ##sy, ##na, ##ptic, ##ally, labeled, neurons, in, ventral, te, ##gm, ##ental, area, (, vt, ##a, ), at, 1, week, (, f, and, f, ′, ), and, 3, weeks, p, ., i, ., (, g, and, g, ′, ), with, sir, (, d, and, e, ,, mage, ##nta, ), and, δ, ##g, -, ra, ##bies, (, d, ′, and, e, ′, ,, cy, ##an, ), ., (, h, ), number, of, sir, or, δ, ##g, -, ra, ##bies, positive, neurons, at, 1, and, 3, weeks, p, ., i, ., in, b, ##la, and, vt, ##a, normal, ##ized, to, 1, week, time, points, (, mean, ±, se, ##m, ,, n, =, 3, animals, per, time, point, ), ., (, i, ), efficiency, of, spreading, at, 1, week, p, ., i, ., as, number, of, inputs, normal, ##ized, to, number, of, starting, cells, ,, and, of, sir, and, δ, ##g, -, ra, ##bies, in, b, ##la, and, vt, ##a, (, sir, =, 1, ,, mean, ±, se, ##m, ,, n, =, 3, animals, ), ., (, j, ), scheme, of, retro, ##grade, intra, ##ne, ##uron, ##al, spreading, from, vt, ##a, ., (, k, –, m, ′, ′, ), retro, ##grade, ##ly, labeled, neurons, with, sir, and, ra, ##av, ##2, -, retro, (, sir, ,, mage, ##nta, ;, ra, ##av, ##2, -, retro, ,, cy, ##an, ), in, medial, pre, ##front, ##al, cortex, (, mp, ##fc, ), (, k, –, k, ′, ′, ), ,, lateral, h, ##yp, ##oth, ##ala, ##mus, (, l, ##h, ), (, l, –, l, ′, ′, ), ,, and, na, ##c, (, m, –, m, ′, ′, ), ., (, n, ), number, of, sir, -, and, ra, ##av, ##2, -, retro, -, infected, neurons, in, na, ##c, ,, l, ##h, ,, and, p, ##fc, (, mean, ±, se, ##m, ,, n, =, 3, animals, ), scale, bars, ,, 1, ,, 000, μ, ##m, (, k, –, m, ), ;, 50, μ, ##m, (, k, ′, ,, k, ′, ′, ,, l, ′, ,, l, ′, ′, ,, m, ′, ,, and, m, ′, ′, ), ., see, also, figure, s, ##6, .'},\n", - " {'article_id': '76475dafc6b33daa80494c8b8a21bffc',\n", - " 'section_name': 'Investigating Network Dynamics with SiR',\n", - " 'text': 'The absence of cytotoxicity and unaltered electrophysiological responses support the use of SiR for long-term circuit manipulations. The presence of functional connectivity between SiR-infected neurons and no adverse effects on synaptic properties also indicate that network function is likely to be preserved following SiR infection. In order to test whether network-dependent computations are also preserved and whether SiR can be used to monitor neural activity in vivo, we looked at a prototypical example of network-dependent computation, orientation tuning in visual cortex. We first targeted V1 neurons projecting to V2 (V1 ^> V2) by injecting oG pseudotyped SiR^CRE in the V2 area of Rosa-LoxP-STOP-LoxP-tdTomato mice. At the same time, we injected an AAV^GCaMP6s in the ipsilateral V1 (Figure 6A). Retrograde spreading of SiR^CRE from V2 induced recombination of the Rosa locus permanently labeling V1 ^> V2 neurons (Figures 6B–6B′′; Movie S1). We then monitored the Ca^2+ dynamics of SiR-infected V1 ^> V2 neurons in vivo 4 weeks p.i., under a two-photon microscope, while anesthetized animals were exposed to moving gratings of different orientations across the visual field (Figure 6C) (Benucci et al., 2009). Infected V1 ^> V2 neurons showed significant increases in fluorescence at particular grating orientations resulting in a cellular tuning curve showing direction or orientation selectivity (Figures 6G and 6H). Notably, recorded Ca^2+ responses, as well as the percentage of active neurons, were similar between SiR-traced neurons (GCaMP6s^ON-tdTomato^ON) and neighboring non-SiR V1 neurons (GCaMP6s^ON-tdTomato^OFF) (Figures 6E and 6F). Furthermore, to exclude the possibility of long-term deleterious effects on circuit function following SiR infection, we repeated functional imaging experiments at 2 and 4 months p.i. (Figure S7). In both cases, we found no significant difference in percentage of active neurons or stimulus-driven responses between GCaMP6s^ON-tdTomato^ON and GCaMP6s^ON-tdTomato^OFF neurons (Figures S7F–S7H′′). These data indicate that SiR-traced networks preserve unaltered computational properties and that SiR can be used in combination with GCaMP6s to monitor the Ca^2+ dynamic with no upper bounds to the temporal window for the optical investigation.Figure 6Unaltered Orientation Tuning Responses of SiR-Traced V1 Neurons(A) Schematic of SiR^CRE and AAV^GCaMP6s injection in Rosa-LoxP-STOP-LoxP-tdTomato mice in V2 and V1, respectively.(B–B′′) Two-photon maximal projection of V1 neurons after SiR^CRE injection. In cyan neurons expressing GCaMP6s (B), in magenta neurons expressing tdTomato (B′), and in the merge neurons expressing both (B′′, merge). Arrows and arrowheads highlight representative GCaMP6s or GCaMP6s-tdTomato expressing neurons, respectively. Scale bar, 50 μm.(C) Schematic of visual stimulation set up.(D) Outline of the active ROIs from the same field of view shown in (B).(E) Representative Ca^2+ traces of GCaMP6s (cyan) and GCaMP6s-tdTomato (magenta) neurons. Scale bars, 200 s, 20% dF/F_0.(F) Mean percentage of active neurons after 4 weeks from SiR injection (n = 163 GCaMP6s neurons [cyan], n = 78 GCaMP6s-tdTomato neurons [magenta]; mean ± SEM).(G) Changes in fluorescence over time reflecting visual responses to drifting gratings at the preferred direction of each neuron.(H) Example of tuning curve of V1-infected neurons (mean ± SEM). Scale bars, 5 s, 10% dF/F_0.See also Figure S7 and Movie S1.Figure S7The Orientation Tuning Responses of SiR traced V1 neurons are preserved up to 4 months from the injection, Related to Figure 6(A) Schematic of SiR^CRE and AAV^GCaMP6s injection in Rosa-LoxP-STOP-LoxP-tdTomato mice in V2 and V1 respectively. (B) Schematic of visual stimulation set up. (C-E’’’) Two-photon maximal projection of V1 neurons 1, 2, or 4 months after SiR^CRE injection. In cyan neurons expressing GCaMP6s (C, D, E), in magenta neurons expressing tdTomato (C’, D’, E’) and in the merge neurons expressing both (C’’, D’’, E’’ merge). Arrows and arrowheads highlight representative GCaMP6s (cyan) or GCaMP6s-tdTomato (magenta) expressing neurons respectively. Scale bar: 20 μm. (C’’’, D’’’, E’’’) Outline of the active ROIs from the same field of view showed in panel C, D and E. (F, G, H) Representative Ca^2+ traces of GCaMP6s (cyan) and GCaMP6s-tdTomato (magenta) neurons. Scale bars: 100 s, 20% dF/F_0. (F’, G’, H’) Mean percentage of active neurons after 1, 2 or 4 months from SiR injection (n = 241, 156, 231 respectively, mean ± SEM). (F’’, G’’, H’’) Example of tuning curve of V1 infected neurons after 1, 2 or 4 months (GCaMP6s neurons (cyan) and GCaMP6s-tdTomato neurons (magenta); dF/F_0 mean ± SEM).',\n", - " 'paragraph_id': 16,\n", - " 'tokenizer': 'the, absence, of, cy, ##to, ##to, ##xi, ##city, and, una, ##lter, ##ed, electro, ##phy, ##sio, ##logical, responses, support, the, use, of, sir, for, long, -, term, circuit, manipulation, ##s, ., the, presence, of, functional, connectivity, between, sir, -, infected, neurons, and, no, adverse, effects, on, syn, ##ap, ##tic, properties, also, indicate, that, network, function, is, likely, to, be, preserved, following, sir, infection, ., in, order, to, test, whether, network, -, dependent, computation, ##s, are, also, preserved, and, whether, sir, can, be, used, to, monitor, neural, activity, in, vivo, ,, we, looked, at, a, proto, ##typical, example, of, network, -, dependent, computation, ,, orientation, tuning, in, visual, cortex, ., we, first, targeted, v, ##1, neurons, projecting, to, v, ##2, (, v, ##1, ^, >, v, ##2, ), by, in, ##ject, ##ing, og, pseudo, ##type, ##d, sir, ^, cr, ##e, in, the, v, ##2, area, of, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, td, ##tom, ##ato, mice, ., at, the, same, time, ,, we, injected, an, aa, ##v, ^, g, ##camp, ##6, ##s, in, the, ip, ##sil, ##ater, ##al, v, ##1, (, figure, 6, ##a, ), ., retro, ##grade, spreading, of, sir, ^, cr, ##e, from, v, ##2, induced, rec, ##om, ##bina, ##tion, of, the, rosa, locus, permanently, labeling, v, ##1, ^, >, v, ##2, neurons, (, figures, 6, ##b, –, 6, ##b, ′, ′, ;, movie, s, ##1, ), ., we, then, monitored, the, ca, ^, 2, +, dynamics, of, sir, -, infected, v, ##1, ^, >, v, ##2, neurons, in, vivo, 4, weeks, p, ., i, ., ,, under, a, two, -, photon, microscope, ,, while, an, ##est, ##het, ##ized, animals, were, exposed, to, moving, gr, ##ating, ##s, of, different, orientation, ##s, across, the, visual, field, (, figure, 6, ##c, ), (, ben, ##ucci, et, al, ., ,, 2009, ), ., infected, v, ##1, ^, >, v, ##2, neurons, showed, significant, increases, in, flu, ##orescence, at, particular, gr, ##ating, orientation, ##s, resulting, in, a, cellular, tuning, curve, showing, direction, or, orientation, select, ##ivity, (, figures, 6, ##g, and, 6, ##h, ), ., notably, ,, recorded, ca, ^, 2, +, responses, ,, as, well, as, the, percentage, of, active, neurons, ,, were, similar, between, sir, -, traced, neurons, (, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, on, ), and, neighboring, non, -, sir, v, ##1, neurons, (, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, off, ), (, figures, 6, ##e, and, 6, ##f, ), ., furthermore, ,, to, exclude, the, possibility, of, long, -, term, del, ##eter, ##ious, effects, on, circuit, function, following, sir, infection, ,, we, repeated, functional, imaging, experiments, at, 2, and, 4, months, p, ., i, ., (, figure, s, ##7, ), ., in, both, cases, ,, we, found, no, significant, difference, in, percentage, of, active, neurons, or, stimulus, -, driven, responses, between, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, on, and, g, ##camp, ##6, ##s, ^, on, -, td, ##tom, ##ato, ^, off, neurons, (, figures, s, ##7, ##f, –, s, ##7, ##h, ′, ′, ), ., these, data, indicate, that, sir, -, traced, networks, preserve, una, ##lter, ##ed, computational, properties, and, that, sir, can, be, used, in, combination, with, g, ##camp, ##6, ##s, to, monitor, the, ca, ^, 2, +, dynamic, with, no, upper, bounds, to, the, temporal, window, for, the, optical, investigation, ., figure, 6, ##una, ##lter, ##ed, orientation, tuning, responses, of, sir, -, traced, v, ##1, neurons, (, a, ), sc, ##hema, ##tic, of, sir, ^, cr, ##e, and, aa, ##v, ^, g, ##camp, ##6, ##s, injection, in, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, td, ##tom, ##ato, mice, in, v, ##2, and, v, ##1, ,, respectively, ., (, b, –, b, ′, ′, ), two, -, photon, maximal, projection, of, v, ##1, neurons, after, sir, ^, cr, ##e, injection, ., in, cy, ##an, neurons, expressing, g, ##camp, ##6, ##s, (, b, ), ,, in, mage, ##nta, neurons, expressing, td, ##tom, ##ato, (, b, ′, ), ,, and, in, the, merge, neurons, expressing, both, (, b, ′, ′, ,, merge, ), ., arrows, and, arrow, ##heads, highlight, representative, g, ##camp, ##6, ##s, or, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, expressing, neurons, ,, respectively, ., scale, bar, ,, 50, μ, ##m, ., (, c, ), sc, ##hema, ##tic, of, visual, stimulation, set, up, ., (, d, ), outline, of, the, active, roi, ##s, from, the, same, field, of, view, shown, in, (, b, ), ., (, e, ), representative, ca, ^, 2, +, traces, of, g, ##camp, ##6, ##s, (, cy, ##an, ), and, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, (, mage, ##nta, ), neurons, ., scale, bars, ,, 200, s, ,, 20, %, d, ##f, /, f, _, 0, ., (, f, ), mean, percentage, of, active, neurons, after, 4, weeks, from, sir, injection, (, n, =, 163, g, ##camp, ##6, ##s, neurons, [, cy, ##an, ], ,, n, =, 78, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, neurons, [, mage, ##nta, ], ;, mean, ±, se, ##m, ), ., (, g, ), changes, in, flu, ##orescence, over, time, reflecting, visual, responses, to, drifting, gr, ##ating, ##s, at, the, preferred, direction, of, each, ne, ##uron, ., (, h, ), example, of, tuning, curve, of, v, ##1, -, infected, neurons, (, mean, ±, se, ##m, ), ., scale, bars, ,, 5, s, ,, 10, %, d, ##f, /, f, _, 0, ., see, also, figure, s, ##7, and, movie, s, ##1, ., figure, s, ##7th, ##e, orientation, tuning, responses, of, sir, traced, v, ##1, neurons, are, preserved, up, to, 4, months, from, the, injection, ,, related, to, figure, 6, (, a, ), sc, ##hema, ##tic, of, sir, ^, cr, ##e, and, aa, ##v, ^, g, ##camp, ##6, ##s, injection, in, rosa, -, lo, ##x, ##p, -, stop, -, lo, ##x, ##p, -, td, ##tom, ##ato, mice, in, v, ##2, and, v, ##1, respectively, ., (, b, ), sc, ##hema, ##tic, of, visual, stimulation, set, up, ., (, c, -, e, ’, ’, ’, ), two, -, photon, maximal, projection, of, v, ##1, neurons, 1, ,, 2, ,, or, 4, months, after, sir, ^, cr, ##e, injection, ., in, cy, ##an, neurons, expressing, g, ##camp, ##6, ##s, (, c, ,, d, ,, e, ), ,, in, mage, ##nta, neurons, expressing, td, ##tom, ##ato, (, c, ’, ,, d, ’, ,, e, ’, ), and, in, the, merge, neurons, expressing, both, (, c, ’, ’, ,, d, ’, ’, ,, e, ’, ’, merge, ), ., arrows, and, arrow, ##heads, highlight, representative, g, ##camp, ##6, ##s, (, cy, ##an, ), or, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, (, mage, ##nta, ), expressing, neurons, respectively, ., scale, bar, :, 20, μ, ##m, ., (, c, ’, ’, ’, ,, d, ’, ’, ’, ,, e, ’, ’, ’, ), outline, of, the, active, roi, ##s, from, the, same, field, of, view, showed, in, panel, c, ,, d, and, e, ., (, f, ,, g, ,, h, ), representative, ca, ^, 2, +, traces, of, g, ##camp, ##6, ##s, (, cy, ##an, ), and, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, (, mage, ##nta, ), neurons, ., scale, bars, :, 100, s, ,, 20, %, d, ##f, /, f, _, 0, ., (, f, ’, ,, g, ’, ,, h, ’, ), mean, percentage, of, active, neurons, after, 1, ,, 2, or, 4, months, from, sir, injection, (, n, =, 241, ,, 156, ,, 231, respectively, ,, mean, ±, se, ##m, ), ., (, f, ’, ’, ,, g, ’, ’, ,, h, ’, ’, ), example, of, tuning, curve, of, v, ##1, infected, neurons, after, 1, ,, 2, or, 4, months, (, g, ##camp, ##6, ##s, neurons, (, cy, ##an, ), and, g, ##camp, ##6, ##s, -, td, ##tom, ##ato, neurons, (, mage, ##nta, ), ;, d, ##f, /, f, _, 0, mean, ±, se, ##m, ), .'},\n", - " {'article_id': '9341682e47b256a3d4291c4898437a36',\n", - " 'section_name': 'Discussion',\n", - " 'text': 'There was a trend to increase one derivative of aspartic acid, N-acetylaspartic (NAA), after death (Simmons et al. 1991). NAA is the second most concentrated molecule in the brain after glutamate, and like glutamate, it may function as a neurotransmitter (Yan et al. 2003). NAA, which is synthesized primarily in neurons, is the second most concentrated molecule in the brain after glutamate, and like glutamate, it may function as a neurotransmitter (Yan et al. 2003). However, its role in these cells remains unclear. One of the main hypotheses is that NAA is involved in cell signaling together with NAAG, controlling the interactions of brain cells and preserving the nervous system (Baslow 2000). NAA is also considered to be an important marker of neuronal viability in many cerebral pathologies, where a decline in its concentration is interpreted as a sign of neuronal or axonal dysfunction or death (Tyson and Sutherland 1998). Nevertheless, an increment in NAA concentration also induces many alterations such as oxidative stress, Canavan disease or genotoxicity and protein interaction due to an increase in nitric oxide produced by the elevated concentration of NAA (Surendran and Bhatnagar 2011). Compared with other organs, the brain has a high content of lipids, some two-thirds of which are phospholipids (Ohkubo and Tanaka 2010). Hippocampal pyramidal neurons represent by far the most abundant type of neuron in the hippocampus, and their dendritic arbor is covered by dendritic spines. Dendritic spines are the main target of excitatory glutamatergic synapses and are considered to be critical for cognition, learning and memory. Thus, many researchers are interested in the study of possible alterations of dendritic spines in brain diseases (DeFelipe 2015). These structures contain a complex mixture of ions, lipids, proteins and other signaling molecules which must be continually restored (Sorra and Harris 2000). In fact, it is well known that cholesterol and sphingolipids (SL) are enriched in dendritic spines. The extraction of cholesterol or inhibition of its synthesis leads to the disappearance of dendritic spines, which proves that cholesterol is a core component of dendritic spines (Dotti et al. 2014). Cholesterol and cholesterol esters were identified by two techniques (GC–MS and LC–MS), but differences over time were not statistically significant after data analysis, indicating that degradation 5 h PT is negligible. This is in line with the study by Williams et al. (1978); they found no appreciable changes in the density and morphology of spines in the dendritic arbors of pyramidal neurons of the mouse with fixation latencies of 5 min to 6 h, but, with latencies of more than 6 h, they observed a reduction in the density of dendritic spines and morphological changes of these structures. SL make up approximately 20% of the hippocampus, including sphingomyelin, cerebrosides, cerebroside sulfates and gangliosides. SL act as important signaling molecules in neuronal tissue, and they have received wide attention due to the relatively high levels of gangliosides found. However, recent studies have shown that simple SL, such as ceramide, sphingosine-1-phosphate and glucosylceramide (GlcCer), also play important roles in neuronal function such as in regulation of neuronal growth rates, differentiation and cell death (Buccoliero and Futerman 2003). Ceramide, a second messenger in neurons, contributes to spine plasticity thanks to its capacity to favor membrane fusogenicity promoting receptor clustering (Kronke 1999). Although ceramide is the best characterized SL, its glucosyl derivative, GlcCer also has important functions since it regulates the rate of axonal and dendritic growth (Boldin and Futerman 1997; Harel and Futerman 1993). However, GlcCer is found in low concentrations since it is a metabolic intermediate in the biosynthetic pathway leading to formation of other GSLs. The proper formation and long-term maintenance of neuronal connectivity are crucial for correct functioning of the brain. The long-lasting stability of dendrite and spine structure in the nervous system is highly dependent on the actin cytoskeleton, which is particularly well developed in these structures (Koleske 2013). Sphingomyelin, one of the most abundant SL in neuronal membranes, has an important role in the spine membrane–cytoskeleton cross talk since it modulates membrane binding and the activity of main regulators of the actin cytoskeleton at synapses (Dotti et al. 2014). Sphingosine 1-phosphate is a bioactive lipid that controls a wide range of the cellular processes described above, and it is also involved in cytoskeletal organization. Moreover, it plays a pivotal role is the formation of memory (Kanno et al. 2010). However, no significant differences in any of these compounds were observed over time.',\n", - " 'paragraph_id': 57,\n", - " 'tokenizer': 'there, was, a, trend, to, increase, one, derivative, of, as, ##par, ##tic, acid, ,, n, -, ace, ##ty, ##las, ##par, ##tic, (, na, ##a, ), ,, after, death, (, simmons, et, al, ., 1991, ), ., na, ##a, is, the, second, most, concentrated, molecule, in, the, brain, after, g, ##lu, ##tama, ##te, ,, and, like, g, ##lu, ##tama, ##te, ,, it, may, function, as, a, ne, ##uro, ##tra, ##ns, ##mit, ##ter, (, yan, et, al, ., 2003, ), ., na, ##a, ,, which, is, synthesized, primarily, in, neurons, ,, is, the, second, most, concentrated, molecule, in, the, brain, after, g, ##lu, ##tama, ##te, ,, and, like, g, ##lu, ##tama, ##te, ,, it, may, function, as, a, ne, ##uro, ##tra, ##ns, ##mit, ##ter, (, yan, et, al, ., 2003, ), ., however, ,, its, role, in, these, cells, remains, unclear, ., one, of, the, main, h, ##yp, ##oth, ##eses, is, that, na, ##a, is, involved, in, cell, signaling, together, with, na, ##ag, ,, controlling, the, interactions, of, brain, cells, and, preserving, the, nervous, system, (, bas, ##low, 2000, ), ., na, ##a, is, also, considered, to, be, an, important, marker, of, ne, ##uron, ##al, via, ##bility, in, many, cerebral, path, ##ologies, ,, where, a, decline, in, its, concentration, is, interpreted, as, a, sign, of, ne, ##uron, ##al, or, ax, ##onal, dysfunction, or, death, (, tyson, and, sutherland, 1998, ), ., nevertheless, ,, an, inc, ##rem, ##ent, in, na, ##a, concentration, also, induce, ##s, many, alterations, such, as, ox, ##ida, ##tive, stress, ,, can, ##ava, ##n, disease, or, gen, ##oto, ##xi, ##city, and, protein, interaction, due, to, an, increase, in, ni, ##tric, oxide, produced, by, the, elevated, concentration, of, na, ##a, (, sure, ##ndra, ##n, and, b, ##hat, ##nagar, 2011, ), ., compared, with, other, organs, ,, the, brain, has, a, high, content, of, lip, ##ids, ,, some, two, -, thirds, of, which, are, ph, ##os, ##ph, ##oli, ##pid, ##s, (, oh, ##ku, ##bo, and, tanaka, 2010, ), ., hip, ##po, ##camp, ##al, pyramid, ##al, neurons, represent, by, far, the, most, abundant, type, of, ne, ##uron, in, the, hip, ##po, ##camp, ##us, ,, and, their, den, ##dr, ##itic, arbor, is, covered, by, den, ##dr, ##itic, spines, ., den, ##dr, ##itic, spines, are, the, main, target, of, ex, ##cit, ##atory, g, ##lu, ##tama, ##ter, ##gic, syn, ##ap, ##ses, and, are, considered, to, be, critical, for, cognition, ,, learning, and, memory, ., thus, ,, many, researchers, are, interested, in, the, study, of, possible, alterations, of, den, ##dr, ##itic, spines, in, brain, diseases, (, def, ##eli, ##pe, 2015, ), ., these, structures, contain, a, complex, mixture, of, ions, ,, lip, ##ids, ,, proteins, and, other, signaling, molecules, which, must, be, continually, restored, (, so, ##rra, and, harris, 2000, ), ., in, fact, ,, it, is, well, known, that, cho, ##les, ##terol, and, sp, ##hing, ##oli, ##pid, ##s, (, sl, ), are, enriched, in, den, ##dr, ##itic, spines, ., the, extraction, of, cho, ##les, ##terol, or, inhibition, of, its, synthesis, leads, to, the, disappearance, of, den, ##dr, ##itic, spines, ,, which, proves, that, cho, ##les, ##terol, is, a, core, component, of, den, ##dr, ##itic, spines, (, dot, ##ti, et, al, ., 2014, ), ., cho, ##les, ##terol, and, cho, ##les, ##terol, este, ##rs, were, identified, by, two, techniques, (, g, ##c, –, ms, and, lc, –, ms, ), ,, but, differences, over, time, were, not, statistical, ##ly, significant, after, data, analysis, ,, indicating, that, degradation, 5, h, pt, is, ne, ##gli, ##gible, ., this, is, in, line, with, the, study, by, williams, et, al, ., (, 1978, ), ;, they, found, no, app, ##re, ##cia, ##ble, changes, in, the, density, and, morphology, of, spines, in, the, den, ##dr, ##itic, arbor, ##s, of, pyramid, ##al, neurons, of, the, mouse, with, fix, ##ation, late, ##ncies, of, 5, min, to, 6, h, ,, but, ,, with, late, ##ncies, of, more, than, 6, h, ,, they, observed, a, reduction, in, the, density, of, den, ##dr, ##itic, spines, and, morphological, changes, of, these, structures, ., sl, make, up, approximately, 20, %, of, the, hip, ##po, ##camp, ##us, ,, including, sp, ##hing, ##omy, ##elin, ,, ce, ##re, ##bro, ##side, ##s, ,, ce, ##re, ##bro, ##side, sulfate, ##s, and, gang, ##lio, ##side, ##s, ., sl, act, as, important, signaling, molecules, in, ne, ##uron, ##al, tissue, ,, and, they, have, received, wide, attention, due, to, the, relatively, high, levels, of, gang, ##lio, ##side, ##s, found, ., however, ,, recent, studies, have, shown, that, simple, sl, ,, such, as, ce, ##ram, ##ide, ,, sp, ##hing, ##osi, ##ne, -, 1, -, phosphate, and, g, ##lu, ##cos, ##yl, ##cera, ##mide, (, g, ##lc, ##cer, ), ,, also, play, important, roles, in, ne, ##uron, ##al, function, such, as, in, regulation, of, ne, ##uron, ##al, growth, rates, ,, differentiation, and, cell, death, (, bu, ##cco, ##lier, ##o, and, fu, ##ter, ##man, 2003, ), ., ce, ##ram, ##ide, ,, a, second, messenger, in, neurons, ,, contributes, to, spine, plastic, ##ity, thanks, to, its, capacity, to, favor, membrane, fu, ##so, ##genic, ##ity, promoting, receptor, cluster, ##ing, (, k, ##ron, ##ke, 1999, ), ., although, ce, ##ram, ##ide, is, the, best, characterized, sl, ,, its, g, ##lu, ##cos, ##yl, derivative, ,, g, ##lc, ##cer, also, has, important, functions, since, it, regulates, the, rate, of, ax, ##onal, and, den, ##dr, ##itic, growth, (, bold, ##in, and, fu, ##ter, ##man, 1997, ;, hare, ##l, and, fu, ##ter, ##man, 1993, ), ., however, ,, g, ##lc, ##cer, is, found, in, low, concentrations, since, it, is, a, metabolic, intermediate, in, the, bio, ##sy, ##nt, ##hetic, pathway, leading, to, formation, of, other, gs, ##ls, ., the, proper, formation, and, long, -, term, maintenance, of, ne, ##uron, ##al, connectivity, are, crucial, for, correct, functioning, of, the, brain, ., the, long, -, lasting, stability, of, den, ##dr, ##ite, and, spine, structure, in, the, nervous, system, is, highly, dependent, on, the, act, ##in, cy, ##tos, ##kel, ##eto, ##n, ,, which, is, particularly, well, developed, in, these, structures, (, ko, ##les, ##ke, 2013, ), ., sp, ##hing, ##omy, ##elin, ,, one, of, the, most, abundant, sl, in, ne, ##uron, ##al, membranes, ,, has, an, important, role, in, the, spine, membrane, –, cy, ##tos, ##kel, ##eto, ##n, cross, talk, since, it, mod, ##ulates, membrane, binding, and, the, activity, of, main, regulators, of, the, act, ##in, cy, ##tos, ##kel, ##eto, ##n, at, syn, ##ap, ##ses, (, dot, ##ti, et, al, ., 2014, ), ., sp, ##hing, ##osi, ##ne, 1, -, phosphate, is, a, bio, ##active, lip, ##id, that, controls, a, wide, range, of, the, cellular, processes, described, above, ,, and, it, is, also, involved, in, cy, ##tos, ##kel, ##eta, ##l, organization, ., moreover, ,, it, plays, a, pivotal, role, is, the, formation, of, memory, (, kan, ##no, et, al, ., 2010, ), ., however, ,, no, significant, differences, in, any, of, these, compounds, were, observed, over, time, .'},\n", - " {'article_id': 'fa6756244b8fbdeb59549a9046a5eecc',\n", - " 'section_name': '4. Assessment of Intermediate-term Recognition Memory by Measuring Novel Object Recognition111213',\n", - " 'text': 'For each phase of this test, thoroughly clean the open field arena with an unscented bleach germicidal wipe, 70% EtOH followed by dH_2O prior to initial use.One day prior to object exposure, habituate the mice to the open field arena.\\nPrior to the start of the habituation session, set up the data acquisition system or video cameras and confirm proper tracking of mice in the maze. Calibrate the distance in the arena using captured video images of a ruler or other object of known length. Mark the corners of the arena in the software to permit scoring of positional biases. NOTE: The behavioral methods in this procedure will work with a variety of data acquisition systems and the authors assume anyone performing this procedure is proficient in the use of their chosen data acquisition system. Power analyses indicate that sample sizes of 15-20 mice per group are required for a β ≤0.2.Remove the cage from the rack and gently place on a table in close proximity to the arena.Remove the mouse from the home cage and gently place the mouse in the center of the arena. Turn on the tracking software and/or video recording system immediately after placing the mouse into the arena.Allow mice to freely explore the arena for 30 min. NOTE: During this period, investigators will not disturb the mice.After the habituation session, place mice back into their home cage and clean the arena thoroughly with an unscented bleach germicidal wipe, 70% EtOH followed by dH_2O.Repeat from step 4.2.2 until all mice have been habituated to the arena.After all mice have been habituated to the arena, analyze the video. NOTE: Endpoints to analyze include total distance traveled in the arena and time spent near each corner. If relevant to the mouse model, stereotyped behaviors are included in these analyses (i.e., myoclonic corner jumping, circling, etc.). Mice exhibiting biases in time spent in particular regions of the arena are excluded from further experimentation as this will influence object exploration. NOTE: The first phase of novel object recognition involves familiarizing mice to an object. Herein this portion of the novel object recognition procedure will be referred to as the Sample phase.Prior to the start of a sample phase session, place objects into the arena and fix them to the floor with a mounting putty so that animals cannot move the objects. Align two identical objects to a particular wall with enough distance between the walls and objects so that the mice can freely explore the objects from all angles.Set up the data acquisition system or video cameras and confirm proper tracking of mice and objects in the maze. Calibrate the distances in the arena using captured video images of a ruler or other object of known length.Mark the corners of the arena in the software to permit scoring of positional biases. Mark objects in software and track their exploratory behavior separately for each object (i.e., \"Object A\" and \"Object B\").Remove the cage from the rack and gently place it on a table in close proximity to the arena.Remove the mouse from the home cage and gently place it into the center of the arena, facing the objects.Allow the mouse to freely explore the objects for 15 min. During this period do not disturb the mice.At the end of the session, gently place the mouse back into its home cage. Clean the arena and objects with 70% EtOH and dH_2O. Place these objects back into the arena.Repeat step 4.2.11 until all mice are familiarized to an object.Once all mice have been familiarized to an object, analyze the videos. NOTE: Object explorations are counted once the following criteria have been met: the mouse is oriented toward the object, the snout is within 2 cm of the object, the midpoint of the animal\\'s body is beyond 2 cm from the object, and the previous criteria have been fulfilled for at least 1 s. Additionally, if an animal has satisfied the exploration criteria but exhibits immobility for > 10 s then the exploratory bout is deemed finished.Calculate an object bias score for each mouse as follows. NOTE: Mice exhibiting an object bias score below 20% or above 80% are excluded from further experimentation.The final phase of novel object recognition involves assessing exploratory behavior directed toward both a novel and familiar object in the environment, referred to here as the Test phase. This phase is performed 2-3 h after completion of sample phase.\\nPrior to the start of a test phase session, place objects into the arena and fix them to the floor so that the animals cannot move the objects. Place the objects in the same position in the arena relative to the sample phase13.Balance the relative position of novel and familiar objects across genotypes and treatment groups.Ensure there is enough distance between the walls and objects so that the mice can freely explore the objects from all angles.Setup the data acquisition system and/or video cameras. Confirm proper tracking of mice and objects in the maze. Calibrate distances in the arena using captured video images of a ruler or other object of known length.Mark corners of the arena in the software to permit scoring of positional biases. Mark objects in software and track exploratory behavior for each object individually (i.e., \"Novel\" and \"Familiar\").Remove the cage from the rack and gently place it on a table in close proximity to the arena.Gently place animals into the center of the arena, facing the objects. Record mice freely exploring objects for 10 min.At the end of the test session, remove mice from the arena and place mice back into their home cage. Thoroughly clean arena and objects with an unscented bleach germicidal wipe, 70% EtOH and dH_2O after each session.Repeat from step 4.4.3 until all animals have been assessed.Once object exploration is measured for all mice, videos are analyzed. NOTE: Object explorations are counted once the following criteria have been met: the mouse is oriented toward the object, the snout is within 2 cm of the object, the midpoint of the animal\\'s body is beyond 2 cm from the object, and the previous criteria have been fulfilled for at least 1 s. Additionally, if an animal has satisfied the exploration criteria but exhibits immobility for > 10 s then the exploratory bout is deemed finished.Assess novel object recognition by comparing time spent exploring the novel to familiar object. Three methods are commonly reported in the literature. Analyze raw time spent exploring both novel and familiar objects using a repeated measure test. This method is best used when genotype and/or treatment do not affect total exploration time.Calculate novelty preference, using the equation: NOTE: This provides the percentage of time spent exploring the novel object relative to the total time exploring objects. Values range from 0% (no exploration of novel object) to 100% (exploration only of the novel object), with a value of 50% indicating equal time spent exploring novel and familiar objects.Calculate discrimination index11, using the equation: NOTE: This yields the difference in time spent exploring the novel and familiar objects relative to the total time spent exploring objects. Values range from -1 (exploration only of the familiar object) to +1 (exploration only of the novel object, with a value of 0 indicating equal time spent exploring novel and familiar objects.Remove animals that do not participate in the test session due to hyperdynamic locomotion or other stereotypies, from consideration11. NOTE: Criteria used for removal must be objective and determined a priori for the mouse model (i.e., <5^th percentile for total exploration time and either >100 average turn angle during test session or >50^th percentile time exhibiting myoclonic corner jumping).',\n", - " 'paragraph_id': 6,\n", - " 'tokenizer': 'for, each, phase, of, this, test, ,, thoroughly, clean, the, open, field, arena, with, an, un, ##scent, ##ed, b, ##lea, ##ch, ge, ##rmi, ##ci, ##dal, wipe, ,, 70, %, et, ##oh, followed, by, dh, _, 2, ##o, prior, to, initial, use, ., one, day, prior, to, object, exposure, ,, habit, ##uate, the, mice, to, the, open, field, arena, ., prior, to, the, start, of, the, habit, ##uation, session, ,, set, up, the, data, acquisition, system, or, video, cameras, and, confirm, proper, tracking, of, mice, in, the, maze, ., cal, ##ib, ##rate, the, distance, in, the, arena, using, captured, video, images, of, a, ruler, or, other, object, of, known, length, ., mark, the, corners, of, the, arena, in, the, software, to, permit, scoring, of, position, ##al, bias, ##es, ., note, :, the, behavioral, methods, in, this, procedure, will, work, with, a, variety, of, data, acquisition, systems, and, the, authors, assume, anyone, performing, this, procedure, is, proficient, in, the, use, of, their, chosen, data, acquisition, system, ., power, analyses, indicate, that, sample, sizes, of, 15, -, 20, mice, per, group, are, required, for, a, β, ≤, ##0, ., 2, ., remove, the, cage, from, the, rack, and, gently, place, on, a, table, in, close, proximity, to, the, arena, ., remove, the, mouse, from, the, home, cage, and, gently, place, the, mouse, in, the, center, of, the, arena, ., turn, on, the, tracking, software, and, /, or, video, recording, system, immediately, after, placing, the, mouse, into, the, arena, ., allow, mice, to, freely, explore, the, arena, for, 30, min, ., note, :, during, this, period, ,, investigators, will, not, disturb, the, mice, ., after, the, habit, ##uation, session, ,, place, mice, back, into, their, home, cage, and, clean, the, arena, thoroughly, with, an, un, ##scent, ##ed, b, ##lea, ##ch, ge, ##rmi, ##ci, ##dal, wipe, ,, 70, %, et, ##oh, followed, by, dh, _, 2, ##o, ., repeat, from, step, 4, ., 2, ., 2, until, all, mice, have, been, habit, ##uated, to, the, arena, ., after, all, mice, have, been, habit, ##uated, to, the, arena, ,, analyze, the, video, ., note, :, end, ##points, to, analyze, include, total, distance, traveled, in, the, arena, and, time, spent, near, each, corner, ., if, relevant, to, the, mouse, model, ,, stereo, ##type, ##d, behaviors, are, included, in, these, analyses, (, i, ., e, ., ,, my, ##oc, ##lon, ##ic, corner, jumping, ,, circling, ,, etc, ., ), ., mice, exhibiting, bias, ##es, in, time, spent, in, particular, regions, of, the, arena, are, excluded, from, further, experimentation, as, this, will, influence, object, exploration, ., note, :, the, first, phase, of, novel, object, recognition, involves, familiar, ##izing, mice, to, an, object, ., here, ##in, this, portion, of, the, novel, object, recognition, procedure, will, be, referred, to, as, the, sample, phase, ., prior, to, the, start, of, a, sample, phase, session, ,, place, objects, into, the, arena, and, fix, them, to, the, floor, with, a, mounting, put, ##ty, so, that, animals, cannot, move, the, objects, ., align, two, identical, objects, to, a, particular, wall, with, enough, distance, between, the, walls, and, objects, so, that, the, mice, can, freely, explore, the, objects, from, all, angles, ., set, up, the, data, acquisition, system, or, video, cameras, and, confirm, proper, tracking, of, mice, and, objects, in, the, maze, ., cal, ##ib, ##rate, the, distances, in, the, arena, using, captured, video, images, of, a, ruler, or, other, object, of, known, length, ., mark, the, corners, of, the, arena, in, the, software, to, permit, scoring, of, position, ##al, bias, ##es, ., mark, objects, in, software, and, track, their, ex, ##pl, ##ora, ##tory, behavior, separately, for, each, object, (, i, ., e, ., ,, \", object, a, \", and, \", object, b, \", ), ., remove, the, cage, from, the, rack, and, gently, place, it, on, a, table, in, close, proximity, to, the, arena, ., remove, the, mouse, from, the, home, cage, and, gently, place, it, into, the, center, of, the, arena, ,, facing, the, objects, ., allow, the, mouse, to, freely, explore, the, objects, for, 15, min, ., during, this, period, do, not, disturb, the, mice, ., at, the, end, of, the, session, ,, gently, place, the, mouse, back, into, its, home, cage, ., clean, the, arena, and, objects, with, 70, %, et, ##oh, and, dh, _, 2, ##o, ., place, these, objects, back, into, the, arena, ., repeat, step, 4, ., 2, ., 11, until, all, mice, are, familiar, ##ized, to, an, object, ., once, all, mice, have, been, familiar, ##ized, to, an, object, ,, analyze, the, videos, ., note, :, object, exploration, ##s, are, counted, once, the, following, criteria, have, been, met, :, the, mouse, is, oriented, toward, the, object, ,, the, snout, is, within, 2, cm, of, the, object, ,, the, mid, ##point, of, the, animal, \\', s, body, is, beyond, 2, cm, from, the, object, ,, and, the, previous, criteria, have, been, fulfilled, for, at, least, 1, s, ., additionally, ,, if, an, animal, has, satisfied, the, exploration, criteria, but, exhibits, im, ##mo, ##bility, for, >, 10, s, then, the, ex, ##pl, ##ora, ##tory, bout, is, deemed, finished, ., calculate, an, object, bias, score, for, each, mouse, as, follows, ., note, :, mice, exhibiting, an, object, bias, score, below, 20, %, or, above, 80, %, are, excluded, from, further, experimentation, ., the, final, phase, of, novel, object, recognition, involves, assessing, ex, ##pl, ##ora, ##tory, behavior, directed, toward, both, a, novel, and, familiar, object, in, the, environment, ,, referred, to, here, as, the, test, phase, ., this, phase, is, performed, 2, -, 3, h, after, completion, of, sample, phase, ., prior, to, the, start, of, a, test, phase, session, ,, place, objects, into, the, arena, and, fix, them, to, the, floor, so, that, the, animals, cannot, move, the, objects, ., place, the, objects, in, the, same, position, in, the, arena, relative, to, the, sample, phase, ##13, ., balance, the, relative, position, of, novel, and, familiar, objects, across, gen, ##otype, ##s, and, treatment, groups, ., ensure, there, is, enough, distance, between, the, walls, and, objects, so, that, the, mice, can, freely, explore, the, objects, from, all, angles, ., setup, the, data, acquisition, system, and, /, or, video, cameras, ., confirm, proper, tracking, of, mice, and, objects, in, the, maze, ., cal, ##ib, ##rate, distances, in, the, arena, using, captured, video, images, of, a, ruler, or, other, object, of, known, length, ., mark, corners, of, the, arena, in, the, software, to, permit, scoring, of, position, ##al, bias, ##es, ., mark, objects, in, software, and, track, ex, ##pl, ##ora, ##tory, behavior, for, each, object, individually, (, i, ., e, ., ,, \", novel, \", and, \", familiar, \", ), ., remove, the, cage, from, the, rack, and, gently, place, it, on, a, table, in, close, proximity, to, the, arena, ., gently, place, animals, into, the, center, of, the, arena, ,, facing, the, objects, ., record, mice, freely, exploring, objects, for, 10, min, ., at, the, end, of, the, test, session, ,, remove, mice, from, the, arena, and, place, mice, back, into, their, home, cage, ., thoroughly, clean, arena, and, objects, with, an, un, ##scent, ##ed, b, ##lea, ##ch, ge, ##rmi, ##ci, ##dal, wipe, ,, 70, %, et, ##oh, and, dh, _, 2, ##o, after, each, session, ., repeat, from, step, 4, ., 4, ., 3, until, all, animals, have, been, assessed, ., once, object, exploration, is, measured, for, all, mice, ,, videos, are, analyzed, ., note, :, object, exploration, ##s, are, counted, once, the, following, criteria, have, been, met, :, the, mouse, is, oriented, toward, the, object, ,, the, snout, is, within, 2, cm, of, the, object, ,, the, mid, ##point, of, the, animal, \\', s, body, is, beyond, 2, cm, from, the, object, ,, and, the, previous, criteria, have, been, fulfilled, for, at, least, 1, s, ., additionally, ,, if, an, animal, has, satisfied, the, exploration, criteria, but, exhibits, im, ##mo, ##bility, for, >, 10, s, then, the, ex, ##pl, ##ora, ##tory, bout, is, deemed, finished, ., assess, novel, object, recognition, by, comparing, time, spent, exploring, the, novel, to, familiar, object, ., three, methods, are, commonly, reported, in, the, literature, ., analyze, raw, time, spent, exploring, both, novel, and, familiar, objects, using, a, repeated, measure, test, ., this, method, is, best, used, when, gen, ##otype, and, /, or, treatment, do, not, affect, total, exploration, time, ., calculate, novelty, preference, ,, using, the, equation, :, note, :, this, provides, the, percentage, of, time, spent, exploring, the, novel, object, relative, to, the, total, time, exploring, objects, ., values, range, from, 0, %, (, no, exploration, of, novel, object, ), to, 100, %, (, exploration, only, of, the, novel, object, ), ,, with, a, value, of, 50, %, indicating, equal, time, spent, exploring, novel, and, familiar, objects, ., calculate, discrimination, index, ##11, ,, using, the, equation, :, note, :, this, yields, the, difference, in, time, spent, exploring, the, novel, and, familiar, objects, relative, to, the, total, time, spent, exploring, objects, ., values, range, from, -, 1, (, exploration, only, of, the, familiar, object, ), to, +, 1, (, exploration, only, of, the, novel, object, ,, with, a, value, of, 0, indicating, equal, time, spent, exploring, novel, and, familiar, objects, ., remove, animals, that, do, not, participate, in, the, test, session, due, to, hyper, ##dy, ##nami, ##c, loco, ##mot, ##ion, or, other, stereo, ##ty, ##pies, ,, from, consideration, ##11, ., note, :, criteria, used, for, removal, must, be, objective, and, determined, a, prior, ##i, for, the, mouse, model, (, i, ., e, ., ,, <, 5, ^, th, percent, ##ile, for, total, exploration, time, and, either, >, 100, average, turn, angle, during, test, session, or, >, 50, ^, th, percent, ##ile, time, exhibiting, my, ##oc, ##lon, ##ic, corner, jumping, ), .'},\n", - " {'article_id': '0f8950051fe4f7639803646d2824d50d',\n", - " 'section_name': 'Neuropathology',\n", - " 'text': 'Post mortem examination restricted to the central nervous system had been performed on five of the affected TIA1 mutation carriers (Tables 1 and 2). In four of the five cases, the entire spinal cord was available for examination; whereas, in case NWU-1, only the upper segments of cervical spinal cord were available. Microscopic evaluation was performed on 5 μm-thick sections of formalin fixed, paraffin-embedded material representing a wide range of anatomical regions (Table 2). Histochemical stains included hematoxylin and eosin (HE), HE combined with Luxol fast blue (HE/LFB), modified Bielschowsky silver stain, Gallyas silver stain, Masson trichrome, Periodic Acid Schiff with and without diastase, Alcian Blue (pH 2.5) and Congo red. Standard immunohistochemistry (IHC) was performed using the Ventana BenchMark XT automated staining system with primary antibodies against alpha-synuclein (Thermo Scientific; 1:10,000 following microwave antigen retrieval), beta amyloid (DAKO; 1:100 with initial incubation for 3 h at room temperature), hyperphosphorylated tau (clone AT-8; Innogenetics, Ghent, Belgium; 1:2000 following microwave antigen retrieval), phosphorylation-independent TDP-43 (ProteinTech; 1:1000 following microwave antigen retrieval), ubiquitin (DAKO; 1:500 following microwave antigen retrieval), FUS (Sigma-Aldrich; 1:1000 following microwave antigen retrieval), p62 (BD Biosciences; 1:500 following microwave antigen retrieval), poly-(A) binding protein (PABP; Santa Cruz; 1:200 following microwave antigen retrieval), hnRNP A1 (Santa Cruz; 1:100 following microwave antigen retrieval), hnRNP A3 (Sigma-Aldrich; 1:100 following microwave antigen retrieval) and hnRNP A2/B1 (Santa Cruz; 1:500 following microwave antigen retrieval). In addition, we tested a number of commercial monoclonal and polyclonal antibodies against different epitopes of human TIA1, raised in different species (Table 3).Table 2Semiquantitative analysis of neurodegeneration and TDP-ir pathology in TIA1 mutation carriersNeurodegenerationTDP-43 ImmunohistochemistryNWU-1TOR-1UBCU2-14UBCU2-1ALS752-1NWU-1TOR-1UBCU2-14UBCU2-1ALS752-1FTD, ALSFTD, prob. ALSFTD, prob. ALSALS, early FTDALSFTD, ALSFTD, prob. ALSFTD, prob. ALSALS, early FTDALSpyramidal motor systemmotor cortex++++++++++++++CN XII++++++++++++++++++++++++CST++++++++++n/an/an/an/an/aant. horn++++++++++++++++++++++++++neocortexprefrontal++++++++–++++++++++++++temporal+++++–++++++++++parietal––+++–++++++++++striatonigral systemcaudate+–+++–++++++++++++putamen–––––++++++++GP–––––+++++SN+++++++++++++++++++++++limbic systemhip. CA–––––+++++hip. dentate+++–––+++++++++++thalamus+––––+–+–+midbrainPAG+–+++–++++++cerebello-pontine systemcb cortex––––––––––cb dentate+–––––––––basis pontis–––––+–+–+The patients are ordered according to their earliest and/or predominant clinical features from predominant FTD (left) to pure ALS (right). ALS amyotrophic lateral sclerosis, ant. anterior, cb cerebellar, CA cornu ammonis, CN XII twelfth cranial nerve (hypoglossal) nucleus, CST corticospinal tract, deg. non-specific changes of chronic degeneration, FTD frontotemporal dementia, GP globus pallidus, hip. hippocampal, n/a not applicable, PAG periaqueductal grey matter, prob. probable, SN substantia nigra. Semiquantitative grading of pathology; −, none; +, mild; ++, moderate; +++, severe\\nTable 3TIA1 antibodies used for immunohistochemistry and double label immunofluorescenceAntibodySpeciesEpitopeDilutionSanta Cruz #sc-1751Goat polyclonal (clone C-20)near C-terminus1:300Santa Cruz #sc-48371Mouse monoclonal (clone D-9)aa 21-140 (near N-terminus)1:200Santa Cruz #sc-28237Rabbit polyclonal (clone H-120)aa 21-140 (near N-terminus)1:300Abcam #ab140595Rabbit monoclonalaa 350 to the C-terminus1:100Abcam #ab40693Rabbit polyclonalaa 350 to the C-terminus1:500ProteinTech #12133-2-APRabbit polyclonalhuman TIA1-GST fusion protein1:100#, catalogue number; GST glutathione S-transferase',\n", - " 'paragraph_id': 5,\n", - " 'tokenizer': 'post, mort, ##em, examination, restricted, to, the, central, nervous, system, had, been, performed, on, five, of, the, affected, tia, ##1, mutation, carriers, (, tables, 1, and, 2, ), ., in, four, of, the, five, cases, ,, the, entire, spinal, cord, was, available, for, examination, ;, whereas, ,, in, case, nw, ##u, -, 1, ,, only, the, upper, segments, of, cervical, spinal, cord, were, available, ., microscopic, evaluation, was, performed, on, 5, μ, ##m, -, thick, sections, of, formal, ##in, fixed, ,, para, ##ffin, -, embedded, material, representing, a, wide, range, of, anatomical, regions, (, table, 2, ), ., his, ##to, ##chemical, stains, included, hem, ##ato, ##xy, ##lin, and, e, ##osi, ##n, (, he, ), ,, he, combined, with, lux, ##ol, fast, blue, (, he, /, l, ##fb, ), ,, modified, bi, ##els, ##cho, ##ws, ##ky, silver, stain, ,, gall, ##yas, silver, stain, ,, mass, ##on, tri, ##chrome, ,, periodic, acid, sc, ##hiff, with, and, without, dia, ##sta, ##se, ,, al, ##cian, blue, (, ph, 2, ., 5, ), and, congo, red, ., standard, im, ##mun, ##oh, ##isto, ##chemist, ##ry, (, i, ##hc, ), was, performed, using, the, vent, ##ana, bench, ##mark, x, ##t, automated, stain, ##ing, system, with, primary, antibodies, against, alpha, -, syn, ##uc, ##lein, (, the, ##rm, ##o, scientific, ;, 1, :, 10, ,, 000, following, microwave, antigen, retrieval, ), ,, beta, amy, ##loid, (, da, ##ko, ;, 1, :, 100, with, initial, inc, ##uba, ##tion, for, 3, h, at, room, temperature, ), ,, hyper, ##ph, ##os, ##ph, ##ory, ##lated, tau, (, clone, at, -, 8, ;, inn, ##ogen, ##etic, ##s, ,, ghent, ,, belgium, ;, 1, :, 2000, following, microwave, antigen, retrieval, ), ,, ph, ##os, ##ph, ##ory, ##lation, -, independent, td, ##p, -, 43, (, protein, ##tech, ;, 1, :, 1000, following, microwave, antigen, retrieval, ), ,, u, ##bi, ##qui, ##tin, (, da, ##ko, ;, 1, :, 500, following, microwave, antigen, retrieval, ), ,, fu, ##s, (, sigma, -, al, ##drich, ;, 1, :, 1000, following, microwave, antigen, retrieval, ), ,, p, ##6, ##2, (, b, ##d, bio, ##sc, ##ience, ##s, ;, 1, :, 500, following, microwave, antigen, retrieval, ), ,, poly, -, (, a, ), binding, protein, (, pa, ##b, ##p, ;, santa, cruz, ;, 1, :, 200, following, microwave, antigen, retrieval, ), ,, h, ##nr, ##np, a1, (, santa, cruz, ;, 1, :, 100, following, microwave, antigen, retrieval, ), ,, h, ##nr, ##np, a, ##3, (, sigma, -, al, ##drich, ;, 1, :, 100, following, microwave, antigen, retrieval, ), and, h, ##nr, ##np, a2, /, b1, (, santa, cruz, ;, 1, :, 500, following, microwave, antigen, retrieval, ), ., in, addition, ,, we, tested, a, number, of, commercial, mono, ##cl, ##onal, and, poly, ##cl, ##onal, antibodies, against, different, ep, ##ito, ##pes, of, human, tia, ##1, ,, raised, in, different, species, (, table, 3, ), ., table, 2, ##se, ##mi, ##qua, ##nti, ##tative, analysis, of, ne, ##uro, ##de, ##gen, ##eration, and, td, ##p, -, ir, pathology, in, tia, ##1, mutation, carriers, ##ne, ##uro, ##de, ##gen, ##eration, ##t, ##dp, -, 43, im, ##mun, ##oh, ##isto, ##chemist, ##ryn, ##wu, -, 1, ##tor, -, 1, ##ub, ##cu, ##2, -, 14, ##ub, ##cu, ##2, -, 1a, ##ls, ##75, ##2, -, 1, ##n, ##wu, -, 1, ##tor, -, 1, ##ub, ##cu, ##2, -, 14, ##ub, ##cu, ##2, -, 1a, ##ls, ##75, ##2, -, 1, ##ft, ##d, ,, als, ##ft, ##d, ,, pro, ##b, ., als, ##ft, ##d, ,, pro, ##b, ., als, ##als, ,, early, ft, ##dal, ##sf, ##t, ##d, ,, als, ##ft, ##d, ,, pro, ##b, ., als, ##ft, ##d, ,, pro, ##b, ., als, ##als, ,, early, ft, ##dal, ##sp, ##yra, ##mi, ##dal, motor, system, ##moto, ##r, cortex, +, +, +, +, +, +, +, +, +, +, +, +, +, +, cn, xii, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, cs, ##t, +, +, +, +, +, +, +, +, +, +, n, /, an, /, an, /, an, /, an, /, aa, ##nt, ., horn, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, neo, ##cor, ##te, ##x, ##pre, ##front, ##al, +, +, +, +, +, +, +, +, –, +, +, +, +, +, +, +, +, +, +, +, +, +, +, temporal, +, +, +, +, +, –, +, +, +, +, +, +, +, +, +, +, par, ##ie, ##tal, –, –, +, +, +, –, +, +, +, +, +, +, +, +, +, +, st, ##ria, ##ton, ##ig, ##ral, system, ##ca, ##uda, ##te, +, –, +, +, +, –, +, +, +, +, +, +, +, +, +, +, +, +, put, ##amen, –, –, –, –, –, +, +, +, +, +, +, +, +, gp, –, –, –, –, –, +, +, +, +, +, s, ##n, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, +, limb, ##ic, system, ##hip, ., ca, –, –, –, –, –, +, +, +, +, +, hip, ., dent, ##ate, +, +, +, –, –, –, +, +, +, +, +, +, +, +, +, +, +, tha, ##lam, ##us, +, –, –, –, –, +, –, +, –, +, mid, ##bra, ##in, ##pa, ##g, +, –, +, +, +, –, +, +, +, +, +, +, ce, ##re, ##bell, ##o, -, pont, ##ine, system, ##cb, cortex, –, –, –, –, –, –, –, –, –, –, cb, dent, ##ate, +, –, –, –, –, –, –, –, –, –, basis, pont, ##is, –, –, –, –, –, +, –, +, –, +, the, patients, are, ordered, according, to, their, earliest, and, /, or, predominant, clinical, features, from, predominant, ft, ##d, (, left, ), to, pure, als, (, right, ), ., als, amy, ##ot, ##rop, ##hic, lateral, sc, ##ler, ##osis, ,, ant, ., anterior, ,, cb, ce, ##re, ##bella, ##r, ,, ca, corn, ##u, am, ##mon, ##is, ,, cn, xii, twelfth, cr, ##anial, nerve, (, h, ##yp, ##og, ##los, ##sal, ), nucleus, ,, cs, ##t, co, ##rti, ##cos, ##pina, ##l, tract, ,, de, ##g, ., non, -, specific, changes, of, chronic, de, ##gen, ##eration, ,, ft, ##d, front, ##ote, ##mp, ##ora, ##l, dementia, ,, gp, g, ##lo, ##bus, pal, ##lid, ##us, ,, hip, ., hip, ##po, ##camp, ##al, ,, n, /, a, not, applicable, ,, pa, ##g, per, ##ia, ##que, ##du, ##cta, ##l, grey, matter, ,, pro, ##b, ., probable, ,, s, ##n, sub, ##stan, ##tia, ni, ##gra, ., semi, ##qua, ##nti, ##tative, grading, of, pathology, ;, −, ,, none, ;, +, ,, mild, ;, +, +, ,, moderate, ;, +, +, +, ,, severe, table, 3, ##tia, ##1, antibodies, used, for, im, ##mun, ##oh, ##isto, ##chemist, ##ry, and, double, label, im, ##mun, ##of, ##lu, ##orescence, ##ant, ##ib, ##od, ##ys, ##pe, ##cies, ##ep, ##ito, ##ped, ##il, ##ution, ##sant, ##a, cruz, #, sc, -, 1751, ##go, ##at, poly, ##cl, ##onal, (, clone, c, -, 20, ), near, c, -, terminus, ##1, :, 300, ##sant, ##a, cruz, #, sc, -, 48, ##37, ##1, ##mous, ##e, mono, ##cl, ##onal, (, clone, d, -, 9, ), aa, 21, -, 140, (, near, n, -, terminus, ), 1, :, 200, ##sant, ##a, cruz, #, sc, -, 282, ##37, ##ra, ##bb, ##it, poly, ##cl, ##onal, (, clone, h, -, 120, ), aa, 21, -, 140, (, near, n, -, terminus, ), 1, :, 300, ##ab, ##cam, #, ab, ##14, ##0, ##59, ##5, ##ra, ##bb, ##it, mono, ##cl, ##onal, ##aa, 350, to, the, c, -, terminus, ##1, :, 100, ##ab, ##cam, #, ab, ##40, ##6, ##9, ##3, ##ra, ##bb, ##it, poly, ##cl, ##onal, ##aa, 350, to, the, c, -, terminus, ##1, :, 500, ##pro, ##tein, ##tech, #, 121, ##33, -, 2, -, apr, ##ab, ##bit, poly, ##cl, ##onal, ##hum, ##an, tia, ##1, -, gs, ##t, fusion, protein, ##1, :, 100, #, ,, catalogue, number, ;, gs, ##t, g, ##lu, ##tat, ##hi, ##one, s, -, transfer, ##ase'},\n", - " {'article_id': '076b3623a95c1f37b2253931ea58f8bf',\n", - " 'section_name': 'Figure Caption',\n", - " 'text': 'Elevated splenic IFNγ during co‐infection induces splenic CXCL9/CXCL10 and suppresses CXCR3 expression on CD8^+ T cells to limit migration capacity toward the brainALevels of IFNγ protein in the spleen of naïve, PbA, and PbA + CHIKV groups on 2, 4, and 6 dpi (n≥5 per group). Data comparison between PbA and PbA + CHIKV groups was done by Mann–Whitney two‐tailed analysis (6 dpi; *P=0.0317).B, CLevels of CXCL9 and CXCL10 protein in the spleen of WT naïve (n=5), WT + PbA (n=5), WT + PbA + CHIKV (n=5), IFNγ^−/− + PbA (n=4), and IFNγ^−/− + PbA + CHIKV (n=4) on 6 dpi. Data comparison between PbA and PbA + CHIKV groups in the respective WT and IFNγ^−/− background was done by Mann–Whitney two‐tailed analysis (CXCL9–WT + PbA versus WT + PbA + CHIKV; *P=0.0238, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.7429. CXCL10–WT + PbA versus WT + PbA + CHIKV; **P=0.0079, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.3429).DNumber of total CD8^+ T cells and Pb1‐specific CD8^+ T cells in the spleen of WT + PbA (n=5), WT + PbA + CHIKV (n=4), IFNγ^−/− + PbA (n=5), and IFNγ^−/− + PbA + CHIKV (n=6) on 6 dpi. Data comparison between PbA and PbA + CHIKV groups in the respective WT and IFNγ^−/− background was done by Mann–Whitney two‐tailed analysis (total CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0159, IFNγ^−/−+ PbA versus IFNγ^−/−+ PbA + CHIKV; ^ns\\nP=0.0823, Pb1‐specific CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0317, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.4286).E, FCXCR3 surface expression on total CD8^+ T cells and Pb1‐specific CD8^+ T cells in the spleen of WT + PbA (n=5), WT + PbA + CHIKV (n=4), IFNγ^−/− + PbA (n=5), and IFNγ^−/− + PbA + CHIKV (n=6) on 6 dpi. Representative histograms showing CXCR3 expression are shown. Threshold of CXCR3^+ cells is delineated by black dotted line. Data comparison between PbA and PbA + CHIKV groups in the respective WT and IFNγ^−/− background was done by Mann–Whitney two‐tailed analysis (total CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0159, IFNγ^−/−+ PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.0823, Pb1‐specific CD8^+ T cells–WT + PbA versus WT + PbA + CHIKV; *P=0.0159, IFNγ^−/− + PbA versus IFNγ^−/− + PbA + CHIKV; ^ns\\nP=0.9307).GIn vivo migration assay measuring the migratory capacity of LFA‐1^+ and Pb1‐specific CD8^+ T cells from IFNγ^−/− + PbA donors (n=4) and IFNγ^−/− + PbA + CHIKV donors (n=3) toward the brain of WT PbA recipients. 7 × 10^6 isolated donors’ CD8^+ T cells (6 dpi) were transferred into PbA recipient at 5 dpi and harvested 22 h post‐transfer. All data are expressed as ratio of recovered cells to initial numbers of cell transferred into the recipients for each specific cell type. Mann–Whitney two‐tailed analysis (LFA‐1^+CD8^+ T cells: ^ns\\nP=0.9999, Pb1‐specific CD8^+ T cells: ^ns\\nP=0.6286).Data information: For all cytokines or chemokines, quantifications were measured by ELISA using cell lysate from the organ and determined as pg/μg of total protein. Each data point shown in the dot plots was obtained from 1 mouse.',\n", - " 'paragraph_id': 52,\n", - " 'tokenizer': 'elevated, sp, ##len, ##ic, if, ##n, ##γ, during, co, ‐, infection, induce, ##s, sp, ##len, ##ic, c, ##x, ##cl, ##9, /, c, ##x, ##cl, ##10, and, suppress, ##es, c, ##x, ##cr, ##3, expression, on, cd, ##8, ^, +, t, cells, to, limit, migration, capacity, toward, the, brain, ##ale, ##vel, ##s, of, if, ##n, ##γ, protein, in, the, sp, ##leen, of, naive, ,, pba, ,, and, pba, +, chi, ##k, ##v, groups, on, 2, ,, 4, ,, and, 6, d, ##pi, (, n, ##≥, ##5, per, group, ), ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, 6, d, ##pi, ;, *, p, =, 0, ., 03, ##17, ), ., b, ,, cl, ##eve, ##ls, of, c, ##x, ##cl, ##9, and, c, ##x, ##cl, ##10, protein, in, the, sp, ##leen, of, w, ##t, naive, (, n, =, 5, ), ,, w, ##t, +, pba, (, n, =, 5, ), ,, w, ##t, +, pba, +, chi, ##k, ##v, (, n, =, 5, ), ,, if, ##n, ##γ, ^, −, /, −, +, pba, (, n, =, 4, ), ,, and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, (, n, =, 4, ), on, 6, d, ##pi, ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, in, the, respective, w, ##t, and, if, ##n, ##γ, ^, −, /, −, background, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, c, ##x, ##cl, ##9, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 02, ##38, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 74, ##29, ., c, ##x, ##cl, ##10, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, *, p, =, 0, ., 00, ##7, ##9, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 34, ##29, ), ., d, ##num, ##ber, of, total, cd, ##8, ^, +, t, cells, and, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, in, the, sp, ##leen, of, w, ##t, +, pba, (, n, =, 5, ), ,, w, ##t, +, pba, +, chi, ##k, ##v, (, n, =, 4, ), ,, if, ##n, ##γ, ^, −, /, −, +, pba, (, n, =, 5, ), ,, and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, (, n, =, 6, ), on, 6, d, ##pi, ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, in, the, respective, w, ##t, and, if, ##n, ##γ, ^, −, /, −, background, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, total, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 01, ##59, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 08, ##23, ,, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 03, ##17, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 42, ##86, ), ., e, ,, fc, ##x, ##cr, ##3, surface, expression, on, total, cd, ##8, ^, +, t, cells, and, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, in, the, sp, ##leen, of, w, ##t, +, pba, (, n, =, 5, ), ,, w, ##t, +, pba, +, chi, ##k, ##v, (, n, =, 4, ), ,, if, ##n, ##γ, ^, −, /, −, +, pba, (, n, =, 5, ), ,, and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, (, n, =, 6, ), on, 6, d, ##pi, ., representative, his, ##to, ##gram, ##s, showing, c, ##x, ##cr, ##3, expression, are, shown, ., threshold, of, c, ##x, ##cr, ##3, ^, +, cells, is, del, ##ine, ##ated, by, black, dotted, line, ., data, comparison, between, pba, and, pba, +, chi, ##k, ##v, groups, in, the, respective, w, ##t, and, if, ##n, ##γ, ^, −, /, −, background, was, done, by, mann, –, whitney, two, ‐, tailed, analysis, (, total, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 01, ##59, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 08, ##23, ,, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, –, w, ##t, +, pba, versus, w, ##t, +, pba, +, chi, ##k, ##v, ;, *, p, =, 0, ., 01, ##59, ,, if, ##n, ##γ, ^, −, /, −, +, pba, versus, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, ;, ^, ns, p, =, 0, ., 930, ##7, ), ., gin, vivo, migration, ass, ##ay, measuring, the, migratory, capacity, of, l, ##fa, ‐, 1, ^, +, and, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, from, if, ##n, ##γ, ^, −, /, −, +, pba, donors, (, n, =, 4, ), and, if, ##n, ##γ, ^, −, /, −, +, pba, +, chi, ##k, ##v, donors, (, n, =, 3, ), toward, the, brain, of, w, ##t, pba, recipients, ., 7, ×, 10, ^, 6, isolated, donors, ’, cd, ##8, ^, +, t, cells, (, 6, d, ##pi, ), were, transferred, into, pba, recipient, at, 5, d, ##pi, and, harvested, 22, h, post, ‐, transfer, ., all, data, are, expressed, as, ratio, of, recovered, cells, to, initial, numbers, of, cell, transferred, into, the, recipients, for, each, specific, cell, type, ., mann, –, whitney, two, ‐, tailed, analysis, (, l, ##fa, ‐, 1, ^, +, cd, ##8, ^, +, t, cells, :, ^, ns, p, =, 0, ., 999, ##9, ,, p, ##b, ##1, ‐, specific, cd, ##8, ^, +, t, cells, :, ^, ns, p, =, 0, ., 62, ##86, ), ., data, information, :, for, all, cy, ##tok, ##ines, or, che, ##mo, ##kin, ##es, ,, quan, ##ti, ##fication, ##s, were, measured, by, elisa, using, cell, l, ##ys, ##ate, from, the, organ, and, determined, as, pg, /, μ, ##g, of, total, protein, ., each, data, point, shown, in, the, dot, plots, was, obtained, from, 1, mouse, .'},\n", - " {'article_id': '076b3623a95c1f37b2253931ea58f8bf',\n", - " 'section_name': 'Figure Caption',\n", - " 'text': \"Increased IFNγ producing CD4^+ T cells in the spleen drives the enhanced splenic IFNγ on 6 dpi during concurrent co‐infectionRepresentative histogram showing IFNγ production in CD4^+ T cells, CD8^+ T cells, NK cells, NKT cells, and neutrophils in the spleen of naïve (n=5), CHIKV (n=5), PbA (n=6), and PbA + CHIKV (n=8) on 6 dpi. Black dotted line represents threshold setting for IFNγ^+ cells.Numbers of CD4^+ T cells, CD8^+ T cells, NK cells, NKT cells, and neutrophils in the spleen of naïve (n=5), CHIKV (n=5), PbA (n=6), and PbA + CHIKV (n=8) on 6 dpi. CD4^+, CD8^+ T cells, NK cells, NKT cells, and neutrophils were defined as CD3^+CD4^+, CD3^+CD8^+, CD3^−NK1.1^+, CD3^+NK1.1^+, and CD3^−CD11b^+Ly6G^+ cells, respectively. All data analyzed by one‐way ANOVA with Tukey's post‐test. For CD4^+ T cells: naïve versus PbA + CHIKV; *mean diff=−1.49 × 10^7, PbA versus PbA + CHIKV; *mean diff=−1.57 × 10^7. For CD8^+ T cells: naïve versus PbA + CHIKV; *mean diff=−9.61 × 10^6, CHIKV versus PbA + CHIKV; *mean diff=−9.43 × 10^6, PbA versus PbA + CHIKV; *mean diff=−9.75 × 10^6. For NK cells: naïve versus PbA; ***mean diff=5.22 × 10^6, naïve versus PbA + CHIKV; **mean diff=4.03 × 10^6, CHIKV versus PbA; ***mean diff=5.39 × 10^6, CHIKV versus PbA + CHIKV; **mean diff=4.20 × 10^6. For NKT cells: naïve versus PbA; *mean diff=7.95 × 10^5, CHIKV versus PbA; *mean diff=7.34 × 10^5, PbA versus PbA + CHIKV; **mean diff=−8.19 × 10^5. For neutrophils: naïve versus PbA; *mean diff=1.51 × 10^6, CHIKV versus PbA; *mean diff=1.34 × 10^6, CHIKV versus PbA + CHIKV; *mean diff=−1.32 × 10^6, PbA versus PbA + CHIKV; ***mean diff=−2.66 × 10^6.Numbers of IFNγ‐producing CD4^+ T cells, CD8^+ T cells, NK cells, NKT cells, and neutrophils in the spleen of naïve (n=5), CHIKV (n=5), PbA (n=6) and PbA + CHIKV (n=8) on 6 dpi. All data analyzed by one‐way ANOVA with Tukey's post‐test. For IFNγ^+CD4^+ T cells: naïve versus PbA + CHIKV; ***mean diff=−5.99 × 10^6, CHIKV versus PbA + CHIKV; ***mean diff=−5.52 × 10^6, PbA versus PbA + CHIKV; ***mean diff=−3.95 × 10^6. For IFNγ^+CD8^+ T cells: naïve versus PbA + CHIKV; *mean diff=−9.28 × 10^5, CHIKV versus PbA + CHIKV; **mean diff=−1.08 × 10^6. For IFNγ^+ NK cells: naïve versus CHIKV; ***mean diff=1.83 × 10^5, naïve versus PbA; ***mean diff=2.81 × 10^5, naïve versus PbA + CHIKV; ***mean diff=2.83 × 10^5. For IFNγ^+ NKT cells: naïve versus PbA + CHIKV; *mean diff=−68295, CHIKV versus PbA + CHIKV; **mean diff=−93362, PbA versus PbA + CHIKV; **mean diff=−80084. For IFNγ^+ neutrophils: naïve versus PbA; *mean diff=1.58 × 10^6, CHIKV versus PbA; *mean diff=1.40 × 10^6, PbA versus PbA + CHIKV; ***mean diff=−2.50 × 10^6.\",\n", - " 'paragraph_id': 53,\n", - " 'tokenizer': \"increased, if, ##n, ##γ, producing, cd, ##4, ^, +, t, cells, in, the, sp, ##leen, drives, the, enhanced, sp, ##len, ##ic, if, ##n, ##γ, on, 6, d, ##pi, during, concurrent, co, ‐, infection, ##re, ##pres, ##ent, ##ative, his, ##to, ##gram, showing, if, ##n, ##γ, production, in, cd, ##4, ^, +, t, cells, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, in, the, sp, ##leen, of, naive, (, n, =, 5, ), ,, chi, ##k, ##v, (, n, =, 5, ), ,, pba, (, n, =, 6, ), ,, and, pba, +, chi, ##k, ##v, (, n, =, 8, ), on, 6, d, ##pi, ., black, dotted, line, represents, threshold, setting, for, if, ##n, ##γ, ^, +, cells, ., numbers, of, cd, ##4, ^, +, t, cells, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, in, the, sp, ##leen, of, naive, (, n, =, 5, ), ,, chi, ##k, ##v, (, n, =, 5, ), ,, pba, (, n, =, 6, ), ,, and, pba, +, chi, ##k, ##v, (, n, =, 8, ), on, 6, d, ##pi, ., cd, ##4, ^, +, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, were, defined, as, cd, ##3, ^, +, cd, ##4, ^, +, ,, cd, ##3, ^, +, cd, ##8, ^, +, ,, cd, ##3, ^, −, ##nk, ##1, ., 1, ^, +, ,, cd, ##3, ^, +, nk, ##1, ., 1, ^, +, ,, and, cd, ##3, ^, −, ##cd, ##11, ##b, ^, +, l, ##y, ##6, ##g, ^, +, cells, ,, respectively, ., all, data, analyzed, by, one, ‐, way, an, ##ova, with, tu, ##key, ', s, post, ‐, test, ., for, cd, ##4, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##1, ., 49, ×, 10, ^, 7, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##1, ., 57, ×, 10, ^, 7, ., for, cd, ##8, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 61, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 43, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 75, ×, 10, ^, 6, ., for, nk, cells, :, naive, versus, pba, ;, *, *, *, mean, di, ##ff, =, 5, ., 22, ×, 10, ^, 6, ,, naive, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, 4, ., 03, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, ;, *, *, *, mean, di, ##ff, =, 5, ., 39, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, 4, ., 20, ×, 10, ^, 6, ., for, nk, ##t, cells, :, naive, versus, pba, ;, *, mean, di, ##ff, =, 7, ., 95, ×, 10, ^, 5, ,, chi, ##k, ##v, versus, pba, ;, *, mean, di, ##ff, =, 7, ., 34, ×, 10, ^, 5, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##8, ., 19, ×, 10, ^, 5, ., for, ne, ##ut, ##rop, ##hil, ##s, :, naive, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 51, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 34, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##1, ., 32, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##2, ., 66, ×, 10, ^, 6, ., numbers, of, if, ##n, ##γ, ‐, producing, cd, ##4, ^, +, t, cells, ,, cd, ##8, ^, +, t, cells, ,, nk, cells, ,, nk, ##t, cells, ,, and, ne, ##ut, ##rop, ##hil, ##s, in, the, sp, ##leen, of, naive, (, n, =, 5, ), ,, chi, ##k, ##v, (, n, =, 5, ), ,, pba, (, n, =, 6, ), and, pba, +, chi, ##k, ##v, (, n, =, 8, ), on, 6, d, ##pi, ., all, data, analyzed, by, one, ‐, way, an, ##ova, with, tu, ##key, ', s, post, ‐, test, ., for, if, ##n, ##γ, ^, +, cd, ##4, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##5, ., 99, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##5, ., 52, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##3, ., 95, ×, 10, ^, 6, ., for, if, ##n, ##γ, ^, +, cd, ##8, ^, +, t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##9, ., 28, ×, 10, ^, 5, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##1, ., 08, ×, 10, ^, 6, ., for, if, ##n, ##γ, ^, +, nk, cells, :, naive, versus, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, 1, ., 83, ×, 10, ^, 5, ,, naive, versus, pba, ;, *, *, *, mean, di, ##ff, =, 2, ., 81, ×, 10, ^, 5, ,, naive, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, 2, ., 83, ×, 10, ^, 5, ., for, if, ##n, ##γ, ^, +, nk, ##t, cells, :, naive, versus, pba, +, chi, ##k, ##v, ;, *, mean, di, ##ff, =, −, ##6, ##8, ##29, ##5, ,, chi, ##k, ##v, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##9, ##33, ##6, ##2, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, mean, di, ##ff, =, −, ##80, ##0, ##8, ##4, ., for, if, ##n, ##γ, ^, +, ne, ##ut, ##rop, ##hil, ##s, :, naive, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 58, ×, 10, ^, 6, ,, chi, ##k, ##v, versus, pba, ;, *, mean, di, ##ff, =, 1, ., 40, ×, 10, ^, 6, ,, pba, versus, pba, +, chi, ##k, ##v, ;, *, *, *, mean, di, ##ff, =, −, ##2, ., 50, ×, 10, ^, 6, .\"},\n", - " {'article_id': 'a3907f2d4d6a3e337073dd74e676efbc',\n", - " 'section_name': 'INTRODUCTION',\n", - " 'text': \"Endogenous circadian clocks enable organisms to predict and adapt to environmental 24h rhythms that are caused by the earth's rotation around its own axis. The hence resulting circadian rhythms in physiology and behavior persist even in the absence of environmental Zeitgebers under constant conditions. Over the past years, the molecular mechanism driving circadian rhythmicity, several interlocked transcriptional and translational feedback loops could be described in large detail for the common model organisms, for example, Synechococcus elongatus, Neurospora crassa, Arabidopsis thaliana, Drosophila melanogaster, and Mus musculus (reviewed by Brown, Kowalska, & Dallmann, 2012). In Drosophila melanogaster ca. 150 clock neurons in the central nervous system, named after their size and location, show oscillations of core clock gene expression (e.g., period, timeless and clock). The neurons are further subdivided according to their neurochemical content and so far described function. Classically, they are divided into four lateral and three dorsal groups. Two of the lateral groups, the small and the large ventrolateral neurons (s‐LN_vs and l‐LNv_s, respectively; Figure 1) express the neuropeptide pigment dispersing factor (PDF), which has been shown to be an important signaling molecule of the circadian clock that modulates the other PDF‐responsive cell groups of the circadian system by slowing down their Ca^2+ oscillations (Liang, Holy, & Taghert, 2016, 2017). Further, it has been shown that the four PDF expressing s‐LN_vs are important to sustain rhythmicity in constant darkness (Helfrich‐Förster, 1998; Renn, Park, Rosbash, Hall, & Taghert, 1999). Since the s‐LN_vs are also important for the generation and proper timing of the morning activity peak, which is part of the characteristic bimodal locomotor activity pattern of Drosophila melanogaster, the small PDF cells are often referred to as M‐cells (Morning oscillators, Main‐pacemakers; Grima, Chélot, Xia, & Rouyer, 2004; Stoleru, Peng, Agosto, & Rosbash, 2004; Rieger, Shafer, Tomioka, & Helfrich‐Förster, 2006). In contrast, the evening activity peak is generated and controlled by the so‐called E‐cells, which comprise the 5th PDF lacking s‐LN_v, three Cryptochrome (CRY) expressing dorsolateral Neurons (LN_ds), three CRY lacking LN_ds, and six to eight dorsal neurons (DN_1). The classification in M‐ and E‐cells in respect to the traditional dual‐oscillator model (Pittendrigh & Daan, 1976), as well as more recent working models (Yao & Shafer, 2014) attribute the lateral clock neurons (LN_s) an essential role for the generation of the bimodal locomotor activity rhythm. The latter study nicely showed the diverse responsiveness of the CRY expressing E‐cells to secreted PDF, suggesting that the E‐oscillator is composed of different functional subunits (E1‐E3; Yao & Shafer, 2014) and that the circadian system is more likely a multi‐oscillator system (Rieger et al., 2006; Shafer, Helfrich‐Förster, Renn, & Taghert, 2006; Yao & Shafer, 2014). The E‐cells cannot only be distinguished by their properties, but also by their neurochemistry. The E1‐oscillator consists of two CRY expressing LN_ds which coexpress the short neuropeptide F (sNPF; Johard et al., 2009; Yao & Shafer, 2014), a peptide that has been shown to have an implication in promoting sleep by an inhibitory effect of the s‐LN_vs (Shang et al., 2013). Further, the two E1‐cells express the receptor for PDF (PDFR) and are strongly coupled to the s‐LN_vs' output (Yao & Shafer, 2014). The E2‐oscillator comprises one CRY expressing LN_d and the PDF lacking 5th s‐LN_v (Yao & Shafer, 2014). The two neurons also express the PDFR, but additionally contain the ion transport peptide (ITP), which gets rhythmically released in the dorsal brain to enhance evening activity and inhibit nocturnal activity (Hermann‐Luibl, Yoshii, Senthilan, Dircksen, & Helfrich‐Förster, 2014). The molecular oscillations of the E2‐cells are less strongly coupled to the M‐cells' output compared to the E1‐cells (Rieger et al., 2006; Yao & Shafer, 2014). The three remaining CRY negative LN_ds lack PDFR expression and form the E3‐unit, which is not directly coupled to the M‐cells' PDF‐signaling (Yao & Shafer, 2014).\",\n", - " 'paragraph_id': 2,\n", - " 'tokenizer': \"end, ##ogen, ##ous, circa, ##dian, clocks, enable, organisms, to, predict, and, adapt, to, environmental, 24, ##h, rhythms, that, are, caused, by, the, earth, ', s, rotation, around, its, own, axis, ., the, hence, resulting, circa, ##dian, rhythms, in, physiology, and, behavior, persist, even, in, the, absence, of, environmental, ze, ##it, ##ge, ##bers, under, constant, conditions, ., over, the, past, years, ,, the, molecular, mechanism, driving, circa, ##dian, rhythmic, ##ity, ,, several, inter, ##lock, ##ed, transcription, ##al, and, translation, ##al, feedback, loops, could, be, described, in, large, detail, for, the, common, model, organisms, ,, for, example, ,, syn, ##ech, ##oco, ##ccus, el, ##onga, ##tus, ,, ne, ##uro, ##sp, ##ora, cr, ##ass, ##a, ,, arab, ##ido, ##psis, tha, ##lian, ##a, ,, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, ,, and, mu, ##s, mu, ##scu, ##lus, (, reviewed, by, brown, ,, ko, ##wal, ##ska, ,, &, dal, ##lman, ##n, ,, 2012, ), ., in, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, ca, ., 150, clock, neurons, in, the, central, nervous, system, ,, named, after, their, size, and, location, ,, show, os, ##ci, ##llation, ##s, of, core, clock, gene, expression, (, e, ., g, ., ,, period, ,, timeless, and, clock, ), ., the, neurons, are, further, subdivided, according, to, their, ne, ##uro, ##chemical, content, and, so, far, described, function, ., classical, ##ly, ,, they, are, divided, into, four, lateral, and, three, dorsal, groups, ., two, of, the, lateral, groups, ,, the, small, and, the, large, vent, ##rol, ##ater, ##al, neurons, (, s, ‐, l, ##n, _, vs, and, l, ‐, l, ##n, ##v, _, s, ,, respectively, ;, figure, 1, ), express, the, ne, ##uro, ##pe, ##pt, ##ide, pigment, di, ##sper, ##sing, factor, (, pdf, ), ,, which, has, been, shown, to, be, an, important, signaling, molecule, of, the, circa, ##dian, clock, that, mod, ##ulates, the, other, pdf, ‐, responsive, cell, groups, of, the, circa, ##dian, system, by, slowing, down, their, ca, ^, 2, +, os, ##ci, ##llation, ##s, (, liang, ,, holy, ,, &, tag, ##her, ##t, ,, 2016, ,, 2017, ), ., further, ,, it, has, been, shown, that, the, four, pdf, expressing, s, ‐, l, ##n, _, vs, are, important, to, sustain, rhythmic, ##ity, in, constant, darkness, (, he, ##lf, ##rich, ‐, forster, ,, 1998, ;, ren, ##n, ,, park, ,, ro, ##sb, ##ash, ,, hall, ,, &, tag, ##her, ##t, ,, 1999, ), ., since, the, s, ‐, l, ##n, _, vs, are, also, important, for, the, generation, and, proper, timing, of, the, morning, activity, peak, ,, which, is, part, of, the, characteristic, bi, ##mo, ##dal, loco, ##moto, ##r, activity, pattern, of, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, ,, the, small, pdf, cells, are, often, referred, to, as, m, ‐, cells, (, morning, os, ##ci, ##lla, ##tors, ,, main, ‐, pace, ##makers, ;, grim, ##a, ,, che, ##lot, ,, xi, ##a, ,, &, ro, ##uy, ##er, ,, 2004, ;, stole, ##ru, ,, peng, ,, ago, ##sto, ,, &, ro, ##sb, ##ash, ,, 2004, ;, ri, ##eger, ,, sha, ##fer, ,, tom, ##io, ##ka, ,, &, he, ##lf, ##rich, ‐, forster, ,, 2006, ), ., in, contrast, ,, the, evening, activity, peak, is, generated, and, controlled, by, the, so, ‐, called, e, ‐, cells, ,, which, comprise, the, 5th, pdf, lacking, s, ‐, l, ##n, _, v, ,, three, crypt, ##och, ##rom, ##e, (, cry, ), expressing, do, ##rso, ##lateral, neurons, (, l, ##n, _, ds, ), ,, three, cry, lacking, l, ##n, _, ds, ,, and, six, to, eight, dorsal, neurons, (, d, ##n, _, 1, ), ., the, classification, in, m, ‐, and, e, ‐, cells, in, respect, to, the, traditional, dual, ‐, os, ##ci, ##lla, ##tor, model, (, pitt, ##end, ##ri, ##gh, &, da, ##an, ,, 1976, ), ,, as, well, as, more, recent, working, models, (, yao, &, sha, ##fer, ,, 2014, ), attribute, the, lateral, clock, neurons, (, l, ##n, _, s, ), an, essential, role, for, the, generation, of, the, bi, ##mo, ##dal, loco, ##moto, ##r, activity, rhythm, ., the, latter, study, nicely, showed, the, diverse, responsive, ##ness, of, the, cry, expressing, e, ‐, cells, to, secret, ##ed, pdf, ,, suggesting, that, the, e, ‐, os, ##ci, ##lla, ##tor, is, composed, of, different, functional, subunit, ##s, (, e, ##1, ‐, e, ##3, ;, yao, &, sha, ##fer, ,, 2014, ), and, that, the, circa, ##dian, system, is, more, likely, a, multi, ‐, os, ##ci, ##lla, ##tor, system, (, ri, ##eger, et, al, ., ,, 2006, ;, sha, ##fer, ,, he, ##lf, ##rich, ‐, forster, ,, ren, ##n, ,, &, tag, ##her, ##t, ,, 2006, ;, yao, &, sha, ##fer, ,, 2014, ), ., the, e, ‐, cells, cannot, only, be, distinguished, by, their, properties, ,, but, also, by, their, ne, ##uro, ##chemist, ##ry, ., the, e, ##1, ‐, os, ##ci, ##lla, ##tor, consists, of, two, cry, expressing, l, ##n, _, ds, which, coe, ##x, ##press, the, short, ne, ##uro, ##pe, ##pt, ##ide, f, (, s, ##np, ##f, ;, jo, ##hard, et, al, ., ,, 2009, ;, yao, &, sha, ##fer, ,, 2014, ), ,, a, peptide, that, has, been, shown, to, have, an, implication, in, promoting, sleep, by, an, inhibitor, ##y, effect, of, the, s, ‐, l, ##n, _, vs, (, shang, et, al, ., ,, 2013, ), ., further, ,, the, two, e, ##1, ‐, cells, express, the, receptor, for, pdf, (, pdf, ##r, ), and, are, strongly, coupled, to, the, s, ‐, l, ##n, _, vs, ', output, (, yao, &, sha, ##fer, ,, 2014, ), ., the, e, ##2, ‐, os, ##ci, ##lla, ##tor, comprises, one, cry, expressing, l, ##n, _, d, and, the, pdf, lacking, 5th, s, ‐, l, ##n, _, v, (, yao, &, sha, ##fer, ,, 2014, ), ., the, two, neurons, also, express, the, pdf, ##r, ,, but, additionally, contain, the, ion, transport, peptide, (, it, ##p, ), ,, which, gets, rhythmic, ##ally, released, in, the, dorsal, brain, to, enhance, evening, activity, and, inhibit, nocturnal, activity, (, hermann, ‐, lu, ##ib, ##l, ,, yo, ##shi, ##i, ,, sent, ##hila, ##n, ,, dir, ##cks, ##en, ,, &, he, ##lf, ##rich, ‐, forster, ,, 2014, ), ., the, molecular, os, ##ci, ##llation, ##s, of, the, e, ##2, ‐, cells, are, less, strongly, coupled, to, the, m, ‐, cells, ', output, compared, to, the, e, ##1, ‐, cells, (, ri, ##eger, et, al, ., ,, 2006, ;, yao, &, sha, ##fer, ,, 2014, ), ., the, three, remaining, cry, negative, l, ##n, _, ds, lack, pdf, ##r, expression, and, form, the, e, ##3, ‐, unit, ,, which, is, not, directly, coupled, to, the, m, ‐, cells, ', pdf, ‐, signaling, (, yao, &, sha, ##fer, ,, 2014, ), .\"},\n", - " {'article_id': 'ae8d1efced67593c317a1f1bc67a68a1',\n", - " 'section_name': 'Studies included in this review',\n", - " 'text': 'Table 1 presents some of the features of the papers included in the present work. Of the 29 studies, the first study [36] was published 50 years ago, in 1966. However, the majority of the studies (n = 15; 52%) were published in 2012–2016, and 24 (83%) of the studies found were published in the last 8 years. Only 4 (14%) were published before 2005. Most studies were conducted in the United States of America (n = 19; 65.52%), followed by the United Kingdom (n = 4; 13.79%) and Australia (n = 2; 6.90%). The remaining four studies were from Canada, India, Poland and Spain.Table 1Main features of the manuscripts included in this review (n = 29)FeaturesNumber (%)StudiesPublication year2012–201615 (51.72)I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV2007–20119 (31.03)XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV2002–20071 (3.45)XXV1966–20014 (13.79)XXVI, XXVII, XXVIII, XXIXPlace of the studyAustralia Canada India Poland Spain UK USA2 (6.90)1 (3.45)1 (3.45)1 (3.45)1 (3.45)4 (13.79)19 (65.52)XI, XIIIIVXVIIIVIIIII, III, XII, XXIIIIV, VI, VII, IX, X, XIV, XV, XVI, XVII, XIX, XX, XXI, XXII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIXType of participantsFaculty members and students1 (3.45)XXIIMaster’s degree health care professional students1 (3.45)XXINon-specified undergraduate students with neuroanatomy experience4 (13.79)VI, VIII, XI, XIIIParticipants without neuroanatomy experience3 (10.34)VII, IX, XVIUndergraduate or graduate biology students3 (10.34)XIV, XVII, XXIVUndergraduate biomedical students1 (3.45)IIUndergraduate medical students11 (37.93)I, III, IV, V, XII, XVIII, XX, XXIII, XXVII, XXVIII, XXIXUndergraduate psychology students4 (13.79)X, XIV, XV, XXVIUndergraduate or graduate physical/ocupational therapy students3 (10.35)XIX, XXIV, XXVNumber of participants+ 2013 (10.35)II, XVIII, XXIII151–2003 (10.35)XIII, XXVII, XXVIII101–1504 (13.79)V, XI, XX, XXIX51–10011 (37.93)IV, VI, VII, VIII, IX, XII, XV, XVI, XIX, XXI, XXII,0–508 (27.59)I, III, X, XIV, XVII, XXIV, XXV, XXVITeaching toolDigital tool14 (50.00)I, II, IV, VII, VIII, IX, XVI, XIX, XX, XXI, XXII, XXIII, XXV, XXVIINon-digital tool14 (50.00)III, V, VI, X, XI, XII, XIII, XIV, XV, XVII, XXIV, XXVI, XXVIII, XXIXType of teaching tool3D computer neuroanatomy tools 3D physical models Apps installed in tablets Case studies Computer-based neuroanatomy tools Equivalence-based instruction, EBI Face-to-face teaching Flipped classroom Inquiry-based laboratory instruction Intensive mode of delivery Interpolation of questions Near-peer teaching Renaissance artists’ depictions Self-instructional stations Truncated lectures, conceptual exercises and manipulatives6 (21.43)1 (3.57)1 (3.57)3 (10.71)6 (21.43)2 (7.14)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)1 (3.57)I, IV, VII, VIII, IX, XVI,XXIIXIVXIX, XXI, XXII, XXIII, XXV, XXVIIIII, XVXIIIVVIXIXXIXXIIXXXVIIIXXIV',\n", - " 'paragraph_id': 11,\n", - " 'tokenizer': 'table, 1, presents, some, of, the, features, of, the, papers, included, in, the, present, work, ., of, the, 29, studies, ,, the, first, study, [, 36, ], was, published, 50, years, ago, ,, in, 1966, ., however, ,, the, majority, of, the, studies, (, n, =, 15, ;, 52, %, ), were, published, in, 2012, –, 2016, ,, and, 24, (, 83, %, ), of, the, studies, found, were, published, in, the, last, 8, years, ., only, 4, (, 14, %, ), were, published, before, 2005, ., most, studies, were, conducted, in, the, united, states, of, america, (, n, =, 19, ;, 65, ., 52, %, ), ,, followed, by, the, united, kingdom, (, n, =, 4, ;, 13, ., 79, %, ), and, australia, (, n, =, 2, ;, 6, ., 90, %, ), ., the, remaining, four, studies, were, from, canada, ,, india, ,, poland, and, spain, ., table, 1, ##main, features, of, the, manuscripts, included, in, this, review, (, n, =, 29, ), features, ##num, ##ber, (, %, ), studies, ##pu, ##bl, ##ication, year, ##20, ##12, –, 2016, ##15, (, 51, ., 72, ), i, ,, ii, ,, iii, ,, iv, ,, v, ,, vi, ,, vii, ,, viii, ,, ix, ,, x, ,, xi, ,, xii, ,, xiii, ,, xiv, ,, xv, ##200, ##7, –, 2011, ##9, (, 31, ., 03, ), xvi, ,, xvi, ##i, ,, xvi, ##ii, ,, xi, ##x, ,, xx, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iii, ,, xx, ##iv, ##200, ##2, –, 2007, ##1, (, 3, ., 45, ), xx, ##v, ##19, ##66, –, 2001, ##4, (, 13, ., 79, ), xx, ##vi, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##pl, ##ace, of, the, study, ##aus, ##tral, ##ia, canada, india, poland, spain, uk, usa, ##2, (, 6, ., 90, ), 1, (, 3, ., 45, ), 1, (, 3, ., 45, ), 1, (, 3, ., 45, ), 1, (, 3, ., 45, ), 4, (, 13, ., 79, ), 19, (, 65, ., 52, ), xi, ,, xiii, ##iv, ##x, ##vi, ##ii, ##vi, ##iii, ##i, ,, iii, ,, xii, ,, xx, ##iii, ##iv, ,, vi, ,, vii, ,, ix, ,, x, ,, xiv, ,, xv, ,, xvi, ,, xvi, ##i, ,, xi, ##x, ,, xx, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iv, ,, xx, ##v, ,, xx, ##vi, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##type, of, participants, ##fa, ##cu, ##lty, members, and, students, ##1, (, 3, ., 45, ), xx, ##ii, ##master, ’, s, degree, health, care, professional, students, ##1, (, 3, ., 45, ), xx, ##ino, ##n, -, specified, undergraduate, students, with, ne, ##uro, ##ana, ##tom, ##y, experience, ##4, (, 13, ., 79, ), vi, ,, viii, ,, xi, ,, xiii, ##par, ##tic, ##ip, ##ants, without, ne, ##uro, ##ana, ##tom, ##y, experience, ##3, (, 10, ., 34, ), vii, ,, ix, ,, xvi, ##under, ##grad, ##uate, or, graduate, biology, students, ##3, (, 10, ., 34, ), xiv, ,, xvi, ##i, ,, xx, ##iv, ##under, ##grad, ##uate, biomedical, students, ##1, (, 3, ., 45, ), ii, ##under, ##grad, ##uate, medical, students, ##11, (, 37, ., 93, ), i, ,, iii, ,, iv, ,, v, ,, xii, ,, xvi, ##ii, ,, xx, ,, xx, ##iii, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##under, ##grad, ##uate, psychology, students, ##4, (, 13, ., 79, ), x, ,, xiv, ,, xv, ,, xx, ##vi, ##under, ##grad, ##uate, or, graduate, physical, /, o, ##cup, ##ation, ##al, therapy, students, ##3, (, 10, ., 35, ), xi, ##x, ,, xx, ##iv, ,, xx, ##vn, ##umber, of, participants, +, 2013, (, 10, ., 35, ), ii, ,, xvi, ##ii, ,, xx, ##iii, ##15, ##1, –, 2003, (, 10, ., 35, ), xiii, ,, xx, ##vi, ##i, ,, xx, ##vi, ##ii, ##10, ##1, –, 150, ##4, (, 13, ., 79, ), v, ,, xi, ,, xx, ,, xx, ##ix, ##51, –, 100, ##11, (, 37, ., 93, ), iv, ,, vi, ,, vii, ,, viii, ,, ix, ,, xii, ,, xv, ,, xvi, ,, xi, ##x, ,, xx, ##i, ,, xx, ##ii, ,, 0, –, 50, ##8, (, 27, ., 59, ), i, ,, iii, ,, x, ,, xiv, ,, xvi, ##i, ,, xx, ##iv, ,, xx, ##v, ,, xx, ##vite, ##achi, ##ng, tool, ##di, ##git, ##al, tool, ##14, (, 50, ., 00, ), i, ,, ii, ,, iv, ,, vii, ,, viii, ,, ix, ,, xvi, ,, xi, ##x, ,, xx, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iii, ,, xx, ##v, ,, xx, ##vi, ##ino, ##n, -, digital, tool, ##14, (, 50, ., 00, ), iii, ,, v, ,, vi, ,, x, ,, xi, ,, xii, ,, xiii, ,, xiv, ,, xv, ,, xvi, ##i, ,, xx, ##iv, ,, xx, ##vi, ,, xx, ##vi, ##ii, ,, xx, ##ix, ##type, of, teaching, tool, ##3d, computer, ne, ##uro, ##ana, ##tom, ##y, tools, 3d, physical, models, apps, installed, in, tablets, case, studies, computer, -, based, ne, ##uro, ##ana, ##tom, ##y, tools, equivalence, -, based, instruction, ,, e, ##bi, face, -, to, -, face, teaching, flipped, classroom, inquiry, -, based, laboratory, instruction, intensive, mode, of, delivery, inter, ##pol, ##ation, of, questions, near, -, peer, teaching, renaissance, artists, ’, depictions, self, -, instructional, stations, truncated, lectures, ,, conceptual, exercises, and, mani, ##pu, ##lative, ##s, ##6, (, 21, ., 43, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 3, (, 10, ., 71, ), 6, (, 21, ., 43, ), 2, (, 7, ., 14, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), 1, (, 3, ., 57, ), i, ,, iv, ,, vii, ,, viii, ,, ix, ,, xvi, ,, xx, ##ii, ##xi, ##v, ##xi, ##x, ,, xx, ##i, ,, xx, ##ii, ,, xx, ##iii, ,, xx, ##v, ,, xx, ##vi, ##iii, ##i, ,, xv, ##xi, ##ii, ##v, ##vi, ##xi, ##xx, ##ix, ##xi, ##ix, ##xx, ##vi, ##ii, ##xx, ##iv'},\n", - " {'article_id': 'ae8d1efced67593c317a1f1bc67a68a1',\n", - " 'section_name': 'Computer-based neuroanatomy tools',\n", - " 'text': 'Table 2 summarizes each study included in this review, including the teaching tool used, aims, methodology employed, and main results/conclusion. Some researchers [23–28] focused their studies on the impact of using computer-based tools for teaching neuroanatomy. More specifically, McKeough et al. [23, 24] investigated the effect of a computer-based tool on students’ performance and their attitudes. Before and after test questions revealed that scores improved significantly after working with the learning model. In addition, students reported the computer-aided neuroanatomy learning modules as a valuable and enjoyable learning tool, and perceived their clinical-self efficacy as higher as a result of working with them.Table 2Summary description of the 29 studies included in this review (listed by year of publication)TitleAuthors (year)University, countryParticipants (number)Teaching toolAimMethodologyMain results/conclusionEvaluation of an online three-dimensional interactive resource for undergraduate neuroanatomy education^IAllen et al. (2016)Western University, CanadaSecond-year undergraduate medical students (n = 47)3D computer neuroanatomy model (digital tool)To evaluate the impact on learning of a novel, interactive 3D neuroanatomy model.Participants were divided into 2 groups, each accessing 2 learning modalities (3D model and a cadaveric laboratory session). After each modality, students completed a test. (mix between- and within- subject design)Participants were pleased to work with the 3D model. In addition, their learning outcomes significantly improved after accessing this teaching tool.Mobile technology: students perceived benefits of apps for learning neuroanatomy^IIMorris et al. (2016)University of Leeds, UKUndergraduate biomedical students enrolled in a level 2 course (n = 519)5 apps installed in tablet (Apple iPad) devices (digital tool)To examine the students’ use of apps in a neuroanatomy practical class: their perceptions and learning outcomes.There were three cohorts of students (3-year study). The neuroanatomy practical session included the use of tablet devices. After the session the students completed a questionnaire about the use of the apps.Students made extensive use of the apps, considered them easy to use and beneficial for learning. Compared with the year before the trial started, there was an increase in the students’ performance.The student experience of applied equivalence-based instruction for neuroanatomy teaching^IIIGreville et al. (2016)Swansea University, UKFirst- and second-year undergraduate medical students (n = 43)Equivalence-based instruction, EBI (non-digital tool)To develop and assess the effectiveness of EBI learning resources.Initially participants completed a pre-test. Then the learning of the relations occurred, followed by a post-test design to assess students’ learning. (within-subject design)The EBI resources were an effective, efficient and well-received method for teaching neuroanatomy.Development and assessment of a new 3D neuroanatomy teaching tool for MRI training^IVDrapkin et al. (2015)Brown University, USAFirst-year undergraduate medical students (n = 73)3D computer neuroanatomy model (digital tool)To create and evaluate the efficacy of a computerized 3D neuroanatomy teaching toolParticipants were divided into two groups. The first group was taught using the 3D teaching tool, and the second using traditional methods. Scores from an MRI identification quiz and survey were compared. (between-subject design)The 3D teaching tool was an effective way to train students to read an MRI of the brain and particularly effective for teaching C-shaped internal brain structures.Perception of MBBS students to “flipped class room” approach in neuroanatomy module^VVeeramani et al. (2015)Jawaharlal Institute of Postgraduate Medical Education and Research, IndiaFirst-year undergraduate medical students (n = 130)Flipped classroom (non-digital tool)To examine the impact of a flipped classroom approach (i.e., assess students’ perception and the impact on their performance and attitudes)Pre- and post-tests were designed to test the learning aims of the session. The perception of the students was also assessed. (within- subject design)Results showed significant differences between the pre and post-test scores. Student response to the flipped classroom structure was largely positiveA mind of their own: Using inquiry-based teaching to build critical thinking skills and intellectual engagement in an undergraduate neuroanatomy course^VIGreenwald & Quitadamo (2014)A regional university in the Pacific Northwest, USAUndergraduate students enrolled in a human neuroanatomy course (n = 85)Inquiry-based clinical case, IBCC (non-digital tool)To determine which teaching method (conventional and IBCC) produces greater gains in critical thinking and content knowledgeParticipants were divided into two groups: conventional and Experimental group. All students were analyzed for exam and course grade performance. Critical thinking pre- and post- tests were analyzed. (mix between- and within- subject design)Using the California critical thinking skills test, students in the conventional neuroanatomy course gained less than 3 national percentile ranks, whereas IBCC students gained over 7.5 within one academic term.Computer-based learning: graphical integration of whole and sectional neuroanatomy improves long-term retention^VIINaaz et al. (2014)University of Louisville, USAVolunteers between 16 and 34 years, with minimal or no knowledge of neuroanatomy (n = 64)3D computer neuroanatomy models (digital tool)To examine if instruction with graphically integrated representations of whole and sectional neuroanatomy is effectiveParticipants were divided into two groups. After a pretest, participants learned sectional anatomy using one of the two learning programs: sections only or 2-D/3-D. Then tests of generalization were completed. (between- subject design)It showed that the use of graphical representation helps students to achieve a deeper understanding of complex spatial relationsEnhancing neuroanatomy education using computer-based instructional material^VIIIPalomera et al. (2014)University of Salamanca, SpainUndergraduate students enrolled in a medical anatomy course (n = 65)3D computer neuroanatomy models (digital tool)To develop a computer-based tool based on 3D images, and to examine if the for this tool depends on their visuospatial abilityParticipants completed an online rating-scale to measure the educational value that they assigned to the teaching tool. In addition, the student’s visuospatial aptitude was assessed. (between-subject design)Findings showed that students assigned a high educational value to this tool, regardless of their visuospatial skills.Computer-based learning: Interleaving whole and sectional representation of neuroanatomy^IXPani et al. (2013)University of Louisville, USAUndergraduate students with rudimentary knowledge of neuroanatomy (n = 59)3D computer neuroanatomy model (digital tool)To compare a basic transfer method for learning whole and sectional neuroanatomy with a method in which both forms of representation were interleaved.There were 3 experimental conditions: i) section only, ii) whole then sections; and iii) alternation. (between-subject design)Interleaved learning of whole and sectional neuroanatomy was more efficient than the basic transfer method.Da Vinci coding? Using renaissance artists’ depictions of the brain to engage student interest in neuroanatomy^XWatson (2013)Lewis & Clark College, USAUndergraduate psychology students (n = 27)Renaissance artists’ depictions of the central nervous system (non-digital tool)To increase students’ interest in the study of neuroanatomyThere were interactive classroom exercises using well-known Renaissance artists’ depictions of the brain. Then participants completed a feedback questionnaire.These exercises increased the interest of the students in the topic. The authors suggest that these exercises may be a useful addition to courses that introduce or review neuroanatomical concepts.Intensive mode delivery of a neuroanatomy unit: Lower final grades but higher student satisfaction^XIWhillier, & Lystad, (2013)Macquarie University, AustraliaUndergraduate students enrolled in the traditional and intensive neuroanatomy units (n = 125)Intensive mode of delivery (non-digital tool)To compare the intensive and traditional units of neuroanatomy for undergraduate students.The intensive mode neuroanatomy unit showed the students the same quantity and quality of material to the same standard, including the hours. However, the material was delivered in a shorter timeframe. (between-subject design)Students obtained lower final grades in the new intensive mode delivery but reported having similar overall satisfaction with their laboratory practical classes.Near-peer teaching in clinical neuroanatomy^XIIHall et al. (2013)University of Southampton, UKUndergraduate medical students (n = 60)Near-peer teaching (non-digital tool)To develop and deliver a near-peer programme of study.Two medical students organized and delivered the teaching to their colleges in a series of seven sessions. At the end of each session, participants were asked to fill a feedback questionnaire. (within-subject design)Students’ perceived level of knowledge increased after the near-peer teaching sessions, supporting the use of this teaching tool in neuroanatomy courses.The effect of face-to-face teaching on student knowledge and satisfaction in an undergraduate neuroanatomy course^XIIIWhillier & Lystad, (2013)Macquarie University, AustraliaUndergraduate students enrolled in the new and old neuroanatomy units (n = 181)Face-to-face teaching (non-digital tool)To examine if face-to-face teaching has an impact on student performance and overall satisfaction with the course.Two groups of students (old and restructured unit of neuroanatomy) were analyzed. A questionnaire was used to compare them in terms of the rate they gave to the course, satisfaction, and final grades. (between-subject design)The increase in total face-to-face teaching hours in the restructured unit of neuroanatomy does not improve student grades. However, it does increase student satisfaction.Using case studies as a semester-long tool to teach neuroanatomy and structure-function relationships to undergraduates^XIVKennedy (2013)Denison Univer, USAUndergraduate biology and psychology students (n = 50)Case studies (non-digital tool)To investigate the effect of teaching neuroanatomy through presentation and discussion of case studies.Students were expected to collaborate with their colleges in small groups. In each case study, the entire class was asked to participate in some aspect of the case.Students report enjoying learning brain structure using this method, and commented positively on the class activities associated with learning brain anatomy.Using equivalence-based instruction to increase efficiency in teaching neuroanatomy^XVPytte & Fienup (2012)Queens College, USAUndergraduate students, primarily of psychology majors (n = 93)Equivalence-Based Instruction, EBI (non-digital tool)To study if EBI is effective in teaching neuroanatomy in a large classroom settingFourteen brain regions were identified, and conditional relations were explicitly taught during three lectures. Then, students completed test to evaluate some relations that were taught and some not taught.Selection of associations by the teacher can encourage the spontaneous emergence of novel associations within a concept or category. Therefore, it can increase the efficiency of teaching.Computer-based learning of neuroanatomy: a longitudinal study of llearning, transfer, and retention^XVIChariker et al. (2011)University of Louisville, USAUndergraduate students who reported minimal knowledge of neuroanatomy (n = 72)3D computer neuroanatomy model (digital tool)To determine the effectiveness of new methods for teaching neuroanatomy with computer-based instructionUsing a 3D graphical model of the human brain, students learned either sectional anatomy alone (with perceptually continuous or discrete navigation) or whole anatomy followed by sectional anatomy. Participants were tested immediately and after 2–3 weeks. (between-subject design)Results showed efficient learning, good long-term retention, and successful transfer to the interpretation of biomedical images. They suggest that computer-based learning can be a valuable teaching tool.Human brains engaged in rat brains: student-driven neuroanatomy research in an introductory biology lab course^XVIIGardner et al. (2011)Purdue University, USAFirst-year undergraduate students interested in majoring in biology (n = 13)Inquiry-based laboratory instruction (non-digital tool)To increase student interest in biology by exposing them to novel research projectsStudents acquired basic lab skills within the context of a research question of a member of the faculty. Biology students who were not taking the research-based, Bio-CASPiE course, formed the comparison group for pre- and post-semester questionnaires. (mix between-within- subject design)The inquiry-based laboratory instruction increased students’ motivation and excitement, encouraged good scientific practices, and can potentially benefit departmental research.The study techniques of Asian, American, and European medical students during gross anatomy and neuroanatomy courses in Poland^XVIIIZurada et al. (2011)Medical University in Poland, PolandInternational medical students, from the Polish, American, and Taiwanese divisions (n = 705)–To investigate similarities and differences among American, Asian, and European medical students in terms of their study methods.Participants completed a questionnaire in which they reported which methods they used to study, and which of the methods they believed were most efficient for comprehension, memorization, and review. (between-subject design)Results showed some differences in study techniques among students from the different ethnic back- grounds (e.g., Polish and American preferred the use of dissections and prosected specimens)Effectiveness of a computer-aided neuroanatomy program for entry-level physical therapy students: anatomy and clinical examination of the dorsal column-medial lemniscal system^XIXMcKeoughet al. (2010)California State University & University of the Pacific, USAUndergraduate physical therapy students (n = 61)Computer-aided instruction, CAI (digital tool)To determine if a computer- aided instruction learning module improves students’ neuroanatomy knowledgeStudents completed a paper-and-pencil test on the neuroanatomy/physiology and clinical examination of the DCML system, both before and after working with the teaching tool (within-subject design)Findings showed that clinical examination post-test scores improved significantly from the pre-test scoresA Novel Three-Dimensional Tool for Teaching Human Neuroanatomy^XXEstevez et al. (2010)Boston University School of Medicine, USAFirst-year undergraduate medical students (n = 101)3D physical neuroanatomy model (digital tool)To develop and assess a new tool forg teaching 3D neuroanatomy to first-year medical studentsFirst, all students were presented to traditional 2D methods. Then, the experimental group constructed 3D color-coded physical models, while the control group re-examined 2D brain cross-sections. (between-subject design)3D computer model was an effective method for teaching spatial relationships of brain anatomy and seems to better prepare students for visualization of 3D neuroanatomyAttitudes of health care students about computer-aided neuroanatomy instruction^XXIMcKeough& Bagatell (2009)A University in the West Coast, USAMaster’s degree health care professional students (n = 77)Computer-aided instruction, CAI (digital tool)To examine students’ attitudes toward CAI, which factors help their development, and their implications.Three computer-aided neuroanatomy learning modules were used. Students independently reviewed the modules as supplements to lecture and completed a survey to evaluate teaching effectiveness (within-subject design)The CAI modules examined in this study were effective as adjuncts to lecture in helping the students learn and make clinical applications of neuroanatomy informationA usability study of users’ perceptions toward a multimedia computer-assisted learning tool for neuroanatomy^XXIIGould et al. (2008)University of Kentucky & University of Louisville & Nova Southeastern University, USAFaculty and students from some institutions across the country (n = 62)Computer-aided instruction, CAI (digital tool)To assess users’ perceptions of the computer-based tool: “Anatomy of the Central Nervous System: A Multimedia Course”First, participants used the multimedia prototype. Then they completed a usability questionnaire designed to measure two usability properties: program need and program applicabilityThis study showed that the CAI was well-designed for all users, and demonstrates the importance of integrating quality properties of usability with principles of human learning.Attitudes to e-learning, learning style and achievement in learning neuroanatomy by medical students^XXIIISvirko & Mellanby (2008)Oxford University, UKSecond-year pre-clinical undergraduate medical students (n = 205)Computer-aided learning, CAL (digital tool)To investigate the impact of an online course on encouraging students to learn and their academic performance.The students approach to learning towards the CAL course and towards their studies in general was compared. Student attitudes and ratings were also assessed.Findings revealed that students reported using significantly less deep approach to learning for the CAL course.Using truncated lectures, conceptual exercises, and manipulatives to improve learning in the neuroanatomy classroom^XXIVKrontiris-Litowitz (2008)Youngstown State University, USAUndergraduate biology and graduate biology and physical therapy students (n = 19)Truncated lectures, conceptual exercises, and manipulatives (non-digital tool)To use truncated lectures, conceptual exercises, and manipulatives to make learning more effective and increase critical thinkingThe curriculum was revised. More specifically, it became shorter, included practice problems that presented the spinal tracts in an applied context, and included a manipulative. Student’s learning was then assessed and compared with previous classes. (between-subject design).Students’ learning was more effective under the revised curriculum, suggesting that this revised curriculum could potentially be applied to other topics.Design and utility of a web-based computer-assisted instructional tool for neuroanatomy self-study and review for physical and occupational therapy graduate students^XXIVForeman et al. (2005)University of Utah, USAUndergraduate physical therapy and occupational therapy students (n = 43)Computer-assisted instruction, CAI (digital tool)To develop a CAI, and assess their design and utility to teach neuroanatomy.A questionnaire addressed navigation, clarity of the images, benefit of the CAI tool, and students rating. Students were also asked to compare this tool with traditional learning tools.Design and utility of a web-based computer-assisted instructional tool for neuroanatomy self-study and review for physical and occupational therapy graduate students^XXIVA neuroanatomy teaching activity using case studies and collaboration^XXVISheldon (2000)University of Michigan, USAUndergraduatestudents of an introductory psychology course (n = 28)Case studies and collaboration (non-digital tool)To evaluate an easier and less time-consuming method for teaching neuroanatomy.Students collaborated and applied their neuroanatomy knowledge to several case studies during classes.Findings showed that students assessed this method as very enjoyable and helpful for remembering or learning the material.Computer-based neuroanatomy laboratory for medical students^XXVIILamperti & Sodicoff (1997)Temple University, USAFirst-year undergraduate medical students (n = 185)Computer-based neuroanatomy laboratory (digital tool)To develop a computer-based laboratory program to substitute the traditional glass-slide laboratoryThey compared the performances of those classes that previously had the traditional laboratory with two succeeding classes that used computer program (between-subject design).Test scores showed that the students’ performance on laboratory material was similar in both classes.Teaching of neuroanatomy by means of self-instructional laboratory stations^XXVIIIFisher et al. (1980)University of Michigan Medical School, USAFirst-year undergraduate medical students (n = 200)Self-instructional stations (non-digital tool)To teach neuroanatomy using self-instructional laboratory stationsNeuroanatomical laboratory material was presented in a series of six self-instructional stations. Five weeks later, short examinations tests occurred.Results of the tests indicated a mastery of station material as defined by the objectives and an ability to use the material in applied problems.Cognitive processes in learning neuroanatomy^XXIXGeeartsma & Matzke (1966)University of Kansas, USAFirst-year undergraduate medical students (n = 107)Interpolation of questions (non-digital tool)To investigate the effect of interpolation of questions into a lecture presentation.Participants were divided into 2 matched groups. Each group was shown lectures on the visual system which differed only in regard to taxomic level of 10 questions posed lecture. Performance was then measured (between-subject design).Emphasis on recall questions aids performance on subsequent recall questions more than emphasis on problem-solving questions helps in the solution of subsequent problem-solving questions.',\n", - " 'paragraph_id': 14,\n", - " 'tokenizer': 'table, 2, sum, ##mar, ##izes, each, study, included, in, this, review, ,, including, the, teaching, tool, used, ,, aims, ,, methodology, employed, ,, and, main, results, /, conclusion, ., some, researchers, [, 23, –, 28, ], focused, their, studies, on, the, impact, of, using, computer, -, based, tools, for, teaching, ne, ##uro, ##ana, ##tom, ##y, ., more, specifically, ,, mc, ##ke, ##ough, et, al, ., [, 23, ,, 24, ], investigated, the, effect, of, a, computer, -, based, tool, on, students, ’, performance, and, their, attitudes, ., before, and, after, test, questions, revealed, that, scores, improved, significantly, after, working, with, the, learning, model, ., in, addition, ,, students, reported, the, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, learning, modules, as, a, valuable, and, enjoyable, learning, tool, ,, and, perceived, their, clinical, -, self, efficacy, as, higher, as, a, result, of, working, with, them, ., table, 2, ##sum, ##mar, ##y, description, of, the, 29, studies, included, in, this, review, (, listed, by, year, of, publication, ), title, ##au, ##thor, ##s, (, year, ), university, ,, country, ##par, ##tic, ##ip, ##ants, (, number, ), teaching, tool, ##ai, ##mme, ##th, ##od, ##ology, ##main, results, /, conclusion, ##eva, ##lu, ##ation, of, an, online, three, -, dimensional, interactive, resource, for, undergraduate, ne, ##uro, ##ana, ##tom, ##y, education, ^, ia, ##llen, et, al, ., (, 2016, ), western, university, ,, canada, ##se, ##con, ##d, -, year, undergraduate, medical, students, (, n, =, 47, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, evaluate, the, impact, on, learning, of, a, novel, ,, interactive, 3d, ne, ##uro, ##ana, ##tom, ##y, model, ., participants, were, divided, into, 2, groups, ,, each, access, ##ing, 2, learning, mod, ##ali, ##ties, (, 3d, model, and, a, cad, ##aver, ##ic, laboratory, session, ), ., after, each, mod, ##ality, ,, students, completed, a, test, ., (, mix, between, -, and, within, -, subject, design, ), participants, were, pleased, to, work, with, the, 3d, model, ., in, addition, ,, their, learning, outcomes, significantly, improved, after, access, ##ing, this, teaching, tool, ., mobile, technology, :, students, perceived, benefits, of, apps, for, learning, ne, ##uro, ##ana, ##tom, ##y, ^, ii, ##mo, ##rri, ##s, et, al, ., (, 2016, ), university, of, leeds, ,, uk, ##under, ##grad, ##uate, biomedical, students, enrolled, in, a, level, 2, course, (, n, =, 51, ##9, ), 5, apps, installed, in, tablet, (, apple, ipad, ), devices, (, digital, tool, ), to, examine, the, students, ’, use, of, apps, in, a, ne, ##uro, ##ana, ##tom, ##y, practical, class, :, their, perceptions, and, learning, outcomes, ., there, were, three, co, ##hort, ##s, of, students, (, 3, -, year, study, ), ., the, ne, ##uro, ##ana, ##tom, ##y, practical, session, included, the, use, of, tablet, devices, ., after, the, session, the, students, completed, a, question, ##naire, about, the, use, of, the, apps, ., students, made, extensive, use, of, the, apps, ,, considered, them, easy, to, use, and, beneficial, for, learning, ., compared, with, the, year, before, the, trial, started, ,, there, was, an, increase, in, the, students, ’, performance, ., the, student, experience, of, applied, equivalence, -, based, instruction, for, ne, ##uro, ##ana, ##tom, ##y, teaching, ^, iii, ##gre, ##ville, et, al, ., (, 2016, ), swansea, university, ,, uk, ##fi, ##rst, -, and, second, -, year, undergraduate, medical, students, (, n, =, 43, ), equivalence, -, based, instruction, ,, e, ##bi, (, non, -, digital, tool, ), to, develop, and, assess, the, effectiveness, of, e, ##bi, learning, resources, ., initially, participants, completed, a, pre, -, test, ., then, the, learning, of, the, relations, occurred, ,, followed, by, a, post, -, test, design, to, assess, students, ’, learning, ., (, within, -, subject, design, ), the, e, ##bi, resources, were, an, effective, ,, efficient, and, well, -, received, method, for, teaching, ne, ##uro, ##ana, ##tom, ##y, ., development, and, assessment, of, a, new, 3d, ne, ##uro, ##ana, ##tom, ##y, teaching, tool, for, mri, training, ^, iv, ##dra, ##p, ##kin, et, al, ., (, 2015, ), brown, university, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 73, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, create, and, evaluate, the, efficacy, of, a, computer, ##ized, 3d, ne, ##uro, ##ana, ##tom, ##y, teaching, tool, ##par, ##tic, ##ip, ##ants, were, divided, into, two, groups, ., the, first, group, was, taught, using, the, 3d, teaching, tool, ,, and, the, second, using, traditional, methods, ., scores, from, an, mri, identification, quiz, and, survey, were, compared, ., (, between, -, subject, design, ), the, 3d, teaching, tool, was, an, effective, way, to, train, students, to, read, an, mri, of, the, brain, and, particularly, effective, for, teaching, c, -, shaped, internal, brain, structures, ., perception, of, mb, ##bs, students, to, “, flipped, class, room, ”, approach, in, ne, ##uro, ##ana, ##tom, ##y, module, ^, v, ##ve, ##era, ##mani, et, al, ., (, 2015, ), jaw, ##aha, ##rl, ##al, institute, of, postgraduate, medical, education, and, research, ,, india, ##fi, ##rst, -, year, undergraduate, medical, students, (, n, =, 130, ), flipped, classroom, (, non, -, digital, tool, ), to, examine, the, impact, of, a, flipped, classroom, approach, (, i, ., e, ., ,, assess, students, ’, perception, and, the, impact, on, their, performance, and, attitudes, ), pre, -, and, post, -, tests, were, designed, to, test, the, learning, aims, of, the, session, ., the, perception, of, the, students, was, also, assessed, ., (, within, -, subject, design, ), results, showed, significant, differences, between, the, pre, and, post, -, test, scores, ., student, response, to, the, flipped, classroom, structure, was, largely, positive, ##a, mind, of, their, own, :, using, inquiry, -, based, teaching, to, build, critical, thinking, skills, and, intellectual, engagement, in, an, undergraduate, ne, ##uro, ##ana, ##tom, ##y, course, ^, vi, ##gree, ##n, ##wald, &, quit, ##ada, ##mo, (, 2014, ), a, regional, university, in, the, pacific, northwest, ,, usa, ##under, ##grad, ##uate, students, enrolled, in, a, human, ne, ##uro, ##ana, ##tom, ##y, course, (, n, =, 85, ), inquiry, -, based, clinical, case, ,, ib, ##cc, (, non, -, digital, tool, ), to, determine, which, teaching, method, (, conventional, and, ib, ##cc, ), produces, greater, gains, in, critical, thinking, and, content, knowledge, ##par, ##tic, ##ip, ##ants, were, divided, into, two, groups, :, conventional, and, experimental, group, ., all, students, were, analyzed, for, exam, and, course, grade, performance, ., critical, thinking, pre, -, and, post, -, tests, were, analyzed, ., (, mix, between, -, and, within, -, subject, design, ), using, the, california, critical, thinking, skills, test, ,, students, in, the, conventional, ne, ##uro, ##ana, ##tom, ##y, course, gained, less, than, 3, national, percent, ##ile, ranks, ,, whereas, ib, ##cc, students, gained, over, 7, ., 5, within, one, academic, term, ., computer, -, based, learning, :, graphical, integration, of, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, improves, long, -, term, retention, ^, vii, ##na, ##az, et, al, ., (, 2014, ), university, of, louisville, ,, usa, ##vo, ##lun, ##tee, ##rs, between, 16, and, 34, years, ,, with, minimal, or, no, knowledge, of, ne, ##uro, ##ana, ##tom, ##y, (, n, =, 64, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, models, (, digital, tool, ), to, examine, if, instruction, with, graphical, ##ly, integrated, representations, of, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, is, effective, ##par, ##tic, ##ip, ##ants, were, divided, into, two, groups, ., after, a, pre, ##test, ,, participants, learned, sectional, anatomy, using, one, of, the, two, learning, programs, :, sections, only, or, 2, -, d, /, 3, -, d, ., then, tests, of, general, ##ization, were, completed, ., (, between, -, subject, design, ), it, showed, that, the, use, of, graphical, representation, helps, students, to, achieve, a, deeper, understanding, of, complex, spatial, relations, ##en, ##han, ##cing, ne, ##uro, ##ana, ##tom, ##y, education, using, computer, -, based, instructional, material, ^, viii, ##pal, ##ome, ##ra, et, al, ., (, 2014, ), university, of, salamanca, ,, spain, ##under, ##grad, ##uate, students, enrolled, in, a, medical, anatomy, course, (, n, =, 65, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, models, (, digital, tool, ), to, develop, a, computer, -, based, tool, based, on, 3d, images, ,, and, to, examine, if, the, for, this, tool, depends, on, their, vis, ##uo, ##sp, ##ati, ##al, ability, ##par, ##tic, ##ip, ##ants, completed, an, online, rating, -, scale, to, measure, the, educational, value, that, they, assigned, to, the, teaching, tool, ., in, addition, ,, the, student, ’, s, vis, ##uo, ##sp, ##ati, ##al, apt, ##itude, was, assessed, ., (, between, -, subject, design, ), findings, showed, that, students, assigned, a, high, educational, value, to, this, tool, ,, regardless, of, their, vis, ##uo, ##sp, ##ati, ##al, skills, ., computer, -, based, learning, :, inter, ##lea, ##ving, whole, and, sectional, representation, of, ne, ##uro, ##ana, ##tom, ##y, ^, ix, ##pani, et, al, ., (, 2013, ), university, of, louisville, ,, usa, ##under, ##grad, ##uate, students, with, ru, ##diment, ##ary, knowledge, of, ne, ##uro, ##ana, ##tom, ##y, (, n, =, 59, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, compare, a, basic, transfer, method, for, learning, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, with, a, method, in, which, both, forms, of, representation, were, inter, ##lea, ##ved, ., there, were, 3, experimental, conditions, :, i, ), section, only, ,, ii, ), whole, then, sections, ;, and, iii, ), alter, ##nation, ., (, between, -, subject, design, ), inter, ##lea, ##ved, learning, of, whole, and, sectional, ne, ##uro, ##ana, ##tom, ##y, was, more, efficient, than, the, basic, transfer, method, ., da, vinci, coding, ?, using, renaissance, artists, ’, depictions, of, the, brain, to, engage, student, interest, in, ne, ##uro, ##ana, ##tom, ##y, ^, x, ##wat, ##son, (, 2013, ), lewis, &, clark, college, ,, usa, ##under, ##grad, ##uate, psychology, students, (, n, =, 27, ), renaissance, artists, ’, depictions, of, the, central, nervous, system, (, non, -, digital, tool, ), to, increase, students, ’, interest, in, the, study, of, ne, ##uro, ##ana, ##tom, ##ythe, ##re, were, interactive, classroom, exercises, using, well, -, known, renaissance, artists, ’, depictions, of, the, brain, ., then, participants, completed, a, feedback, question, ##naire, ., these, exercises, increased, the, interest, of, the, students, in, the, topic, ., the, authors, suggest, that, these, exercises, may, be, a, useful, addition, to, courses, that, introduce, or, review, ne, ##uro, ##ana, ##tom, ##ical, concepts, ., intensive, mode, delivery, of, a, ne, ##uro, ##ana, ##tom, ##y, unit, :, lower, final, grades, but, higher, student, satisfaction, ^, xi, ##w, ##hill, ##ier, ,, &, l, ##yst, ##ad, ,, (, 2013, ), macquarie, university, ,, australia, ##under, ##grad, ##uate, students, enrolled, in, the, traditional, and, intensive, ne, ##uro, ##ana, ##tom, ##y, units, (, n, =, 125, ), intensive, mode, of, delivery, (, non, -, digital, tool, ), to, compare, the, intensive, and, traditional, units, of, ne, ##uro, ##ana, ##tom, ##y, for, undergraduate, students, ., the, intensive, mode, ne, ##uro, ##ana, ##tom, ##y, unit, showed, the, students, the, same, quantity, and, quality, of, material, to, the, same, standard, ,, including, the, hours, ., however, ,, the, material, was, delivered, in, a, shorter, time, ##frame, ., (, between, -, subject, design, ), students, obtained, lower, final, grades, in, the, new, intensive, mode, delivery, but, reported, having, similar, overall, satisfaction, with, their, laboratory, practical, classes, ., near, -, peer, teaching, in, clinical, ne, ##uro, ##ana, ##tom, ##y, ^, xii, ##hall, et, al, ., (, 2013, ), university, of, southampton, ,, uk, ##under, ##grad, ##uate, medical, students, (, n, =, 60, ), near, -, peer, teaching, (, non, -, digital, tool, ), to, develop, and, deliver, a, near, -, peer, programme, of, study, ., two, medical, students, organized, and, delivered, the, teaching, to, their, colleges, in, a, series, of, seven, sessions, ., at, the, end, of, each, session, ,, participants, were, asked, to, fill, a, feedback, question, ##naire, ., (, within, -, subject, design, ), students, ’, perceived, level, of, knowledge, increased, after, the, near, -, peer, teaching, sessions, ,, supporting, the, use, of, this, teaching, tool, in, ne, ##uro, ##ana, ##tom, ##y, courses, ., the, effect, of, face, -, to, -, face, teaching, on, student, knowledge, and, satisfaction, in, an, undergraduate, ne, ##uro, ##ana, ##tom, ##y, course, ^, xiii, ##w, ##hill, ##ier, &, l, ##yst, ##ad, ,, (, 2013, ), macquarie, university, ,, australia, ##under, ##grad, ##uate, students, enrolled, in, the, new, and, old, ne, ##uro, ##ana, ##tom, ##y, units, (, n, =, 181, ), face, -, to, -, face, teaching, (, non, -, digital, tool, ), to, examine, if, face, -, to, -, face, teaching, has, an, impact, on, student, performance, and, overall, satisfaction, with, the, course, ., two, groups, of, students, (, old, and, rest, ##ructured, unit, of, ne, ##uro, ##ana, ##tom, ##y, ), were, analyzed, ., a, question, ##naire, was, used, to, compare, them, in, terms, of, the, rate, they, gave, to, the, course, ,, satisfaction, ,, and, final, grades, ., (, between, -, subject, design, ), the, increase, in, total, face, -, to, -, face, teaching, hours, in, the, rest, ##ructured, unit, of, ne, ##uro, ##ana, ##tom, ##y, does, not, improve, student, grades, ., however, ,, it, does, increase, student, satisfaction, ., using, case, studies, as, a, semester, -, long, tool, to, teach, ne, ##uro, ##ana, ##tom, ##y, and, structure, -, function, relationships, to, undergraduate, ##s, ^, xiv, ##ken, ##ned, ##y, (, 2013, ), denis, ##on, un, ##iver, ,, usa, ##under, ##grad, ##uate, biology, and, psychology, students, (, n, =, 50, ), case, studies, (, non, -, digital, tool, ), to, investigate, the, effect, of, teaching, ne, ##uro, ##ana, ##tom, ##y, through, presentation, and, discussion, of, case, studies, ., students, were, expected, to, collaborate, with, their, colleges, in, small, groups, ., in, each, case, study, ,, the, entire, class, was, asked, to, participate, in, some, aspect, of, the, case, ., students, report, enjoying, learning, brain, structure, using, this, method, ,, and, commented, positively, on, the, class, activities, associated, with, learning, brain, anatomy, ., using, equivalence, -, based, instruction, to, increase, efficiency, in, teaching, ne, ##uro, ##ana, ##tom, ##y, ^, xv, ##py, ##tte, &, fi, ##en, ##up, (, 2012, ), queens, college, ,, usa, ##under, ##grad, ##uate, students, ,, primarily, of, psychology, majors, (, n, =, 93, ), equivalence, -, based, instruction, ,, e, ##bi, (, non, -, digital, tool, ), to, study, if, e, ##bi, is, effective, in, teaching, ne, ##uro, ##ana, ##tom, ##y, in, a, large, classroom, setting, ##fo, ##urt, ##een, brain, regions, were, identified, ,, and, conditional, relations, were, explicitly, taught, during, three, lectures, ., then, ,, students, completed, test, to, evaluate, some, relations, that, were, taught, and, some, not, taught, ., selection, of, associations, by, the, teacher, can, encourage, the, spontaneous, emergence, of, novel, associations, within, a, concept, or, category, ., therefore, ,, it, can, increase, the, efficiency, of, teaching, ., computer, -, based, learning, of, ne, ##uro, ##ana, ##tom, ##y, :, a, longitudinal, study, of, ll, ##ear, ##ning, ,, transfer, ,, and, retention, ^, xvi, ##cha, ##rik, ##er, et, al, ., (, 2011, ), university, of, louisville, ,, usa, ##under, ##grad, ##uate, students, who, reported, minimal, knowledge, of, ne, ##uro, ##ana, ##tom, ##y, (, n, =, 72, ), 3d, computer, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, determine, the, effectiveness, of, new, methods, for, teaching, ne, ##uro, ##ana, ##tom, ##y, with, computer, -, based, instruction, ##using, a, 3d, graphical, model, of, the, human, brain, ,, students, learned, either, sectional, anatomy, alone, (, with, per, ##ce, ##pt, ##ually, continuous, or, discrete, navigation, ), or, whole, anatomy, followed, by, sectional, anatomy, ., participants, were, tested, immediately, and, after, 2, –, 3, weeks, ., (, between, -, subject, design, ), results, showed, efficient, learning, ,, good, long, -, term, retention, ,, and, successful, transfer, to, the, interpretation, of, biomedical, images, ., they, suggest, that, computer, -, based, learning, can, be, a, valuable, teaching, tool, ., human, brains, engaged, in, rat, brains, :, student, -, driven, ne, ##uro, ##ana, ##tom, ##y, research, in, an, introductory, biology, lab, course, ^, xvi, ##iga, ##rd, ##ner, et, al, ., (, 2011, ), purdue, university, ,, usaf, ##irs, ##t, -, year, undergraduate, students, interested, in, major, ##ing, in, biology, (, n, =, 13, ), inquiry, -, based, laboratory, instruction, (, non, -, digital, tool, ), to, increase, student, interest, in, biology, by, exposing, them, to, novel, research, projects, ##st, ##ude, ##nts, acquired, basic, lab, skills, within, the, context, of, a, research, question, of, a, member, of, the, faculty, ., biology, students, who, were, not, taking, the, research, -, based, ,, bio, -, cas, ##pie, course, ,, formed, the, comparison, group, for, pre, -, and, post, -, semester, question, ##naire, ##s, ., (, mix, between, -, within, -, subject, design, ), the, inquiry, -, based, laboratory, instruction, increased, students, ’, motivation, and, excitement, ,, encouraged, good, scientific, practices, ,, and, can, potentially, benefit, departmental, research, ., the, study, techniques, of, asian, ,, american, ,, and, european, medical, students, during, gross, anatomy, and, ne, ##uro, ##ana, ##tom, ##y, courses, in, poland, ^, xvi, ##ii, ##zu, ##rada, et, al, ., (, 2011, ), medical, university, in, poland, ,, poland, ##int, ##ern, ##ation, ##al, medical, students, ,, from, the, polish, ,, american, ,, and, taiwanese, divisions, (, n, =, 70, ##5, ), –, to, investigate, similarities, and, differences, among, american, ,, asian, ,, and, european, medical, students, in, terms, of, their, study, methods, ., participants, completed, a, question, ##naire, in, which, they, reported, which, methods, they, used, to, study, ,, and, which, of, the, methods, they, believed, were, most, efficient, for, comprehension, ,, memo, ##rization, ,, and, review, ., (, between, -, subject, design, ), results, showed, some, differences, in, study, techniques, among, students, from, the, different, ethnic, back, -, grounds, (, e, ., g, ., ,, polish, and, american, preferred, the, use, of, di, ##sse, ##ctions, and, prose, ##cted, specimens, ), effectiveness, of, a, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, program, for, entry, -, level, physical, therapy, students, :, anatomy, and, clinical, examination, of, the, dorsal, column, -, medial, le, ##m, ##nis, ##cal, system, ^, xi, ##x, ##mc, ##ke, ##ough, ##et, al, ., (, 2010, ), california, state, university, &, university, of, the, pacific, ,, usa, ##under, ##grad, ##uate, physical, therapy, students, (, n, =, 61, ), computer, -, aided, instruction, ,, cai, (, digital, tool, ), to, determine, if, a, computer, -, aided, instruction, learning, module, improves, students, ’, ne, ##uro, ##ana, ##tom, ##y, knowledge, ##st, ##ude, ##nts, completed, a, paper, -, and, -, pencil, test, on, the, ne, ##uro, ##ana, ##tom, ##y, /, physiology, and, clinical, examination, of, the, dc, ##ml, system, ,, both, before, and, after, working, with, the, teaching, tool, (, within, -, subject, design, ), findings, showed, that, clinical, examination, post, -, test, scores, improved, significantly, from, the, pre, -, test, scores, ##a, novel, three, -, dimensional, tool, for, teaching, human, ne, ##uro, ##ana, ##tom, ##y, ^, xx, ##est, ##eve, ##z, et, al, ., (, 2010, ), boston, university, school, of, medicine, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 101, ), 3d, physical, ne, ##uro, ##ana, ##tom, ##y, model, (, digital, tool, ), to, develop, and, assess, a, new, tool, for, ##g, teaching, 3d, ne, ##uro, ##ana, ##tom, ##y, to, first, -, year, medical, students, ##fi, ##rst, ,, all, students, were, presented, to, traditional, 2d, methods, ., then, ,, the, experimental, group, constructed, 3d, color, -, coded, physical, models, ,, while, the, control, group, re, -, examined, 2d, brain, cross, -, sections, ., (, between, -, subject, design, ), 3d, computer, model, was, an, effective, method, for, teaching, spatial, relationships, of, brain, anatomy, and, seems, to, better, prepare, students, for, visual, ##ization, of, 3d, ne, ##uro, ##ana, ##tom, ##yat, ##ti, ##tu, ##des, of, health, care, students, about, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, instruction, ^, xx, ##im, ##cke, ##ough, &, bag, ##ate, ##ll, (, 2009, ), a, university, in, the, west, coast, ,, usa, ##master, ’, s, degree, health, care, professional, students, (, n, =, 77, ), computer, -, aided, instruction, ,, cai, (, digital, tool, ), to, examine, students, ’, attitudes, toward, cai, ,, which, factors, help, their, development, ,, and, their, implications, ., three, computer, -, aided, ne, ##uro, ##ana, ##tom, ##y, learning, modules, were, used, ., students, independently, reviewed, the, modules, as, supplements, to, lecture, and, completed, a, survey, to, evaluate, teaching, effectiveness, (, within, -, subject, design, ), the, cai, modules, examined, in, this, study, were, effective, as, adjunct, ##s, to, lecture, in, helping, the, students, learn, and, make, clinical, applications, of, ne, ##uro, ##ana, ##tom, ##y, information, ##a, usa, ##bility, study, of, users, ’, perceptions, toward, a, multimedia, computer, -, assisted, learning, tool, for, ne, ##uro, ##ana, ##tom, ##y, ^, xx, ##ii, ##go, ##uld, et, al, ., (, 2008, ), university, of, kentucky, &, university, of, louisville, &, nova, southeastern, university, ,, usaf, ##ac, ##ult, ##y, and, students, from, some, institutions, across, the, country, (, n, =, 62, ), computer, -, aided, instruction, ,, cai, (, digital, tool, ), to, assess, users, ’, perceptions, of, the, computer, -, based, tool, :, “, anatomy, of, the, central, nervous, system, :, a, multimedia, course, ”, first, ,, participants, used, the, multimedia, prototype, ., then, they, completed, a, usa, ##bility, question, ##naire, designed, to, measure, two, usa, ##bility, properties, :, program, need, and, program, app, ##lica, ##bility, ##thi, ##s, study, showed, that, the, cai, was, well, -, designed, for, all, users, ,, and, demonstrates, the, importance, of, integrating, quality, properties, of, usa, ##bility, with, principles, of, human, learning, ., attitudes, to, e, -, learning, ,, learning, style, and, achievement, in, learning, ne, ##uro, ##ana, ##tom, ##y, by, medical, students, ^, xx, ##iii, ##s, ##vir, ##ko, &, mel, ##lan, ##by, (, 2008, ), oxford, university, ,, uk, ##se, ##con, ##d, -, year, pre, -, clinical, undergraduate, medical, students, (, n, =, 205, ), computer, -, aided, learning, ,, cal, (, digital, tool, ), to, investigate, the, impact, of, an, online, course, on, encouraging, students, to, learn, and, their, academic, performance, ., the, students, approach, to, learning, towards, the, cal, course, and, towards, their, studies, in, general, was, compared, ., student, attitudes, and, ratings, were, also, assessed, ., findings, revealed, that, students, reported, using, significantly, less, deep, approach, to, learning, for, the, cal, course, ., using, truncated, lectures, ,, conceptual, exercises, ,, and, mani, ##pu, ##lative, ##s, to, improve, learning, in, the, ne, ##uro, ##ana, ##tom, ##y, classroom, ^, xx, ##iv, ##kr, ##ont, ##iri, ##s, -, lit, ##ow, ##itz, (, 2008, ), young, ##stown, state, university, ,, usa, ##under, ##grad, ##uate, biology, and, graduate, biology, and, physical, therapy, students, (, n, =, 19, ), truncated, lectures, ,, conceptual, exercises, ,, and, mani, ##pu, ##lative, ##s, (, non, -, digital, tool, ), to, use, truncated, lectures, ,, conceptual, exercises, ,, and, mani, ##pu, ##lative, ##s, to, make, learning, more, effective, and, increase, critical, thinking, ##the, curriculum, was, revised, ., more, specifically, ,, it, became, shorter, ,, included, practice, problems, that, presented, the, spinal, tracts, in, an, applied, context, ,, and, included, a, mani, ##pu, ##lative, ., student, ’, s, learning, was, then, assessed, and, compared, with, previous, classes, ., (, between, -, subject, design, ), ., students, ’, learning, was, more, effective, under, the, revised, curriculum, ,, suggesting, that, this, revised, curriculum, could, potentially, be, applied, to, other, topics, ., design, and, utility, of, a, web, -, based, computer, -, assisted, instructional, tool, for, ne, ##uro, ##ana, ##tom, ##y, self, -, study, and, review, for, physical, and, occupational, therapy, graduate, students, ^, xx, ##iv, ##for, ##eman, et, al, ., (, 2005, ), university, of, utah, ,, usa, ##under, ##grad, ##uate, physical, therapy, and, occupational, therapy, students, (, n, =, 43, ), computer, -, assisted, instruction, ,, cai, (, digital, tool, ), to, develop, a, cai, ,, and, assess, their, design, and, utility, to, teach, ne, ##uro, ##ana, ##tom, ##y, ., a, question, ##naire, addressed, navigation, ,, clarity, of, the, images, ,, benefit, of, the, cai, tool, ,, and, students, rating, ., students, were, also, asked, to, compare, this, tool, with, traditional, learning, tools, ., design, and, utility, of, a, web, -, based, computer, -, assisted, instructional, tool, for, ne, ##uro, ##ana, ##tom, ##y, self, -, study, and, review, for, physical, and, occupational, therapy, graduate, students, ^, xx, ##iva, ne, ##uro, ##ana, ##tom, ##y, teaching, activity, using, case, studies, and, collaboration, ^, xx, ##vish, ##eld, ##on, (, 2000, ), university, of, michigan, ,, usa, ##under, ##grad, ##uate, ##st, ##ude, ##nts, of, an, introductory, psychology, course, (, n, =, 28, ), case, studies, and, collaboration, (, non, -, digital, tool, ), to, evaluate, an, easier, and, less, time, -, consuming, method, for, teaching, ne, ##uro, ##ana, ##tom, ##y, ., students, collaborated, and, applied, their, ne, ##uro, ##ana, ##tom, ##y, knowledge, to, several, case, studies, during, classes, ., findings, showed, that, students, assessed, this, method, as, very, enjoyable, and, helpful, for, remembering, or, learning, the, material, ., computer, -, based, ne, ##uro, ##ana, ##tom, ##y, laboratory, for, medical, students, ^, xx, ##vi, ##ila, ##mp, ##ert, ##i, &, so, ##dic, ##off, (, 1997, ), temple, university, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 185, ), computer, -, based, ne, ##uro, ##ana, ##tom, ##y, laboratory, (, digital, tool, ), to, develop, a, computer, -, based, laboratory, program, to, substitute, the, traditional, glass, -, slide, laboratory, ##the, ##y, compared, the, performances, of, those, classes, that, previously, had, the, traditional, laboratory, with, two, succeeding, classes, that, used, computer, program, (, between, -, subject, design, ), ., test, scores, showed, that, the, students, ’, performance, on, laboratory, material, was, similar, in, both, classes, ., teaching, of, ne, ##uro, ##ana, ##tom, ##y, by, means, of, self, -, instructional, laboratory, stations, ^, xx, ##vi, ##ii, ##fish, ##er, et, al, ., (, 1980, ), university, of, michigan, medical, school, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 200, ), self, -, instructional, stations, (, non, -, digital, tool, ), to, teach, ne, ##uro, ##ana, ##tom, ##y, using, self, -, instructional, laboratory, stations, ##ne, ##uro, ##ana, ##tom, ##ical, laboratory, material, was, presented, in, a, series, of, six, self, -, instructional, stations, ., five, weeks, later, ,, short, examinations, tests, occurred, ., results, of, the, tests, indicated, a, mastery, of, station, material, as, defined, by, the, objectives, and, an, ability, to, use, the, material, in, applied, problems, ., cognitive, processes, in, learning, ne, ##uro, ##ana, ##tom, ##y, ^, xx, ##ix, ##gee, ##arts, ##ma, &, mat, ##z, ##ke, (, 1966, ), university, of, kansas, ,, usaf, ##irs, ##t, -, year, undergraduate, medical, students, (, n, =, 107, ), inter, ##pol, ##ation, of, questions, (, non, -, digital, tool, ), to, investigate, the, effect, of, inter, ##pol, ##ation, of, questions, into, a, lecture, presentation, ., participants, were, divided, into, 2, matched, groups, ., each, group, was, shown, lectures, on, the, visual, system, which, differed, only, in, regard, to, tax, ##omic, level, of, 10, questions, posed, lecture, ., performance, was, then, measured, (, between, -, subject, design, ), ., emphasis, on, recall, questions, aids, performance, on, subsequent, recall, questions, more, than, emphasis, on, problem, -, solving, questions, helps, in, the, solution, of, subsequent, problem, -, solving, questions, .'},\n", - " {'article_id': '300a4d420106d0d9ca46d886abf7ae4a',\n", - " 'section_name': 'MEMRI can detect canonical and novel sexual dimorphisms',\n", - " 'text': 'To compare structure volumes between sexes, an atlas that segments 182 structures in the adult mouse brain^25 was overlaid onto the p65 consensus average brain. Figure 3a (i, ii) shows segmentations of the MeA, BNST, and MPON, which are canonical sexually dimorphic areas. Extensive literature has shown that these areas are larger in the male brain. MEMRI captures these sexual dimorphisms (top-panels, Fig. 3b–d) and shows that these dimorphisms emerge between p10 and p17. Males tend to have bigger brains than females^18; as MEMRI allows for whole-brain imaging, we were also able to identify dimorphisms in brain structure relative volumes—that is, subjects’ structure volumes divided by their whole-brain volume. Similar to absolute volumes, males had larger relative volumes of BNST, MeA, and MPON. However, relative volumetric sex differences emerged earlier than the absolute volume differences, around p5. Moreover, several structures, such as the periaqueductal gray (PAG) (Fig. 3e), exhibited no sex-dependent growth differences in absolute volumes, but did exhibit significant differences in relative volumes. Compared with male-enlarged structures, the PAG became relatively larger in females at a later developmental time, around p29 (summary structure data in Table 1 and Supplementary table 1). Correction for whole-brain size using relative volume measurements from MEMRI data reveal time courses of well-established and novel sexual dimorphisms, highlighting the strength of whole-brain MRI.Fig. 3MEMRI captures sex differences in brain structure sizes. a Sagittal and coronal slices of the average p65 brain showing segmentations of mouse brain structures: bed nucleus of the stria terminalis (BNST), medial preoptic nucleus (MPON), medial nucleus of the amygdala (MeA), and periaqueductal gray (PAG). b–e the absolute and relative volumes of these structures over time. Points in these plots represent measurement at a time point for individual mice and lines connect the measurements for the same mouse over time. Shaded regions represent standard error estimated using linear mixed-effects models. Relative volume corrects for whole-brain size differences between subjects and is expressed as a percent difference from the average volume of the brain structure. Using linear mixed-effects models, we recapitulate known canonical sex differences in absolute volumes of the MeA (, P<10^−10), BNST (, P<10^−12), and MPON (, P<10^−3). Sex differences in these structures emerge pre-puberty, at around p10. Using relative volumes to correct for whole brain size, we see that sex differences in these structures are preserved but differences emerge earlier in development around p5. PAG relative volume also shows a significant effect of interaction between sex and age (, P<10^−2), which is not found in the absolute volumes (, P = 0.2). Taken together, these results indicate that relative volumes obtained by MEMRI are a sensitive marker for detecting canonical and novel sexual dimorphisms in neuroanatomyTable 1Mean volume of sexually dimorphic structures in males and femalesBed nucleus of the stria terminalisMedial preoptic nucleusMedial amygdalaPeriaqueductal grayAgeMFMFMFMFAbsolute volume (mm^3)30.5890.5830.08560.08440.5060.4902.6302.58050.7190.7240.1030.1020.5730.5782.9502.98070.8570.8500.1170.1150.6600.6533.3103.310101.0601.0100.1520.1470.8000.7643.9603.860171.1601.1100.1840.1780.9730.9334.0703.990231.1101.0600.1490.1460.9760.9383.8203.770291.1001.0500.1500.1460.9660.9173.7403.670361.1301.0600.1580.1521.0000.9303.7603.690651.2001.1200.1680.1581.0600.9834.0103.970Relative volume (% Brain)30.28100.28500.03940.04000.24200.24100.97400.984050.28000.27500.03970.03820.24400.24000.98300.970070.28100.27400.04000.03890.24500.23800.97500.9580100.27800.27100.03960.03900.24400.23600.95900.9510170.27600.26500.03990.03880.24400.23500.97000.9580230.27400.26300.03930.03860.24500.23500.96200.9490290.27000.26200.03830.03780.24300.23500.95800.9560360.26900.26300.03800.03800.24300.23400.94000.9590650.27700.26400.03860.03730.24300.23100.92400.9340',\n", - " 'paragraph_id': 11,\n", - " 'tokenizer': 'to, compare, structure, volumes, between, sexes, ,, an, atlas, that, segments, 182, structures, in, the, adult, mouse, brain, ^, 25, was, over, ##laid, onto, the, p, ##65, consensus, average, brain, ., figure, 3a, (, i, ,, ii, ), shows, segment, ##ations, of, the, me, ##a, ,, bn, ##st, ,, and, mp, ##on, ,, which, are, canonical, sexually, dim, ##or, ##phic, areas, ., extensive, literature, has, shown, that, these, areas, are, larger, in, the, male, brain, ., me, ##m, ##ri, captures, these, sexual, dim, ##or, ##phi, ##sms, (, top, -, panels, ,, fig, ., 3, ##b, –, d, ), and, shows, that, these, dim, ##or, ##phi, ##sms, emerge, between, p, ##10, and, p, ##17, ., males, tend, to, have, bigger, brains, than, females, ^, 18, ;, as, me, ##m, ##ri, allows, for, whole, -, brain, imaging, ,, we, were, also, able, to, identify, dim, ##or, ##phi, ##sms, in, brain, structure, relative, volumes, —, that, is, ,, subjects, ’, structure, volumes, divided, by, their, whole, -, brain, volume, ., similar, to, absolute, volumes, ,, males, had, larger, relative, volumes, of, bn, ##st, ,, me, ##a, ,, and, mp, ##on, ., however, ,, relative, volume, ##tric, sex, differences, emerged, earlier, than, the, absolute, volume, differences, ,, around, p, ##5, ., moreover, ,, several, structures, ,, such, as, the, per, ##ia, ##que, ##du, ##cta, ##l, gray, (, pa, ##g, ), (, fig, ., 3, ##e, ), ,, exhibited, no, sex, -, dependent, growth, differences, in, absolute, volumes, ,, but, did, exhibit, significant, differences, in, relative, volumes, ., compared, with, male, -, enlarged, structures, ,, the, pa, ##g, became, relatively, larger, in, females, at, a, later, developmental, time, ,, around, p, ##29, (, summary, structure, data, in, table, 1, and, supplementary, table, 1, ), ., correction, for, whole, -, brain, size, using, relative, volume, measurements, from, me, ##m, ##ri, data, reveal, time, courses, of, well, -, established, and, novel, sexual, dim, ##or, ##phi, ##sms, ,, highlighting, the, strength, of, whole, -, brain, mri, ., fig, ., 3, ##me, ##m, ##ri, captures, sex, differences, in, brain, structure, sizes, ., a, sa, ##git, ##tal, and, corona, ##l, slices, of, the, average, p, ##65, brain, showing, segment, ##ations, of, mouse, brain, structures, :, bed, nucleus, of, the, st, ##ria, terminal, ##is, (, bn, ##st, ), ,, medial, pre, ##op, ##tic, nucleus, (, mp, ##on, ), ,, medial, nucleus, of, the, amy, ##g, ##dal, ##a, (, me, ##a, ), ,, and, per, ##ia, ##que, ##du, ##cta, ##l, gray, (, pa, ##g, ), ., b, –, e, the, absolute, and, relative, volumes, of, these, structures, over, time, ., points, in, these, plots, represent, measurement, at, a, time, point, for, individual, mice, and, lines, connect, the, measurements, for, the, same, mouse, over, time, ., shaded, regions, represent, standard, error, estimated, using, linear, mixed, -, effects, models, ., relative, volume, correct, ##s, for, whole, -, brain, size, differences, between, subjects, and, is, expressed, as, a, percent, difference, from, the, average, volume, of, the, brain, structure, ., using, linear, mixed, -, effects, models, ,, we, rec, ##ap, ##it, ##ulate, known, canonical, sex, differences, in, absolute, volumes, of, the, me, ##a, (, ,, p, <, 10, ^, −, ##10, ), ,, bn, ##st, (, ,, p, <, 10, ^, −, ##12, ), ,, and, mp, ##on, (, ,, p, <, 10, ^, −, ##3, ), ., sex, differences, in, these, structures, emerge, pre, -, pub, ##erty, ,, at, around, p, ##10, ., using, relative, volumes, to, correct, for, whole, brain, size, ,, we, see, that, sex, differences, in, these, structures, are, preserved, but, differences, emerge, earlier, in, development, around, p, ##5, ., pa, ##g, relative, volume, also, shows, a, significant, effect, of, interaction, between, sex, and, age, (, ,, p, <, 10, ^, −, ##2, ), ,, which, is, not, found, in, the, absolute, volumes, (, ,, p, =, 0, ., 2, ), ., taken, together, ,, these, results, indicate, that, relative, volumes, obtained, by, me, ##m, ##ri, are, a, sensitive, marker, for, detecting, canonical, and, novel, sexual, dim, ##or, ##phi, ##sms, in, ne, ##uro, ##ana, ##tom, ##yt, ##able, 1, ##me, ##an, volume, of, sexually, dim, ##or, ##phic, structures, in, males, and, females, ##bed, nucleus, of, the, st, ##ria, terminal, ##ism, ##ed, ##ial, pre, ##op, ##tic, nucleus, ##media, ##l, amy, ##g, ##dal, ##ape, ##ria, ##que, ##du, ##cta, ##l, gray, ##age, ##m, ##fm, ##fm, ##fm, ##fa, ##bs, ##ol, ##ute, volume, (, mm, ^, 3, ), 30, ., 58, ##90, ., 58, ##30, ., 08, ##56, ##0, ., 08, ##44, ##0, ., 50, ##60, ., 490, ##2, ., 630, ##2, ., 580, ##50, ., 71, ##90, ., 72, ##40, ., 103, ##0, ., 102, ##0, ., 57, ##30, ., 57, ##8, ##2, ., 950, ##2, ., 980, ##70, ., 85, ##70, ., 850, ##0, ., 117, ##0, ., 115, ##0, ., 660, ##0, ., 65, ##33, ., 310, ##3, ., 310, ##10, ##1, ., 06, ##01, ., 01, ##00, ., 152, ##0, ., 147, ##0, ., 800, ##0, ., 76, ##43, ., 960, ##3, ., 86, ##01, ##7, ##1, ., 160, ##1, ., 1100, ., 1840, ., 1780, ., 97, ##30, ., 93, ##34, ., 07, ##0, ##3, ., 99, ##0, ##23, ##1, ., 110, ##1, ., 06, ##00, ., 149, ##0, ., 146, ##0, ., 97, ##60, ., 93, ##8, ##3, ., 820, ##3, ., 770, ##29, ##1, ., 100, ##1, ., 050, ##0, ., 1500, ., 146, ##0, ., 96, ##60, ., 91, ##7, ##3, ., 740, ##3, ., 670, ##36, ##1, ., 130, ##1, ., 06, ##00, ., 1580, ., 152, ##1, ., 000, ##0, ., 930, ##3, ., 760, ##3, ., 690, ##65, ##1, ., 2001, ., 1200, ., 1680, ., 158, ##1, ., 06, ##00, ., 98, ##34, ., 01, ##0, ##3, ., 97, ##0, ##rel, ##ative, volume, (, %, brain, ), 30, ., 281, ##00, ., 285, ##00, ., 03, ##9, ##40, ., 04, ##00, ##0, ., 242, ##00, ., 241, ##00, ., 97, ##400, ., 98, ##40, ##50, ., 280, ##00, ., 275, ##00, ., 03, ##9, ##70, ., 03, ##8, ##20, ., 244, ##00, ., 240, ##00, ., 98, ##30, ##0, ., 97, ##00, ##70, ., 281, ##00, ., 274, ##00, ., 04, ##00, ##0, ., 03, ##8, ##90, ., 245, ##00, ., 238, ##00, ., 97, ##500, ., 95, ##80, ##100, ., 278, ##00, ., 271, ##00, ., 03, ##9, ##60, ., 03, ##90, ##0, ., 244, ##00, ., 236, ##00, ., 95, ##90, ##0, ., 95, ##10, ##17, ##0, ., 276, ##00, ., 265, ##00, ., 03, ##9, ##90, ., 03, ##8, ##80, ., 244, ##00, ., 235, ##00, ., 97, ##00, ##0, ., 95, ##80, ##23, ##0, ., 274, ##00, ., 263, ##00, ., 03, ##9, ##30, ., 03, ##86, ##0, ., 245, ##00, ., 235, ##00, ., 96, ##200, ., 94, ##90, ##29, ##0, ., 270, ##00, ., 262, ##00, ., 03, ##8, ##30, ., 03, ##7, ##80, ., 243, ##00, ., 235, ##00, ., 95, ##80, ##0, ., 95, ##60, ##36, ##0, ., 269, ##00, ., 263, ##00, ., 03, ##80, ##0, ., 03, ##80, ##0, ., 243, ##00, ., 234, ##00, ., 94, ##00, ##0, ., 95, ##90, ##65, ##0, ., 277, ##00, ., 264, ##00, ., 03, ##86, ##0, ., 03, ##7, ##30, ., 243, ##00, ., 231, ##00, ., 92, ##400, ., 93, ##40'},\n", - " {'article_id': 'b083da95424dc116271fbbff7680bc97',\n", - " 'section_name': 'Case report of 103 year old female',\n", - " 'text': 'Case 100069 was a female centenarian with a fit physique included in the 100-plus Study at the age of 102. She finished the first stage of tertiary education, and had enjoyed a total of 18 years of education (ISCED level 5). At baseline she scored 27 points on the MMSE and 3/5 points on the CDT. She volunteered to undergo an MRI and PIB-PET scan 1 month after inclusion into the study. The MRI scan revealed moderate hippocampal atrophy (MTA score 2), white matter abnormalities (Fazekas score II), and few microbleeds. The PET scan using [^11C]PiB as an amyloid tracer was positive throughout the brain, with the highest signal in the frontal area (Fig. 4). The centenarian died 10 months after inclusion of cachexia. Proxies reported maintained cognitive health until the terminal phase. Brain autopsy was performed with a post mortem delay of 8.5 h. Overall, no major abnormalities were observed at the macroscopic level. Mild atrophy of the temporal lobe was observed and arteries were mildly atherosclerotic. Two small meningeomas were observed in the left part of the scull, as well as a small (0.6 cm) old cortical infarct in the medial frontal gyrus. The substantia nigra appeared relatively pale. Neuropathological evaluation revealed intermediate AD neuropathologic changes (A3B2C1). Consistent with the positive amyloid PET scan in vivo, we observed Aβ pathology in the form of classical and diffuse plaques (Thal stage Aβ 4), as well as capillary CAA-type 1 (capCAA) (Thal stage CAA 2) (Fig. 5 panel d-f) during the post-mortem neuropathological analysis. Diffuse Aβ deposits were detected in the frontal, frontobasal, occipital, temporal and parietal cortex, the molecular layer, CA1 and subiculum of the hippocampus, as well as the caudate nucleus, putamen and nucleus accumbens. A relatively low number of classic senile plaques with a dense core was observed throughout the neocortex. Prominent presence of CAA was observed in the parietal cortex and the leptomeninges. Capillary CAA (type 1) was observed in moderate levels in the frontal cortex (Fig. 5, panel f), the cerebellum, sporadically in the occipital cortex, and was absent in the temporal cortex. Together, the relatively high levels of CAA might explain the high signal of the [^11C]PiB-PET, as CAA is also known to be detected by this tracer (Farid et al., 2017 [15]), as well as the abnormalities observed on the MRI.Fig. 4Dynamic [^11C]PiB-PET and MRI scan of case 100069. The scan was performed by the ECAT EXACT HR1 scanner (Siemens/CTI) 1 month after study inclusion. PET scan for amyloid is positive in the frontal area, MRI shows moderate hippocampal atrophy (MTA score 2) as well as vascular lesions in the white matter (Fazekas score II), suggesting amyloid angiopathyFig. 5Representative neuropathological lesions found in the hippocampus (a, d, g, j), middle temporal lobe cortex (b, e, h, i, k), amygdala (c) and frontal lobe cortex (f) of case 100069. Shown are exemplary pTDP-43 accumulations (a-c) in the hippocampal subregion CA1 (a1) and dentate gyrus (DG) (a2), temporal pole cortex (T) (b) and Amygdala (Amy) (c), Aβ positivity (d-f) in the form of diffuse and classical plaques in the hippocampal CA1 region (d) and temporal pole cortex (e), as well as CAA of large vessels and capillaries in the frontal lobe (F2) (f). pTau immuno-staining (g-i) is shown as (pre)tangles and neuritic plaque like structures in the hippocampal CA1 region (g) and temporal pole cortex (h1 and h2), as well as astroglial pTau in ARTAG in the temporal pole cortex (i1 and i2). GVD (CK1δ granules) (j-k) is shown in the hippocampus (j) and temporal pole cortex (k). Scale bar 25 μm',\n", - " 'paragraph_id': 24,\n", - " 'tokenizer': 'case, 1000, ##6, ##9, was, a, female, cent, ##ena, ##rian, with, a, fit, ph, ##ys, ##ique, included, in, the, 100, -, plus, study, at, the, age, of, 102, ., she, finished, the, first, stage, of, tertiary, education, ,, and, had, enjoyed, a, total, of, 18, years, of, education, (, is, ##ced, level, 5, ), ., at, baseline, she, scored, 27, points, on, the, mm, ##se, and, 3, /, 5, points, on, the, cd, ##t, ., she, volunteered, to, undergo, an, mri, and, pi, ##b, -, pet, scan, 1, month, after, inclusion, into, the, study, ., the, mri, scan, revealed, moderate, hip, ##po, ##camp, ##al, at, ##rop, ##hy, (, mt, ##a, score, 2, ), ,, white, matter, abnormalities, (, fa, ##zek, ##as, score, ii, ), ,, and, few, micro, ##ble, ##ed, ##s, ., the, pet, scan, using, [, ^, 11, ##c, ], pi, ##b, as, an, amy, ##loid, trace, ##r, was, positive, throughout, the, brain, ,, with, the, highest, signal, in, the, frontal, area, (, fig, ., 4, ), ., the, cent, ##ena, ##rian, died, 10, months, after, inclusion, of, cache, ##xia, ., pro, ##xie, ##s, reported, maintained, cognitive, health, until, the, terminal, phase, ., brain, autopsy, was, performed, with, a, post, mort, ##em, delay, of, 8, ., 5, h, ., overall, ,, no, major, abnormalities, were, observed, at, the, macro, ##scopic, level, ., mild, at, ##rop, ##hy, of, the, temporal, lobe, was, observed, and, arteries, were, mildly, at, ##her, ##os, ##cle, ##rot, ##ic, ., two, small, men, ##inge, ##oma, ##s, were, observed, in, the, left, part, of, the, sc, ##ull, ,, as, well, as, a, small, (, 0, ., 6, cm, ), old, co, ##rti, ##cal, in, ##far, ##ct, in, the, medial, frontal, g, ##yr, ##us, ., the, sub, ##stan, ##tia, ni, ##gra, appeared, relatively, pale, ., ne, ##uro, ##path, ##ological, evaluation, revealed, intermediate, ad, ne, ##uro, ##path, ##olo, ##gic, changes, (, a, ##3, ##b, ##2, ##c, ##1, ), ., consistent, with, the, positive, amy, ##loid, pet, scan, in, vivo, ,, we, observed, a, ##β, pathology, in, the, form, of, classical, and, diffuse, plaques, (, tha, ##l, stage, a, ##β, 4, ), ,, as, well, as, cap, ##illa, ##ry, ca, ##a, -, type, 1, (, cap, ##ca, ##a, ), (, tha, ##l, stage, ca, ##a, 2, ), (, fig, ., 5, panel, d, -, f, ), during, the, post, -, mort, ##em, ne, ##uro, ##path, ##ological, analysis, ., diffuse, a, ##β, deposits, were, detected, in, the, frontal, ,, front, ##ob, ##asa, ##l, ,, o, ##cci, ##pit, ##al, ,, temporal, and, par, ##ie, ##tal, cortex, ,, the, molecular, layer, ,, ca, ##1, and, sub, ##ic, ##ulum, of, the, hip, ##po, ##camp, ##us, ,, as, well, as, the, ca, ##uda, ##te, nucleus, ,, put, ##amen, and, nucleus, acc, ##umb, ##ens, ., a, relatively, low, number, of, classic, sen, ##ile, plaques, with, a, dense, core, was, observed, throughout, the, neo, ##cor, ##te, ##x, ., prominent, presence, of, ca, ##a, was, observed, in, the, par, ##ie, ##tal, cortex, and, the, le, ##pt, ##ome, ##ning, ##es, ., cap, ##illa, ##ry, ca, ##a, (, type, 1, ), was, observed, in, moderate, levels, in, the, frontal, cortex, (, fig, ., 5, ,, panel, f, ), ,, the, ce, ##re, ##bell, ##um, ,, sporadic, ##ally, in, the, o, ##cci, ##pit, ##al, cortex, ,, and, was, absent, in, the, temporal, cortex, ., together, ,, the, relatively, high, levels, of, ca, ##a, might, explain, the, high, signal, of, the, [, ^, 11, ##c, ], pi, ##b, -, pet, ,, as, ca, ##a, is, also, known, to, be, detected, by, this, trace, ##r, (, far, ##id, et, al, ., ,, 2017, [, 15, ], ), ,, as, well, as, the, abnormalities, observed, on, the, mri, ., fig, ., 4, ##dy, ##nami, ##c, [, ^, 11, ##c, ], pi, ##b, -, pet, and, mri, scan, of, case, 1000, ##6, ##9, ., the, scan, was, performed, by, the, ec, ##at, exact, hr, ##1, scanner, (, siemens, /, ct, ##i, ), 1, month, after, study, inclusion, ., pet, scan, for, amy, ##loid, is, positive, in, the, frontal, area, ,, mri, shows, moderate, hip, ##po, ##camp, ##al, at, ##rop, ##hy, (, mt, ##a, score, 2, ), as, well, as, vascular, lesions, in, the, white, matter, (, fa, ##zek, ##as, score, ii, ), ,, suggesting, amy, ##loid, ang, ##io, ##pathy, ##fi, ##g, ., 5, ##re, ##pres, ##ent, ##ative, ne, ##uro, ##path, ##ological, lesions, found, in, the, hip, ##po, ##camp, ##us, (, a, ,, d, ,, g, ,, j, ), ,, middle, temporal, lobe, cortex, (, b, ,, e, ,, h, ,, i, ,, k, ), ,, amy, ##g, ##dal, ##a, (, c, ), and, frontal, lobe, cortex, (, f, ), of, case, 1000, ##6, ##9, ., shown, are, exemplary, pt, ##dp, -, 43, accumulation, ##s, (, a, -, c, ), in, the, hip, ##po, ##camp, ##al, sub, ##region, ca, ##1, (, a1, ), and, dent, ##ate, g, ##yr, ##us, (, d, ##g, ), (, a2, ), ,, temporal, pole, cortex, (, t, ), (, b, ), and, amy, ##g, ##dal, ##a, (, amy, ), (, c, ), ,, a, ##β, po, ##sit, ##ivity, (, d, -, f, ), in, the, form, of, diffuse, and, classical, plaques, in, the, hip, ##po, ##camp, ##al, ca, ##1, region, (, d, ), and, temporal, pole, cortex, (, e, ), ,, as, well, as, ca, ##a, of, large, vessels, and, cap, ##illa, ##ries, in, the, frontal, lobe, (, f, ##2, ), (, f, ), ., pt, ##au, im, ##mun, ##o, -, stain, ##ing, (, g, -, i, ), is, shown, as, (, pre, ), tangle, ##s, and, ne, ##uri, ##tic, plaque, like, structures, in, the, hip, ##po, ##camp, ##al, ca, ##1, region, (, g, ), and, temporal, pole, cortex, (, h, ##1, and, h, ##2, ), ,, as, well, as, astro, ##glia, ##l, pt, ##au, in, art, ##ag, in, the, temporal, pole, cortex, (, i, ##1, and, i, ##2, ), ., g, ##vd, (, ck, ##1, ##δ, gran, ##ules, ), (, j, -, k, ), is, shown, in, the, hip, ##po, ##camp, ##us, (, j, ), and, temporal, pole, cortex, (, k, ), ., scale, bar, 25, μ, ##m'},\n", - " {'article_id': '88fab0c4347e89402bfac9036ffbcc7e',\n", - " 'section_name': 'DUSP1/MKP-1 in innate and adaptive immunity',\n", - " 'text': 'Given the wide range of roles that MAPKs perform in the development and function of cells of the immune system [[22], [23], [24]] it was perhaps no surprise that amongst the first phenotypes detected in DUSP1^−/− mice was a failure to regulate stress-activated JNK and p38 signalling in macrophages and dendritic cells (Fig. 2: Table 2). These cells are key mediators of the innate immune response in which the p38 and JNK MAPKs lie downstream of the toll-like receptors (TLRs), which are activated by a wide variety of pathogen-derived stimuli and act to regulate the expression of both pro and anti-inflammatory cytokines and chemokines [22]. Several groups demonstrated that loss of DUSP1/MKP-1 led to elevated JNK and p38 activities in macrophages exposed to the bacterial endotoxin lipopolysaccharide (LPS) [[25], [26], [27], [28]]. This led to an initial increase in the expression of pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFα), interleukin-6 (IL-6), interleukin-12 (IL-12) and interferon-gamma (IFN-γ) while, at later times, levels of the anti-inflammatory mediator interleukin-10 (IL-10) were increased [25]. These cellular effects were accompanied by pathological changes such as inflammatory tissue infiltration, hypotension and multiple organ failure, all of which are markers of the severe septic shock and increased mortality observed in LPS-injected DUSP1^−/− mice when compared to wild type controls.Fig. 2DUSP1/MKP-1 in innate immunity. Schematic showing the regulation of MAP kinase activities in cells of the innate immune system by DUSP1/MKP-1 and the consequences of genetic deletion of this MKP on the physiological responses of these cell populations. For details see text.Fig. 2Table 2Immunological phenotypes of MKP KO mice.Table 2GroupGene/MKPImmunological phenotypes of MKP KO miceReferencesNuclear, inducible MKPsDUSP1/MKP-1Increased pro-inflammatory cytokine production & innate immune response LPS challenge.[25]Impaired resolution of inflammation.[30]Decreased adaptive immune response & viral clearance.[33]Protection from autoimmune encephalitis (EAE).[33]Increased sensitivity to bacterial infections.[35]Exacerbates inflammatory phenotypes including: colitis, anaphylaxis and psoriasis.[[40], [41], [42]]DUSP2Protection from experimentally-induced arthritis.[86]Decreased macrophage cytokine expression & mast cell survival.[86]Increased susceptibility to DSS-induced model of intestinal inflammation.[87]Altered T-cell balance, via the promotion of Th17 differentiation and inhibition of Treg generation.[87]DUSP4/MKP-2Increased susceptibility to Leishmania mexicana, Leishmania donovani & Toxoplasma gondii infection.[[97], [98], [99]]Resistant to LPS-induced endotoxic shock.[100]Increased CD4+ T-cell proliferation.[101]Protection from autoimmune encephalitis (EAE).[102]DUSP5Negatively regulates Il-33 mediated eosinophil survival.[119]Resistant to helminth infection, due to enhanced eosinophil activity.[119]Regulates CD8+ populations in response to LCMV infection.[120]Cytoplasmic ERK-selective MKPsDUSP6/MKP-3Exacerbates intestinal colitis.[150]Decreased CD4+ T-cell proliferation, altered T-cell polarisation & impaired Treg function.[150]DUSP7/MKP-XN/ADUSP9/MKP-4N/AJNK/p38-selective MKPsDUSP8N/ADUSP10/MKP-5Impaired T cell expansion, but enhanced priming of T-cells by APCs.[185]Protection from autoimmune encephalitis (EAE).[185]Increased cytokine and ROS production in macrophages, neutrophils and T cells.[187]Protection from DSS-induced intestinal inflammation.[191]DUSP16/MKP-7Impaired GM-CSF-driven proliferation of bone marrow progenitors.[195]Increased CD4+ T-cell proliferation & a reduced Th17 cell population.[196]Protection from autoimmune encephalitis (EAE).[196]LCMV, lymphocytic choriomeningitis virus. DSS, dextran sodium sulfate.',\n", - " 'paragraph_id': 7,\n", - " 'tokenizer': 'given, the, wide, range, of, roles, that, map, ##ks, perform, in, the, development, and, function, of, cells, of, the, immune, system, [, [, 22, ], ,, [, 23, ], ,, [, 24, ], ], it, was, perhaps, no, surprise, that, amongst, the, first, ph, ##eno, ##type, ##s, detected, in, du, ##sp, ##1, ^, −, /, −, mice, was, a, failure, to, regulate, stress, -, activated, j, ##nk, and, p, ##38, signalling, in, macro, ##pha, ##ges, and, den, ##dr, ##itic, cells, (, fig, ., 2, :, table, 2, ), ., these, cells, are, key, media, ##tors, of, the, innate, immune, response, in, which, the, p, ##38, and, j, ##nk, map, ##ks, lie, downstream, of, the, toll, -, like, receptors, (, t, ##lr, ##s, ), ,, which, are, activated, by, a, wide, variety, of, pathogen, -, derived, stimuli, and, act, to, regulate, the, expression, of, both, pro, and, anti, -, inflammatory, cy, ##tok, ##ines, and, che, ##mo, ##kin, ##es, [, 22, ], ., several, groups, demonstrated, that, loss, of, du, ##sp, ##1, /, mk, ##p, -, 1, led, to, elevated, j, ##nk, and, p, ##38, activities, in, macro, ##pha, ##ges, exposed, to, the, bacterial, end, ##oto, ##xin, lip, ##op, ##ol, ##ys, ##ac, ##cha, ##ride, (, lp, ##s, ), [, [, 25, ], ,, [, 26, ], ,, [, 27, ], ,, [, 28, ], ], ., this, led, to, an, initial, increase, in, the, expression, of, pro, -, inflammatory, cy, ##tok, ##ines, such, as, tu, ##mour, nec, ##rosis, factor, alpha, (, tn, ##f, ##α, ), ,, inter, ##le, ##uki, ##n, -, 6, (, il, -, 6, ), ,, inter, ##le, ##uki, ##n, -, 12, (, il, -, 12, ), and, inter, ##fer, ##on, -, gamma, (, if, ##n, -, γ, ), while, ,, at, later, times, ,, levels, of, the, anti, -, inflammatory, media, ##tor, inter, ##le, ##uki, ##n, -, 10, (, il, -, 10, ), were, increased, [, 25, ], ., these, cellular, effects, were, accompanied, by, path, ##ological, changes, such, as, inflammatory, tissue, in, ##filtration, ,, h, ##yp, ##ote, ##ns, ##ion, and, multiple, organ, failure, ,, all, of, which, are, markers, of, the, severe, sept, ##ic, shock, and, increased, mortality, observed, in, lp, ##s, -, injected, du, ##sp, ##1, ^, −, /, −, mice, when, compared, to, wild, type, controls, ., fig, ., 2d, ##us, ##p, ##1, /, mk, ##p, -, 1, in, innate, immunity, ., sc, ##hema, ##tic, showing, the, regulation, of, map, kinase, activities, in, cells, of, the, innate, immune, system, by, du, ##sp, ##1, /, mk, ##p, -, 1, and, the, consequences, of, genetic, del, ##eti, ##on, of, this, mk, ##p, on, the, physiological, responses, of, these, cell, populations, ., for, details, see, text, ., fig, ., 2, ##table, 2, ##im, ##mun, ##ological, ph, ##eno, ##type, ##s, of, mk, ##p, ko, mice, ., table, 2, ##group, ##gen, ##e, /, mk, ##pi, ##mm, ##uno, ##logical, ph, ##eno, ##type, ##s, of, mk, ##p, ko, mice, ##re, ##ference, ##s, ##nu, ##cle, ##ar, ,, ind, ##ucible, mk, ##ps, ##dus, ##p, ##1, /, mk, ##p, -, 1, ##in, ##cre, ##ase, ##d, pro, -, inflammatory, cy, ##tok, ##ine, production, &, innate, immune, response, lp, ##s, challenge, ., [, 25, ], impaired, resolution, of, inflammation, ., [, 30, ], decreased, adaptive, immune, response, &, viral, clearance, ., [, 33, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 33, ], increased, sensitivity, to, bacterial, infections, ., [, 35, ], ex, ##ace, ##rba, ##tes, inflammatory, ph, ##eno, ##type, ##s, including, :, coli, ##tis, ,, ana, ##phy, ##la, ##xi, ##s, and, ps, ##oria, ##sis, ., [, [, 40, ], ,, [, 41, ], ,, [, 42, ], ], du, ##sp, ##2, ##pro, ##tec, ##tion, from, experimental, ##ly, -, induced, arthritis, ., [, 86, ], decreased, macro, ##pha, ##ge, cy, ##tok, ##ine, expression, &, mast, cell, survival, ., [, 86, ], increased, su, ##sc, ##ept, ##ibility, to, ds, ##s, -, induced, model, of, int, ##estinal, inflammation, ., [, 87, ], altered, t, -, cell, balance, ,, via, the, promotion, of, th, ##17, differentiation, and, inhibition, of, tre, ##g, generation, ., [, 87, ], du, ##sp, ##4, /, mk, ##p, -, 2, ##in, ##cre, ##ase, ##d, su, ##sc, ##ept, ##ibility, to, lei, ##sh, ##mania, mexican, ##a, ,, lei, ##sh, ##mania, donovan, ##i, &, to, ##x, ##op, ##las, ##ma, go, ##ndi, ##i, infection, ., [, [, 97, ], ,, [, 98, ], ,, [, 99, ], ], resistant, to, lp, ##s, -, induced, end, ##oto, ##xi, ##c, shock, ., [, 100, ], increased, cd, ##4, +, t, -, cell, proliferation, ., [, 101, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 102, ], du, ##sp, ##5, ##ne, ##gative, ##ly, regulates, il, -, 33, mediated, e, ##osi, ##no, ##phi, ##l, survival, ., [, 119, ], resistant, to, helm, ##int, ##h, infection, ,, due, to, enhanced, e, ##osi, ##no, ##phi, ##l, activity, ., [, 119, ], regulates, cd, ##8, +, populations, in, response, to, lc, ##m, ##v, infection, ., [, 120, ], cy, ##top, ##las, ##mic, er, ##k, -, selective, mk, ##ps, ##dus, ##p, ##6, /, mk, ##p, -, 3, ##ex, ##ace, ##rba, ##tes, int, ##estinal, coli, ##tis, ., [, 150, ], decreased, cd, ##4, +, t, -, cell, proliferation, ,, altered, t, -, cell, polar, ##isation, &, impaired, tre, ##g, function, ., [, 150, ], du, ##sp, ##7, /, mk, ##p, -, x, ##n, /, ad, ##us, ##p, ##9, /, mk, ##p, -, 4, ##n, /, aj, ##nk, /, p, ##38, -, selective, mk, ##ps, ##dus, ##p, ##8, ##n, /, ad, ##us, ##p, ##10, /, mk, ##p, -, 5, ##im, ##pa, ##ired, t, cell, expansion, ,, but, enhanced, pri, ##ming, of, t, -, cells, by, ap, ##cs, ., [, 185, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 185, ], increased, cy, ##tok, ##ine, and, ro, ##s, production, in, macro, ##pha, ##ges, ,, ne, ##ut, ##rop, ##hil, ##s, and, t, cells, ., [, 187, ], protection, from, ds, ##s, -, induced, int, ##estinal, inflammation, ., [, 191, ], du, ##sp, ##16, /, mk, ##p, -, 7, ##im, ##pa, ##ired, gm, -, cs, ##f, -, driven, proliferation, of, bone, marrow, pro, ##gen, ##itors, ., [, 195, ], increased, cd, ##4, +, t, -, cell, proliferation, &, a, reduced, th, ##17, cell, population, ., [, 196, ], protection, from, auto, ##im, ##mun, ##e, en, ##ce, ##pha, ##lit, ##is, (, ea, ##e, ), ., [, 196, ], lc, ##m, ##v, ,, l, ##ym, ##ph, ##oc, ##ytic, cho, ##rio, ##men, ##ing, ##itis, virus, ., ds, ##s, ,, dex, ##tra, ##n, sodium, sulfate, .'},\n", - " {'article_id': '8b10c2efdaec5aa6769f1e69e0d78bea',\n", - " 'section_name': 'Brain neurochemistry',\n", - " 'text': 'To further explore the interrelationship between parous-induced neuroinflammation and neurotransmitters, we systematically analyzed the neurochemistry both in the prefrontal cortex and in the hippocampus of rats. As shown in Tables 2 and 3, DA level were significantly decreased both in the prefrontal cortex (p < 0.01) and in the hippocampus (p < 0.05) of parous groups, while its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) remain stable. Parous rats that exposed to control diet also exhibited decreased norepinephrine (NE, p < 0.01 for prefrontal cortex), without altering the metabolites vanilmandelic acid (VMA) and 4-Hydroxy-3-methoxyphenylglycol (MHPG). However, virgin rats that with daily supply of Ω-3 fatty acids exhibited decreased NE (p < 0.01 for prefrontal cortex) and increased VMA (p < 0.05 for prefrontal cortex). It was worth to mention that both parous and Ω-3 fatty acids supplementation did not affect the serotonin (5-HT) level, but parous rats that exposed to daily supplementary of Ω-3 fatty acids exhibited decreased 5-hydroxy indole acetic acid (5-HIAA, p < 0.01) and the 5-HT turnover (the ratio of 5-HIAA to 5-HT, p < 0.05). Unexpectedly, parous resulted in significant increase of γ-aminobutyric acid (GABA) status (Table 2, p < 0.01) and glutamine (GLN, Table 2, p < 0.01) in the prefrontal cortex. Conversely, we find opposite trend in the hippocampus which exhibit decrease of GABA (p < 0.01) and GLN (p < 0.01) in parous.Table 2The content of major neurotransmitters and their metabolites in the prefrontal cortexCompoundVirginParousControlSupplementaryControlSupplementaryDA (ng/g)5.3 ± 0.65.4 ± 1.22.2 ± 0.3^##3.4 ± 0.3^#DOPAC (ng/g)6.8 ± 0.910.1 ± 1.910.1 ± 1.07.7 ± 0.5HVA (ng/g)1.1 ± 0.21.3 ± 0.31.3 ± 0.11.8 ± 0.2NE (ng/g)8.2 ± 1.83.8 ± 0.9**3.3 ± 0.6^##5.9 ± 0.7MHPG (ng/g)0.7 ± 0.10.9 ± 0.10.9 ± 0.11.1 ± 0.1VMA(ng/g)1.2 ± 0.12.0 ± 0.4*0.6 ± 0.10.5 ± 0.1^##TRY (ug/g)9.2 ± 1.66.7 ± 1.48.2 ± 0.712.0 ± 1.0^##,*5-HT (ng/g)153.7 ± 14.0127.7 ± 31.3116.0 ± 14.6178.6 ± 26.15-HIAA (ng/g)373.9 ± 45.6355.6 ± 27.0304.0 ± 25.8215.3 ± 11.02^##,*5-HIAA/5-HT3.0 ± 0.43.2 ± 0.82.8 ± 0.41.2 ± 0.2^#,*KYN (ng/g)540.7 ± 99.0429.0 ± 101.2526.1 ± 51.4622.2 ± 58.8GABA (ug/g)292.6 ± 41.5200.3 ± 49.8602.7 ± 82.8^##730.1 ± 99.2^##GLU (ug/g)0.4 ± 0.060.3 ± 0.050.5 ± 0.060.7 ± 0.07GLN (ug/g)178.2 ± 25.2132.0 ± 35.8356.7 ± 41.5^#501.0 ± 64.2^##Data are means ± SEM (n = 6–7). ^#p < 0.05, ^##p < 0.01 compared to virgin group; *p < 0.05, **p < 0.01compared to control groupTable 3The content of major neurotransmitters and their metabolites in the hippocampusCompoundVirginParousControlSupplementaryControlSupplementaryDA (ng/g)6.3 ± 0.85.0 ± 0.74.2 ± 0.4^#3.6 ± 0.5^#DOPAC (ng/g)3.1 ± 0.52.0 ± 0.23.1 ± 0.73.5 ± 0.7HVA (ng/g)0.5 ± 0.10.4 ± 0.10.3 ± 0.00.4 ± 0.1NE (ng/g)3.8 ± 0.43.5 ± 0.52.7 ± 0.33.0 ± 0.3MHPG (ng/g)0.4 ± 0.00.3 ± 0.00.3 ± 0.00.3 ± 0.0VMA(ng/g)4.0 ± 0.33.5 ± 0.74.5 ± 0.43.5 ± 0.4TRY (ug/g)4.8 ± 0.34.0 ± 0.13.7 ± 0.14.6 ± 0.45-HT (ng/g)129.6 ± 17.9105.5 ± 14.0108.1 ± 9.1121.1 ± 12.35-HIAA (ng/g)194.5 ± 30.3166.8 ± 29.6123.4 ± 9.571.8 ± 14.1^##5-HIAA/5-HT1.8 ± 0.52.3 ± 0.60.7 ± 0.10.7 ± 0.2^#KYN (ng/g)282.6 ± 24.5242.4 ± 6.9222.8 ± 8.8239.3 ± 14.4GABA (ug/g)63.3 ± 5.049.5 ± 3.131.6 ± 1.5^##34.4 ± 1.5GLU (ug/g)0.1 ± 0.00.1 ± 0.00.1 ± 0.00.1 ± 0.0GLN (ug/g)48.3 ± 3.738.0 ± 3.729.2 ± 1.3^##32.5 ± 1.1Data are means ± SEM (n = 6–7). ^#p < 0.05, ^##p < 0.01 compared to virgin group; *p < 0.05, **p < 0.01compared to control group',\n", - " 'paragraph_id': 18,\n", - " 'tokenizer': 'to, further, explore, the, inter, ##rel, ##ations, ##hip, between, par, ##ous, -, induced, ne, ##uro, ##in, ##fl, ##am, ##mation, and, ne, ##uro, ##tra, ##ns, ##mit, ##ters, ,, we, systematically, analyzed, the, ne, ##uro, ##chemist, ##ry, both, in, the, pre, ##front, ##al, cortex, and, in, the, hip, ##po, ##camp, ##us, of, rats, ., as, shown, in, tables, 2, and, 3, ,, da, level, were, significantly, decreased, both, in, the, pre, ##front, ##al, cortex, (, p, <, 0, ., 01, ), and, in, the, hip, ##po, ##camp, ##us, (, p, <, 0, ., 05, ), of, par, ##ous, groups, ,, while, its, meta, ##bol, ##ites, 3, ,, 4, -, di, ##hy, ##dro, ##xy, ##ph, ##en, ##yla, ##ce, ##tic, acid, (, do, ##pac, ), and, homo, ##vani, ##lli, ##c, acid, (, h, ##va, ), remain, stable, ., par, ##ous, rats, that, exposed, to, control, diet, also, exhibited, decreased, nor, ##ep, ##ine, ##ph, ##rine, (, ne, ,, p, <, 0, ., 01, for, pre, ##front, ##al, cortex, ), ,, without, altering, the, meta, ##bol, ##ites, van, ##il, ##man, ##del, ##ic, acid, (, v, ##ma, ), and, 4, -, hydro, ##xy, -, 3, -, met, ##ho, ##xy, ##ph, ##en, ##yl, ##gly, ##col, (, m, ##hp, ##g, ), ., however, ,, virgin, rats, that, with, daily, supply, of, ω, -, 3, fatty, acids, exhibited, decreased, ne, (, p, <, 0, ., 01, for, pre, ##front, ##al, cortex, ), and, increased, v, ##ma, (, p, <, 0, ., 05, for, pre, ##front, ##al, cortex, ), ., it, was, worth, to, mention, that, both, par, ##ous, and, ω, -, 3, fatty, acids, supplement, ##ation, did, not, affect, the, ser, ##oton, ##in, (, 5, -, h, ##t, ), level, ,, but, par, ##ous, rats, that, exposed, to, daily, supplementary, of, ω, -, 3, fatty, acids, exhibited, decreased, 5, -, hydro, ##xy, indo, ##le, ace, ##tic, acid, (, 5, -, hi, ##aa, ,, p, <, 0, ., 01, ), and, the, 5, -, h, ##t, turnover, (, the, ratio, of, 5, -, hi, ##aa, to, 5, -, h, ##t, ,, p, <, 0, ., 05, ), ., unexpectedly, ,, par, ##ous, resulted, in, significant, increase, of, γ, -, amino, ##bu, ##ty, ##ric, acid, (, ga, ##ba, ), status, (, table, 2, ,, p, <, 0, ., 01, ), and, g, ##lu, ##tam, ##ine, (, g, ##ln, ,, table, 2, ,, p, <, 0, ., 01, ), in, the, pre, ##front, ##al, cortex, ., conversely, ,, we, find, opposite, trend, in, the, hip, ##po, ##camp, ##us, which, exhibit, decrease, of, ga, ##ba, (, p, <, 0, ., 01, ), and, g, ##ln, (, p, <, 0, ., 01, ), in, par, ##ous, ., table, 2, ##the, content, of, major, ne, ##uro, ##tra, ##ns, ##mit, ##ters, and, their, meta, ##bol, ##ites, in, the, pre, ##front, ##al, cortex, ##com, ##po, ##und, ##vir, ##gin, ##par, ##ous, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##da, (, ng, /, g, ), 5, ., 3, ±, 0, ., 65, ., 4, ±, 1, ., 22, ., 2, ±, 0, ., 3, ^, #, #, 3, ., 4, ±, 0, ., 3, ^, #, do, ##pac, (, ng, /, g, ), 6, ., 8, ±, 0, ., 910, ., 1, ±, 1, ., 910, ., 1, ±, 1, ., 07, ., 7, ±, 0, ., 5, ##h, ##va, (, ng, /, g, ), 1, ., 1, ±, 0, ., 21, ., 3, ±, 0, ., 31, ., 3, ±, 0, ., 11, ., 8, ±, 0, ., 2, ##ne, (, ng, /, g, ), 8, ., 2, ±, 1, ., 83, ., 8, ±, 0, ., 9, *, *, 3, ., 3, ±, 0, ., 6, ^, #, #, 5, ., 9, ±, 0, ., 7, ##m, ##hp, ##g, (, ng, /, g, ), 0, ., 7, ±, 0, ., 10, ., 9, ±, 0, ., 10, ., 9, ±, 0, ., 11, ., 1, ±, 0, ., 1, ##v, ##ma, (, ng, /, g, ), 1, ., 2, ±, 0, ., 12, ., 0, ±, 0, ., 4, *, 0, ., 6, ±, 0, ., 10, ., 5, ±, 0, ., 1, ^, #, #, try, (, u, ##g, /, g, ), 9, ., 2, ±, 1, ., 66, ., 7, ±, 1, ., 48, ., 2, ±, 0, ., 71, ##2, ., 0, ±, 1, ., 0, ^, #, #, ,, *, 5, -, h, ##t, (, ng, /, g, ), 153, ., 7, ±, 14, ., 01, ##27, ., 7, ±, 31, ., 311, ##6, ., 0, ±, 14, ., 61, ##7, ##8, ., 6, ±, 26, ., 15, -, hi, ##aa, (, ng, /, g, ), 37, ##3, ., 9, ±, 45, ., 63, ##55, ., 6, ±, 27, ., 03, ##0, ##4, ., 0, ±, 25, ., 82, ##15, ., 3, ±, 11, ., 02, ^, #, #, ,, *, 5, -, hi, ##aa, /, 5, -, h, ##t, ##3, ., 0, ±, 0, ., 43, ., 2, ±, 0, ., 82, ., 8, ±, 0, ., 41, ., 2, ±, 0, ., 2, ^, #, ,, *, ky, ##n, (, ng, /, g, ), 540, ., 7, ±, 99, ., 04, ##29, ., 0, ±, 101, ., 252, ##6, ., 1, ±, 51, ., 46, ##22, ., 2, ±, 58, ., 8, ##ga, ##ba, (, u, ##g, /, g, ), 292, ., 6, ±, 41, ., 520, ##0, ., 3, ±, 49, ., 86, ##0, ##2, ., 7, ±, 82, ., 8, ^, #, #, 730, ., 1, ±, 99, ., 2, ^, #, #, g, ##lu, (, u, ##g, /, g, ), 0, ., 4, ±, 0, ., 06, ##0, ., 3, ±, 0, ., 050, ., 5, ±, 0, ., 06, ##0, ., 7, ±, 0, ., 07, ##gl, ##n, (, u, ##g, /, g, ), 178, ., 2, ±, 25, ., 213, ##2, ., 0, ±, 35, ., 83, ##56, ., 7, ±, 41, ., 5, ^, #, 501, ., 0, ±, 64, ., 2, ^, #, #, data, are, means, ±, se, ##m, (, n, =, 6, –, 7, ), ., ^, #, p, <, 0, ., 05, ,, ^, #, #, p, <, 0, ., 01, compared, to, virgin, group, ;, *, p, <, 0, ., 05, ,, *, *, p, <, 0, ., 01, ##com, ##par, ##ed, to, control, group, ##table, 3, ##the, content, of, major, ne, ##uro, ##tra, ##ns, ##mit, ##ters, and, their, meta, ##bol, ##ites, in, the, hip, ##po, ##camp, ##us, ##com, ##po, ##und, ##vir, ##gin, ##par, ##ous, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##con, ##tro, ##ls, ##up, ##ple, ##ment, ##ary, ##da, (, ng, /, g, ), 6, ., 3, ±, 0, ., 85, ., 0, ±, 0, ., 74, ., 2, ±, 0, ., 4, ^, #, 3, ., 6, ±, 0, ., 5, ^, #, do, ##pac, (, ng, /, g, ), 3, ., 1, ±, 0, ., 52, ., 0, ±, 0, ., 23, ., 1, ±, 0, ., 73, ., 5, ±, 0, ., 7, ##h, ##va, (, ng, /, g, ), 0, ., 5, ±, 0, ., 10, ., 4, ±, 0, ., 10, ., 3, ±, 0, ., 00, ., 4, ±, 0, ., 1, ##ne, (, ng, /, g, ), 3, ., 8, ±, 0, ., 43, ., 5, ±, 0, ., 52, ., 7, ±, 0, ., 33, ., 0, ±, 0, ., 3, ##m, ##hp, ##g, (, ng, /, g, ), 0, ., 4, ±, 0, ., 00, ., 3, ±, 0, ., 00, ., 3, ±, 0, ., 00, ., 3, ±, 0, ., 0, ##v, ##ma, (, ng, /, g, ), 4, ., 0, ±, 0, ., 33, ., 5, ±, 0, ., 74, ., 5, ±, 0, ., 43, ., 5, ±, 0, ., 4, ##try, (, u, ##g, /, g, ), 4, ., 8, ±, 0, ., 34, ., 0, ±, 0, ., 13, ., 7, ±, 0, ., 14, ., 6, ±, 0, ., 45, -, h, ##t, (, ng, /, g, ), 129, ., 6, ±, 17, ., 910, ##5, ., 5, ±, 14, ., 01, ##0, ##8, ., 1, ±, 9, ., 112, ##1, ., 1, ±, 12, ., 35, -, hi, ##aa, (, ng, /, g, ), 194, ., 5, ±, 30, ., 316, ##6, ., 8, ±, 29, ., 61, ##23, ., 4, ±, 9, ., 57, ##1, ., 8, ±, 14, ., 1, ^, #, #, 5, -, hi, ##aa, /, 5, -, h, ##t, ##1, ., 8, ±, 0, ., 52, ., 3, ±, 0, ., 60, ., 7, ±, 0, ., 10, ., 7, ±, 0, ., 2, ^, #, ky, ##n, (, ng, /, g, ), 282, ., 6, ±, 24, ., 52, ##42, ., 4, ±, 6, ., 92, ##22, ., 8, ±, 8, ., 82, ##39, ., 3, ±, 14, ., 4, ##ga, ##ba, (, u, ##g, /, g, ), 63, ., 3, ±, 5, ., 04, ##9, ., 5, ±, 3, ., 131, ., 6, ±, 1, ., 5, ^, #, #, 34, ., 4, ±, 1, ., 5, ##gl, ##u, (, u, ##g, /, g, ), 0, ., 1, ±, 0, ., 00, ., 1, ±, 0, ., 00, ., 1, ±, 0, ., 00, ., 1, ±, 0, ., 0, ##gl, ##n, (, u, ##g, /, g, ), 48, ., 3, ±, 3, ., 73, ##8, ., 0, ±, 3, ., 72, ##9, ., 2, ±, 1, ., 3, ^, #, #, 32, ., 5, ±, 1, ., 1, ##da, ##ta, are, means, ±, se, ##m, (, n, =, 6, –, 7, ), ., ^, #, p, <, 0, ., 05, ,, ^, #, #, p, <, 0, ., 01, compared, to, virgin, group, ;, *, p, <, 0, ., 05, ,, *, *, p, <, 0, ., 01, ##com, ##par, ##ed, to, control, group'},\n", - " {'article_id': '1003e6984412debd4e0706f54060e4b5',\n", - " 'section_name': '',\n", - " 'text': 'Discovering diversity: identify and provide experimental access to the different brain cell types to determine their roles in health and disease. Characterization of all the cell types in the nervous system is within reach, and a cell “census” of neuronal and glial cell types will aid in the development of tools that can precisely target and manipulate them.The (BICCN), launched in 2017 based on extraordinary early progress, is the single largest BRAIN Initiative project to date and plans to invest US$250 million over the next five years to construct a comprehensive reference of diverse cell types in human, monkey, and mouse brains. This team science program will provide essential characterization for the diversity of cell types, an open-access 3D digital mouse brain cell reference atlas, and a comprehensive neural circuit diagram, as well as genomic access to specific cell types to monitor, map, or modulate their activity. These tools will serve as unprecedented resources for the scientific community to develop a deep understanding of neural circuit function across species. To achieve its goals, the BICCN requires its scientists to work together with agreed upon standards, methods, and a common framework for assembling the large variety of data coming from multiple laboratories, a social neuroscience experiment in itself.Maps at multiple scales: generate circuit diagrams that vary in resolution, from synapses to the whole brain. As our ability to map neuronal connections within local circuits; micro-, meso-, and macroconnectomes; and between distributed brain systems improves, scalable circuit maps will relate structure to function.Successful efforts have been made in serial section electron microscopy and their analytic pipelines to enable whole brain connectomics in Drosophila and zebrafish as well as in regions of the mouse cortex. Improved track-tracing tools that leverage multiphoton imaging, expansion microscopy, and advanced techniques like viral circuit tracing have been devised and applied to identify synaptic inputs to specific neurons. Innovative whole brain–clearing techniques like clear lipid-exchanged acrylamide-hybridized rigid imaging/immunostaining/in situ hyrbridization-compatible tissue-hydrogel (CLARITY) enable morphological assessment in 3D and should be adaptable to postmortem human tissue.The brain in action: produce a dynamic picture of the functioning brain by developing and applying improved methods for large‐scale monitoring of neural activity. Various neuronal-recording methods continue to emerge and offer innovative ways to record neuronal activity at a single-cell level from ever more cells over larger brain regions in awake behaving animals. Successful efforts have visualized network brain activity over wide areas of the mouse cortex while preserving the ability to focus at single-cell resolution. Investigator teams are recording longer and from more brain regions in patients undergoing deep brain stimulation to understand human circuit activity underlying speech, movement, intention, and emotion.Demonstrating causality: link brain activity to behavior with precise interventional tools that change neural circuit dynamics. Tools that enable circuit manipulation open the door to probe how neural activity gives rise to behavior. Teams of scientists are monitoring and modulating neural activity linked to behavior both in awake behaving animals and in patients undergoing deep brain stimulation for disorders such as epilepsy, Parkinsons disease, chronic pain, obsessive compulsive disorders, and depression.Identifying fundamental principles: produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data-analysis tools. The ability to capture neural activity in thousands to millions of neurons poses analytic challenges but offers a new opportunity to understand the language of the brain and the rules that underly its information processing. Progress relies on engaging statisticians, mathematicians, and computer scientists to join the effort. Teams of scientists are capturing neural activity in specific circuits and developing models that explain and predict key circuit characteristics as well as theories of fundamental brain processes.Advancing human neuroscience: develop innovative technologies to understand the human brain and treat its disorders; create and support integrated human brain research networks. The burden of illness due to neurologic, psychiatric, and substance-abuse disorders is due largely to disordered brain circuits. The ability to measure and characterize activity in these circuits will change diagnostics and provide targets to precisely modulate them, ultimately changing the landscape of therapeutics. Early examples are the tuning of closed-loop deep brain stimulation devices based on measures of brain activity in patients with essential tremor and Parkinsons disease. Ultimately, the tools and technologies that emerge from BRAIN are expected to open the door to new FDA-approved drug therapies and devices for neurological and psychiatric disorders over the next decade.From BRAIN Initiative to the brain: integrate new technological and conceptual approaches produced in Goals 1–6 to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease. Taken together, the goals outlined above lay the foundation for a comprehensive, integrated, and mechanistic understanding of brain function across species to understand the basis of our human capabilities. Since the NIH BRAIN Initiative began, more than 500 awards have gone out to investigators around the world, reflecting an investment of nearly US$1 billion.',\n", - " 'paragraph_id': 4,\n", - " 'tokenizer': 'discovering, diversity, :, identify, and, provide, experimental, access, to, the, different, brain, cell, types, to, determine, their, roles, in, health, and, disease, ., characterization, of, all, the, cell, types, in, the, nervous, system, is, within, reach, ,, and, a, cell, “, census, ”, of, ne, ##uron, ##al, and, g, ##lia, ##l, cell, types, will, aid, in, the, development, of, tools, that, can, precisely, target, and, manipulate, them, ., the, (, bi, ##cc, ##n, ), ,, launched, in, 2017, based, on, extraordinary, early, progress, ,, is, the, single, largest, brain, initiative, project, to, date, and, plans, to, invest, us, $, 250, million, over, the, next, five, years, to, construct, a, comprehensive, reference, of, diverse, cell, types, in, human, ,, monkey, ,, and, mouse, brains, ., this, team, science, program, will, provide, essential, characterization, for, the, diversity, of, cell, types, ,, an, open, -, access, 3d, digital, mouse, brain, cell, reference, atlas, ,, and, a, comprehensive, neural, circuit, diagram, ,, as, well, as, gen, ##omic, access, to, specific, cell, types, to, monitor, ,, map, ,, or, mod, ##ulate, their, activity, ., these, tools, will, serve, as, unprecedented, resources, for, the, scientific, community, to, develop, a, deep, understanding, of, neural, circuit, function, across, species, ., to, achieve, its, goals, ,, the, bi, ##cc, ##n, requires, its, scientists, to, work, together, with, agreed, upon, standards, ,, methods, ,, and, a, common, framework, for, ass, ##em, ##bling, the, large, variety, of, data, coming, from, multiple, laboratories, ,, a, social, neuroscience, experiment, in, itself, ., maps, at, multiple, scales, :, generate, circuit, diagrams, that, vary, in, resolution, ,, from, syn, ##ap, ##ses, to, the, whole, brain, ., as, our, ability, to, map, ne, ##uron, ##al, connections, within, local, circuits, ;, micro, -, ,, me, ##so, -, ,, and, macro, ##con, ##ne, ##ct, ##ome, ##s, ;, and, between, distributed, brain, systems, improves, ,, scala, ##ble, circuit, maps, will, relate, structure, to, function, ., successful, efforts, have, been, made, in, serial, section, electron, microscopy, and, their, analytic, pipeline, ##s, to, enable, whole, brain, connect, ##omics, in, dr, ##oso, ##phila, and, zebra, ##fish, as, well, as, in, regions, of, the, mouse, cortex, ., improved, track, -, tracing, tools, that, leverage, multi, ##ph, ##oton, imaging, ,, expansion, microscopy, ,, and, advanced, techniques, like, viral, circuit, tracing, have, been, devised, and, applied, to, identify, syn, ##ap, ##tic, inputs, to, specific, neurons, ., innovative, whole, brain, –, clearing, techniques, like, clear, lip, ##id, -, exchanged, ac, ##ryl, ##ami, ##de, -, hybrid, ##ized, rigid, imaging, /, im, ##mun, ##osta, ##ining, /, in, situ, h, ##yr, ##bri, ##di, ##zation, -, compatible, tissue, -, hydro, ##gel, (, clarity, ), enable, morphological, assessment, in, 3d, and, should, be, adapt, ##able, to, post, ##mo, ##rte, ##m, human, tissue, ., the, brain, in, action, :, produce, a, dynamic, picture, of, the, functioning, brain, by, developing, and, applying, improved, methods, for, large, ‐, scale, monitoring, of, neural, activity, ., various, ne, ##uron, ##al, -, recording, methods, continue, to, emerge, and, offer, innovative, ways, to, record, ne, ##uron, ##al, activity, at, a, single, -, cell, level, from, ever, more, cells, over, larger, brain, regions, in, awake, be, ##ha, ##ving, animals, ., successful, efforts, have, visual, ##ized, network, brain, activity, over, wide, areas, of, the, mouse, cortex, while, preserving, the, ability, to, focus, at, single, -, cell, resolution, ., investigator, teams, are, recording, longer, and, from, more, brain, regions, in, patients, undergoing, deep, brain, stimulation, to, understand, human, circuit, activity, underlying, speech, ,, movement, ,, intention, ,, and, emotion, ., demonstrating, causal, ##ity, :, link, brain, activity, to, behavior, with, precise, intervention, ##al, tools, that, change, neural, circuit, dynamics, ., tools, that, enable, circuit, manipulation, open, the, door, to, probe, how, neural, activity, gives, rise, to, behavior, ., teams, of, scientists, are, monitoring, and, mod, ##ulating, neural, activity, linked, to, behavior, both, in, awake, be, ##ha, ##ving, animals, and, in, patients, undergoing, deep, brain, stimulation, for, disorders, such, as, ep, ##ile, ##psy, ,, parkinson, ##s, disease, ,, chronic, pain, ,, ob, ##ses, ##sive, com, ##pu, ##ls, ##ive, disorders, ,, and, depression, ., identifying, fundamental, principles, :, produce, conceptual, foundations, for, understanding, the, biological, basis, of, mental, processes, through, development, of, new, theoretical, and, data, -, analysis, tools, ., the, ability, to, capture, neural, activity, in, thousands, to, millions, of, neurons, poses, analytic, challenges, but, offers, a, new, opportunity, to, understand, the, language, of, the, brain, and, the, rules, that, under, ##ly, its, information, processing, ., progress, relies, on, engaging, stat, ##istic, ##ians, ,, mathematicians, ,, and, computer, scientists, to, join, the, effort, ., teams, of, scientists, are, capturing, neural, activity, in, specific, circuits, and, developing, models, that, explain, and, predict, key, circuit, characteristics, as, well, as, theories, of, fundamental, brain, processes, ., advancing, human, neuroscience, :, develop, innovative, technologies, to, understand, the, human, brain, and, treat, its, disorders, ;, create, and, support, integrated, human, brain, research, networks, ., the, burden, of, illness, due, to, ne, ##uro, ##logic, ,, psychiatric, ,, and, substance, -, abuse, disorders, is, due, largely, to, disorder, ##ed, brain, circuits, ., the, ability, to, measure, and, character, ##ize, activity, in, these, circuits, will, change, diagnostic, ##s, and, provide, targets, to, precisely, mod, ##ulate, them, ,, ultimately, changing, the, landscape, of, therapeutic, ##s, ., early, examples, are, the, tuning, of, closed, -, loop, deep, brain, stimulation, devices, based, on, measures, of, brain, activity, in, patients, with, essential, tremor, and, parkinson, ##s, disease, ., ultimately, ,, the, tools, and, technologies, that, emerge, from, brain, are, expected, to, open, the, door, to, new, fda, -, approved, drug, the, ##ra, ##pies, and, devices, for, neurological, and, psychiatric, disorders, over, the, next, decade, ., from, brain, initiative, to, the, brain, :, integrate, new, technological, and, conceptual, approaches, produced, in, goals, 1, –, 6, to, discover, how, dynamic, patterns, of, neural, activity, are, transformed, into, cognition, ,, emotion, ,, perception, ,, and, action, in, health, and, disease, ., taken, together, ,, the, goals, outlined, above, lay, the, foundation, for, a, comprehensive, ,, integrated, ,, and, me, ##chan, ##istic, understanding, of, brain, function, across, species, to, understand, the, basis, of, our, human, capabilities, ., since, the, ni, ##h, brain, initiative, began, ,, more, than, 500, awards, have, gone, out, to, investigators, around, the, world, ,, reflecting, an, investment, of, nearly, us, $, 1, billion, .'},\n", - " {'article_id': 'c1bebb31c874aa2fad9ac008fc3fbe24',\n", - " 'section_name': 'Cav-1 and neuroinflammation (Fig. 3)',\n", - " 'text': 'In the endothelium, after exposure to LPS, cav-1 was phosphorylated at Tyr(14) which resulted in interaction between cav-1 and toll-like receptor 4 (TLR4), and then TLR4 promoted activation of MyD88, leading to NF-κB activation and the generation of proinflammatory cytokines [130]. Cav-1 OE dose-dependently increased monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and plasminogen activator inhibitor-1 (PAI-1) mRNA levels in human umbilical vein ECs. Pigment epithelium-derived factor binding to cav-1 could inhibit the pro-inflammatory effects of cav-1 in endothelial cells [131]. Cav-1 can affect NF-κB to influence the inflammatory response. Signaling by the proinflammatory cytokine interleukin-1β (IL-1β) is dependent on ROS, because after IL-1β binding to its receptor (IL-1R1), ROS generated by Nox2 is responsible for the downstream recruitment of IL-1R1 effectors (IRAK, TRAF6, IkappaB kinase kinases) and ultimately for activation of NF-κB. Lipid rafts and cav-1 coordinate IL-1β-dependent activation of NF-κB. Inhibiting cav-1-mediated endocytosis can prevent NF-κB activation [132]. Cav-1 gene KO lungs displayed suppression of NF-κB activity and reduced transcription of iNOS and intercellular adhesion molecule 1 (ICAM-1) [133]. Secondary to the loss of cav-1, eNOS is activated, which inhibits the innate immune response to LPS through interleukin-1 receptor-associated kinase 4 (IRAK4) nitration. IRAK4 is a signaling factor required for NF-κB activation and innate immunity. Cav-1 KO can impair the activity of NF-κB and reduce LPS-induced lung injury [134]. Cav-1 appears to have different roles in different cells. In macrophages, the interaction of cav-1 with TLR4 has an opposite outcome compared with that in endothelium, whereby overexpression of cav-1 decreased LPS-induced TNF-α and IL-6 proinflammatory cytokine production and augmented anti-inflammatory cytokine IL-10 production. Cav-1 regulates LPS-induced inflammatory cytokine production through the MKK3/p38 MAPK pathway [135]. It is valuable to mention that TLR4 activation by LPS also stimulates heme oxygenase-1 (HO-1) transporting to the caveolae by a p38 MAPK-dependent mechanism and producing carbon oxide (CO). CO has anti-inflammatory effects and augments the cav-1/TLR4 interaction in murine macrophages [136]. In PMN leukocytes, cav-1 appears to promote activation, adhesion, and transendothelial migration and shows a positive role in PMN activation-induced lung and vascular injury [137]. Cav-1 also plays a key role in antigen-presenting cells, leading to the activation of T lymphocytes [138]. Furthermore, apoptosis of thymocytes in cav-1-deficient mice was higher than that in wild type mice, indicating that cav-1 is a key regulator of thymocyte apoptosis during inflammation [139]. In addition, cav-1 has a possible role in microglial activation. Cav-1 was remarkably reduced and localized in the plasmalemma and cytoplasmic vesicles of inactive microglia, whereas active (amoeboid-shaped) microglia exhibited increased cav-1 expression [46]. Recently, Portugal et al. found that cav-1 in microglia induced the internalization of plasma membrane sodium-vitamin C cotransporter 2 (SVCT2), triggering a proinflammatory phenotype in microglia and inducing microglia activation [140]. Besides, cav-1 transfection into Fatty acid-binding proteins-KO astrocytes remarkably enhanced TLR4 recruitment into lipid raft and tumor necrosis factor-ɑ production after LPS stimulation [141]. Together, in non-pathological states or after LPS stimulation, cav-1 in endothelial cells increases proinflammatory cytokines, while cav-1 inhibits LPS-induced inflammatory effects in murine macrophages. Cav-1 is involved in activation of microglia, PMN, and T lymphocytes.',\n", - " 'paragraph_id': 22,\n", - " 'tokenizer': 'in, the, end, ##oth, ##eli, ##um, ,, after, exposure, to, lp, ##s, ,, ca, ##v, -, 1, was, ph, ##os, ##ph, ##ory, ##lated, at, ty, ##r, (, 14, ), which, resulted, in, interaction, between, ca, ##v, -, 1, and, toll, -, like, receptor, 4, (, t, ##lr, ##4, ), ,, and, then, t, ##lr, ##4, promoted, activation, of, my, ##d, ##8, ##8, ,, leading, to, n, ##f, -, κ, ##b, activation, and, the, generation, of, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ines, [, 130, ], ., ca, ##v, -, 1, o, ##e, dose, -, dependent, ##ly, increased, mono, ##cy, ##te, che, ##mo, ##att, ##rac, ##tan, ##t, protein, -, 1, (, mc, ##p, -, 1, ), ,, vascular, cell, ad, ##hesion, molecule, -, 1, (, vc, ##am, -, 1, ), ,, and, pl, ##as, ##min, ##ogen, act, ##iva, ##tor, inhibitor, -, 1, (, pa, ##i, -, 1, ), mrna, levels, in, human, um, ##bil, ##ical, vein, ec, ##s, ., pigment, ep, ##ith, ##eli, ##um, -, derived, factor, binding, to, ca, ##v, -, 1, could, inhibit, the, pro, -, inflammatory, effects, of, ca, ##v, -, 1, in, end, ##oth, ##elial, cells, [, 131, ], ., ca, ##v, -, 1, can, affect, n, ##f, -, κ, ##b, to, influence, the, inflammatory, response, ., signaling, by, the, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ine, inter, ##le, ##uki, ##n, -, 1, ##β, (, il, -, 1, ##β, ), is, dependent, on, ro, ##s, ,, because, after, il, -, 1, ##β, binding, to, its, receptor, (, il, -, 1, ##r, ##1, ), ,, ro, ##s, generated, by, no, ##x, ##2, is, responsible, for, the, downstream, recruitment, of, il, -, 1, ##r, ##1, effect, ##ors, (, ira, ##k, ,, tr, ##af, ##6, ,, ik, ##app, ##ab, kinase, kinase, ##s, ), and, ultimately, for, activation, of, n, ##f, -, κ, ##b, ., lip, ##id, raft, ##s, and, ca, ##v, -, 1, coordinate, il, -, 1, ##β, -, dependent, activation, of, n, ##f, -, κ, ##b, ., inhibit, ##ing, ca, ##v, -, 1, -, mediated, end, ##oc, ##yt, ##osis, can, prevent, n, ##f, -, κ, ##b, activation, [, 132, ], ., ca, ##v, -, 1, gene, ko, lungs, displayed, suppression, of, n, ##f, -, κ, ##b, activity, and, reduced, transcription, of, in, ##os, and, inter, ##cellular, ad, ##hesion, molecule, 1, (, ic, ##am, -, 1, ), [, 133, ], ., secondary, to, the, loss, of, ca, ##v, -, 1, ,, en, ##os, is, activated, ,, which, inhibit, ##s, the, innate, immune, response, to, lp, ##s, through, inter, ##le, ##uki, ##n, -, 1, receptor, -, associated, kinase, 4, (, ira, ##k, ##4, ), ni, ##tra, ##tion, ., ira, ##k, ##4, is, a, signaling, factor, required, for, n, ##f, -, κ, ##b, activation, and, innate, immunity, ., ca, ##v, -, 1, ko, can, imp, ##air, the, activity, of, n, ##f, -, κ, ##b, and, reduce, lp, ##s, -, induced, lung, injury, [, 134, ], ., ca, ##v, -, 1, appears, to, have, different, roles, in, different, cells, ., in, macro, ##pha, ##ges, ,, the, interaction, of, ca, ##v, -, 1, with, t, ##lr, ##4, has, an, opposite, outcome, compared, with, that, in, end, ##oth, ##eli, ##um, ,, whereby, over, ##ex, ##press, ##ion, of, ca, ##v, -, 1, decreased, lp, ##s, -, induced, tn, ##f, -, α, and, il, -, 6, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ine, production, and, augmented, anti, -, inflammatory, cy, ##tok, ##ine, il, -, 10, production, ., ca, ##v, -, 1, regulates, lp, ##s, -, induced, inflammatory, cy, ##tok, ##ine, production, through, the, mk, ##k, ##3, /, p, ##38, map, ##k, pathway, [, 135, ], ., it, is, valuable, to, mention, that, t, ##lr, ##4, activation, by, lp, ##s, also, stimulate, ##s, hem, ##e, oxygen, ##ase, -, 1, (, ho, -, 1, ), transporting, to, the, cave, ##ola, ##e, by, a, p, ##38, map, ##k, -, dependent, mechanism, and, producing, carbon, oxide, (, co, ), ., co, has, anti, -, inflammatory, effects, and, aug, ##ments, the, ca, ##v, -, 1, /, t, ##lr, ##4, interaction, in, mu, ##rine, macro, ##pha, ##ges, [, 136, ], ., in, pm, ##n, le, ##uk, ##ocytes, ,, ca, ##v, -, 1, appears, to, promote, activation, ,, ad, ##hesion, ,, and, trans, ##end, ##oth, ##elial, migration, and, shows, a, positive, role, in, pm, ##n, activation, -, induced, lung, and, vascular, injury, [, 137, ], ., ca, ##v, -, 1, also, plays, a, key, role, in, antigen, -, presenting, cells, ,, leading, to, the, activation, of, t, l, ##ym, ##ph, ##ocytes, [, 138, ], ., furthermore, ,, ap, ##op, ##tosis, of, thy, ##mo, ##cytes, in, ca, ##v, -, 1, -, def, ##icient, mice, was, higher, than, that, in, wild, type, mice, ,, indicating, that, ca, ##v, -, 1, is, a, key, regulator, of, thy, ##mo, ##cy, ##te, ap, ##op, ##tosis, during, inflammation, [, 139, ], ., in, addition, ,, ca, ##v, -, 1, has, a, possible, role, in, micro, ##glia, ##l, activation, ., ca, ##v, -, 1, was, remarkably, reduced, and, localized, in, the, plasma, ##lem, ##ma, and, cy, ##top, ##las, ##mic, ve, ##sic, ##les, of, inactive, micro, ##glia, ,, whereas, active, (, am, ##oe, ##bo, ##id, -, shaped, ), micro, ##glia, exhibited, increased, ca, ##v, -, 1, expression, [, 46, ], ., recently, ,, portugal, et, al, ., found, that, ca, ##v, -, 1, in, micro, ##glia, induced, the, internal, ##ization, of, plasma, membrane, sodium, -, vitamin, c, cot, ##ran, ##sport, ##er, 2, (, sv, ##ct, ##2, ), ,, triggering, a, pro, ##in, ##fl, ##am, ##mat, ##ory, ph, ##eno, ##type, in, micro, ##glia, and, inducing, micro, ##glia, activation, [, 140, ], ., besides, ,, ca, ##v, -, 1, trans, ##fect, ##ion, into, fatty, acid, -, binding, proteins, -, ko, astro, ##cytes, remarkably, enhanced, t, ##lr, ##4, recruitment, into, lip, ##id, raft, and, tumor, nec, ##rosis, factor, -, ɑ, production, after, lp, ##s, stimulation, [, 141, ], ., together, ,, in, non, -, path, ##ological, states, or, after, lp, ##s, stimulation, ,, ca, ##v, -, 1, in, end, ##oth, ##elial, cells, increases, pro, ##in, ##fl, ##am, ##mat, ##ory, cy, ##tok, ##ines, ,, while, ca, ##v, -, 1, inhibit, ##s, lp, ##s, -, induced, inflammatory, effects, in, mu, ##rine, macro, ##pha, ##ges, ., ca, ##v, -, 1, is, involved, in, activation, of, micro, ##glia, ,, pm, ##n, ,, and, t, l, ##ym, ##ph, ##ocytes, .'},\n", - " {'article_id': 'd1cbb8890196b1d896c3ca4b9ecf0978',\n", - " 'section_name': 'High-throughput brain activity mapping (HT-BAMing) technology',\n", - " 'text': 'Advances in microscopy techniques^17 and the development of novel calcium-sensitive fluorescent reporters^11 have enabled recording of brain-wide activity in larval zebrafish with single-cell resolution^12. Here, changes in the fluorescence of calcium-sensitive fluorophores provides an established proxy for imaging of neuronal activity^11,12,18. However, the challenges posed by handling of zebrafish larvae prohibit the wide application to large-scale analysis, and as a result the throughput for these experiments is quite limited and can be greatly improved by robotic automation and microfluidic systems^19,20. With the goal of investigating whole-brain CNS physiology on a large scale, we developed an autonomous system capable of orienting and immobilizing multiple awake, nonanesthetized animals for high-throughput recording of brain-wide neuronal activity. This system was based on our recent development of a microfluidic chip that utilizes hydrodynamic force to trap, position, and orient zebrafish larvae^13,14 (Fig. 1a−c). The processing throughput was further enhanced by a system for larvae loading and transportation that employs digitally controlled syringe pumps, electromagnetic valves and video detection to enable automatic feeding of larvae into the microfluidic chip (Supplementary Fig. 1). In this study, all larvae were loaded with a dorsal-up orientation to facilitate brain imaging from above. The use of transgenic zebrafish (elavl3:GCaMP5G) with a genetically encoded calcium indicator (Fig. 1d) allowed for real-time whole-brain imaging, and subsequent analysis of drug-induced changes in neuronal activity (Supplementary Fig. 1d). To generate the functional BAM of a larva in response to a 15-min period of chemical perfusion, or treatment, each larva was imaged over a 10-min period before and after treatment (Fig. 1e). Readings from multiple focal planes along the Z-axis (ventral direction) were acquired, and the accumulated number of calcium transients were derived from the fluorescence fluctuations of each Z-plane with a lateral resolution of 15.21 μm^2. The difference in calcium transient counts between the post- and pretreatment periods was calculated and projected (by summing up along the Z-axis) to a two-dimensional surface to construct a BAM that reflects changes in brain activity and physiology of an individual larva in response to treatment (Fig. 1a, e). For each compound, BAMs from five individual larvae were acquired following treatment with a 10 μM dose. To avoid false-positive or false-negative errors potentially introduced by variation among different individuals, the five BAMs for each compound were statistically compared by T-score test at every 15.21 μm^2 unit across the whole projection surface to extract the brain regions significantly regulated by compound treatment. In addition, a significance score was assigned to each unit to form a T-score brain activity map (T-score BAM) unique to each compound (Supplementary Fig. 2). In the control larvae, (dimethyl sulfoxide) DMSO treatment resulted in white-noise-like T-score BAMs (n = 50) (Supplementary Fig. 3).Fig. 1High-throughput brain activity mapping (HT-BAMing) in zebrafish larvae. a Illustration of the HT-BAMing technology. b Image sequences showing the autonomous larva loading and immobilization in the microfluidic chip. Red arrows indicate the direction of the bulk flow. Scale bar, 2 mm. c Immobilization of multiple awake larvae in a microfluidic chip with a dorsal-up orientation. Scale bar, 5 mm. d Representative brain image of a larva (from elavl3:GCaMP5G transgenic line) trapped in the system. Inset shows the merged image of the larva trapped in the chip. The white dotted line indicates the trapping channel. Scale bar, 100 μm. e Representative curves showing the change of calcium fluorescence fluctuation in selected neuronal cells from a zebrafish brain. The sample showing inhibition was treated with the typical antipsychotic loxapine, while the sample data showing excitation follows treatment with pyrithioxine. f−h T-score BAMs showing the regulation of brain physiology induced by different CNS drugs including f loxapine, a dibenzoxazepine-class typical antipsychotic; g pyrithioxine, a synthetic, dimeric, disulfide bridged, derivative of vitamin B6 (pyridoxine) with reported psychostimulant/nootropic activity; and h ethopropazine, a phenothiazine derivative with anticholinergic, antihistamine, and antiadenergic activities used as an antiparkinsonian medication',\n", - " 'paragraph_id': 3,\n", - " 'tokenizer': 'advances, in, microscopy, techniques, ^, 17, and, the, development, of, novel, calcium, -, sensitive, fluorescent, reporters, ^, 11, have, enabled, recording, of, brain, -, wide, activity, in, la, ##rval, zebra, ##fish, with, single, -, cell, resolution, ^, 12, ., here, ,, changes, in, the, flu, ##orescence, of, calcium, -, sensitive, flu, ##oro, ##ph, ##ores, provides, an, established, proxy, for, imaging, of, ne, ##uron, ##al, activity, ^, 11, ,, 12, ,, 18, ., however, ,, the, challenges, posed, by, handling, of, zebra, ##fish, larvae, prohibit, the, wide, application, to, large, -, scale, analysis, ,, and, as, a, result, the, through, ##put, for, these, experiments, is, quite, limited, and, can, be, greatly, improved, by, robotic, automation, and, micro, ##fl, ##uid, ##ic, systems, ^, 19, ,, 20, ., with, the, goal, of, investigating, whole, -, brain, cn, ##s, physiology, on, a, large, scale, ,, we, developed, an, autonomous, system, capable, of, orient, ##ing, and, im, ##mo, ##bil, ##izing, multiple, awake, ,, non, ##ane, ##st, ##het, ##ized, animals, for, high, -, through, ##put, recording, of, brain, -, wide, ne, ##uron, ##al, activity, ., this, system, was, based, on, our, recent, development, of, a, micro, ##fl, ##uid, ##ic, chip, that, utilizes, hydro, ##dy, ##nami, ##c, force, to, trap, ,, position, ,, and, orient, zebra, ##fish, larvae, ^, 13, ,, 14, (, fig, ., 1a, ##−, ##c, ), ., the, processing, through, ##put, was, further, enhanced, by, a, system, for, larvae, loading, and, transportation, that, employs, digitally, controlled, sy, ##ring, ##e, pumps, ,, electromagnetic, valves, and, video, detection, to, enable, automatic, feeding, of, larvae, into, the, micro, ##fl, ##uid, ##ic, chip, (, supplementary, fig, ., 1, ), ., in, this, study, ,, all, larvae, were, loaded, with, a, dorsal, -, up, orientation, to, facilitate, brain, imaging, from, above, ., the, use, of, trans, ##genic, zebra, ##fish, (, el, ##av, ##l, ##3, :, g, ##camp, ##5, ##g, ), with, a, genetically, encoded, calcium, indicator, (, fig, ., 1, ##d, ), allowed, for, real, -, time, whole, -, brain, imaging, ,, and, subsequent, analysis, of, drug, -, induced, changes, in, ne, ##uron, ##al, activity, (, supplementary, fig, ., 1, ##d, ), ., to, generate, the, functional, bam, of, a, la, ##rva, in, response, to, a, 15, -, min, period, of, chemical, per, ##fusion, ,, or, treatment, ,, each, la, ##rva, was, image, ##d, over, a, 10, -, min, period, before, and, after, treatment, (, fig, ., 1, ##e, ), ., readings, from, multiple, focal, planes, along, the, z, -, axis, (, ventral, direction, ), were, acquired, ,, and, the, accumulated, number, of, calcium, transient, ##s, were, derived, from, the, flu, ##orescence, fluctuations, of, each, z, -, plane, with, a, lateral, resolution, of, 15, ., 21, μ, ##m, ^, 2, ., the, difference, in, calcium, transient, counts, between, the, post, -, and, pre, ##tre, ##at, ##ment, periods, was, calculated, and, projected, (, by, sum, ##ming, up, along, the, z, -, axis, ), to, a, two, -, dimensional, surface, to, construct, a, bam, that, reflects, changes, in, brain, activity, and, physiology, of, an, individual, la, ##rva, in, response, to, treatment, (, fig, ., 1a, ,, e, ), ., for, each, compound, ,, bam, ##s, from, five, individual, larvae, were, acquired, following, treatment, with, a, 10, μ, ##m, dose, ., to, avoid, false, -, positive, or, false, -, negative, errors, potentially, introduced, by, variation, among, different, individuals, ,, the, five, bam, ##s, for, each, compound, were, statistical, ##ly, compared, by, t, -, score, test, at, every, 15, ., 21, μ, ##m, ^, 2, unit, across, the, whole, projection, surface, to, extract, the, brain, regions, significantly, regulated, by, compound, treatment, ., in, addition, ,, a, significance, score, was, assigned, to, each, unit, to, form, a, t, -, score, brain, activity, map, (, t, -, score, bam, ), unique, to, each, compound, (, supplementary, fig, ., 2, ), ., in, the, control, larvae, ,, (, dime, ##thy, ##l, sul, ##fo, ##xide, ), d, ##ms, ##o, treatment, resulted, in, white, -, noise, -, like, t, -, score, bam, ##s, (, n, =, 50, ), (, supplementary, fig, ., 3, ), ., fig, ., 1, ##hi, ##gh, -, through, ##put, brain, activity, mapping, (, h, ##t, -, bam, ##ing, ), in, zebra, ##fish, larvae, ., a, illustration, of, the, h, ##t, -, bam, ##ing, technology, ., b, image, sequences, showing, the, autonomous, la, ##rva, loading, and, im, ##mo, ##bil, ##ization, in, the, micro, ##fl, ##uid, ##ic, chip, ., red, arrows, indicate, the, direction, of, the, bulk, flow, ., scale, bar, ,, 2, mm, ., c, im, ##mo, ##bil, ##ization, of, multiple, awake, larvae, in, a, micro, ##fl, ##uid, ##ic, chip, with, a, dorsal, -, up, orientation, ., scale, bar, ,, 5, mm, ., d, representative, brain, image, of, a, la, ##rva, (, from, el, ##av, ##l, ##3, :, g, ##camp, ##5, ##g, trans, ##genic, line, ), trapped, in, the, system, ., ins, ##et, shows, the, merged, image, of, the, la, ##rva, trapped, in, the, chip, ., the, white, dotted, line, indicates, the, trapping, channel, ., scale, bar, ,, 100, μ, ##m, ., e, representative, curves, showing, the, change, of, calcium, flu, ##orescence, flu, ##ct, ##uation, in, selected, ne, ##uron, ##al, cells, from, a, zebra, ##fish, brain, ., the, sample, showing, inhibition, was, treated, with, the, typical, anti, ##psy, ##cho, ##tic, lo, ##xa, ##pine, ,, while, the, sample, data, showing, ex, ##cit, ##ation, follows, treatment, with, p, ##yr, ##ith, ##io, ##xin, ##e, ., f, ##−, ##h, t, -, score, bam, ##s, showing, the, regulation, of, brain, physiology, induced, by, different, cn, ##s, drugs, including, f, lo, ##xa, ##pine, ,, a, di, ##ben, ##zo, ##xa, ##ze, ##pine, -, class, typical, anti, ##psy, ##cho, ##tic, ;, g, p, ##yr, ##ith, ##io, ##xin, ##e, ,, a, synthetic, ,, dime, ##ric, ,, di, ##sul, ##fide, bridge, ##d, ,, derivative, of, vitamin, b, ##6, (, p, ##yr, ##ido, ##xin, ##e, ), with, reported, psycho, ##sti, ##mu, ##lan, ##t, /, no, ##ot, ##rop, ##ic, activity, ;, and, h, et, ##hop, ##rop, ##azi, ##ne, ,, a, ph, ##eno, ##thi, ##azi, ##ne, derivative, with, anti, ##cho, ##liner, ##gic, ,, anti, ##his, ##tam, ##ine, ,, and, anti, ##ade, ##ner, ##gic, activities, used, as, an, anti, ##park, ##ins, ##onia, ##n, medication'},\n", - " {'article_id': '616dd196a48d6d0e8ede1867f5502755',\n", - " 'section_name': 'Genetic architecture of microglial activation',\n", - " 'text': 'Given the imperfect correlation between MF and IT PAM measures (Spearman ρ = 0.66), we performed two separate genome-wide association studies (GWAS). All significant and suggestive GWAS results are listed in Table 2 (details in Supplementary Datas 4 and 5). For IT PAM, a single locus on chromosome 1 reached genome-wide significance (rs183093970; linear regression β = 0.154, SE = 0.024, p = 5.47 × 10^−10) (Fig. 4a, b). However, while the 191 kb region encompassed by this lead SNP contains three independent signals, all three have low minor allele frequency (MAF) (0.02 > MAF > 0.015). Notably, this association was driven by only seven individuals in our sample carrying minor alleles tagging this haplotype and should therefore be considered cautiously. Beyond this genome-wide significant locus, 27 additional independent regions were associated at p < 1 × 10^−5, and mapping based on position and combined eQTL evidence identified a total of 52 candidate genes as possible functional targets of these variants (Fig. 4c).Table 2Independent loci identified by cortical PAM GWASPAM regionChLead SNPSNP positionA1A2Freq (A1)Beta (A1)P-valueGenes mapped to locus (combined positional and/or eQTL mapping)MF1rs299732583641424AT0.629−0.03891.88E−08RP11-170N11.11rs157864165383761TC0.14150.04438.60E−06RXRG1rs651691193958320TC0.55310.03176.45E−062rs12623587232160554AC0.29−0.03216.00E−06C2orf72, PSMD1, HTR2B, ARMC93rs78461316104858434TC0.05870.07492.54E−077rs14121965270367062CT0.02260.10838.72E−0610rs61860520134826645TC0.0543−0.07194.02E−06TTC40, LINC0116611rs13866235792058950CA0.05550.0743.49E−07NDUFB11P1, FAT3, PGAM1P913rs9514523106927120TC0.1871−0.03869.20E−0613rs9521336110023731CT0.21460.03781.96E−06MYO16-AS1, LINC0039914rs2105997107209226TA0.22760.03888.46E−06IGHV4-39, HOMER2P1, IGHV4-61, IGHV3-64, IGHV3-66, IGHV1-69, IGHV3-72, IGHV3-73, IGHV3-7415rs14470530167855035CT0.02630.111.74E−07AAGAB, RPS24P16, MAP2K5, SKOR1IT1rs5626755821005316TG0.12870.04316.40E−06MUL1, CDA, PINK1, PINK1-AS, DDOST, KIF171rs11328527570896319AG0.2344−0.03283.10E−06HHLA3, CTH1rs18309397088454261GA0.01470.15355.47E−101rs147836155113501607TC0.01290.13462.46E−06SLC16A1, SLC16A1-AS12rs14825939328713654GC0.02040.10383.30E−06PLB12rs14141897040576095TG0.01020.15934.82E−07SLC8A12rs1701813880154236GC0.050.05887.53E−06CTNNA22rs79341575129133292CG0.05510.0632.75E−06GPR172rs60200364160708050AG0.06230.05552.14E−06BAZ2B, LY75, LY75-CD302, PLA2R1, ITGB62rs2348117201598521TG0.8893−0.04149.76E−06AOX3P, AOX2P, AC007163.3, PPIL3, RNU6-312P3rs9289581139405842TG0.370.02718.32E−06NMNAT34rs765679522398514TC0.8175−0.0371.22E−06GPR1254rs11410589923027094GA0.01580.11978.10E−07RP11-412P11.14rs1001171786136864AG0.3774−0.02826.09E−064rs77601419148249054TC0.0150.11682.22E−067rs77033896115513816AG0.01690.12626.84E−07TFEC, CAV18rs1749432220673550GA0.0750.05354.18E−0611rs13962992576144667GA0.01210.13475.91E−06RP11-111M22.2, C11orf30, LRRC3211rs2084308111051351TA0.0280.09674.29E−0713rs732823541998022TC0.9439−0.06076.72E−06MTRF1, OR7E36P13rs956798248605441GA0.13750.03943.08E−06LINC00444, LINC00562, SUCLA2, SUCLA2-AS1, NUDT15, MED4, MED4-AS1, POLR2KP213rs11737272061819169TC0.01490.10928.97E−0613rs149383020112585032AG0.03410.07875.09E−0714rs14443456391361842GA0.01350.12656.79E−06RPS6KA514rs13789921691830706TC0.02770.09113.06E−06GPR68, CCDC88C, SMEK117rs11264535866248531TC0.03840.0699.94E−06KPNA2, LRRC37A16P, AMZ2, ARSG18rs14822222265675614TC0.01690.11331.47E−06RP11-638L3.120rs713369985467150GA0.0180.12661.17E−07LINC00654Ch chromosome, A1 allele 1 (effect allele), A2 allele 2, eQTL expression quantitative trait loci, Freq allele frequency, IT inferior temporal cortex, MF midfrontal cortexFig. 4Genome-wide association studies (GWAS) of PAM with TSPO PET imaging follow-up. a Manhattan plot, (b) Q–Q plot, and (c) locus summary chart for inferior temporal cortex (IT) PAM, and corresponding, (d) Manhattan plot, (e) Q–Q plot, and (f) locus summary chart for midfrontal cortex (MF) PAM GWAS. Both analyses co-varied for genotype platform, age at death, sex, postmortem interval, APOE ε4 status, and top three EIGENSTRAT principal components. g Regional association plot highlighting the MF PAM genome-wide significant locus surrounding rs2997325 (p = 1.88 × 10^−8, n = 225). The color of each dot represents degree of linkage disequilibrium at that SNP based on 1000 Genomes Phase 3 reference data. The combined annotation-dependent depletion (CADD) score is plotted below the regional association plot on a scale from 0 to 20, where 20 indicates a variant with highest predicted deleteriousness. The RegulomeDB score is plotted below the CADD score, and summarizes evidence for effects on regulatory elements of each plotted SNP (5 = transcription factor-binding site or DNAase peak, 6 = other motif altered, 7 = no evidence). Below the RegulomeDB plot is an eQTL plot showing –log_10(p-values) for association of each plotted SNP with the expression of the mapped gene RP11-170N11.1 (LINC01361). h Strip chart showing the significant relationship between MF PAM (on y-axis as GWAS covariate-only model residuals) and rs2997325 genotype. i Whisker plot showing the means and standard deviations of [^11C]-PBR28 standard uptake value ratio (SUVR) for the left entorhinal cortex in the PET imaging sample from the Indiana Memory and Aging Study (p = 0.02, r^2 = 17.1, n = 27), stratified by rs2997325 genotype. Model co-varied for TSPO rs6971 genotype, APOE ε4 status, age at study entry, and sex. Tissue enrichment analyses for (j) IT and (k) MF PAM gene sets in 30 general tissue types from GTEx v7 show Bonferroni significant enrichment (two-sided) of only the MF gene set with colon, salivary gland, breast, small intestine, stomach, lung, and blood vessel tissues. Heat maps showing enrichment for all 53 tissue types in GTEx v7, including uni-directional analyses for up-regulation and down-regulation specifically can be found in Supplementary Figure 5',\n", - " 'paragraph_id': 9,\n", - " 'tokenizer': 'given, the, imperfect, correlation, between, m, ##f, and, it, pam, measures, (, spear, ##man, ρ, =, 0, ., 66, ), ,, we, performed, two, separate, genome, -, wide, association, studies, (, g, ##was, ), ., all, significant, and, suggest, ##ive, g, ##was, results, are, listed, in, table, 2, (, details, in, supplementary, data, ##s, 4, and, 5, ), ., for, it, pam, ,, a, single, locus, on, chromosome, 1, reached, genome, -, wide, significance, (, rs, ##18, ##30, ##9, ##39, ##70, ;, linear, regression, β, =, 0, ., 154, ,, se, =, 0, ., 02, ##4, ,, p, =, 5, ., 47, ×, 10, ^, −, ##10, ), (, fig, ., 4a, ,, b, ), ., however, ,, while, the, 191, kb, region, encompassed, by, this, lead, s, ##np, contains, three, independent, signals, ,, all, three, have, low, minor, all, ##ele, frequency, (, ma, ##f, ), (, 0, ., 02, >, ma, ##f, >, 0, ., 01, ##5, ), ., notably, ,, this, association, was, driven, by, only, seven, individuals, in, our, sample, carrying, minor, all, ##eles, tag, ##ging, this, ha, ##pl, ##otype, and, should, therefore, be, considered, cautiously, ., beyond, this, genome, -, wide, significant, locus, ,, 27, additional, independent, regions, were, associated, at, p, <, 1, ×, 10, ^, −, ##5, ,, and, mapping, based, on, position, and, combined, e, ##q, ##tl, evidence, identified, a, total, of, 52, candidate, genes, as, possible, functional, targets, of, these, variants, (, fig, ., 4, ##c, ), ., table, 2, ##ind, ##ep, ##end, ##ent, lo, ##ci, identified, by, co, ##rti, ##cal, pam, g, ##was, ##pa, ##m, region, ##ch, ##lea, ##d, s, ##np, ##s, ##np, position, ##a1, ##a, ##2, ##fr, ##e, ##q, (, a1, ), beta, (, a1, ), p, -, value, ##gen, ##es, mapped, to, locus, (, combined, position, ##al, and, /, or, e, ##q, ##tl, mapping, ), m, ##f, ##1, ##rs, ##29, ##9, ##7, ##32, ##58, ##36, ##41, ##42, ##4, ##at, ##0, ., 62, ##9, ##−, ##0, ., 03, ##8, ##9, ##1, ., 88, ##e, ##−, ##0, ##8, ##rp, ##11, -, 170, ##n, ##11, ., 11, ##rs, ##15, ##7, ##86, ##41, ##65, ##38, ##37, ##6, ##1, ##tc, ##0, ., 141, ##50, ., 04, ##43, ##8, ., 60, ##e, ##−, ##0, ##6, ##r, ##x, ##rg, ##1, ##rs, ##65, ##16, ##9, ##11, ##9, ##39, ##58, ##32, ##0, ##tc, ##0, ., 55, ##31, ##0, ., 03, ##17, ##6, ., 45, ##e, ##−, ##0, ##6, ##2, ##rs, ##12, ##6, ##23, ##58, ##7, ##23, ##21, ##60, ##55, ##4, ##ac, ##0, ., 29, ##−, ##0, ., 03, ##21, ##6, ., 00, ##e, ##−, ##0, ##6, ##c, ##2, ##orf, ##7, ##2, ,, ps, ##md, ##1, ,, h, ##tr, ##2, ##b, ,, arm, ##c, ##9, ##3, ##rs, ##7, ##8, ##46, ##13, ##16, ##10, ##48, ##58, ##43, ##4, ##tc, ##0, ., 05, ##8, ##70, ., 07, ##49, ##2, ., 54, ##e, ##−, ##0, ##7, ##7, ##rs, ##14, ##12, ##19, ##65, ##27, ##0, ##36, ##70, ##6, ##2, ##ct, ##0, ., 02, ##26, ##0, ., 108, ##38, ., 72, ##e, ##−, ##0, ##6, ##10, ##rs, ##6, ##18, ##60, ##52, ##01, ##34, ##8, ##26, ##64, ##5, ##tc, ##0, ., 05, ##43, ##−, ##0, ., 07, ##19, ##4, ., 02, ##e, ##−, ##0, ##6, ##tt, ##c, ##40, ,, lin, ##c, ##01, ##16, ##6, ##11, ##rs, ##13, ##86, ##6, ##23, ##57, ##9, ##20, ##58, ##9, ##50, ##ca, ##0, ., 05, ##55, ##0, ., 07, ##43, ., 49, ##e, ##−, ##0, ##7, ##nd, ##uf, ##b, ##11, ##p, ##1, ,, fat, ##3, ,, pga, ##m, ##1, ##p, ##9, ##13, ##rs, ##9, ##51, ##45, ##23, ##10, ##6, ##9, ##27, ##12, ##0, ##tc, ##0, ., 1871, ##−, ##0, ., 03, ##86, ##9, ., 20, ##e, ##−, ##0, ##6, ##13, ##rs, ##9, ##52, ##13, ##36, ##11, ##00, ##23, ##7, ##31, ##ct, ##0, ., 214, ##60, ., 03, ##7, ##8, ##1, ., 96, ##e, ##−, ##0, ##6, ##my, ##o, ##16, -, as, ##1, ,, lin, ##c, ##00, ##39, ##9, ##14, ##rs, ##21, ##0, ##59, ##9, ##7, ##10, ##7, ##20, ##9, ##22, ##6, ##ta, ##0, ., 227, ##60, ., 03, ##8, ##8, ##8, ., 46, ##e, ##−, ##0, ##6, ##igh, ##v, ##4, -, 39, ,, homer, ##2, ##p, ##1, ,, i, ##gh, ##v, ##4, -, 61, ,, i, ##gh, ##v, ##3, -, 64, ,, i, ##gh, ##v, ##3, -, 66, ,, i, ##gh, ##v, ##1, -, 69, ,, i, ##gh, ##v, ##3, -, 72, ,, i, ##gh, ##v, ##3, -, 73, ,, i, ##gh, ##v, ##3, -, 74, ##15, ##rs, ##14, ##47, ##0, ##53, ##01, ##6, ##7, ##85, ##50, ##35, ##ct, ##0, ., 02, ##6, ##30, ., 111, ., 74, ##e, ##−, ##0, ##7, ##aa, ##ga, ##b, ,, r, ##ps, ##24, ##p, ##16, ,, map, ##2, ##k, ##5, ,, sk, ##or, ##1, ##it, ##1, ##rs, ##56, ##26, ##75, ##58, ##21, ##00, ##53, ##16, ##t, ##g, ##0, ., 128, ##70, ., 04, ##31, ##6, ., 40, ##e, ##−, ##0, ##6, ##mu, ##l, ##1, ,, cd, ##a, ,, pink, ##1, ,, pink, ##1, -, as, ,, dd, ##ost, ,, ki, ##f, ##17, ##1, ##rs, ##11, ##32, ##85, ##27, ##57, ##0, ##8, ##9, ##6, ##31, ##9, ##ag, ##0, ., 234, ##4, ##−, ##0, ., 03, ##28, ##3, ., 10, ##e, ##−, ##0, ##6, ##hh, ##la, ##3, ,, ct, ##h, ##1, ##rs, ##18, ##30, ##9, ##39, ##70, ##8, ##8, ##45, ##42, ##6, ##1, ##ga, ##0, ., 01, ##47, ##0, ., 153, ##55, ., 47, ##e, ##−1, ##01, ##rs, ##14, ##7, ##8, ##36, ##15, ##51, ##13, ##50, ##16, ##0, ##7, ##tc, ##0, ., 01, ##29, ##0, ., 134, ##6, ##2, ., 46, ##e, ##−, ##0, ##6, ##sl, ##c, ##16, ##a1, ,, sl, ##c, ##16, ##a1, -, as, ##12, ##rs, ##14, ##8, ##25, ##9, ##39, ##32, ##8, ##7, ##13, ##65, ##4, ##gc, ##0, ., 02, ##0, ##40, ., 103, ##8, ##3, ., 30, ##e, ##−, ##0, ##6, ##pl, ##b, ##12, ##rs, ##14, ##14, ##18, ##9, ##70, ##40, ##57, ##60, ##9, ##5, ##t, ##g, ##0, ., 01, ##0, ##20, ., 159, ##34, ., 82, ##e, ##−, ##0, ##7, ##sl, ##c, ##8, ##a1, ##2, ##rs, ##17, ##01, ##8, ##13, ##8, ##80, ##15, ##42, ##36, ##gc, ##0, ., 050, ., 05, ##8, ##8, ##7, ., 53, ##e, ##−, ##0, ##6, ##ct, ##nna, ##22, ##rs, ##7, ##9, ##34, ##15, ##75, ##12, ##9, ##13, ##32, ##9, ##2, ##c, ##g, ##0, ., 05, ##51, ##0, ., 06, ##32, ., 75, ##e, ##−, ##0, ##6, ##gp, ##r, ##17, ##2, ##rs, ##60, ##200, ##36, ##41, ##60, ##70, ##80, ##50, ##ag, ##0, ., 06, ##23, ##0, ., 05, ##55, ##2, ., 14, ##e, ##−, ##0, ##6, ##ba, ##z, ##2, ##b, ,, l, ##y, ##75, ,, l, ##y, ##75, -, cd, ##30, ##2, ,, pl, ##a, ##2, ##r, ##1, ,, it, ##gb, ##6, ##2, ##rs, ##23, ##48, ##11, ##7, ##20, ##15, ##9, ##85, ##21, ##t, ##g, ##0, ., 88, ##9, ##3, ##−, ##0, ., 04, ##14, ##9, ., 76, ##e, ##−, ##0, ##6, ##ao, ##x, ##3, ##p, ,, ao, ##x, ##2, ##p, ,, ac, ##00, ##7, ##16, ##3, ., 3, ,, pp, ##il, ##3, ,, rn, ##u, ##6, -, 312, ##p, ##3, ##rs, ##9, ##28, ##9, ##58, ##11, ##39, ##40, ##58, ##42, ##t, ##g, ##0, ., 370, ., 02, ##7, ##18, ., 32, ##e, ##−, ##0, ##6, ##n, ##m, ##nat, ##34, ##rs, ##7, ##65, ##6, ##7, ##9, ##52, ##23, ##9, ##85, ##14, ##tc, ##0, ., 81, ##75, ##−, ##0, ., 03, ##7, ##1, ., 22, ##e, ##−, ##0, ##6, ##gp, ##r, ##12, ##54, ##rs, ##11, ##41, ##0, ##58, ##9, ##9, ##23, ##0, ##27, ##0, ##9, ##4, ##ga, ##0, ., 01, ##58, ##0, ., 119, ##7, ##8, ., 10, ##e, ##−, ##0, ##7, ##rp, ##11, -, 412, ##p, ##11, ., 14, ##rs, ##100, ##11, ##7, ##17, ##86, ##13, ##6, ##86, ##4, ##ag, ##0, ., 37, ##7, ##4, ##−, ##0, ., 02, ##8, ##26, ., 09, ##e, ##−, ##0, ##64, ##rs, ##7, ##7, ##60, ##14, ##19, ##14, ##8, ##24, ##90, ##54, ##tc, ##0, ., 01, ##50, ., 116, ##8, ##2, ., 22, ##e, ##−, ##0, ##6, ##7, ##rs, ##7, ##70, ##33, ##8, ##9, ##6, ##11, ##55, ##13, ##8, ##16, ##ag, ##0, ., 01, ##6, ##90, ., 126, ##26, ., 84, ##e, ##−, ##0, ##7, ##tf, ##ec, ,, ca, ##v, ##18, ##rs, ##17, ##49, ##43, ##22, ##20, ##6, ##7, ##35, ##50, ##ga, ##0, ., 07, ##50, ., 05, ##35, ##4, ., 18, ##e, ##−, ##0, ##6, ##11, ##rs, ##13, ##9, ##6, ##29, ##9, ##25, ##7, ##6, ##14, ##46, ##6, ##7, ##ga, ##0, ., 01, ##21, ##0, ., 134, ##75, ., 91, ##e, ##−, ##0, ##6, ##rp, ##11, -, 111, ##m, ##22, ., 2, ,, c1, ##1, ##orf, ##30, ,, l, ##rr, ##c, ##32, ##11, ##rs, ##20, ##8, ##43, ##0, ##8, ##11, ##10, ##51, ##35, ##1, ##ta, ##0, ., 02, ##80, ., 09, ##6, ##7, ##4, ., 29, ##e, ##−, ##0, ##7, ##13, ##rs, ##7, ##32, ##8, ##23, ##54, ##19, ##9, ##80, ##22, ##tc, ##0, ., 94, ##39, ##−, ##0, ., 06, ##0, ##7, ##6, ., 72, ##e, ##−, ##0, ##6, ##mt, ##rf, ##1, ,, or, ##7, ##e, ##36, ##p, ##13, ##rs, ##9, ##56, ##7, ##9, ##8, ##24, ##86, ##0, ##54, ##41, ##ga, ##0, ., 137, ##50, ., 03, ##9, ##43, ., 08, ##e, ##−, ##0, ##6, ##lin, ##c, ##00, ##44, ##4, ,, lin, ##c, ##00, ##56, ##2, ,, su, ##cl, ##a, ##2, ,, su, ##cl, ##a, ##2, -, as, ##1, ,, nu, ##dt, ##15, ,, med, ##4, ,, med, ##4, -, as, ##1, ,, pol, ##r, ##2, ##k, ##p, ##21, ##3, ##rs, ##11, ##7, ##37, ##27, ##20, ##6, ##18, ##19, ##16, ##9, ##tc, ##0, ., 01, ##49, ##0, ., 109, ##28, ., 97, ##e, ##−, ##0, ##6, ##13, ##rs, ##14, ##9, ##38, ##30, ##20, ##11, ##25, ##85, ##0, ##32, ##ag, ##0, ., 03, ##41, ##0, ., 07, ##8, ##75, ., 09, ##e, ##−, ##0, ##7, ##14, ##rs, ##14, ##44, ##34, ##56, ##39, ##13, ##6, ##18, ##42, ##ga, ##0, ., 01, ##35, ##0, ., 126, ##56, ., 79, ##e, ##−, ##0, ##6, ##rp, ##s, ##6, ##ka, ##51, ##4, ##rs, ##13, ##7, ##8, ##9, ##9, ##21, ##6, ##9, ##18, ##30, ##70, ##6, ##tc, ##0, ., 02, ##7, ##70, ., 09, ##11, ##3, ., 06, ##e, ##−, ##0, ##6, ##gp, ##r, ##6, ##8, ,, cc, ##dc, ##8, ##8, ##c, ,, sm, ##ek, ##11, ##7, ##rs, ##11, ##26, ##45, ##35, ##86, ##6, ##24, ##85, ##31, ##tc, ##0, ., 03, ##8, ##40, ., 06, ##9, ##9, ., 94, ##e, ##−, ##0, ##6, ##k, ##p, ##na, ##2, ,, l, ##rr, ##c, ##37, ##a1, ##6, ##p, ,, am, ##z, ##2, ,, ars, ##g, ##18, ##rs, ##14, ##8, ##22, ##22, ##22, ##65, ##6, ##75, ##6, ##14, ##tc, ##0, ., 01, ##6, ##90, ., 113, ##31, ., 47, ##e, ##−, ##0, ##6, ##rp, ##11, -, 63, ##8, ##l, ##3, ., 120, ##rs, ##7, ##13, ##36, ##9, ##9, ##85, ##46, ##7, ##15, ##0, ##ga, ##0, ., 01, ##80, ., 126, ##6, ##1, ., 17, ##e, ##−, ##0, ##7, ##lin, ##c, ##00, ##65, ##4, ##ch, chromosome, ,, a1, all, ##ele, 1, (, effect, all, ##ele, ), ,, a2, all, ##ele, 2, ,, e, ##q, ##tl, expression, quantitative, trait, lo, ##ci, ,, fr, ##e, ##q, all, ##ele, frequency, ,, it, inferior, temporal, cortex, ,, m, ##f, mid, ##front, ##al, cortex, ##fi, ##g, ., 4, ##gen, ##ome, -, wide, association, studies, (, g, ##was, ), of, pam, with, ts, ##po, pet, imaging, follow, -, up, ., a, manhattan, plot, ,, (, b, ), q, –, q, plot, ,, and, (, c, ), locus, summary, chart, for, inferior, temporal, cortex, (, it, ), pam, ,, and, corresponding, ,, (, d, ), manhattan, plot, ,, (, e, ), q, –, q, plot, ,, and, (, f, ), locus, summary, chart, for, mid, ##front, ##al, cortex, (, m, ##f, ), pam, g, ##was, ., both, analyses, co, -, varied, for, gen, ##otype, platform, ,, age, at, death, ,, sex, ,, post, ##mo, ##rte, ##m, interval, ,, ap, ##oe, ε, ##4, status, ,, and, top, three, e, ##igen, ##stra, ##t, principal, components, ., g, regional, association, plot, highlighting, the, m, ##f, pam, genome, -, wide, significant, locus, surrounding, rs, ##29, ##9, ##7, ##32, ##5, (, p, =, 1, ., 88, ×, 10, ^, −, ##8, ,, n, =, 225, ), ., the, color, of, each, dot, represents, degree, of, link, ##age, di, ##se, ##quil, ##ib, ##rium, at, that, s, ##np, based, on, 1000, genome, ##s, phase, 3, reference, data, ., the, combined, ann, ##ota, ##tion, -, dependent, de, ##ple, ##tion, (, cad, ##d, ), score, is, plotted, below, the, regional, association, plot, on, a, scale, from, 0, to, 20, ,, where, 20, indicates, a, variant, with, highest, predicted, del, ##eter, ##ious, ##ness, ., the, reg, ##ulo, ##med, ##b, score, is, plotted, below, the, cad, ##d, score, ,, and, sum, ##mar, ##izes, evidence, for, effects, on, regulatory, elements, of, each, plotted, s, ##np, (, 5, =, transcription, factor, -, binding, site, or, dna, ##ase, peak, ,, 6, =, other, motif, altered, ,, 7, =, no, evidence, ), ., below, the, reg, ##ulo, ##med, ##b, plot, is, an, e, ##q, ##tl, plot, showing, –, log, _, 10, (, p, -, values, ), for, association, of, each, plotted, s, ##np, with, the, expression, of, the, mapped, gene, r, ##p, ##11, -, 170, ##n, ##11, ., 1, (, lin, ##c, ##01, ##36, ##1, ), ., h, strip, chart, showing, the, significant, relationship, between, m, ##f, pam, (, on, y, -, axis, as, g, ##was, co, ##var, ##iate, -, only, model, residual, ##s, ), and, rs, ##29, ##9, ##7, ##32, ##5, gen, ##otype, ., i, w, ##his, ##ker, plot, showing, the, means, and, standard, deviation, ##s, of, [, ^, 11, ##c, ], -, p, ##br, ##28, standard, up, ##take, value, ratio, (, suv, ##r, ), for, the, left, en, ##tor, ##hin, ##al, cortex, in, the, pet, imaging, sample, from, the, indiana, memory, and, aging, study, (, p, =, 0, ., 02, ,, r, ^, 2, =, 17, ., 1, ,, n, =, 27, ), ,, st, ##rat, ##ified, by, rs, ##29, ##9, ##7, ##32, ##5, gen, ##otype, ., model, co, -, varied, for, ts, ##po, rs, ##6, ##9, ##7, ##1, gen, ##otype, ,, ap, ##oe, ε, ##4, status, ,, age, at, study, entry, ,, and, sex, ., tissue, enrichment, analyses, for, (, j, ), it, and, (, k, ), m, ##f, pam, gene, sets, in, 30, general, tissue, types, from, gt, ##ex, v, ##7, show, bon, ##fer, ##ron, ##i, significant, enrichment, (, two, -, sided, ), of, only, the, m, ##f, gene, set, with, colon, ,, saliva, ##ry, gland, ,, breast, ,, small, int, ##est, ##ine, ,, stomach, ,, lung, ,, and, blood, vessel, tissues, ., heat, maps, showing, enrichment, for, all, 53, tissue, types, in, gt, ##ex, v, ##7, ,, including, un, ##i, -, directional, analyses, for, up, -, regulation, and, down, -, regulation, specifically, can, be, found, in, supplementary, figure, 5'},\n", - " {'article_id': '342d06e10bcae551eb609061dc71a20c',\n", - " 'section_name': 'Multiplex brain immunofluorescent labeling with subclass switched R-mAbs',\n", - " 'text': 'One benefit of subclass switching R-mAbs is the ability to perform multiplex immunolabeling not previously possible due to IgG subclass conflicts. Examples of such enrichment in cellular protein localization are shown in Figure 4. Figure 4A shows labeling with the subclass switched IgG2a R-mAb derived from the widely used pan-voltage-gated sodium channel or ‘pan-Nav channel’ IgG1 mAb K58/35 (Rasband et al., 1999). Like the corresponding mAb, K58/35 R-mAb gives robust labeling of Nav channels concentrated on the axon initial segment (AIS, arrows in Figure 4A main panel), and at nodes of Ranvier (arrows in Figure 4A insets). Importantly, subclass switching allowed Nav channel labeling at nodes to be verified by co-labeling with K65/35 an IgG1 subclass antibody directed against CASPR, a protein concentrated at paranodes (Menegoz et al., 1997; Peles et al., 1997). Similarly, simultaneous labeling for the highly-related GABA-A receptor β1 and β3 subunits (Zhang et al., 1991) with their widely used respective mAbs N96/55 and N87/25 could not be performed as both are IgG1 subclass. Switching the N96/55 mAb to the IgG2a N96/55R R-mAb allowed simultaneous detection of these two highly-related but distinct GABA-A receptor subunits. In Figure 4B localization of GABA-A receptor β1 and β3 subunits appeared completely non-overlapping in separate layers of cerebellum. Figure 4C illustrates localization of protein Kv2.1 and AnkyrinG in separate subcellular neuronal compartments. Labeling for the K89/34R R-mAb (IgG2a, red), specific for the Kv2.1 channel, highly expressed in the plasma membrane of the cell body and proximal dendrites (arrows in panel C1) is shown together with labeling for N106/65 (green), an IgG1 mAb specific for AnkyrinG, a scaffolding protein highly expressed in the AIS (arrows in panel C2) and at nodes of Ranvier. Subclass switching N229A/32 (IgG1, GABA-AR α6) to IgG2a, allows comparison with Kv4.2 potassium channel (K57/1, IgG1) in the cerebellum where both are highly expressed in the granule cell layer (Figure 4D). While both are prominently found in the glomerular synapses present on the dendrites of these cells, simultaneous labeling reveals that some cells express both (Figure 4D, magenta) while others appear to predominantly express Kv4.2 (Figure 4D, blue). Labeling for both proteins is in contrast to that for mAb N147/6 (IgG2b) which recognizes all isoforms of the QKI transcription factor and labels oligodendrocytes within the granule cell layer and throughout the Purkinje cell layer (PCL, green). In Figure 4E, localization of pan-QKI (N147/6, IgG2b, blue) is compared with GFAP (N206A/8, IgG1, green) predominantly thought to be in astrocytes. Surprisingly many (but not all) cells co-label both proteins. We also labeled cortical neurons with these two mAbs (pan-QKI in blue, GFAP in green). Multiplex labeling for the neuron-specific Kv2.1 channel, using subclass-switched K89/34R (IgG2a, red) confirms non-neuronal localization of both proteins. Lastly, we labeled for the postsynaptic scaffold protein PSD-93 using R-mAb N18/30R (IgG2a, red), which in the cerebellum is prominently localized to Purkinje cell somata and dendrites (Brenman et al., 1998). As shown in Figure 4F, the R-mAb labeling is consistent with the established localization of PSD-93. Because of subclass switching the N18/30R R-mAb, this labeling can now be contrasted with labeling for the excitatory presynaptic terminal marker VGluT1, labeled with mAb N28/9 (IgG1, blue), which exhibits robust labeling of parallel fiber synapses in the molecular layer, and glomerular synapses in the granule cell layer. Together these results demonstrate the utility of employing subclass-switched R-mAbs to obtain labeling combinations not possible with native mAbs.',\n", - " 'paragraph_id': 15,\n", - " 'tokenizer': 'one, benefit, of, sub, ##class, switching, r, -, mab, ##s, is, the, ability, to, perform, multiple, ##x, im, ##mun, ##ola, ##bel, ##ing, not, previously, possible, due, to, i, ##gg, sub, ##class, conflicts, ., examples, of, such, enrichment, in, cellular, protein, local, ##ization, are, shown, in, figure, 4, ., figure, 4a, shows, labeling, with, the, sub, ##class, switched, i, ##gg, ##2, ##a, r, -, mab, derived, from, the, widely, used, pan, -, voltage, -, gate, ##d, sodium, channel, or, ‘, pan, -, na, ##v, channel, ’, i, ##gg, ##1, mab, k, ##58, /, 35, (, ras, ##band, et, al, ., ,, 1999, ), ., like, the, corresponding, mab, ,, k, ##58, /, 35, r, -, mab, gives, robust, labeling, of, na, ##v, channels, concentrated, on, the, ax, ##on, initial, segment, (, ai, ##s, ,, arrows, in, figure, 4a, main, panel, ), ,, and, at, nodes, of, ran, ##vier, (, arrows, in, figure, 4a, ins, ##ets, ), ., importantly, ,, sub, ##class, switching, allowed, na, ##v, channel, labeling, at, nodes, to, be, verified, by, co, -, labeling, with, k, ##65, /, 35, an, i, ##gg, ##1, sub, ##class, antibody, directed, against, cas, ##pr, ,, a, protein, concentrated, at, para, ##no, ##des, (, men, ##ego, ##z, et, al, ., ,, 1997, ;, pe, ##les, et, al, ., ,, 1997, ), ., similarly, ,, simultaneous, labeling, for, the, highly, -, related, ga, ##ba, -, a, receptor, β, ##1, and, β, ##3, subunit, ##s, (, zhang, et, al, ., ,, 1991, ), with, their, widely, used, respective, mab, ##s, n, ##9, ##6, /, 55, and, n, ##8, ##7, /, 25, could, not, be, performed, as, both, are, i, ##gg, ##1, sub, ##class, ., switching, the, n, ##9, ##6, /, 55, mab, to, the, i, ##gg, ##2, ##a, n, ##9, ##6, /, 55, ##r, r, -, mab, allowed, simultaneous, detection, of, these, two, highly, -, related, but, distinct, ga, ##ba, -, a, receptor, subunit, ##s, ., in, figure, 4, ##b, local, ##ization, of, ga, ##ba, -, a, receptor, β, ##1, and, β, ##3, subunit, ##s, appeared, completely, non, -, overlapping, in, separate, layers, of, ce, ##re, ##bell, ##um, ., figure, 4, ##c, illustrates, local, ##ization, of, protein, kv, ##2, ., 1, and, an, ##ky, ##ring, in, separate, sub, ##cellular, ne, ##uron, ##al, compartments, ., labeling, for, the, k, ##8, ##9, /, 34, ##r, r, -, mab, (, i, ##gg, ##2, ##a, ,, red, ), ,, specific, for, the, kv, ##2, ., 1, channel, ,, highly, expressed, in, the, plasma, membrane, of, the, cell, body, and, pro, ##xi, ##mal, den, ##dr, ##ites, (, arrows, in, panel, c1, ), is, shown, together, with, labeling, for, n, ##10, ##6, /, 65, (, green, ), ,, an, i, ##gg, ##1, mab, specific, for, an, ##ky, ##ring, ,, a, sc, ##af, ##folding, protein, highly, expressed, in, the, ai, ##s, (, arrows, in, panel, c2, ), and, at, nodes, of, ran, ##vier, ., sub, ##class, switching, n, ##22, ##9, ##a, /, 32, (, i, ##gg, ##1, ,, ga, ##ba, -, ar, α, ##6, ), to, i, ##gg, ##2, ##a, ,, allows, comparison, with, kv, ##4, ., 2, potassium, channel, (, k, ##57, /, 1, ,, i, ##gg, ##1, ), in, the, ce, ##re, ##bell, ##um, where, both, are, highly, expressed, in, the, gran, ##ule, cell, layer, (, figure, 4, ##d, ), ., while, both, are, prominently, found, in, the, g, ##lom, ##er, ##ular, syn, ##ap, ##ses, present, on, the, den, ##dr, ##ites, of, these, cells, ,, simultaneous, labeling, reveals, that, some, cells, express, both, (, figure, 4, ##d, ,, mage, ##nta, ), while, others, appear, to, predominantly, express, kv, ##4, ., 2, (, figure, 4, ##d, ,, blue, ), ., labeling, for, both, proteins, is, in, contrast, to, that, for, mab, n, ##14, ##7, /, 6, (, i, ##gg, ##2, ##b, ), which, recognizes, all, iso, ##forms, of, the, q, ##ki, transcription, factor, and, labels, ol, ##igo, ##den, ##dro, ##cytes, within, the, gran, ##ule, cell, layer, and, throughout, the, pu, ##rkin, ##je, cell, layer, (, pc, ##l, ,, green, ), ., in, figure, 4, ##e, ,, local, ##ization, of, pan, -, q, ##ki, (, n, ##14, ##7, /, 6, ,, i, ##gg, ##2, ##b, ,, blue, ), is, compared, with, g, ##fa, ##p, (, n, ##20, ##6, ##a, /, 8, ,, i, ##gg, ##1, ,, green, ), predominantly, thought, to, be, in, astro, ##cytes, ., surprisingly, many, (, but, not, all, ), cells, co, -, label, both, proteins, ., we, also, labeled, co, ##rti, ##cal, neurons, with, these, two, mab, ##s, (, pan, -, q, ##ki, in, blue, ,, g, ##fa, ##p, in, green, ), ., multiple, ##x, labeling, for, the, ne, ##uron, -, specific, kv, ##2, ., 1, channel, ,, using, sub, ##class, -, switched, k, ##8, ##9, /, 34, ##r, (, i, ##gg, ##2, ##a, ,, red, ), confirms, non, -, ne, ##uron, ##al, local, ##ization, of, both, proteins, ., lastly, ,, we, labeled, for, the, posts, ##yna, ##ptic, sc, ##af, ##fold, protein, ps, ##d, -, 93, using, r, -, mab, n, ##18, /, 30, ##r, (, i, ##gg, ##2, ##a, ,, red, ), ,, which, in, the, ce, ##re, ##bell, ##um, is, prominently, localized, to, pu, ##rkin, ##je, cell, so, ##mata, and, den, ##dr, ##ites, (, br, ##en, ##man, et, al, ., ,, 1998, ), ., as, shown, in, figure, 4, ##f, ,, the, r, -, mab, labeling, is, consistent, with, the, established, local, ##ization, of, ps, ##d, -, 93, ., because, of, sub, ##class, switching, the, n, ##18, /, 30, ##r, r, -, mab, ,, this, labeling, can, now, be, contrasted, with, labeling, for, the, ex, ##cit, ##atory, pre, ##sy, ##na, ##ptic, terminal, marker, v, ##gl, ##ut, ##1, ,, labeled, with, mab, n, ##28, /, 9, (, i, ##gg, ##1, ,, blue, ), ,, which, exhibits, robust, labeling, of, parallel, fiber, syn, ##ap, ##ses, in, the, molecular, layer, ,, and, g, ##lom, ##er, ##ular, syn, ##ap, ##ses, in, the, gran, ##ule, cell, layer, ., together, these, results, demonstrate, the, utility, of, employing, sub, ##class, -, switched, r, -, mab, ##s, to, obtain, labeling, combinations, not, possible, with, native, mab, ##s, .'},\n", - " {'article_id': '9526704a47665f9cf9741e7fd30ad68d',\n", - " 'section_name': 'INTRODUCTION',\n", - " 'text': 'The autonomic space model provides a conceptual framework in which to understand reciprocal, independent, and coactive patterns of sympathetic and parasympathetic cardiac control, both in the context of within‐individual and between‐individual study designs (Berntson, Cacioppo, Binkley et al., 1994; Berntson, Cacioppo, & Quigley, 1994; Berntson, Norman, Hawkley, & Cacioppo, 2008). However, to be useful in empirical studies, the model requires separate measures of cardiac sympathetic and cardiac vagal activity. Although these measures could be obtained by pharmaceutical blockage of sympathetic and vagal activation, to do so is labor intensive, not without risk, hard to justify in children, and of limited practicality in larger‐scaled studies. Noninvasive metrics that predominantly capture either sympathetic or vagal activity are better suited for such studies. This has been a major driver for the development and use of HRV metrics in psychophysiology.BOX 1 What are the neurophysiological drivers of HRV?Both the parasympathetic and sympathetic arms of the ANS act on the cardiac pacemaker cells of the SA node. SA cells exhibit a special capacity for self‐excitation, which is characterized by spontaneous membrane depolarization and the consequent generation of rhythmic action potentials by the voltage clock and Ca^++ mechanisms (Bartos, Grandi, & Ripplinger, 2015) that establish the intrinsic HR (HR in the absence of autonomic or hormonal influences). Several ion channels play a critical role in setting the rhythmic excitation of SA cells. Subsets of these ion channels are influenced by the release of acetylcholine (ACh) by the parasympathetic vagi onto muscarinic M2 receptors and by the release of norepinephrine (NE) by sympathetic motor neurons onto beta‐1 adrenergic receptors. ACh release strongly slows the spontaneous diastolic depolarization and may also increase the depth of repolarization of the SA cells (see Figure 1). This basic autonomic influence on SA activity leads to the well‐known observation that increases in the mean activity of the vagal nerve lead to increases in the heart period.In parallel, increases in mean activity in the vagal nerve are accompanied by an increase in HRV through the principle of vagal gating (Eckberg, 1983, 2003). Vagal gating is based on two fundamental processes. First, tonic efferent vagal activity arising in the structures of the so‐called central autonomic network (Saper, 2002) is subject to phasic (frequency) modulation by other neurophysiological processes at the brain stem level, including cardiorespiratory coupling and the baroreflex (Berntson, Cacioppo, & Quigley, 1993). To elaborate, cardiorespiratory coupling exerts inhibitory influences during inspiration on vagal motor neurons in the nucleus ambiguus (NA), the predominant brainstem source of cardio‐inhibition by the vagal nerve in mammals (Chapleau & Abboud, 2001). This causes a periodic waxing and waning of the tonic vagal influence on SA node cells in phase with the respiratory cycle. This vagal influence translates into a decrease in heart period during inspiration relative to expiration, which is a chief source of high‐frequency HRV within normative rates of breathing. Figure 2a provides a schematic representation of this process.We hasten to note that RSA neither implies a complete absence of vagal inhibition during expiration nor a complete vagal inhibition during inspiration,1 but rather relative changes in responsiveness of vagal motor neurons across the respiratory cycle, with less responsiveness during inspiration and more responsiveness during expiration. The ensuing modulation of central vagal activity by cardiorespiratory coupling and other neurophysiological sources of influence on RSA alter only a small fraction of the total influence of the vagus nerve on the SA node (Craft & Schwartz, 1995; Eckberg, 2003). For example, Craft and Schwartz performed full vagal blockade studies in 20 young (mean age 30) and 19 older (mean age 69) participants. In this study, the heart period shortened from 1,090 ms to 506 ms (Δ584 ms) in young participants, and from 1,053 ms to 718 ms (Δ335 ms) in older participants. These changes dwarf the typical modulation of heart period by phasic (respiratory‐related) inhibition that amounts to an average pvRSA of ~50 ms, with an approximate range of 0–200 ms.It is critical to note here that respiratory influences also entrain sympathetic nervous system (SNS) outflow to SA node cells. The SNS outflow‐induced increase in NE release depolarizes and enhances the excitability of SA cells via metabotropic, cAMP‐mediated, second‐messenger processes. The latter processes not only accelerate the spontaneous depolarization of the SA cells, but also accelerate the speed of neural conduction in cardiac tissue. Compared to the fast (~400 ms) vagal influences, these sympathetic influences on HRV are strongly attenuated by the low‐pass filtering characteristics of slow (i.e., 2–3 s) G‐protein coupled metabotropic cascades that are initiated by NE binding at beta‐1 adrenergic receptors (Berntson et al., 1993; Mark & Herlitze, 2000). Thus, although both steady state and phasic increases in sympathetic SA node activity can shorten basal heart period, high frequency sympathetic fluctuations (e.g., in the respiratory frequency range) do not translate into phasic heart period fluctuations. Accordingly, most HRV metrics that are usually employed in psychophysiology and behavioral medicine (i.e., RMSSD, HF, pvRSA) can be largely ascribed to modulation of the vagal nerve outflow to SA cells.A second fundamental principle in vagal gating is that the amplitude of the phasic modulation of activity in the autonomic motor neurons at the brainstem level (e.g., the NA) is a function of the absolute tonic level of firing of these autonomic motor neurons (Eckberg, 2003). The amplitude of the final modulated vagal signal traveling to the SA node therefore scales with the frequency of the tonic vagal pulse train presumptively arising in brain systems and cell groups comprising the so‐called central autonomic network. This means that the modulation of a pulse train of 12 Hz to vagal motor neurons will yield a larger peak‐to‐trough difference in the vagal signal to the SA node than the modulation of a 6 Hz pulse train. This is illustrated in Figure 2b. Here, we depict a person with lower centrally generated tonic vagal activity than in Figure 2a, which leads to a smaller difference between the shortest and longest beats in inspiration and expiration (50 ms compared to 100 ms). This principle is attributable to the fact that, at high levels of neural activity, there is a larger “carrier signal” to be subjected to phasic (respiratory‐related) inhibition.',\n", - " 'paragraph_id': 3,\n", - " 'tokenizer': 'the, auto, ##no, ##mic, space, model, provides, a, conceptual, framework, in, which, to, understand, reciprocal, ,, independent, ,, and, coa, ##ctive, patterns, of, sympathetic, and, para, ##sy, ##mp, ##ath, ##etic, cardiac, control, ,, both, in, the, context, of, within, ‐, individual, and, between, ‐, individual, study, designs, (, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, bin, ##kley, et, al, ., ,, 1994, ;, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, &, qui, ##gley, ,, 1994, ;, bern, ##tson, ,, norman, ,, hawk, ##ley, ,, &, ca, ##cio, ##pp, ##o, ,, 2008, ), ., however, ,, to, be, useful, in, empirical, studies, ,, the, model, requires, separate, measures, of, cardiac, sympathetic, and, cardiac, va, ##gal, activity, ., although, these, measures, could, be, obtained, by, pharmaceutical, block, ##age, of, sympathetic, and, va, ##gal, activation, ,, to, do, so, is, labor, intensive, ,, not, without, risk, ,, hard, to, justify, in, children, ,, and, of, limited, practical, ##ity, in, larger, ‐, scaled, studies, ., non, ##in, ##vas, ##ive, metric, ##s, that, predominantly, capture, either, sympathetic, or, va, ##gal, activity, are, better, suited, for, such, studies, ., this, has, been, a, major, driver, for, the, development, and, use, of, hr, ##v, metric, ##s, in, psycho, ##phy, ##sio, ##logy, ., box, 1, what, are, the, ne, ##uro, ##phy, ##sio, ##logical, drivers, of, hr, ##v, ?, both, the, para, ##sy, ##mp, ##ath, ##etic, and, sympathetic, arms, of, the, an, ##s, act, on, the, cardiac, pace, ##maker, cells, of, the, sa, node, ., sa, cells, exhibit, a, special, capacity, for, self, ‐, ex, ##cit, ##ation, ,, which, is, characterized, by, spontaneous, membrane, de, ##pol, ##ari, ##zation, and, the, con, ##se, ##quent, generation, of, rhythmic, action, potential, ##s, by, the, voltage, clock, and, ca, ^, +, +, mechanisms, (, bart, ##os, ,, grand, ##i, ,, &, rip, ##pling, ##er, ,, 2015, ), that, establish, the, intrinsic, hr, (, hr, in, the, absence, of, auto, ##no, ##mic, or, ho, ##rm, ##onal, influences, ), ., several, ion, channels, play, a, critical, role, in, setting, the, rhythmic, ex, ##cit, ##ation, of, sa, cells, ., subset, ##s, of, these, ion, channels, are, influenced, by, the, release, of, ace, ##ty, ##lch, ##olin, ##e, (, ac, ##h, ), by, the, para, ##sy, ##mp, ##ath, ##etic, va, ##gi, onto, mu, ##sca, ##rini, ##c, m2, receptors, and, by, the, release, of, nor, ##ep, ##ine, ##ph, ##rine, (, ne, ), by, sympathetic, motor, neurons, onto, beta, ‐, 1, ad, ##ren, ##er, ##gic, receptors, ., ac, ##h, release, strongly, slow, ##s, the, spontaneous, dia, ##sto, ##lic, de, ##pol, ##ari, ##zation, and, may, also, increase, the, depth, of, rep, ##olar, ##ization, of, the, sa, cells, (, see, figure, 1, ), ., this, basic, auto, ##no, ##mic, influence, on, sa, activity, leads, to, the, well, ‐, known, observation, that, increases, in, the, mean, activity, of, the, va, ##gal, nerve, lead, to, increases, in, the, heart, period, ., in, parallel, ,, increases, in, mean, activity, in, the, va, ##gal, nerve, are, accompanied, by, an, increase, in, hr, ##v, through, the, principle, of, va, ##gal, ga, ##ting, (, ec, ##k, ##berg, ,, 1983, ,, 2003, ), ., va, ##gal, ga, ##ting, is, based, on, two, fundamental, processes, ., first, ,, tonic, e, ##ffer, ##ent, va, ##gal, activity, arising, in, the, structures, of, the, so, ‐, called, central, auto, ##no, ##mic, network, (, sap, ##er, ,, 2002, ), is, subject, to, ph, ##asi, ##c, (, frequency, ), modulation, by, other, ne, ##uro, ##phy, ##sio, ##logical, processes, at, the, brain, stem, level, ,, including, card, ##ior, ##es, ##pi, ##rator, ##y, coupling, and, the, bar, ##ore, ##fle, ##x, (, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, &, qui, ##gley, ,, 1993, ), ., to, elaborate, ,, card, ##ior, ##es, ##pi, ##rator, ##y, coupling, ex, ##ert, ##s, inhibitor, ##y, influences, during, inspiration, on, va, ##gal, motor, neurons, in, the, nucleus, am, ##bi, ##gu, ##us, (, na, ), ,, the, predominant, brains, ##tem, source, of, card, ##io, ‐, inhibition, by, the, va, ##gal, nerve, in, mammals, (, cha, ##ple, ##au, &, ab, ##bo, ##ud, ,, 2001, ), ., this, causes, a, periodic, wax, ##ing, and, wan, ##ing, of, the, tonic, va, ##gal, influence, on, sa, node, cells, in, phase, with, the, respiratory, cycle, ., this, va, ##gal, influence, translates, into, a, decrease, in, heart, period, during, inspiration, relative, to, ex, ##piration, ,, which, is, a, chief, source, of, high, ‐, frequency, hr, ##v, within, norma, ##tive, rates, of, breathing, ., figure, 2a, provides, a, sc, ##hema, ##tic, representation, of, this, process, ., we, haste, ##n, to, note, that, rs, ##a, neither, implies, a, complete, absence, of, va, ##gal, inhibition, during, ex, ##piration, nor, a, complete, va, ##gal, inhibition, during, inspiration, ,, 1, but, rather, relative, changes, in, responsive, ##ness, of, va, ##gal, motor, neurons, across, the, respiratory, cycle, ,, with, less, responsive, ##ness, during, inspiration, and, more, responsive, ##ness, during, ex, ##piration, ., the, ensuing, modulation, of, central, va, ##gal, activity, by, card, ##ior, ##es, ##pi, ##rator, ##y, coupling, and, other, ne, ##uro, ##phy, ##sio, ##logical, sources, of, influence, on, rs, ##a, alter, only, a, small, fraction, of, the, total, influence, of, the, va, ##gus, nerve, on, the, sa, node, (, craft, &, schwartz, ,, 1995, ;, ec, ##k, ##berg, ,, 2003, ), ., for, example, ,, craft, and, schwartz, performed, full, va, ##gal, blockade, studies, in, 20, young, (, mean, age, 30, ), and, 19, older, (, mean, age, 69, ), participants, ., in, this, study, ,, the, heart, period, shortened, from, 1, ,, 09, ##0, ms, to, 50, ##6, ms, (, δ, ##58, ##4, ms, ), in, young, participants, ,, and, from, 1, ,, 05, ##3, ms, to, 71, ##8, ms, (, δ, ##33, ##5, ms, ), in, older, participants, ., these, changes, dwarf, the, typical, modulation, of, heart, period, by, ph, ##asi, ##c, (, respiratory, ‐, related, ), inhibition, that, amounts, to, an, average, pv, ##rsa, of, ~, 50, ms, ,, with, an, approximate, range, of, 0, –, 200, ms, ., it, is, critical, to, note, here, that, respiratory, influences, also, en, ##train, sympathetic, nervous, system, (, s, ##ns, ), out, ##flow, to, sa, node, cells, ., the, s, ##ns, out, ##flow, ‐, induced, increase, in, ne, release, de, ##pol, ##ari, ##zes, and, enhance, ##s, the, ex, ##cit, ##ability, of, sa, cells, via, meta, ##bot, ##rop, ##ic, ,, camp, ‐, mediated, ,, second, ‐, messenger, processes, ., the, latter, processes, not, only, accelerate, the, spontaneous, de, ##pol, ##ari, ##zation, of, the, sa, cells, ,, but, also, accelerate, the, speed, of, neural, conduct, ##ion, in, cardiac, tissue, ., compared, to, the, fast, (, ~, 400, ms, ), va, ##gal, influences, ,, these, sympathetic, influences, on, hr, ##v, are, strongly, at, ##ten, ##uated, by, the, low, ‐, pass, filtering, characteristics, of, slow, (, i, ., e, ., ,, 2, –, 3, s, ), g, ‐, protein, coupled, meta, ##bot, ##rop, ##ic, cascade, ##s, that, are, initiated, by, ne, binding, at, beta, ‐, 1, ad, ##ren, ##er, ##gic, receptors, (, bern, ##tson, et, al, ., ,, 1993, ;, mark, &, her, ##litz, ##e, ,, 2000, ), ., thus, ,, although, both, steady, state, and, ph, ##asi, ##c, increases, in, sympathetic, sa, node, activity, can, short, ##en, basal, heart, period, ,, high, frequency, sympathetic, fluctuations, (, e, ., g, ., ,, in, the, respiratory, frequency, range, ), do, not, translate, into, ph, ##asi, ##c, heart, period, fluctuations, ., accordingly, ,, most, hr, ##v, metric, ##s, that, are, usually, employed, in, psycho, ##phy, ##sio, ##logy, and, behavioral, medicine, (, i, ., e, ., ,, rms, ##sd, ,, h, ##f, ,, pv, ##rsa, ), can, be, largely, ascribed, to, modulation, of, the, va, ##gal, nerve, out, ##flow, to, sa, cells, ., a, second, fundamental, principle, in, va, ##gal, ga, ##ting, is, that, the, amplitude, of, the, ph, ##asi, ##c, modulation, of, activity, in, the, auto, ##no, ##mic, motor, neurons, at, the, brains, ##tem, level, (, e, ., g, ., ,, the, na, ), is, a, function, of, the, absolute, tonic, level, of, firing, of, these, auto, ##no, ##mic, motor, neurons, (, ec, ##k, ##berg, ,, 2003, ), ., the, amplitude, of, the, final, mod, ##ulated, va, ##gal, signal, traveling, to, the, sa, node, therefore, scales, with, the, frequency, of, the, tonic, va, ##gal, pulse, train, pre, ##sum, ##ptive, ##ly, arising, in, brain, systems, and, cell, groups, comprising, the, so, ‐, called, central, auto, ##no, ##mic, network, ., this, means, that, the, modulation, of, a, pulse, train, of, 12, hz, to, va, ##gal, motor, neurons, will, yield, a, larger, peak, ‐, to, ‐, trough, difference, in, the, va, ##gal, signal, to, the, sa, node, than, the, modulation, of, a, 6, hz, pulse, train, ., this, is, illustrated, in, figure, 2, ##b, ., here, ,, we, depict, a, person, with, lower, centrally, generated, tonic, va, ##gal, activity, than, in, figure, 2a, ,, which, leads, to, a, smaller, difference, between, the, shortest, and, longest, beats, in, inspiration, and, ex, ##piration, (, 50, ms, compared, to, 100, ms, ), ., this, principle, is, at, ##tri, ##bu, ##table, to, the, fact, that, ,, at, high, levels, of, neural, activity, ,, there, is, a, larger, “, carrier, signal, ”, to, be, subjected, to, ph, ##asi, ##c, (, respiratory, ‐, related, ), inhibition, .'},\n", - " {'article_id': '9526704a47665f9cf9741e7fd30ad68d',\n", - " 'section_name': 'INTRODUCTION',\n", - " 'text': 'As explained in detail in Box 1, specific measures of HRV, such as peak‐to‐valley respiratory sinus arrhythmia (pvRSA) and related metrics of heart period oscillations within common breathing frequencies, capture the inspiratory shortening and expiratory lengthening of heart periods across the respiratory cycle that is predominantly due to variations in cardiac vagal activity. In combination with measures that predominantly capture cardiac sympathetic activity, such as the pre‐ejection period (PEP), metrics of RSA may be interpreted and treated to meaningfully understand autonomic cardiac regulation within a two‐dimensional autonomic space model beyond ambiguous end‐organ activity provided by cardiac chronotropic metrics like heart period (Berntson, Cacioppo, Binkley et al., 1994; Bosch, de Geus, Veerman, Hoogstraten, & Nieuw Amerongen, 2003; Cacioppo et al., 1994). A 2007 special issue of Biological Psychology on cardiac vagal control illustrated its widespread use and highlighted issues pertaining to the use and abuse of various HRV metrics (Allen & Chambers, 2007). A recurrent concern has been the sometimes uncritical use of RSA as an index of vagal tone (see Box 2). In the decade since the publication of that special issue, interest in RSA and other HRV metrics has only expanded and deepened. This interest, however, has partly revived debate over a key and still open question addressed in this paper: Should HRV be “corrected” for heart rate (HR)? Based on a seminal paper by Monfredi and colleagues in 2014 (Monfredi et al., 2014), a rather strong viewpoint has been advocated that HRV is “just a nonlinear surrogate for HR” (Boyett, 2017; Boyett et al., 2017). Clearly, if HRV is confounded by a direct effect of the cardiac chronotropic state itself, this would fundamentally complicate its use to specifically capture one branch of the ANS.BOX 2 RSA and cardiac vagal activityThe observation that RSA scales with levels of tonic vagal activity is the source of the widespread use of RSA as an index of vagal tone, a vague concept variably used to denote parasympathetic activity generated by the central autonomic network, the baroreflex circuitry, or simply the net effect of ACh on the SA node. However, inferring absolute levels of vagal activity at cortical, limbic, brainstem, or even SA node levels from any particular quantitative value of RSA is neither simple nor straightforward for many reasons. First, depth and rate of breathing strongly impact HRV metrics, especially those that index RSA (Eckberg, 2003; Grossman & Kollai, 1993; Grossman & Taylor, 2007; Grossman, Karemaker, & Wieling, 1991; Kollai & Mizsei, 1990; Taylor, Myers, Halliwill, Seidel, & Eckberg, 2001). Within individuals, RSA is inversely related to respiration rate and directly related to tidal volume. Hence, rapid and shallow breathing yields low RSA. The important observation here, which has been demonstrated many times over, is that an increase in RSA by slowing respiratory rate and increasing volume may be seen in the absence of any change in tonic vagal activity, as reflected in unchanged or even slightly decreasing mean heart period (Chapleau & Abboud, 2001). The impact of differences in breathing behavior on between‐individual comparisons of RSA is somewhat harder to gauge, but cannot be ignored. Given the importance of respiratory rate and tidal volume as critical determinants of RSA values independent of cardiac vagal activity, RSA measures are often obtained under controlled breathing conditions or they are statistically corrected for spontaneous variation within and between individuals, albeit with varying degrees of rigor (Ritz & Dahme, 2006).A second reason not to equate RSA with tonic vagal activity is that the translation of fluctuations in vagal activity at the SA node into the actual slowing/speeding of the pacemaker potential is dependent on a complex interplay of postsynaptic signal transducers in the SA cells. Between‐individual differences and within‐individual changes in the efficiency of these transducers will distort any simple one‐to‐one mapping of vagal activity on HRV metrics. A classic example is the paradoxical reduction in HRV metrics at high levels of cardiac vagal activity induced in within‐individual designs by infusing pressor agents (Goldberger, Ahmed, Parker, & Kadish, 1994; Goldberger, Challapalli, Tung, Parker, & Kadish, 2001; Goldberger, Kim, Ahmed, & Kadish, 1996). Here, a saturation of a core element of postsynaptic ACh signal transduction, the SA muscarinic M2 receptors, causes low HRV in the presence of high vagal activity. A similar ceiling effect in the M2‐receptor signaling cascade may occur in regular vigorous exercisers with strong bradycardia. During nighttime, when their heart periods are much longer compared to daytime, these individuals exhibit a paradoxical lowering of RSA (van Lien et al., 2011).Notwithstanding the many pitfalls highlighted thus far, RSA offers our best opportunity for estimating cardiac vagal activity noninvasively, most notably in larger‐scaled research in humans. We lack means for directly recording efferent vagal nerve activity to the heart, and pharmacological blockade suffers from its own disadvantages apart from being only feasible in small sample size studies. Various findings suggest that, in general, we can expect higher RSA with higher average levels of cardiac vagal activity. Within individuals, this is illustrated by gradual pharmacological blockade of ACh effects on the SA cells, which exerts no effects on respiratory behavior but is loyally tracked by parallel changes in RSA (Grossman & Taylor, 2007). Various studies have addressed this issue by administering a parasympathetic antagonist during a resting baseline condition and inferring vagal activity from the resultant decrease in heart period (Fouad, Tarazi, Ferrario, Fighaly, & Alicandri, 1984; Grossman & Kollai, 1993; Hayano et al., 1991; Kollai & Mizsei, 1990). RSA was estimated in parallel (e.g., with the peak‐to‐valley method). If pvRSA was completely proportional to cardiac vagal activity, then a perfect between‐individual correlation of the increases in heart period and pvRSA would have been observed. The actual correlations were quite appreciable but not perfect, even under controlled breathing conditions and incompletely saturated M2 receptors, varying between 0.5 and 0.9.BOX 3 A more in‐depth look at vagal stimulation studiesMost of the vagal stimulation studies presented in Table 1 use a design in which the heart period attained during a steady state phase of vagal stimulation at a fixed frequency is compared to the heart period at prestimulation baseline. This procedure is repeated across a number of different vagal stimulation frequencies. The change in the heart period over the baseline heart period is computed for each frequency and, when plotted against stimulation frequency, typically yields a near‐perfect linear relation. The essence is that each stimulation event starts at the same baseline heart period, typically in the denervated heart (i.e., in the presence of bilateral vagal sectioning with sympathetic ganglia sectioning and/or sympathetic blockade). One could argue that this only indirectly answers the core question of dependency of vagal effects on the ongoing mean heart period. This potential limitation can be addressed by experimental manipulation of the baseline heart period before vagal stimulation commences, by changing cardiac sympathetic activity, or by changing nonautonomic effects on the diastolic depolarization rate, for example, by ivabradine or other blockers of the funny channel (decreasing If). Testing the effects of vagal stimulation under different levels of concurrent cardiac sympathetic nerve stimulation (and hence baseline heart period) has been repeatedly done in the context of testing for accentuated antagonism (Quigley & Berntson, 1996). In mongrel dogs, the relative angle scenario in Figure 3b seemed to best fit the observed relationship between changes in vagal firing and chronotropic effects across different baseline values of heart period (Levy & Zieske, 1969a; Randall et al., 2003; Urthaler, Neely, Hageman, & Smith, 1986). When mean heart period levels were shortened by 30% to 35% through sympathetic stimulation at 4 Hz (S‐stim), a linear relation between vagal stimulation and heart period was again found in all studies, with comparable slopes between the S‐stim and no S‐stim conditions in two of the three studies (Table 1, lower). Combined manipulation of sympathetic and vagal tone by exercise in a conscious animal was used to manipulate basal mean heart period in another study (Stramba‐Badiale et al., 1991). When dogs (with a vagal stimulator) walked on a treadmill, their heart period changed from a resting value of 500 to 299 ms. In spite of this strong decrease in mean heart period, the slope obtained with vagal stimulation was comparable at rest (33.2 ms/Hz) and during exercise (28.8 ms/Hz).We can conclude from these studies that, within a species, there is a relatively linear translation of phasic changes in vagal activity into changes in heart period across a wide range of baseline heart period levels with a reasonably stable slope. This is, again, what would have been predicted by the relative angle scenario in Figure 5b. However, in a dog model where central autonomic outflow was blocked, vagal pacing at 12 Hz produced lower increases in RSA when parallel sympathetic stimulation was applied (Hedman, Tahvanainen, Hartikainen, & Hakumaki, 1995). Pharmacological blockade in humans confirms that RSA is sensitive to moderate‐to‐large changes in cardiac sympathetic activity. As reviewed by Grossman and Taylor (2007), beta‐blockade in parallel increases heart period and RSA, even when vagal activity is not changed. This might be taken to suggest that there is indeed some direct effect of the mean heart period on RSA as would have been predicted by the fixed angle scenario in Figure 5a. Similarly, sympathetic agonists raising blood pressure like dobutamine cause a shortening of the mean heart period with a parallel decrease in HRV, when a baroreflex‐induced increase in vagal activity would be expected (Monfredi et al., 2014). Unfortunately, such effects on HRV could also occur independently of mediation by heart period, because sympathetic antagonists and agonists can interact directly with vagal activity at the brainstem level, and pre‐ and postjunctionally in the SA node (e.g., by the inhibitory action of the NE coreleased and the neuromodulator neuropeptide Y on ACh release (Quigley & Berntson, 1996).A final class of relevant studies are those that used funny channel blockade to increase mean heart period (e.g., zetabradine or ivabradine). Funny channel blockade prolongs heart period, and many studies show that this bradycardia is coupled to a parallel increase in HRV (Borer & Le Heuzey, 2008; Kurtoglu et al., 2014). Vagal activity is still widely regarded to be the primary driver of HRV under ivabradine because atropine completely prevents the increase in HRV (Kozasa et al., 2018; Mangin et al., 1998). Nonetheless, the increase in HRV is counterintuitive, as ivabradine‐evoked bradycardia causes a parallel decrease in blood pressure. The latter causes a reflex increase in sympathetic nerve activity (Dias da Silva et al., 2015) and, one assumes, a reflex decrease in vagal activity in accord with baroreflex action. The observed increase in HRV was therefore explained as reflecting an “intrinsic dependency of HRV on pacemaker cycle length” (Dias da Silva at al., 2015, p. 32). This appears at first sight to be most compatible with the fixed angle scenario of Figure 5b.However, using a murine genetic knockdown of HCN4, Kozasa et al. (2018) reported findings that were at odds with a fixed angle scenario. HCN4 is a main component of the funny channel, and this knockdown model mimics the bradycardic effects of ivabradine, as well as its positive, increasing effects on HRV. In the context of this model, they showed that funny channel action can directly impact the strength of vagal effects in the SA node. By counteracting K+ GIRK channels (reducing K+ efflux), the funny channel protects the SA cells against complete sinus pause under high vagal stimulation. Because the funny channel has a “limiter function” for the bradycardic effects induced by vagal activity, blocking it by ivabradine would act to amplify the effectiveness of phasic—for example, baroreflex or respiration‐induced—increases in vagal activity to induce phasic changes in heart period. The latter changes would serve to boost HRV. In keeping with this notion, amplifying funny channel action by HCN4 overexpression strongly reduced HRV, whereas mean heart period was unchanged. These results can all be explained by the funny channel counteracting the effectiveness of vagal activity without invoking an intrinsic dependency of HRV on heart period. Kozasa et al. (2018) also provide direct support for the relative angle scenario of Figure 5b. In isolated pacemaker cells, the basal diastolic depolarization rate in HCN4 knockdown mice was much slower than in the wild type animals (Kozasa et al., 2018, their figure D, p. 821). When exposed to increasing concentrations of ACh [0 to 30 nmol], the additional decrease in the depolarization rate induced by the same dose of ACh was much lower in the HCN4 knockdown (~35 mV/s) than in the wild type mice (~80 mV/s).',\n", - " 'paragraph_id': 4,\n", - " 'tokenizer': 'as, explained, in, detail, in, box, 1, ,, specific, measures, of, hr, ##v, ,, such, as, peak, ‐, to, ‐, valley, respiratory, sin, ##us, ar, ##rh, ##yt, ##hmi, ##a, (, pv, ##rsa, ), and, related, metric, ##s, of, heart, period, os, ##ci, ##llation, ##s, within, common, breathing, frequencies, ,, capture, the, ins, ##pi, ##rator, ##y, short, ##ening, and, ex, ##pi, ##rator, ##y, length, ##ening, of, heart, periods, across, the, respiratory, cycle, that, is, predominantly, due, to, variations, in, cardiac, va, ##gal, activity, ., in, combination, with, measures, that, predominantly, capture, cardiac, sympathetic, activity, ,, such, as, the, pre, ‐, e, ##ject, ##ion, period, (, pep, ), ,, metric, ##s, of, rs, ##a, may, be, interpreted, and, treated, to, meaningful, ##ly, understand, auto, ##no, ##mic, cardiac, regulation, within, a, two, ‐, dimensional, auto, ##no, ##mic, space, model, beyond, ambiguous, end, ‐, organ, activity, provided, by, cardiac, ch, ##ron, ##ot, ##rop, ##ic, metric, ##s, like, heart, period, (, bern, ##tson, ,, ca, ##cio, ##pp, ##o, ,, bin, ##kley, et, al, ., ,, 1994, ;, bosch, ,, de, ge, ##us, ,, ve, ##erman, ,, ho, ##og, ##stra, ##ten, ,, &, ni, ##eu, ##w, am, ##eron, ##gen, ,, 2003, ;, ca, ##cio, ##pp, ##o, et, al, ., ,, 1994, ), ., a, 2007, special, issue, of, biological, psychology, on, cardiac, va, ##gal, control, illustrated, its, widespread, use, and, highlighted, issues, pertaining, to, the, use, and, abuse, of, various, hr, ##v, metric, ##s, (, allen, &, chambers, ,, 2007, ), ., a, rec, ##urrent, concern, has, been, the, sometimes, un, ##cr, ##itical, use, of, rs, ##a, as, an, index, of, va, ##gal, tone, (, see, box, 2, ), ., in, the, decade, since, the, publication, of, that, special, issue, ,, interest, in, rs, ##a, and, other, hr, ##v, metric, ##s, has, only, expanded, and, deepened, ., this, interest, ,, however, ,, has, partly, revived, debate, over, a, key, and, still, open, question, addressed, in, this, paper, :, should, hr, ##v, be, “, corrected, ”, for, heart, rate, (, hr, ), ?, based, on, a, seminal, paper, by, mon, ##fr, ##ed, ##i, and, colleagues, in, 2014, (, mon, ##fr, ##ed, ##i, et, al, ., ,, 2014, ), ,, a, rather, strong, viewpoint, has, been, advocated, that, hr, ##v, is, “, just, a, nonlinear, sur, ##rogate, for, hr, ”, (, boy, ##ett, ,, 2017, ;, boy, ##ett, et, al, ., ,, 2017, ), ., clearly, ,, if, hr, ##v, is, con, ##founded, by, a, direct, effect, of, the, cardiac, ch, ##ron, ##ot, ##rop, ##ic, state, itself, ,, this, would, fundamentally, com, ##pl, ##icate, its, use, to, specifically, capture, one, branch, of, the, an, ##s, ., box, 2, rs, ##a, and, cardiac, va, ##gal, activity, ##the, observation, that, rs, ##a, scales, with, levels, of, tonic, va, ##gal, activity, is, the, source, of, the, widespread, use, of, rs, ##a, as, an, index, of, va, ##gal, tone, ,, a, vague, concept, var, ##ia, ##bly, used, to, denote, para, ##sy, ##mp, ##ath, ##etic, activity, generated, by, the, central, auto, ##no, ##mic, network, ,, the, bar, ##ore, ##fle, ##x, circuit, ##ry, ,, or, simply, the, net, effect, of, ac, ##h, on, the, sa, node, ., however, ,, in, ##fer, ##ring, absolute, levels, of, va, ##gal, activity, at, co, ##rti, ##cal, ,, limb, ##ic, ,, brains, ##tem, ,, or, even, sa, node, levels, from, any, particular, quantitative, value, of, rs, ##a, is, neither, simple, nor, straightforward, for, many, reasons, ., first, ,, depth, and, rate, of, breathing, strongly, impact, hr, ##v, metric, ##s, ,, especially, those, that, index, rs, ##a, (, ec, ##k, ##berg, ,, 2003, ;, gross, ##man, &, ko, ##lla, ##i, ,, 1993, ;, gross, ##man, &, taylor, ,, 2007, ;, gross, ##man, ,, ka, ##rem, ##aker, ,, &, wi, ##elin, ##g, ,, 1991, ;, ko, ##lla, ##i, &, mi, ##z, ##sei, ,, 1990, ;, taylor, ,, myers, ,, hall, ##i, ##wil, ##l, ,, se, ##ide, ##l, ,, &, ec, ##k, ##berg, ,, 2001, ), ., within, individuals, ,, rs, ##a, is, inverse, ##ly, related, to, res, ##piration, rate, and, directly, related, to, tidal, volume, ., hence, ,, rapid, and, shallow, breathing, yields, low, rs, ##a, ., the, important, observation, here, ,, which, has, been, demonstrated, many, times, over, ,, is, that, an, increase, in, rs, ##a, by, slowing, respiratory, rate, and, increasing, volume, may, be, seen, in, the, absence, of, any, change, in, tonic, va, ##gal, activity, ,, as, reflected, in, unchanged, or, even, slightly, decreasing, mean, heart, period, (, cha, ##ple, ##au, &, ab, ##bo, ##ud, ,, 2001, ), ., the, impact, of, differences, in, breathing, behavior, on, between, ‐, individual, comparisons, of, rs, ##a, is, somewhat, harder, to, gauge, ,, but, cannot, be, ignored, ., given, the, importance, of, respiratory, rate, and, tidal, volume, as, critical, deter, ##mina, ##nts, of, rs, ##a, values, independent, of, cardiac, va, ##gal, activity, ,, rs, ##a, measures, are, often, obtained, under, controlled, breathing, conditions, or, they, are, statistical, ##ly, corrected, for, spontaneous, variation, within, and, between, individuals, ,, albeit, with, varying, degrees, of, rig, ##or, (, ri, ##tz, &, da, ##hm, ##e, ,, 2006, ), ., a, second, reason, not, to, e, ##qua, ##te, rs, ##a, with, tonic, va, ##gal, activity, is, that, the, translation, of, fluctuations, in, va, ##gal, activity, at, the, sa, node, into, the, actual, slowing, /, speeding, of, the, pace, ##maker, potential, is, dependent, on, a, complex, inter, ##play, of, posts, ##yna, ##ptic, signal, trans, ##du, ##cer, ##s, in, the, sa, cells, ., between, ‐, individual, differences, and, within, ‐, individual, changes, in, the, efficiency, of, these, trans, ##du, ##cer, ##s, will, di, ##stor, ##t, any, simple, one, ‐, to, ‐, one, mapping, of, va, ##gal, activity, on, hr, ##v, metric, ##s, ., a, classic, example, is, the, paradox, ##ical, reduction, in, hr, ##v, metric, ##s, at, high, levels, of, cardiac, va, ##gal, activity, induced, in, within, ‐, individual, designs, by, in, ##fus, ##ing, press, ##or, agents, (, goldberg, ##er, ,, ahmed, ,, parker, ,, &, ka, ##dis, ##h, ,, 1994, ;, goldberg, ##er, ,, cha, ##lla, ##pal, ##li, ,, tung, ,, parker, ,, &, ka, ##dis, ##h, ,, 2001, ;, goldberg, ##er, ,, kim, ,, ahmed, ,, &, ka, ##dis, ##h, ,, 1996, ), ., here, ,, a, sat, ##uration, of, a, core, element, of, posts, ##yna, ##ptic, ac, ##h, signal, trans, ##duction, ,, the, sa, mu, ##sca, ##rini, ##c, m2, receptors, ,, causes, low, hr, ##v, in, the, presence, of, high, va, ##gal, activity, ., a, similar, ceiling, effect, in, the, m2, ‐, receptor, signaling, cascade, may, occur, in, regular, vigorous, exercise, ##rs, with, strong, brady, ##card, ##ia, ., during, nighttime, ,, when, their, heart, periods, are, much, longer, compared, to, daytime, ,, these, individuals, exhibit, a, paradox, ##ical, lowering, of, rs, ##a, (, van, lie, ##n, et, al, ., ,, 2011, ), ., notwithstanding, the, many, pit, ##falls, highlighted, thus, far, ,, rs, ##a, offers, our, best, opportunity, for, est, ##imating, cardiac, va, ##gal, activity, non, ##in, ##vas, ##ively, ,, most, notably, in, larger, ‐, scaled, research, in, humans, ., we, lack, means, for, directly, recording, e, ##ffer, ##ent, va, ##gal, nerve, activity, to, the, heart, ,, and, ph, ##arm, ##aco, ##logical, blockade, suffers, from, its, own, disadvantage, ##s, apart, from, being, only, feasible, in, small, sample, size, studies, ., various, findings, suggest, that, ,, in, general, ,, we, can, expect, higher, rs, ##a, with, higher, average, levels, of, cardiac, va, ##gal, activity, ., within, individuals, ,, this, is, illustrated, by, gradual, ph, ##arm, ##aco, ##logical, blockade, of, ac, ##h, effects, on, the, sa, cells, ,, which, ex, ##ert, ##s, no, effects, on, respiratory, behavior, but, is, loyal, ##ly, tracked, by, parallel, changes, in, rs, ##a, (, gross, ##man, &, taylor, ,, 2007, ), ., various, studies, have, addressed, this, issue, by, administering, a, para, ##sy, ##mp, ##ath, ##etic, antagonist, during, a, resting, baseline, condition, and, in, ##fer, ##ring, va, ##gal, activity, from, the, resultant, decrease, in, heart, period, (, f, ##ou, ##ad, ,, tara, ##zi, ,, ferrari, ##o, ,, fig, ##hal, ##y, ,, &, ali, ##can, ##dr, ##i, ,, 1984, ;, gross, ##man, &, ko, ##lla, ##i, ,, 1993, ;, hay, ##ano, et, al, ., ,, 1991, ;, ko, ##lla, ##i, &, mi, ##z, ##sei, ,, 1990, ), ., rs, ##a, was, estimated, in, parallel, (, e, ., g, ., ,, with, the, peak, ‐, to, ‐, valley, method, ), ., if, pv, ##rsa, was, completely, proportional, to, cardiac, va, ##gal, activity, ,, then, a, perfect, between, ‐, individual, correlation, of, the, increases, in, heart, period, and, pv, ##rsa, would, have, been, observed, ., the, actual, correlation, ##s, were, quite, app, ##re, ##cia, ##ble, but, not, perfect, ,, even, under, controlled, breathing, conditions, and, incomplete, ##ly, saturated, m2, receptors, ,, varying, between, 0, ., 5, and, 0, ., 9, ., box, 3, a, more, in, ‐, depth, look, at, va, ##gal, stimulation, studies, ##most, of, the, va, ##gal, stimulation, studies, presented, in, table, 1, use, a, design, in, which, the, heart, period, attained, during, a, steady, state, phase, of, va, ##gal, stimulation, at, a, fixed, frequency, is, compared, to, the, heart, period, at, pre, ##sti, ##mu, ##lation, baseline, ., this, procedure, is, repeated, across, a, number, of, different, va, ##gal, stimulation, frequencies, ., the, change, in, the, heart, period, over, the, baseline, heart, period, is, computed, for, each, frequency, and, ,, when, plotted, against, stimulation, frequency, ,, typically, yields, a, near, ‐, perfect, linear, relation, ., the, essence, is, that, each, stimulation, event, starts, at, the, same, baseline, heart, period, ,, typically, in, the, den, ##er, ##vate, ##d, heart, (, i, ., e, ., ,, in, the, presence, of, bilateral, va, ##gal, section, ##ing, with, sympathetic, gang, ##lia, section, ##ing, and, /, or, sympathetic, blockade, ), ., one, could, argue, that, this, only, indirectly, answers, the, core, question, of, dependency, of, va, ##gal, effects, on, the, ongoing, mean, heart, period, ., this, potential, limitation, can, be, addressed, by, experimental, manipulation, of, the, baseline, heart, period, before, va, ##gal, stimulation, commence, ##s, ,, by, changing, cardiac, sympathetic, activity, ,, or, by, changing, non, ##au, ##ton, ##omic, effects, on, the, dia, ##sto, ##lic, de, ##pol, ##ari, ##zation, rate, ,, for, example, ,, by, iv, ##ab, ##rad, ##ine, or, other, block, ##ers, of, the, funny, channel, (, decreasing, if, ), ., testing, the, effects, of, va, ##gal, stimulation, under, different, levels, of, concurrent, cardiac, sympathetic, nerve, stimulation, (, and, hence, baseline, heart, period, ), has, been, repeatedly, done, in, the, context, of, testing, for, accent, ##uated, ant, ##ago, ##nism, (, qui, ##gley, &, bern, ##tson, ,, 1996, ), ., in, mon, ##gre, ##l, dogs, ,, the, relative, angle, scenario, in, figure, 3, ##b, seemed, to, best, fit, the, observed, relationship, between, changes, in, va, ##gal, firing, and, ch, ##ron, ##ot, ##rop, ##ic, effects, across, different, baseline, values, of, heart, period, (, levy, &, z, ##ies, ##ke, ,, 1969, ##a, ;, randall, et, al, ., ,, 2003, ;, ur, ##thal, ##er, ,, nee, ##ly, ,, ha, ##ge, ##man, ,, &, smith, ,, 1986, ), ., when, mean, heart, period, levels, were, shortened, by, 30, %, to, 35, %, through, sympathetic, stimulation, at, 4, hz, (, s, ‐, st, ##im, ), ,, a, linear, relation, between, va, ##gal, stimulation, and, heart, period, was, again, found, in, all, studies, ,, with, comparable, slopes, between, the, s, ‐, st, ##im, and, no, s, ‐, st, ##im, conditions, in, two, of, the, three, studies, (, table, 1, ,, lower, ), ., combined, manipulation, of, sympathetic, and, va, ##gal, tone, by, exercise, in, a, conscious, animal, was, used, to, manipulate, basal, mean, heart, period, in, another, study, (, st, ##ram, ##ba, ‐, bad, ##ial, ##e, et, al, ., ,, 1991, ), ., when, dogs, (, with, a, va, ##gal, st, ##im, ##ulator, ), walked, on, a, tread, ##mill, ,, their, heart, period, changed, from, a, resting, value, of, 500, to, 299, ms, ., in, spite, of, this, strong, decrease, in, mean, heart, period, ,, the, slope, obtained, with, va, ##gal, stimulation, was, comparable, at, rest, (, 33, ., 2, ms, /, hz, ), and, during, exercise, (, 28, ., 8, ms, /, hz, ), ., we, can, conclude, from, these, studies, that, ,, within, a, species, ,, there, is, a, relatively, linear, translation, of, ph, ##asi, ##c, changes, in, va, ##gal, activity, into, changes, in, heart, period, across, a, wide, range, of, baseline, heart, period, levels, with, a, reasonably, stable, slope, ., this, is, ,, again, ,, what, would, have, been, predicted, by, the, relative, angle, scenario, in, figure, 5, ##b, ., however, ,, in, a, dog, model, where, central, auto, ##no, ##mic, out, ##flow, was, blocked, ,, va, ##gal, pacing, at, 12, hz, produced, lower, increases, in, rs, ##a, when, parallel, sympathetic, stimulation, was, applied, (, he, ##dman, ,, ta, ##h, ##vana, ##inen, ,, hart, ##ika, ##inen, ,, &, ha, ##ku, ##ma, ##ki, ,, 1995, ), ., ph, ##arm, ##aco, ##logical, blockade, in, humans, confirms, that, rs, ##a, is, sensitive, to, moderate, ‐, to, ‐, large, changes, in, cardiac, sympathetic, activity, ., as, reviewed, by, gross, ##man, and, taylor, (, 2007, ), ,, beta, ‐, blockade, in, parallel, increases, heart, period, and, rs, ##a, ,, even, when, va, ##gal, activity, is, not, changed, ., this, might, be, taken, to, suggest, that, there, is, indeed, some, direct, effect, of, the, mean, heart, period, on, rs, ##a, as, would, have, been, predicted, by, the, fixed, angle, scenario, in, figure, 5, ##a, ., similarly, ,, sympathetic, ago, ##nist, ##s, raising, blood, pressure, like, do, ##bu, ##tam, ##ine, cause, a, short, ##ening, of, the, mean, heart, period, with, a, parallel, decrease, in, hr, ##v, ,, when, a, bar, ##ore, ##fle, ##x, ‐, induced, increase, in, va, ##gal, activity, would, be, expected, (, mon, ##fr, ##ed, ##i, et, al, ., ,, 2014, ), ., unfortunately, ,, such, effects, on, hr, ##v, could, also, occur, independently, of, mediation, by, heart, period, ,, because, sympathetic, antagonist, ##s, and, ago, ##nist, ##s, can, interact, directly, with, va, ##gal, activity, at, the, brains, ##tem, level, ,, and, pre, ‐, and, post, ##jun, ##ction, ##ally, in, the, sa, node, (, e, ., g, ., ,, by, the, inhibitor, ##y, action, of, the, ne, core, ##lea, ##sed, and, the, ne, ##uro, ##mo, ##du, ##lat, ##or, ne, ##uro, ##pe, ##pt, ##ide, y, on, ac, ##h, release, (, qui, ##gley, &, bern, ##tson, ,, 1996, ), ., a, final, class, of, relevant, studies, are, those, that, used, funny, channel, blockade, to, increase, mean, heart, period, (, e, ., g, ., ,, zeta, ##bra, ##dine, or, iv, ##ab, ##rad, ##ine, ), ., funny, channel, blockade, pro, ##long, ##s, heart, period, ,, and, many, studies, show, that, this, brady, ##card, ##ia, is, coupled, to, a, parallel, increase, in, hr, ##v, (, bore, ##r, &, le, he, ##uze, ##y, ,, 2008, ;, kurt, ##og, ##lu, et, al, ., ,, 2014, ), ., va, ##gal, activity, is, still, widely, regarded, to, be, the, primary, driver, of, hr, ##v, under, iv, ##ab, ##rad, ##ine, because, at, ##rop, ##ine, completely, prevents, the, increase, in, hr, ##v, (, ko, ##za, ##sa, et, al, ., ,, 2018, ;, man, ##gin, et, al, ., ,, 1998, ), ., nonetheless, ,, the, increase, in, hr, ##v, is, counter, ##int, ##uit, ##ive, ,, as, iv, ##ab, ##rad, ##ine, ‐, ev, ##oked, brady, ##card, ##ia, causes, a, parallel, decrease, in, blood, pressure, ., the, latter, causes, a, reflex, increase, in, sympathetic, nerve, activity, (, dia, ##s, da, silva, et, al, ., ,, 2015, ), and, ,, one, assumes, ,, a, reflex, decrease, in, va, ##gal, activity, in, accord, with, bar, ##ore, ##fle, ##x, action, ., the, observed, increase, in, hr, ##v, was, therefore, explained, as, reflecting, an, “, intrinsic, dependency, of, hr, ##v, on, pace, ##maker, cycle, length, ”, (, dia, ##s, da, silva, at, al, ., ,, 2015, ,, p, ., 32, ), ., this, appears, at, first, sight, to, be, most, compatible, with, the, fixed, angle, scenario, of, figure, 5, ##b, ., however, ,, using, a, mu, ##rine, genetic, knock, ##down, of, hc, ##n, ##4, ,, ko, ##za, ##sa, et, al, ., (, 2018, ), reported, findings, that, were, at, odds, with, a, fixed, angle, scenario, ., hc, ##n, ##4, is, a, main, component, of, the, funny, channel, ,, and, this, knock, ##down, model, mimic, ##s, the, brady, ##card, ##ic, effects, of, iv, ##ab, ##rad, ##ine, ,, as, well, as, its, positive, ,, increasing, effects, on, hr, ##v, ., in, the, context, of, this, model, ,, they, showed, that, funny, channel, action, can, directly, impact, the, strength, of, va, ##gal, effects, in, the, sa, node, ., by, counter, ##act, ##ing, k, +, gi, ##rk, channels, (, reducing, k, +, e, ##ff, ##lux, ), ,, the, funny, channel, protects, the, sa, cells, against, complete, sin, ##us, pause, under, high, va, ##gal, stimulation, ., because, the, funny, channel, has, a, “, limit, ##er, function, ”, for, the, brady, ##card, ##ic, effects, induced, by, va, ##gal, activity, ,, blocking, it, by, iv, ##ab, ##rad, ##ine, would, act, to, amp, ##li, ##fy, the, effectiveness, of, ph, ##asi, ##c, —, for, example, ,, bar, ##ore, ##fle, ##x, or, res, ##piration, ‐, induced, —, increases, in, va, ##gal, activity, to, induce, ph, ##asi, ##c, changes, in, heart, period, ., the, latter, changes, would, serve, to, boost, hr, ##v, ., in, keeping, with, this, notion, ,, amp, ##li, ##fying, funny, channel, action, by, hc, ##n, ##4, over, ##ex, ##press, ##ion, strongly, reduced, hr, ##v, ,, whereas, mean, heart, period, was, unchanged, ., these, results, can, all, be, explained, by, the, funny, channel, counter, ##act, ##ing, the, effectiveness, of, va, ##gal, activity, without, in, ##voking, an, intrinsic, dependency, of, hr, ##v, on, heart, period, ., ko, ##za, ##sa, et, al, ., (, 2018, ), also, provide, direct, support, for, the, relative, angle, scenario, of, figure, 5, ##b, ., in, isolated, pace, ##maker, cells, ,, the, basal, dia, ##sto, ##lic, de, ##pol, ##ari, ##zation, rate, in, hc, ##n, ##4, knock, ##down, mice, was, much, slower, than, in, the, wild, type, animals, (, ko, ##za, ##sa, et, al, ., ,, 2018, ,, their, figure, d, ,, p, ., 82, ##1, ), ., when, exposed, to, increasing, concentrations, of, ac, ##h, [, 0, to, 30, nm, ##ol, ], ,, the, additional, decrease, in, the, de, ##pol, ##ari, ##zation, rate, induced, by, the, same, dose, of, ac, ##h, was, much, lower, in, the, hc, ##n, ##4, knock, ##down, (, ~, 35, mv, /, s, ), than, in, the, wild, type, mice, (, ~, 80, mv, /, s, ), .'},\n", - " {'article_id': '992bfa0b2a3e7bd521e302775dfc0ea8',\n", - " 'section_name': 'Tubulinergic nervous system',\n", - " 'text': 'The tubulinergic nervous system in Echinoderes reveals a circumpharyngeal brain with several longitudinal neurite bundles originating from the neuropil (np) and extending along the introvert and trunk (Fig. 3). The neuropil includes a condensed set of parallel neurites forming a ring measuring 15–20 μm in diameter (Figs. 2b-c, 3a-c, 5b-c, e-e’, 6a and 7a; Additional file 1), which is constricted on the ventral side (Figs. 2b, 3b and 5b-c). From the anterior end of the neuropil, ten radially arranged longitudinal neurite bundles (lnb) extend anteriorly along the introvert, bend toward the body wall and then extend posteriorly along the trunk (Figs. 2b, 3a-c and 7a). At the level of the first trunk segment, eight of those neurite bundles fuse in pairs to form two subdorsal (sdn) and two ventrolateral nerves (vln) (Figs. 2c-d, 3 and 4a). The ventrolateral nerves extend to segment 9 (Figs. 2a and 3a-b). The subdorsal nerves also extend to segment 9 where they converge into a putative ganglion on the dorsal midline (Figs. 2h, 3a and 6a). From there, two neurites extend from that junction to innervate segments 10–11 (Figs. 2f-h, 3a-b and g). Two additional subdorsal neurites, most likely associated with the gonads (gn) extend posteriorly from within segment 6 and converge with the longitudinal dorsal nerves in segment 9 (Figs. 2h, 3a and 7a).Fig. 3Schematic representation of acetylated α-tubulin-LIR in Echinoderes. Only conserved traits across species are represented. For clarity, innervation and external arrangements of species-specific cuticular characters and head scalids have been omitted. Anterior is up in (a-b), dorsal is up in (c-g). a-b Overview of tubulinergic elements of the nervous system in (a) dorsal and (b) ventral views. Arrowheads in (b) mark the anterior-posterior axial positions of cross-section schematics in (c-g). c Introvert. Note the outer ring has 10 radially arranged longitudinal neurite bundles (× 10), the middle ring corresponds with the neuropil, and the inner ring shows 9 oral styles neurites (× 9), without the middorsal neurite (see legend). d Neck. e Segment 1 (arrows mark convergent longitudinal bundles). The two ventral bundles with black dots in (c-e) mark the unfused condition of the ventral nerve cord. f Segments 3–7. g Segment 8. Abbreviations: gn, gonad neurite; gon, gonopore neurite; lnb, longitudinal neurite bundle; ltasn, lateral terminal accessory spine neurite; mcnr, mouth cone nerve ring; ncn, neck circular neurite; nen, nephridial neurite; np, neuropil; osn, oral styles neurite; sdn, subdorsal longitudinal nerve; s1–11, trunk segment number; tn, transverse neurite; tsn, terminal spine neurite; vln, ventrolateral nerve; vnc, ventral nerve cord; vncn, ventral nerve cord neuriteFig. 4Predicted correlations between internal acetylated α-tubulin-LIR and external cuticular structures in Echinoderes. Anterior is up in all panels. Specimen silhouettes with dashed squares indicate the axial region of each z-stack. Color legend applies to all panels. Confocal z-stack projections and SEM micrographs were obtained from different specimens. a-j\\nEchinoderes ohtsukai. k-p\\nEchinoderes horni. a Confocal z-stack of segments 1–3 in lateral view co-labeled for acTub-LIR (acTub) and DNA. b SEM micrograph showing a pair of sensory spots in segment 1 that correspond to the upper boxed area in (d). The upper pair of dashed arrows in (a) correspond to innervation of the sensory spots in (b). c SEM micrograph showing a pair of sensory spots in segment 2 corresponding to the lower boxed area in (d). Lower pair of dashed arrows in (a) correspond to innervation of the sensory spots in (c). g confocal z-stack of segments 6–11 in ventral view co-labeled for acTub-LIR and DNA. e SEM micrograph of a midventral sensory spot corresponding to innervation (dashed arrow) in (g). f SEM of a lateroventral fringed tube from segment 7 corresponding to innervation in (g). h SEM of a lateroventral acicular spine and its innervation in (g). i SEM of a sieve plate on segment 9 and innervation in (g). j SEM of segments 8–11 in ventral view showing the position of the sieve plate (boxed area) magnified in (i). k Confocal z-stack of acTub-LIR within segment 7 in ventral view. l SEM of a ventromedial sensory spot and its corresponding innervation in (k). m SEM of the ventral side of segment 7 showing the relative position (boxed area) of the sensory spot in (l). n Confocal z-stack of acTub-LIR within segments 9–11 in ventral view. o SEM of sensory spots from segment 11 and their correlation with innervation in (n). p SEM of segments 9–11 in ventral view showing the sensory spots (boxed areas) magnified in (o). Scale bars: 20 μm in (a, d, n), 10 μm in (b, c, g, k, j, m, p), 2 μm in (e, f, h, i, o). Abbreviations: lnb, longitudinal neurite bundle; lvs, lateroventral spine; ncn, neck circular neurite; nen, nephridial neurite; s, segment; sdn, subdorsal longitudinal nerve; sn, spine neurite; sp., sieve plate; spn, ss, sensory spot; ssn, sensory spot neurite; tbn, tube neurite; tn, transverse neurite; tsn, terminal spine neurite; vnc, ventral nerve cord. Numbers after abbreviations refer to segment number',\n", - " 'paragraph_id': 7,\n", - " 'tokenizer': 'the, tub, ##ulin, ##er, ##gic, nervous, system, in, ec, ##hin, ##oder, ##es, reveals, a, ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, brain, with, several, longitudinal, ne, ##uri, ##te, bundles, originating, from, the, ne, ##uro, ##pi, ##l, (, np, ), and, extending, along, the, intro, ##vert, and, trunk, (, fig, ., 3, ), ., the, ne, ##uro, ##pi, ##l, includes, a, condensed, set, of, parallel, ne, ##uri, ##tes, forming, a, ring, measuring, 15, –, 20, μ, ##m, in, diameter, (, fig, ##s, ., 2, ##b, -, c, ,, 3a, -, c, ,, 5, ##b, -, c, ,, e, -, e, ’, ,, 6, ##a, and, 7, ##a, ;, additional, file, 1, ), ,, which, is, con, ##st, ##ricted, on, the, ventral, side, (, fig, ##s, ., 2, ##b, ,, 3, ##b, and, 5, ##b, -, c, ), ., from, the, anterior, end, of, the, ne, ##uro, ##pi, ##l, ,, ten, radial, ##ly, arranged, longitudinal, ne, ##uri, ##te, bundles, (, l, ##nb, ), extend, anterior, ##ly, along, the, intro, ##vert, ,, bend, toward, the, body, wall, and, then, extend, posterior, ##ly, along, the, trunk, (, fig, ##s, ., 2, ##b, ,, 3a, -, c, and, 7, ##a, ), ., at, the, level, of, the, first, trunk, segment, ,, eight, of, those, ne, ##uri, ##te, bundles, fuse, in, pairs, to, form, two, sub, ##dor, ##sal, (, sd, ##n, ), and, two, vent, ##rol, ##ater, ##al, nerves, (, v, ##ln, ), (, fig, ##s, ., 2, ##c, -, d, ,, 3, and, 4a, ), ., the, vent, ##rol, ##ater, ##al, nerves, extend, to, segment, 9, (, fig, ##s, ., 2a, and, 3a, -, b, ), ., the, sub, ##dor, ##sal, nerves, also, extend, to, segment, 9, where, they, converge, into, a, put, ##ative, gang, ##lion, on, the, dorsal, mid, ##line, (, fig, ##s, ., 2, ##h, ,, 3a, and, 6, ##a, ), ., from, there, ,, two, ne, ##uri, ##tes, extend, from, that, junction, to, inner, ##vate, segments, 10, –, 11, (, fig, ##s, ., 2, ##f, -, h, ,, 3a, -, b, and, g, ), ., two, additional, sub, ##dor, ##sal, ne, ##uri, ##tes, ,, most, likely, associated, with, the, go, ##nad, ##s, (, g, ##n, ), extend, posterior, ##ly, from, within, segment, 6, and, converge, with, the, longitudinal, dorsal, nerves, in, segment, 9, (, fig, ##s, ., 2, ##h, ,, 3a, and, 7, ##a, ), ., fig, ., 3, ##sche, ##matic, representation, of, ace, ##ty, ##lated, α, -, tub, ##ulin, -, li, ##r, in, ec, ##hin, ##oder, ##es, ., only, conserved, traits, across, species, are, represented, ., for, clarity, ,, inner, ##vation, and, external, arrangements, of, species, -, specific, cut, ##icular, characters, and, head, sc, ##ali, ##ds, have, been, omitted, ., anterior, is, up, in, (, a, -, b, ), ,, dorsal, is, up, in, (, c, -, g, ), ., a, -, b, overview, of, tub, ##ulin, ##er, ##gic, elements, of, the, nervous, system, in, (, a, ), dorsal, and, (, b, ), ventral, views, ., arrow, ##heads, in, (, b, ), mark, the, anterior, -, posterior, axial, positions, of, cross, -, section, sc, ##hema, ##tics, in, (, c, -, g, ), ., c, intro, ##vert, ., note, the, outer, ring, has, 10, radial, ##ly, arranged, longitudinal, ne, ##uri, ##te, bundles, (, ×, 10, ), ,, the, middle, ring, corresponds, with, the, ne, ##uro, ##pi, ##l, ,, and, the, inner, ring, shows, 9, oral, styles, ne, ##uri, ##tes, (, ×, 9, ), ,, without, the, mid, ##dor, ##sal, ne, ##uri, ##te, (, see, legend, ), ., d, neck, ., e, segment, 1, (, arrows, mark, converge, ##nt, longitudinal, bundles, ), ., the, two, ventral, bundles, with, black, dots, in, (, c, -, e, ), mark, the, un, ##fus, ##ed, condition, of, the, ventral, nerve, cord, ., f, segments, 3, –, 7, ., g, segment, 8, ., abbreviation, ##s, :, g, ##n, ,, go, ##nad, ne, ##uri, ##te, ;, go, ##n, ,, go, ##no, ##pore, ne, ##uri, ##te, ;, l, ##nb, ,, longitudinal, ne, ##uri, ##te, bundle, ;, lt, ##as, ##n, ,, lateral, terminal, accessory, spine, ne, ##uri, ##te, ;, mc, ##nr, ,, mouth, cone, nerve, ring, ;, nc, ##n, ,, neck, circular, ne, ##uri, ##te, ;, ne, ##n, ,, ne, ##ph, ##rid, ##ial, ne, ##uri, ##te, ;, np, ,, ne, ##uro, ##pi, ##l, ;, os, ##n, ,, oral, styles, ne, ##uri, ##te, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, s, ##1, –, 11, ,, trunk, segment, number, ;, tn, ,, transverse, ne, ##uri, ##te, ;, ts, ##n, ,, terminal, spine, ne, ##uri, ##te, ;, v, ##ln, ,, vent, ##rol, ##ater, ##al, nerve, ;, v, ##nc, ,, ventral, nerve, cord, ;, v, ##nc, ##n, ,, ventral, nerve, cord, ne, ##uri, ##te, ##fi, ##g, ., 4, ##pre, ##dict, ##ed, correlation, ##s, between, internal, ace, ##ty, ##lated, α, -, tub, ##ulin, -, li, ##r, and, external, cut, ##icular, structures, in, ec, ##hin, ##oder, ##es, ., anterior, is, up, in, all, panels, ., specimen, silhouette, ##s, with, dashed, squares, indicate, the, axial, region, of, each, z, -, stack, ., color, legend, applies, to, all, panels, ., con, ##fo, ##cal, z, -, stack, projections, and, se, ##m, micro, ##graphs, were, obtained, from, different, specimens, ., a, -, j, ec, ##hin, ##oder, ##es, oh, ##tsu, ##kai, ., k, -, p, ec, ##hin, ##oder, ##es, horn, ##i, ., a, con, ##fo, ##cal, z, -, stack, of, segments, 1, –, 3, in, lateral, view, co, -, labeled, for, act, ##ub, -, li, ##r, (, act, ##ub, ), and, dna, ., b, se, ##m, micro, ##graph, showing, a, pair, of, sensory, spots, in, segment, 1, that, correspond, to, the, upper, boxed, area, in, (, d, ), ., the, upper, pair, of, dashed, arrows, in, (, a, ), correspond, to, inner, ##vation, of, the, sensory, spots, in, (, b, ), ., c, se, ##m, micro, ##graph, showing, a, pair, of, sensory, spots, in, segment, 2, corresponding, to, the, lower, boxed, area, in, (, d, ), ., lower, pair, of, dashed, arrows, in, (, a, ), correspond, to, inner, ##vation, of, the, sensory, spots, in, (, c, ), ., g, con, ##fo, ##cal, z, -, stack, of, segments, 6, –, 11, in, ventral, view, co, -, labeled, for, act, ##ub, -, li, ##r, and, dna, ., e, se, ##m, micro, ##graph, of, a, mid, ##vent, ##ral, sensory, spot, corresponding, to, inner, ##vation, (, dashed, arrow, ), in, (, g, ), ., f, se, ##m, of, a, later, ##oven, ##tral, fringe, ##d, tube, from, segment, 7, corresponding, to, inner, ##vation, in, (, g, ), ., h, se, ##m, of, a, later, ##oven, ##tral, ac, ##icular, spine, and, its, inner, ##vation, in, (, g, ), ., i, se, ##m, of, a, si, ##eve, plate, on, segment, 9, and, inner, ##vation, in, (, g, ), ., j, se, ##m, of, segments, 8, –, 11, in, ventral, view, showing, the, position, of, the, si, ##eve, plate, (, boxed, area, ), mag, ##nified, in, (, i, ), ., k, con, ##fo, ##cal, z, -, stack, of, act, ##ub, -, li, ##r, within, segment, 7, in, ventral, view, ., l, se, ##m, of, a, vent, ##rom, ##ed, ##ial, sensory, spot, and, its, corresponding, inner, ##vation, in, (, k, ), ., m, se, ##m, of, the, ventral, side, of, segment, 7, showing, the, relative, position, (, boxed, area, ), of, the, sensory, spot, in, (, l, ), ., n, con, ##fo, ##cal, z, -, stack, of, act, ##ub, -, li, ##r, within, segments, 9, –, 11, in, ventral, view, ., o, se, ##m, of, sensory, spots, from, segment, 11, and, their, correlation, with, inner, ##vation, in, (, n, ), ., p, se, ##m, of, segments, 9, –, 11, in, ventral, view, showing, the, sensory, spots, (, boxed, areas, ), mag, ##nified, in, (, o, ), ., scale, bars, :, 20, μ, ##m, in, (, a, ,, d, ,, n, ), ,, 10, μ, ##m, in, (, b, ,, c, ,, g, ,, k, ,, j, ,, m, ,, p, ), ,, 2, μ, ##m, in, (, e, ,, f, ,, h, ,, i, ,, o, ), ., abbreviation, ##s, :, l, ##nb, ,, longitudinal, ne, ##uri, ##te, bundle, ;, l, ##vs, ,, later, ##oven, ##tral, spine, ;, nc, ##n, ,, neck, circular, ne, ##uri, ##te, ;, ne, ##n, ,, ne, ##ph, ##rid, ##ial, ne, ##uri, ##te, ;, s, ,, segment, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, s, ##n, ,, spine, ne, ##uri, ##te, ;, sp, ., ,, si, ##eve, plate, ;, sp, ##n, ,, ss, ,, sensory, spot, ;, ss, ##n, ,, sensory, spot, ne, ##uri, ##te, ;, tb, ##n, ,, tube, ne, ##uri, ##te, ;, tn, ,, transverse, ne, ##uri, ##te, ;, ts, ##n, ,, terminal, spine, ne, ##uri, ##te, ;, v, ##nc, ,, ventral, nerve, cord, ., numbers, after, abbreviation, ##s, refer, to, segment, number'},\n", - " {'article_id': '992bfa0b2a3e7bd521e302775dfc0ea8',\n", - " 'section_name': 'Comparative neuroanatomy in Kinorhyncha',\n", - " 'text': 'Prior to our investigation, only two studies of kinorhynch nervous systems using immunohistochemistry and confocal microscopy have been performed, and only with a small number of species: Echinoderes spinifurca, Antygomonas paulae Sørensen, 2007, Zelinkaderes brightae Sørensen, 2007 and Setaphyes kielensis (Zelinka, 1928) (summarized in Table 1) [28, 29]. The serotoninergic nervous system was investigated in all these species and tubulin-like immunoreactivity (Tub-LIR) was also characterized in S. kielensis (Pycnophyes kielensis in Altenburger 2016 [28]). The pattern of Tub-LIR in S. kielensis is similar to what we observed in Echinoderes, which included a ring-like neuropil, a ganglionated ventral nerve cord composed of two anterior longitudinal neurite bundles that bifurcate in the posterior end, and transverse peripheral neurites emerging from the ventral nerve cord within at least four trunk segments [28]. Our study represents the first successful experiments with FMRF-LIR in Kinorhyncha; therefore, additional studies using this neural marker on other species are needed for a broader comparative framework. Serotonin- \\\\LIR has revealed a similar architecture in the brain and ventral nerve cord in all species studied so far [28, 29]. The observed variation among genera consisted of the number of neuropil rings (2 in Setaphyes; 4 in Antygomonas, Echinoderes and Zelinkaderes) and the number of neurons associated with the neuropil [28, 29]. Additionally, the posterior end of the serotonergic ventral nerve cord forms either a ring-like structure in species with a midterminal spine (Antygomonas and Zelinkaderes) or an inverted Y-like bifurcation in species without a midterminal spine (Echinoderes and Setaphyes) [29]. As suggested above, there appears to be important correlations between neural organization and species-specific cuticular structures (e.g. terminal spines) situated at the posterior end of kinorhynchs. In the case of 5HT-LIR, we find evidence for potential links between terminal anatomy of the ventral nerve cord and functional morphology of appendage-like characters in mud dragons.Table 1Comparison of nervous system architecture within Kinorhyncha. Abbreviations: np, neuropil; ios, inner oral styles; oos, outer oral styles; so, somata; ss, sensory spots; vnc, ventral nerve cord. Question marks represent absence of dataSpeciesData sourceBrainNumber of longitudinal nervesTransverse neurites (commissures)VncInnervation of introvert scalidsInnervation mouth coneInnervation of neckInnervation of trunk cuticular structuresReferencesA. paulaeCLSMCircumpharyngeal with 3 regions(So-Np-So)??Paired origin of vnc?Serotonin positive nerve ring??[29]E. capitatusTEMCircumpharyngeal with 3 regions(So-Np-So)Ten lobbed anterior somata10 fusing into 5(2 subdorsal, 2 ventrolateral and 1 vnc)2 per trunk segmentPaired origin of vncSingle ganglion per segmentNeurites from the 10 longitudinal nerves9 nerves innervating the oos from the “hindbrain” fusing into 5 nerves innervating iosProximal and terminal nerve ring10 longitudinal nervesSpines, tubes (named “setae”) and ss innervated from the 5 longitudinal nerves of the trunk[24, 25, 38]E. aquiloniusTEMCircumpharyngeal with 3 regions(So-Np-So)8“Circular nerve fibers” in each segmentPaired origin of vncDouble ganglia per segmentNeurites from the anterior perikarya of the brain10 nerves innervating the oos from the \"forebrain\"Proximal and terminal nerve ringNeurites from the longitudinal nervesSpines, ss, tubes innervated from the middorsal, laterodorsal and ventrolateral cords[26]E. horni\\n\\nE. spinifurca\\n\\nE. ohtsukaiCLSMCircumpharyngeal with 3 regions(So-Np-So)Ten lobbed anterior somata10 fusing into 5 (2 subdorsal, 2 ventrolateral and 1 vnc)2 per trunk segment (except for segments 1, 10-11)Paired origin of vncSingle ganglion per segmentRadially arranged neurites arising from the neuropil9 nerves innervating the oos arising from the neuropilAnterior nerve ring10 longitudinal nerves + 2 circularneuritesSpines, ss, tubes, and nephridia innervated from transverse neuritesTerminal spines innervated from longitudinal neurites from the vncPresent study, [29]P. greenlandicusTEMCircumpharyngeal with 3 regions(So-Np-So)8“Circular nerve fibers” in each segmentPaired origin of vncDouble ganglia per segmentNeurites from the anterior perikarya of the brain10 nerves innervating the oos from the \"forebrain\"Proximal and terminal nerve ringNeurites from the longitudinal nervesSpines, ss, tubes innervated from the longitudinal cords[26, 48]P. dentatusTEMCircumpharyngeal with 3 regions(So-Np-So)7?Paired origin of vnc (only illustrated)?9 nerves innervating the oos from the posterior brain region??[34, 49]S. kielensisTEM, CLSMCircumpharyngeal with 3 regions(So-Np-So)8 (TEM)At least one “nerve” per segment (CLSM)Paired origin of vnc (only illustrated) (TEM)1 ganglion per segment (TEM)/ 1 ganglion in vnc segment 6 (CLSM)?9 nerves innervating the oos (TEM)??[28, 48]Z. brightaeCLSMCircumpharyngeal with 3 regions(So-Np-So)??Paired origin of vnc?Serotonin positive nerve ring??[29]Z. floridensisTEMCircumpharyngeal with 3 regions(So-Np-So)12???9 nerves innervating the oos??[49]',\n", - " 'paragraph_id': 30,\n", - " 'tokenizer': 'prior, to, our, investigation, ,, only, two, studies, of, kin, ##or, ##hy, ##nch, nervous, systems, using, im, ##mun, ##oh, ##isto, ##chemist, ##ry, and, con, ##fo, ##cal, microscopy, have, been, performed, ,, and, only, with, a, small, number, of, species, :, ec, ##hin, ##oder, ##es, spin, ##if, ##ur, ##ca, ,, ant, ##y, ##go, ##mona, ##s, paula, ##e, s, ##ø, ##ren, ##sen, ,, 2007, ,, ze, ##link, ##ade, ##res, bright, ##ae, s, ##ø, ##ren, ##sen, ,, 2007, and, set, ##ap, ##hy, ##es, kiel, ##ensis, (, ze, ##link, ##a, ,, 1928, ), (, summarized, in, table, 1, ), [, 28, ,, 29, ], ., the, ser, ##oton, ##iner, ##gic, nervous, system, was, investigated, in, all, these, species, and, tub, ##ulin, -, like, im, ##mun, ##ore, ##act, ##ivity, (, tub, -, li, ##r, ), was, also, characterized, in, s, ., kiel, ##ensis, (, p, ##y, ##c, ##no, ##phy, ##es, kiel, ##ensis, in, alt, ##enburg, ##er, 2016, [, 28, ], ), ., the, pattern, of, tub, -, li, ##r, in, s, ., kiel, ##ensis, is, similar, to, what, we, observed, in, ec, ##hin, ##oder, ##es, ,, which, included, a, ring, -, like, ne, ##uro, ##pi, ##l, ,, a, gang, ##lion, ##ated, ventral, nerve, cord, composed, of, two, anterior, longitudinal, ne, ##uri, ##te, bundles, that, bi, ##fur, ##cate, in, the, posterior, end, ,, and, transverse, peripheral, ne, ##uri, ##tes, emerging, from, the, ventral, nerve, cord, within, at, least, four, trunk, segments, [, 28, ], ., our, study, represents, the, first, successful, experiments, with, fm, ##rf, -, li, ##r, in, kin, ##or, ##hy, ##nch, ##a, ;, therefore, ,, additional, studies, using, this, neural, marker, on, other, species, are, needed, for, a, broader, comparative, framework, ., ser, ##oton, ##in, -, \\\\, li, ##r, has, revealed, a, similar, architecture, in, the, brain, and, ventral, nerve, cord, in, all, species, studied, so, far, [, 28, ,, 29, ], ., the, observed, variation, among, genera, consisted, of, the, number, of, ne, ##uro, ##pi, ##l, rings, (, 2, in, set, ##ap, ##hy, ##es, ;, 4, in, ant, ##y, ##go, ##mona, ##s, ,, ec, ##hin, ##oder, ##es, and, ze, ##link, ##ade, ##res, ), and, the, number, of, neurons, associated, with, the, ne, ##uro, ##pi, ##l, [, 28, ,, 29, ], ., additionally, ,, the, posterior, end, of, the, ser, ##oton, ##er, ##gic, ventral, nerve, cord, forms, either, a, ring, -, like, structure, in, species, with, a, mid, ##ter, ##mina, ##l, spine, (, ant, ##y, ##go, ##mona, ##s, and, ze, ##link, ##ade, ##res, ), or, an, inverted, y, -, like, bi, ##fur, ##cation, in, species, without, a, mid, ##ter, ##mina, ##l, spine, (, ec, ##hin, ##oder, ##es, and, set, ##ap, ##hy, ##es, ), [, 29, ], ., as, suggested, above, ,, there, appears, to, be, important, correlation, ##s, between, neural, organization, and, species, -, specific, cut, ##icular, structures, (, e, ., g, ., terminal, spines, ), situated, at, the, posterior, end, of, kin, ##or, ##hy, ##nch, ##s, ., in, the, case, of, 5, ##ht, -, li, ##r, ,, we, find, evidence, for, potential, links, between, terminal, anatomy, of, the, ventral, nerve, cord, and, functional, morphology, of, app, ##end, ##age, -, like, characters, in, mud, dragons, ., table, 1, ##com, ##par, ##ison, of, nervous, system, architecture, within, kin, ##or, ##hy, ##nch, ##a, ., abbreviation, ##s, :, np, ,, ne, ##uro, ##pi, ##l, ;, ios, ,, inner, oral, styles, ;, o, ##os, ,, outer, oral, styles, ;, so, ,, so, ##mata, ;, ss, ,, sensory, spots, ;, v, ##nc, ,, ventral, nerve, cord, ., question, marks, represent, absence, of, data, ##sp, ##ec, ##ies, ##da, ##ta, source, ##bra, ##inn, ##umber, of, longitudinal, nerves, ##tra, ##ns, ##verse, ne, ##uri, ##tes, (, com, ##mis, ##sure, ##s, ), v, ##nc, ##inn, ##er, ##vation, of, intro, ##vert, sc, ##ali, ##ds, ##inn, ##er, ##vation, mouth, cone, ##inn, ##er, ##vation, of, neck, ##inn, ##er, ##vation, of, trunk, cut, ##icular, structures, ##re, ##ference, ##sa, ., paula, ##ec, ##ls, ##mc, ##ir, ##cum, ##pha, ##ryn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ?, ?, paired, origin, of, v, ##nc, ?, ser, ##oton, ##in, positive, nerve, ring, ?, ?, [, 29, ], e, ., capita, ##tus, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ten, lo, ##bbed, anterior, so, ##mata, ##10, fu, ##sing, into, 5, (, 2, sub, ##dor, ##sal, ,, 2, vent, ##rol, ##ater, ##al, and, 1, v, ##nc, ), 2, per, trunk, segment, ##pa, ##ired, origin, of, v, ##nc, ##sing, ##le, gang, ##lion, per, segment, ##ne, ##uri, ##tes, from, the, 10, longitudinal, nerves, ##9, nerves, inner, ##vating, the, o, ##os, from, the, “, hind, ##bra, ##in, ”, fu, ##sing, into, 5, nerves, inner, ##vating, ios, ##pro, ##xi, ##mal, and, terminal, nerve, ring, ##10, longitudinal, nerves, ##sp, ##ines, ,, tubes, (, named, “, set, ##ae, ”, ), and, ss, inner, ##vate, ##d, from, the, 5, longitudinal, nerves, of, the, trunk, [, 24, ,, 25, ,, 38, ], e, ., a, ##quil, ##oni, ##ust, ##em, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 8, “, circular, nerve, fibers, ”, in, each, segment, ##pa, ##ired, origin, of, v, ##nc, ##dou, ##ble, gang, ##lia, per, segment, ##ne, ##uri, ##tes, from, the, anterior, per, ##ika, ##rya, of, the, brain, ##10, nerves, inner, ##vating, the, o, ##os, from, the, \", fore, ##bra, ##in, \", pro, ##xi, ##mal, and, terminal, nerve, ring, ##ne, ##uri, ##tes, from, the, longitudinal, nerves, ##sp, ##ines, ,, ss, ,, tubes, inner, ##vate, ##d, from, the, mid, ##dor, ##sal, ,, later, ##od, ##ors, ##al, and, vent, ##rol, ##ater, ##al, cords, [, 26, ], e, ., horn, ##i, e, ., spin, ##if, ##ur, ##ca, e, ., oh, ##tsu, ##kai, ##cl, ##sm, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ten, lo, ##bbed, anterior, so, ##mata, ##10, fu, ##sing, into, 5, (, 2, sub, ##dor, ##sal, ,, 2, vent, ##rol, ##ater, ##al, and, 1, v, ##nc, ), 2, per, trunk, segment, (, except, for, segments, 1, ,, 10, -, 11, ), paired, origin, of, v, ##nc, ##sing, ##le, gang, ##lion, per, segment, ##rad, ##ial, ##ly, arranged, ne, ##uri, ##tes, arising, from, the, ne, ##uro, ##pi, ##l, ##9, nerves, inner, ##vating, the, o, ##os, arising, from, the, ne, ##uro, ##pi, ##lan, ##ter, ##ior, nerve, ring, ##10, longitudinal, nerves, +, 2, circular, ##ne, ##uri, ##tes, ##sp, ##ines, ,, ss, ,, tubes, ,, and, ne, ##ph, ##rid, ##ia, inner, ##vate, ##d, from, transverse, ne, ##uri, ##test, ##er, ##mina, ##l, spines, inner, ##vate, ##d, from, longitudinal, ne, ##uri, ##tes, from, the, v, ##nc, ##pres, ##ent, study, ,, [, 29, ], p, ., greenland, ##icus, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 8, “, circular, nerve, fibers, ”, in, each, segment, ##pa, ##ired, origin, of, v, ##nc, ##dou, ##ble, gang, ##lia, per, segment, ##ne, ##uri, ##tes, from, the, anterior, per, ##ika, ##rya, of, the, brain, ##10, nerves, inner, ##vating, the, o, ##os, from, the, \", fore, ##bra, ##in, \", pro, ##xi, ##mal, and, terminal, nerve, ring, ##ne, ##uri, ##tes, from, the, longitudinal, nerves, ##sp, ##ines, ,, ss, ,, tubes, inner, ##vate, ##d, from, the, longitudinal, cords, [, 26, ,, 48, ], p, ., dent, ##atus, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 7, ?, paired, origin, of, v, ##nc, (, only, illustrated, ), ?, 9, nerves, inner, ##vating, the, o, ##os, from, the, posterior, brain, region, ?, ?, [, 34, ,, 49, ], s, ., kiel, ##ensis, ##tem, ,, cl, ##sm, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 8, (, te, ##m, ), at, least, one, “, nerve, ”, per, segment, (, cl, ##sm, ), paired, origin, of, v, ##nc, (, only, illustrated, ), (, te, ##m, ), 1, gang, ##lion, per, segment, (, te, ##m, ), /, 1, gang, ##lion, in, v, ##nc, segment, 6, (, cl, ##sm, ), ?, 9, nerves, inner, ##vating, the, o, ##os, (, te, ##m, ), ?, ?, [, 28, ,, 48, ], z, ., bright, ##ae, ##cl, ##sm, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), ?, ?, paired, origin, of, v, ##nc, ?, ser, ##oton, ##in, positive, nerve, ring, ?, ?, [, 29, ], z, ., fl, ##ori, ##den, ##sis, ##tem, ##ci, ##rc, ##ump, ##har, ##yn, ##ge, ##al, with, 3, regions, (, so, -, np, -, so, ), 12, ?, ?, ?, 9, nerves, inner, ##vating, the, o, ##os, ?, ?, [, 49, ]'},\n", - " {'article_id': '992bfa0b2a3e7bd521e302775dfc0ea8',\n", - " 'section_name': 'FMRFamidergic nervous system',\n", - " 'text': 'Within the brain, FMRF-LIR is localized primarily in the neuropil, and in a combination of at least six or more perikarya and associated neurites within the anterior brain region (Figs. 6b-e, g, h and 7c-c’). FMRF-LIR in the neuropil reveals a broad series of dorsal rings that narrow midventrally along the anterior-posterior axis (Fig. 6h). The associated perikarya extend neurites to dorsal, lateral and ventrolateral locations along the anterior side of the neuropil (Fig. 6c, e, h). All of these anterior perikarya are similar in size, with the exception of a comparatively larger pair of bipolar cells (bpc) that are located at midlateral positions along the brain (Fig. 6b, c, h also indicated with arrowheads). Compared with other cell bodies showing FMRF-LIR, the two bipolar cells are positioned more distally from the neuropil, closer to the base of the introvert scalids, with each cell extending one neurite anteriorly that innervates the first spinoscalids of the introvert (Figs. 6b and 7c-c’). FMRF-LIR was also detected as a thin ring within the basal part of the mouth cone (mcnr) (Figs. 6h and 7c-c’), which appears to correlate with the positions of mouth-cone nerve rings showing acTub-LIR and 5HT-LIR. The two convergent neurites (cne) that extend from the neuropil toward their connections with the ventral nerve cord also showed FMRF-LIR.Fig. 6FMRF-LIR in the nervous system of Echinoderes. Confocal z-stack projections co-labeled for FMRF-LIR (b-e, g-h), acTub-LIR (a, f) and/or DNA (a-b, f-g). Anterior is to the top in (a-b, e-h); dorsal is to the top in (c-d). Specimen silhouettes with dashed squares indicate the axial region of each z-stack. Color legend applies to all panels. a-d\\nEchinoderes spinifurca. e-h\\nEchinoderes horni. a-b Segments 1–9 in dorsal views with head retracted. FMRF-LIR is detected in the neuropil and several somata associated with the anterior end of the brain and introvert. FMRF-LIR is correlated with acTub-LIR within subdorsal nerves (a). c-d Anterior views of cross sections through the brain corresponding to axial positions (c and d) in (b). c multiple FMRF^+ somata (asterisks, arrowheads) anterior to the neuropil. d FMRF^+ ring-like neuropil and ventral nerve cord. The outer contour in c and d is cuticular autofluorescence. e Dorsal view of FMRF-LIR in the neuropil and associated somata (asterisks). f-g Segments 4–8 in ventral view of the same specimen showing acTub-LIR (f) and FMRF-LIR (g) along the ganglionated ventral nerve cord. h Segments 1–4 in ventral view with head retracted showing FMRF-LIR within the neuropil and associated somata (asterisks). Arrowheads mark the position of FMRF^+ bipolar somata. Note the pair of FMRF^+ somata (vncs) in segment 4 along the ventral nerve cord. Scale bars, 20 μm in all panels. Abbreviations: aso, anterior somata; bpc, FMRF^+ bipolar cells; mcnr, mouth cone nerve ring; mdg, middorsal ganglion; np, neuropil; psn, primary spinoscalid neurite; pso, posterior somata; s1–9, segments 1–9; sdn, subdorsal longitudinal nerve; vnc, ventral nerve cord; vncg, ventral nerve cord ganglion; vncs, ventral nerve cord FMRF^+ somataFig. 7Schematic representations of acetylated α-tubulin-LIR, Serotonin-LIR and FMRF-LIR in Echinoderes. a-c Lateral overviews with the head extended. a’-c’ Ventral views of the head. Anterior is to the top in all panels. b-c’ 5HT-LIR and FMRF-LIR are overlaid upon a background of acTub-LIR (gray). The number of 5HT^+ and FMRF^+ somata (vncs) along the ventral nerve cord (b, c) varies among specimens and are representative here. Note the approximate orientations and arrangements of 5HT^+ ventromedial somata (b’) and FMRF^+ bipolar cells (c’) relative to neural rings of the neuropil. Abbreviations: bpc, FMRF^+ bipolar cells; cne, convergent neurites; cnr, complete neural ring; gn, gonad neurite; inr, incomplete neural ring; lnb, longitudinal neurite bundle; mcnr, mouth cone nerve ring; mdsn, middorsal spine neurite; ncn, neck circular neurite; nen, nephridial neurite; np, neuropil; pen, penile spine neurite; sdn, subdorsal longitudinal nerve; tn, transverse neurite; tsn, terminal spine neurite; vln, ventrolateral nerve; vms, 5HT^+ ventromedial somata; vnc, ventral nerve cord; vncs, ventral nerve cord FMRF^+ somata',\n", - " 'paragraph_id': 17,\n", - " 'tokenizer': 'within, the, brain, ,, fm, ##rf, -, li, ##r, is, localized, primarily, in, the, ne, ##uro, ##pi, ##l, ,, and, in, a, combination, of, at, least, six, or, more, per, ##ika, ##rya, and, associated, ne, ##uri, ##tes, within, the, anterior, brain, region, (, fig, ##s, ., 6, ##b, -, e, ,, g, ,, h, and, 7, ##c, -, c, ’, ), ., fm, ##rf, -, li, ##r, in, the, ne, ##uro, ##pi, ##l, reveals, a, broad, series, of, dorsal, rings, that, narrow, mid, ##vent, ##ral, ##ly, along, the, anterior, -, posterior, axis, (, fig, ., 6, ##h, ), ., the, associated, per, ##ika, ##rya, extend, ne, ##uri, ##tes, to, dorsal, ,, lateral, and, vent, ##rol, ##ater, ##al, locations, along, the, anterior, side, of, the, ne, ##uro, ##pi, ##l, (, fig, ., 6, ##c, ,, e, ,, h, ), ., all, of, these, anterior, per, ##ika, ##rya, are, similar, in, size, ,, with, the, exception, of, a, comparatively, larger, pair, of, bipolar, cells, (, bp, ##c, ), that, are, located, at, mid, ##lateral, positions, along, the, brain, (, fig, ., 6, ##b, ,, c, ,, h, also, indicated, with, arrow, ##heads, ), ., compared, with, other, cell, bodies, showing, fm, ##rf, -, li, ##r, ,, the, two, bipolar, cells, are, positioned, more, distal, ##ly, from, the, ne, ##uro, ##pi, ##l, ,, closer, to, the, base, of, the, intro, ##vert, sc, ##ali, ##ds, ,, with, each, cell, extending, one, ne, ##uri, ##te, anterior, ##ly, that, inner, ##vate, ##s, the, first, spin, ##os, ##cal, ##ids, of, the, intro, ##vert, (, fig, ##s, ., 6, ##b, and, 7, ##c, -, c, ’, ), ., fm, ##rf, -, li, ##r, was, also, detected, as, a, thin, ring, within, the, basal, part, of, the, mouth, cone, (, mc, ##nr, ), (, fig, ##s, ., 6, ##h, and, 7, ##c, -, c, ’, ), ,, which, appears, to, co, ##rre, ##late, with, the, positions, of, mouth, -, cone, nerve, rings, showing, act, ##ub, -, li, ##r, and, 5, ##ht, -, li, ##r, ., the, two, converge, ##nt, ne, ##uri, ##tes, (, cn, ##e, ), that, extend, from, the, ne, ##uro, ##pi, ##l, toward, their, connections, with, the, ventral, nerve, cord, also, showed, fm, ##rf, -, li, ##r, ., fig, ., 6, ##fm, ##rf, -, li, ##r, in, the, nervous, system, of, ec, ##hin, ##oder, ##es, ., con, ##fo, ##cal, z, -, stack, projections, co, -, labeled, for, fm, ##rf, -, li, ##r, (, b, -, e, ,, g, -, h, ), ,, act, ##ub, -, li, ##r, (, a, ,, f, ), and, /, or, dna, (, a, -, b, ,, f, -, g, ), ., anterior, is, to, the, top, in, (, a, -, b, ,, e, -, h, ), ;, dorsal, is, to, the, top, in, (, c, -, d, ), ., specimen, silhouette, ##s, with, dashed, squares, indicate, the, axial, region, of, each, z, -, stack, ., color, legend, applies, to, all, panels, ., a, -, d, ec, ##hin, ##oder, ##es, spin, ##if, ##ur, ##ca, ., e, -, h, ec, ##hin, ##oder, ##es, horn, ##i, ., a, -, b, segments, 1, –, 9, in, dorsal, views, with, head, retracted, ., fm, ##rf, -, li, ##r, is, detected, in, the, ne, ##uro, ##pi, ##l, and, several, so, ##mata, associated, with, the, anterior, end, of, the, brain, and, intro, ##vert, ., fm, ##rf, -, li, ##r, is, correlated, with, act, ##ub, -, li, ##r, within, sub, ##dor, ##sal, nerves, (, a, ), ., c, -, d, anterior, views, of, cross, sections, through, the, brain, corresponding, to, axial, positions, (, c, and, d, ), in, (, b, ), ., c, multiple, fm, ##rf, ^, +, so, ##mata, (, as, ##ter, ##isk, ##s, ,, arrow, ##heads, ), anterior, to, the, ne, ##uro, ##pi, ##l, ., d, fm, ##rf, ^, +, ring, -, like, ne, ##uro, ##pi, ##l, and, ventral, nerve, cord, ., the, outer, con, ##tour, in, c, and, d, is, cut, ##icular, auto, ##fl, ##uo, ##res, ##cence, ., e, dorsal, view, of, fm, ##rf, -, li, ##r, in, the, ne, ##uro, ##pi, ##l, and, associated, so, ##mata, (, as, ##ter, ##isk, ##s, ), ., f, -, g, segments, 4, –, 8, in, ventral, view, of, the, same, specimen, showing, act, ##ub, -, li, ##r, (, f, ), and, fm, ##rf, -, li, ##r, (, g, ), along, the, gang, ##lion, ##ated, ventral, nerve, cord, ., h, segments, 1, –, 4, in, ventral, view, with, head, retracted, showing, fm, ##rf, -, li, ##r, within, the, ne, ##uro, ##pi, ##l, and, associated, so, ##mata, (, as, ##ter, ##isk, ##s, ), ., arrow, ##heads, mark, the, position, of, fm, ##rf, ^, +, bipolar, so, ##mata, ., note, the, pair, of, fm, ##rf, ^, +, so, ##mata, (, v, ##nc, ##s, ), in, segment, 4, along, the, ventral, nerve, cord, ., scale, bars, ,, 20, μ, ##m, in, all, panels, ., abbreviation, ##s, :, as, ##o, ,, anterior, so, ##mata, ;, bp, ##c, ,, fm, ##rf, ^, +, bipolar, cells, ;, mc, ##nr, ,, mouth, cone, nerve, ring, ;, md, ##g, ,, mid, ##dor, ##sal, gang, ##lion, ;, np, ,, ne, ##uro, ##pi, ##l, ;, ps, ##n, ,, primary, spin, ##os, ##cal, ##id, ne, ##uri, ##te, ;, ps, ##o, ,, posterior, so, ##mata, ;, s, ##1, –, 9, ,, segments, 1, –, 9, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, v, ##nc, ,, ventral, nerve, cord, ;, v, ##nc, ##g, ,, ventral, nerve, cord, gang, ##lion, ;, v, ##nc, ##s, ,, ventral, nerve, cord, fm, ##rf, ^, +, so, ##mata, ##fi, ##g, ., 7, ##sche, ##matic, representations, of, ace, ##ty, ##lated, α, -, tub, ##ulin, -, li, ##r, ,, ser, ##oton, ##in, -, li, ##r, and, fm, ##rf, -, li, ##r, in, ec, ##hin, ##oder, ##es, ., a, -, c, lateral, overview, ##s, with, the, head, extended, ., a, ’, -, c, ’, ventral, views, of, the, head, ., anterior, is, to, the, top, in, all, panels, ., b, -, c, ’, 5, ##ht, -, li, ##r, and, fm, ##rf, -, li, ##r, are, over, ##laid, upon, a, background, of, act, ##ub, -, li, ##r, (, gray, ), ., the, number, of, 5, ##ht, ^, +, and, fm, ##rf, ^, +, so, ##mata, (, v, ##nc, ##s, ), along, the, ventral, nerve, cord, (, b, ,, c, ), varies, among, specimens, and, are, representative, here, ., note, the, approximate, orientation, ##s, and, arrangements, of, 5, ##ht, ^, +, vent, ##rom, ##ed, ##ial, so, ##mata, (, b, ’, ), and, fm, ##rf, ^, +, bipolar, cells, (, c, ’, ), relative, to, neural, rings, of, the, ne, ##uro, ##pi, ##l, ., abbreviation, ##s, :, bp, ##c, ,, fm, ##rf, ^, +, bipolar, cells, ;, cn, ##e, ,, converge, ##nt, ne, ##uri, ##tes, ;, cn, ##r, ,, complete, neural, ring, ;, g, ##n, ,, go, ##nad, ne, ##uri, ##te, ;, in, ##r, ,, incomplete, neural, ring, ;, l, ##nb, ,, longitudinal, ne, ##uri, ##te, bundle, ;, mc, ##nr, ,, mouth, cone, nerve, ring, ;, md, ##s, ##n, ,, mid, ##dor, ##sal, spine, ne, ##uri, ##te, ;, nc, ##n, ,, neck, circular, ne, ##uri, ##te, ;, ne, ##n, ,, ne, ##ph, ##rid, ##ial, ne, ##uri, ##te, ;, np, ,, ne, ##uro, ##pi, ##l, ;, pen, ,, pen, ##ile, spine, ne, ##uri, ##te, ;, sd, ##n, ,, sub, ##dor, ##sal, longitudinal, nerve, ;, tn, ,, transverse, ne, ##uri, ##te, ;, ts, ##n, ,, terminal, spine, ne, ##uri, ##te, ;, v, ##ln, ,, vent, ##rol, ##ater, ##al, nerve, ;, v, ##ms, ,, 5, ##ht, ^, +, vent, ##rom, ##ed, ##ial, so, ##mata, ;, v, ##nc, ,, ventral, nerve, cord, ;, v, ##nc, ##s, ,, ventral, nerve, cord, fm, ##rf, ^, +, so, ##mata'},\n", - " {'article_id': '0a905352272e1a0791679c71588f27f6',\n", - " 'section_name': 'Figure Caption',\n", - " 'text': 'Humans are equipped with high-threshold and very fast conducting primary afferents.(A) Location of myelinated HTMR receptive fields from recordings in the peroneal and radial nerves. Each red dot represents the location of an individual A-HTMR (n = 18). The pattern of receptive field spots, mapped with a Semmes-Weinstein monofilament, is shown for two A-HTMRs (marked by arrows; top, radial; bottom, peroneal). Receptive field spots were redrawn on photographic images so they can easily be seen. The horizontal lines represent the medial-lateral dimension, and the vertical lines represent the proximal-distal dimension. The average size of an A-HTMR receptive field, mapped using a filament force six times higher than that for an A-LTMR, was 26.8 mm^2 (±6.9; n = 9). This was significantly smaller than the receptive field of field afferents (100.5 ± 7.2 mm^2; n = 51; P < 0.0001, Dunnett’s test) but was not different from that of SA1 afferents (41.6 ± 7.5 mm^2; n = 17; P > 0.05, Dunnett’s test). (B) Brush responses of an A-HTMR and a field afferent. Using a soft or a coarse brush, the skin area centered on the receptive field of the recorded afferent was gently stroked at 3 cm/s. The field afferent responded vigorously to soft brush stroking. The A-HTMR did not respond to soft brush stroking, but it did respond to coarse brush stroking. The mechanical threshold of this A-HTMR was 4 mN, and the conduction velocity was 52 m/s. It responded to pinching, and its receptive field moved with skin translocation. Freq, frequency. (C) Mechanical threshold distribution of HTMRs and LTMRs in the recorded sample. For RA1 afferents, the preferred stimulus is hair movement, so monofilament thresholds were not measured. For A-HTMR, the median mechanical threshold was 10.0 mN (Q, 5.5–20.0; n = 18). This was significantly higher than the mechanical thresholds of all tested A-LTMR types (at least P < 0.001 for all individual comparisons, Dunn’s test) but was not different from C-HTMRs (10.0 mN; Q, 10.0–27.0; n = 5). (D) Spike activity of an A-HTMR to electrical and mechanical stimulations of the receptive field. Individual electrically and mechanically evoked spikes were superimposed on an expanded time scale to show that the electrically stimulated spike (used for latency measurement) was from the same unit as the one that was mechanically probed at the receptive field. (E) Conduction velocities of HTMRs and LTMRs to surface electrical stimulation (and monofilament tapping in case of one HTMR, conducting at 30 m/s). The data show individual and average (±SEM) conduction velocities of single afferents from peroneal (circles) and radial (diamonds) nerves. Conduction velocities of peroneal A-HTMRs (33.5 ± 2.1; n = 13) were statistically indistinguishable from peroneal A-LTMRs [SA1: 39.8 ± 2.3, n = 10; SA2: 38.6 ± 4.0, n = 4; RA1: 36.8 ± 2.8, n = 6; field: 34.3 ± 1.3, n = 18; F(4,46) = 1.70; P = 0.17, one-way analysis of variance (ANOVA)]. All three peroneal C-HTMRs were conducting at 0.9 m/s. In comparison to the peroneal nerve, conduction velocities of A-fiber types were faster in the radial nerve as expected (A-HTMR: 54.5 ± 2.4, n = 4; SA1: 56.8 m/s, n = 1; SA2: 53.0 ± 3.3, n = 3; RA1: 48.7 ± 1.6, n = 3; field: 47.3 ± 0.2, n = 2) (46). Both radial C-HTMRs were conducting at 1.1 m/s. Conduction velocity of RA2 afferents was not measured. (F) Slowly adapting properties of an A-HTMR at higher indentation forces. Spike activity of a field afferent and an A-HTMR during monofilament stimulation at three different forces, applied using electronic filaments with force feedback. Compared to the field afferent, the A-HTMR showed a sustained response at a lower indentation force (see also fig. S1).',\n", - " 'paragraph_id': 51,\n", - " 'tokenizer': 'humans, are, equipped, with, high, -, threshold, and, very, fast, conducting, primary, af, ##fer, ##ents, ., (, a, ), location, of, my, ##elin, ##ated, h, ##tm, ##r, rec, ##eptive, fields, from, recordings, in, the, per, ##one, ##al, and, radial, nerves, ., each, red, dot, represents, the, location, of, an, individual, a, -, h, ##tm, ##r, (, n, =, 18, ), ., the, pattern, of, rec, ##eptive, field, spots, ,, mapped, with, a, se, ##mme, ##s, -, wei, ##nstein, mono, ##fi, ##lam, ##ent, ,, is, shown, for, two, a, -, h, ##tm, ##rs, (, marked, by, arrows, ;, top, ,, radial, ;, bottom, ,, per, ##one, ##al, ), ., rec, ##eptive, field, spots, were, red, ##ra, ##wn, on, photographic, images, so, they, can, easily, be, seen, ., the, horizontal, lines, represent, the, medial, -, lateral, dimension, ,, and, the, vertical, lines, represent, the, pro, ##xi, ##mal, -, distal, dimension, ., the, average, size, of, an, a, -, h, ##tm, ##r, rec, ##eptive, field, ,, mapped, using, a, fi, ##lam, ##ent, force, six, times, higher, than, that, for, an, a, -, lt, ##m, ##r, ,, was, 26, ., 8, mm, ^, 2, (, ±, ##6, ., 9, ;, n, =, 9, ), ., this, was, significantly, smaller, than, the, rec, ##eptive, field, of, field, af, ##fer, ##ents, (, 100, ., 5, ±, 7, ., 2, mm, ^, 2, ;, n, =, 51, ;, p, <, 0, ., 000, ##1, ,, dunne, ##tt, ’, s, test, ), but, was, not, different, from, that, of, sa, ##1, af, ##fer, ##ents, (, 41, ., 6, ±, 7, ., 5, mm, ^, 2, ;, n, =, 17, ;, p, >, 0, ., 05, ,, dunne, ##tt, ’, s, test, ), ., (, b, ), brush, responses, of, an, a, -, h, ##tm, ##r, and, a, field, af, ##fer, ##ent, ., using, a, soft, or, a, coarse, brush, ,, the, skin, area, centered, on, the, rec, ##eptive, field, of, the, recorded, af, ##fer, ##ent, was, gently, stroked, at, 3, cm, /, s, ., the, field, af, ##fer, ##ent, responded, vigorously, to, soft, brush, stroking, ., the, a, -, h, ##tm, ##r, did, not, respond, to, soft, brush, stroking, ,, but, it, did, respond, to, coarse, brush, stroking, ., the, mechanical, threshold, of, this, a, -, h, ##tm, ##r, was, 4, mn, ,, and, the, conduct, ##ion, velocity, was, 52, m, /, s, ., it, responded, to, pinch, ##ing, ,, and, its, rec, ##eptive, field, moved, with, skin, trans, ##lo, ##cation, ., fr, ##e, ##q, ,, frequency, ., (, c, ), mechanical, threshold, distribution, of, h, ##tm, ##rs, and, lt, ##m, ##rs, in, the, recorded, sample, ., for, ra, ##1, af, ##fer, ##ents, ,, the, preferred, stimulus, is, hair, movement, ,, so, mono, ##fi, ##lam, ##ent, threshold, ##s, were, not, measured, ., for, a, -, h, ##tm, ##r, ,, the, median, mechanical, threshold, was, 10, ., 0, mn, (, q, ,, 5, ., 5, –, 20, ., 0, ;, n, =, 18, ), ., this, was, significantly, higher, than, the, mechanical, threshold, ##s, of, all, tested, a, -, lt, ##m, ##r, types, (, at, least, p, <, 0, ., 001, for, all, individual, comparisons, ,, dunn, ’, s, test, ), but, was, not, different, from, c, -, h, ##tm, ##rs, (, 10, ., 0, mn, ;, q, ,, 10, ., 0, –, 27, ., 0, ;, n, =, 5, ), ., (, d, ), spike, activity, of, an, a, -, h, ##tm, ##r, to, electrical, and, mechanical, stimulation, ##s, of, the, rec, ##eptive, field, ., individual, electrically, and, mechanically, ev, ##oked, spikes, were, super, ##im, ##posed, on, an, expanded, time, scale, to, show, that, the, electrically, stimulated, spike, (, used, for, late, ##ncy, measurement, ), was, from, the, same, unit, as, the, one, that, was, mechanically, probe, ##d, at, the, rec, ##eptive, field, ., (, e, ), conduct, ##ion, ve, ##lo, ##cit, ##ies, of, h, ##tm, ##rs, and, lt, ##m, ##rs, to, surface, electrical, stimulation, (, and, mono, ##fi, ##lam, ##ent, tapping, in, case, of, one, h, ##tm, ##r, ,, conducting, at, 30, m, /, s, ), ., the, data, show, individual, and, average, (, ±, ##se, ##m, ), conduct, ##ion, ve, ##lo, ##cit, ##ies, of, single, af, ##fer, ##ents, from, per, ##one, ##al, (, circles, ), and, radial, (, diamonds, ), nerves, ., conduct, ##ion, ve, ##lo, ##cit, ##ies, of, per, ##one, ##al, a, -, h, ##tm, ##rs, (, 33, ., 5, ±, 2, ., 1, ;, n, =, 13, ), were, statistical, ##ly, ind, ##ist, ##ing, ##uis, ##hab, ##le, from, per, ##one, ##al, a, -, lt, ##m, ##rs, [, sa, ##1, :, 39, ., 8, ±, 2, ., 3, ,, n, =, 10, ;, sa, ##2, :, 38, ., 6, ±, 4, ., 0, ,, n, =, 4, ;, ra, ##1, :, 36, ., 8, ±, 2, ., 8, ,, n, =, 6, ;, field, :, 34, ., 3, ±, 1, ., 3, ,, n, =, 18, ;, f, (, 4, ,, 46, ), =, 1, ., 70, ;, p, =, 0, ., 17, ,, one, -, way, analysis, of, variance, (, an, ##ova, ), ], ., all, three, per, ##one, ##al, c, -, h, ##tm, ##rs, were, conducting, at, 0, ., 9, m, /, s, ., in, comparison, to, the, per, ##one, ##al, nerve, ,, conduct, ##ion, ve, ##lo, ##cit, ##ies, of, a, -, fiber, types, were, faster, in, the, radial, nerve, as, expected, (, a, -, h, ##tm, ##r, :, 54, ., 5, ±, 2, ., 4, ,, n, =, 4, ;, sa, ##1, :, 56, ., 8, m, /, s, ,, n, =, 1, ;, sa, ##2, :, 53, ., 0, ±, 3, ., 3, ,, n, =, 3, ;, ra, ##1, :, 48, ., 7, ±, 1, ., 6, ,, n, =, 3, ;, field, :, 47, ., 3, ±, 0, ., 2, ,, n, =, 2, ), (, 46, ), ., both, radial, c, -, h, ##tm, ##rs, were, conducting, at, 1, ., 1, m, /, s, ., conduct, ##ion, velocity, of, ra, ##2, af, ##fer, ##ents, was, not, measured, ., (, f, ), slowly, adapting, properties, of, an, a, -, h, ##tm, ##r, at, higher, ind, ##entation, forces, ., spike, activity, of, a, field, af, ##fer, ##ent, and, an, a, -, h, ##tm, ##r, during, mono, ##fi, ##lam, ##ent, stimulation, at, three, different, forces, ,, applied, using, electronic, fi, ##lam, ##ents, with, force, feedback, ., compared, to, the, field, af, ##fer, ##ent, ,, the, a, -, h, ##tm, ##r, showed, a, sustained, response, at, a, lower, ind, ##entation, force, (, see, also, fig, ., s, ##1, ), .'},\n", - " {'article_id': '8e025c7b000befe6eff45d14ce01b82d',\n", - " 'section_name': 'Figure Caption',\n", - " 'text': 'Illustrations of four key MEMRI applications for studying the visual system, from neuroarchitecture detection (A), to neuronal tract tracing (B), neuronal activity detection (C) and glial activity identification (D). (A) represents detection of neuroarchitecture in the rodent retina and the primate visual cortex. Top row of (A) shows MEMRI detection of distinct bands of the normal (left and middle) and degenerated rodent retinas (right) with alternating dark and light intensity signals, as denoted by the numbering of layers. Note the compromised photoreceptor layer “D” upon degeneration in the Royal College of Surgeons (RCS) rats at postnatal day (P) 90. Bottom row of (A) represents in vivo T1-weighted MRI of the marmoset occipital cortex before (left) and after (middle) systemic Mn^2+ administration. The corresponding histological section stained for cytochrome oxidase activity is shown on the right. The arrows indicate the primary/secondary visual cortex (V1/V2) border; I–III, IV, and V–VI indicate the cortical layers; and WM represents white matter. V1 detected in the T1-enhanced MEMRI scans agrees with the V1 identified in the histological section. The cortical layer IV experiences the strongest layer-specific enhancement, defining the extent of V1. (B) represents the use of MEMRI tract tracing for retinotopic mapping of normal and injured central visual pathways in Sprague-Dawley rats. MEMRI was performed 1 week after partial transection to the right superior intraorbital optic nerve (ON_io) in a,b as shown by the yellow arrowhead in a, and to the temporal and nasal regions of the right optic nerve in c,d, respectively. After intravitreal Mn^2+ injection into both eyes, the intact central visual pathway projected from the left eye could be traced from the left retina to the left optic nerve (ON), optic chiasm (OC), right optic tract (OT), right lateral geniculate nucleus (LGN), right pretectum (PT), and right superior colliculus (SC) in a. In contrast, reduced anterograde Mn^2+ transport was found beyond the site of partial transection in the central visual pathway projected from the right eye in a retinotopic manner following the schematics in the insert in a. b–d in the right column highlight the reduced Mn^2+ enhancement in the lateral, rostral and caudal regions of the left SC, denoted by the solid arrows. Open arrows indicate the hypointensity in the left LGN. (C) shows the use of MEMRI for detection of neuronal activity in the retina (top 2 rows) and the visual cortex (bottom row) of rodents. The heat maps on the top 2 rows of (C) visualize retinal adaptation by MEMRI in either light or dark condition. The horizontal white arrows mark the enhanced inner retina 4 h after systemic Mn^2+ administration (right column) as compared to the control condition without Mn^2+ administration (left column), while the vertical white arrows point to the outer retina that has higher intensity in dark-adapted than light-adapted conditions. The optic nerve (ON) is identified by a black arrow in each image. The bottom row of (C) represents neuronal activity of the visual cortex after systemic Mn^2+ administration and awake visual stimulation. The left image shows the anatomy of cortical regions of interest (ROIs) in terms of Brodmann areas: blue for the binocular division of the primary visual cortex (Area 17), cyan for the lateral division of the accessory visual cortex (Area 18), red for the primary somatosensory cortex (Area 2), and green for the primary auditory cortex (Area 41). A superimposed drawing shows the relevant surface topography. On the right is a voxel-wise analysis of activity-dependent Mn^2+ enhancement in one hemisphere centered in layer IV of the primary visual cortex at a depth from 480 to 690 μm. The top of the image is the rostral side of the cortex while the left side depicts the position of the longitudinal fissure. Values of the P-threshold are indicated on the bottom. The primary visual cortex, represented by the leftmost green open circle, had the highest density of below-threshold voxels. The green shaded band to the left, centered at the longitudinal fissure, is a buffer of the unanalyzed space. (D) shows a series of T1-weighted images of neonatal rats at 3 h, and 7 and 8 days after mild hypoxic-ischemia (H-I) insult at postnatal day (P) 7. The injury was induced by unilateral carotid artery occlusion and exposure to hypoxia at 35°C for 1 h. After MRI scans at day 7, systemic Mn^2+ administration was performed, and the image at day 8 represents MEMRI enhancement. The white arrow points to gray matter injuries in the ipsilesional hemisphere around the visual cortex. This type of gray matter lesion is not visible in the images from hour 3 and day 7 post-insult. Immunohistology of the same rats suggested co-localization of overexpressed glial activity in the same lesion area in MEMRI (not shown). (A–D) are reproduced with permissions from Berkowitz et al. (2006), Yang and Wu (2007), Bissig and Berkowitz (2009); Bock et al. (2009), Chan et al. (2011), and Nair et al. (2011).',\n", - " 'paragraph_id': 46,\n", - " 'tokenizer': 'illustrations, of, four, key, me, ##m, ##ri, applications, for, studying, the, visual, system, ,, from, ne, ##uro, ##ar, ##chi, ##tec, ##ture, detection, (, a, ), ,, to, ne, ##uron, ##al, tract, tracing, (, b, ), ,, ne, ##uron, ##al, activity, detection, (, c, ), and, g, ##lia, ##l, activity, identification, (, d, ), ., (, a, ), represents, detection, of, ne, ##uro, ##ar, ##chi, ##tec, ##ture, in, the, rode, ##nt, re, ##tina, and, the, primate, visual, cortex, ., top, row, of, (, a, ), shows, me, ##m, ##ri, detection, of, distinct, bands, of, the, normal, (, left, and, middle, ), and, de, ##gen, ##erated, rode, ##nt, re, ##tina, ##s, (, right, ), with, alternating, dark, and, light, intensity, signals, ,, as, denoted, by, the, numbering, of, layers, ., note, the, compromised, photo, ##re, ##ce, ##pt, ##or, layer, “, d, ”, upon, de, ##gen, ##eration, in, the, royal, college, of, surgeons, (, rc, ##s, ), rats, at, post, ##nat, ##al, day, (, p, ), 90, ., bottom, row, of, (, a, ), represents, in, vivo, t, ##1, -, weighted, mri, of, the, mar, ##mos, ##et, o, ##cci, ##pit, ##al, cortex, before, (, left, ), and, after, (, middle, ), systemic, mn, ^, 2, +, administration, ., the, corresponding, his, ##to, ##logical, section, stained, for, cy, ##to, ##chrome, ox, ##ida, ##se, activity, is, shown, on, the, right, ., the, arrows, indicate, the, primary, /, secondary, visual, cortex, (, v, ##1, /, v, ##2, ), border, ;, i, –, iii, ,, iv, ,, and, v, –, vi, indicate, the, co, ##rti, ##cal, layers, ;, and, w, ##m, represents, white, matter, ., v, ##1, detected, in, the, t, ##1, -, enhanced, me, ##m, ##ri, scans, agrees, with, the, v, ##1, identified, in, the, his, ##to, ##logical, section, ., the, co, ##rti, ##cal, layer, iv, experiences, the, strongest, layer, -, specific, enhancement, ,, defining, the, extent, of, v, ##1, ., (, b, ), represents, the, use, of, me, ##m, ##ri, tract, tracing, for, re, ##tino, ##top, ##ic, mapping, of, normal, and, injured, central, visual, pathways, in, sp, ##rag, ##ue, -, da, ##wley, rats, ., me, ##m, ##ri, was, performed, 1, week, after, partial, trans, ##ection, to, the, right, superior, intra, ##or, ##bit, ##al, optic, nerve, (, on, _, io, ), in, a, ,, b, as, shown, by, the, yellow, arrow, ##head, in, a, ,, and, to, the, temporal, and, nasal, regions, of, the, right, optic, nerve, in, c, ,, d, ,, respectively, ., after, intra, ##vi, ##tre, ##al, mn, ^, 2, +, injection, into, both, eyes, ,, the, intact, central, visual, pathway, projected, from, the, left, eye, could, be, traced, from, the, left, re, ##tina, to, the, left, optic, nerve, (, on, ), ,, optic, chi, ##as, ##m, (, o, ##c, ), ,, right, optic, tract, (, ot, ), ,, right, lateral, gen, ##iculate, nucleus, (, l, ##gn, ), ,, right, pre, ##tec, ##tum, (, pt, ), ,, and, right, superior, col, ##lic, ##ulus, (, sc, ), in, a, ., in, contrast, ,, reduced, ant, ##ero, ##grade, mn, ^, 2, +, transport, was, found, beyond, the, site, of, partial, trans, ##ection, in, the, central, visual, pathway, projected, from, the, right, eye, in, a, re, ##tino, ##top, ##ic, manner, following, the, sc, ##hema, ##tics, in, the, insert, in, a, ., b, –, d, in, the, right, column, highlight, the, reduced, mn, ^, 2, +, enhancement, in, the, lateral, ,, ro, ##stra, ##l, and, ca, ##uda, ##l, regions, of, the, left, sc, ,, denoted, by, the, solid, arrows, ., open, arrows, indicate, the, h, ##yp, ##oint, ##ens, ##ity, in, the, left, l, ##gn, ., (, c, ), shows, the, use, of, me, ##m, ##ri, for, detection, of, ne, ##uron, ##al, activity, in, the, re, ##tina, (, top, 2, rows, ), and, the, visual, cortex, (, bottom, row, ), of, rodents, ., the, heat, maps, on, the, top, 2, rows, of, (, c, ), visual, ##ize, re, ##tina, ##l, adaptation, by, me, ##m, ##ri, in, either, light, or, dark, condition, ., the, horizontal, white, arrows, mark, the, enhanced, inner, re, ##tina, 4, h, after, systemic, mn, ^, 2, +, administration, (, right, column, ), as, compared, to, the, control, condition, without, mn, ^, 2, +, administration, (, left, column, ), ,, while, the, vertical, white, arrows, point, to, the, outer, re, ##tina, that, has, higher, intensity, in, dark, -, adapted, than, light, -, adapted, conditions, ., the, optic, nerve, (, on, ), is, identified, by, a, black, arrow, in, each, image, ., the, bottom, row, of, (, c, ), represents, ne, ##uron, ##al, activity, of, the, visual, cortex, after, systemic, mn, ^, 2, +, administration, and, awake, visual, stimulation, ., the, left, image, shows, the, anatomy, of, co, ##rti, ##cal, regions, of, interest, (, roi, ##s, ), in, terms, of, bro, ##dman, ##n, areas, :, blue, for, the, bin, ##oc, ##ular, division, of, the, primary, visual, cortex, (, area, 17, ), ,, cy, ##an, for, the, lateral, division, of, the, accessory, visual, cortex, (, area, 18, ), ,, red, for, the, primary, so, ##mat, ##ose, ##nsor, ##y, cortex, (, area, 2, ), ,, and, green, for, the, primary, auditory, cortex, (, area, 41, ), ., a, super, ##im, ##posed, drawing, shows, the, relevant, surface, topography, ., on, the, right, is, a, vox, ##el, -, wise, analysis, of, activity, -, dependent, mn, ^, 2, +, enhancement, in, one, hemisphere, centered, in, layer, iv, of, the, primary, visual, cortex, at, a, depth, from, 480, to, 690, μ, ##m, ., the, top, of, the, image, is, the, ro, ##stra, ##l, side, of, the, cortex, while, the, left, side, depicts, the, position, of, the, longitudinal, fis, ##sure, ., values, of, the, p, -, threshold, are, indicated, on, the, bottom, ., the, primary, visual, cortex, ,, represented, by, the, left, ##most, green, open, circle, ,, had, the, highest, density, of, below, -, threshold, vox, ##els, ., the, green, shaded, band, to, the, left, ,, centered, at, the, longitudinal, fis, ##sure, ,, is, a, buffer, of, the, una, ##nal, ##y, ##zed, space, ., (, d, ), shows, a, series, of, t, ##1, -, weighted, images, of, neon, ##atal, rats, at, 3, h, ,, and, 7, and, 8, days, after, mild, h, ##yp, ##ox, ##ic, -, is, ##che, ##mia, (, h, -, i, ), insult, at, post, ##nat, ##al, day, (, p, ), 7, ., the, injury, was, induced, by, un, ##ila, ##tera, ##l, car, ##ot, ##id, artery, o, ##cc, ##lusion, and, exposure, to, h, ##yp, ##ox, ##ia, at, 35, ##°, ##c, for, 1, h, ., after, mri, scans, at, day, 7, ,, systemic, mn, ^, 2, +, administration, was, performed, ,, and, the, image, at, day, 8, represents, me, ##m, ##ri, enhancement, ., the, white, arrow, points, to, gray, matter, injuries, in, the, ip, ##sil, ##es, ##ional, hemisphere, around, the, visual, cortex, ., this, type, of, gray, matter, les, ##ion, is, not, visible, in, the, images, from, hour, 3, and, day, 7, post, -, insult, ., im, ##mun, ##oh, ##isto, ##logy, of, the, same, rats, suggested, co, -, local, ##ization, of, over, ##ex, ##pressed, g, ##lia, ##l, activity, in, the, same, les, ##ion, area, in, me, ##m, ##ri, (, not, shown, ), ., (, a, –, d, ), are, reproduced, with, permission, ##s, from, be, ##rk, ##ow, ##itz, et, al, ., (, 2006, ), ,, yang, and, wu, (, 2007, ), ,, bis, ##si, ##g, and, be, ##rk, ##ow, ##itz, (, 2009, ), ;, bo, ##ck, et, al, ., (, 2009, ), ,, chan, et, al, ., (, 2011, ), ,, and, nair, et, al, ., (, 2011, ), .'},\n", - " {'article_id': '55db915e9bddb8a4270a57b3de30a9a1',\n", - " 'section_name': 'Decision utility in rats',\n", - " 'text': 'A series of experiments (Caprioli et al. 2007a, 2008, 2009; Celentano et al. 2009; Montanari et al. 2015; Avvisati et al. 2016; De Luca et al. 2019) were conducted in male Sprague–Dawley rats to assess the decision utility of heroin versus cocaine (or amphetamine). Also in these experiments, the rats were tested either at home or outside the home. Decision utility was assessed using different procedures.Between-subject procedures were used to assess the rats’ willingness to pay for heroin or cocaine, as a function of setting. In some experiments (Caprioli et al. 2007a, 2008), the rats were given the choice between a lever that triggered a drug infusion and a control lever that triggered an infusion of vehicle, and the work necessary to obtain the drug was increased progressively across sessions and within session, using a break-point procedure. The rats’ decision to self-administer heroin or cocaine was influenced in an opposite manner by the setting. Rats tested at home self-administered more heroin at home than rats tested outside the home. In contrast, the rats took more cocaine (and amphetamine) outside the home than at home. Furthermore, the rats worked harder for heroin at home than outside the home and for cocaine (or amphetamine) outside the home than at home.Within-subject procedures were used to compare the rats’ willingness to pay for heroin versus cocaine, as a function of setting. In these experiments (Caprioli et al. 2009; Celentano et al. 2009; Montanari et al. 2015; Avvisati et al. 2016), the rats were trained to press on alternate days for heroin and cocaine. One lever was paired with heroin and the other with cocaine (in a counterbalanced fashion), and the work necessary to obtain each drug was increased progressively across sessions. Also, in this case, the rats’ decision was a function of context, which influenced in an opposite manner heroin versus cocaine intake, and of workload. The ratio of cocaine to heroin infusions was greater outside the home than at home (indirectly indicating a preference) and became progressively larger with the increase in workload.Within-subject choice procedures were used in some studies to assess the rats’ preference for heroin or for cocaine. To the best of our knowledge, these are the first and only studies to have directly compared the rewarding effects of heroin and cocaine. In one of these studies (Caprioli et al. 2009), the rats were first trained to self-administer heroin and cocaine on alternate days, as previously described. The rats were then given the opportunity to choose between heroin and cocaine within the same session for several sessions. At the end of the choice sessions, the rats were classified, using a straightforward bootstrapping procedure (Wilson 1927; Newcombe 1988), as cocaine-preferring, heroin-preferring, or nonpreferring. The preference for one drug or the other was influenced in opposite directions by the context. At home, the rats tended to prefer heroin to cocaine; outside the home, the rats tended to prefer cocaine to heroin. Strikingly, the same double dissociation in decision-making was observed when we used an experimental design (see Fig. 3) in which rats were trained to receive the same drug (heroin for some, cocaine for other rats, Figs. 3A–C, 4) when pressing on either lever (De Luca et al. 2019). The rats were then offered the choice between heroin and cocaine, as described above (Fig. 3D). Also in this case, the rats tested at home tended to prefer heroin to cocaine, whereas the rats tested outside the home tended to prefer cocaine to heroin (Fig. 5). In summary, drug preference appears to be influenced to a much greater extent by the context of drug use than by the history of drug use.We also quantified the decision utility of heroin seeking and cocaine seeking after a period of abstinence from the drug (Montanari et al. 2015). The rats were first trained to self-administer heroin and cocaine on alternate days (Fig. 6A–C) and then underwent an extinction procedure (Fig. 6D), during which lever pressing did not result in drug infusion even in the presence of drug-paired cues (e.g., lever extension, cue lights, infusion of vehicle). The rats were then tested in a reinstatement procedure (Fig. 6E), developed to model relapse into drug seeking after a period of abstinence (de Wit and Stewart 1981; Shaham et al. 2003). The ability of a single, noncontingent intravenous drug infusion (drug priming) to precipitate drug seeking was assessed by comparing lever pressing during the reinstatement session to lever pressing under extinction conditions. Heroin priming precipitated heroin seeking in rats tested at home but not in rats tested outside the home, whereas the opposite was observed for cocaine: cocaine priming precipitated cocaine seeking outside the home but not at home (Fig. 7).It is important to notice that rats were able to update the decision utility of a given lever when one drug was substituted for another. When rats that had worked more vigorously for heroin at home than outside the home were shifted to amphetamine self-administration (after a period of washout), the opposite pattern was observed, as they took more amphetamine outside the home than at home (Caprioli et al. 2008).Fig. 3Experimental design of a within-subject study concerned with heroin versus cocaine choice in rats. A-C The rats were first trained to self-administer heroin (25 μg/kg per infusion) and cocaine (400 μg/kg per infusion), on alternate sessions, either at home or outside the home. The training lasted for 12 sessions (see Fig. 4 for results). D The rats were then given the opportunity to choose between heroin and cocaine for seven consecutive sessions. At the end of the choice sessions, the rats were classified as cocaine-preferring, heroin-preferring, or nonpreferring (see Fig. 5 for results). Modified from De Luca et al. (2019)Fig. 4Rats were tested as described in Fig. 3A–C. Mean (±SEM) number of infusions during the training phase for the heroin- and cocaine-trained groups, as a function of setting, time-out (TO) period, maximum number of infusions, and fixed ratio (FR). Single and double asterisks indicate significant effect setting (p < 0.05 and p < 0.01, respectively). Consistent with previous findings (Caprioli et al. 2007a, 2008) and despite the constraints in the maximum number of infusions, rats at home self-administered more heroin than rats outside the home, whereas rats outside the home self-administered more cocaine than rats at home. Modified from De Luca et al. (2019)Fig. 5Rats were tested as described in Fig. 3D. Drug preferences in individual rats (calculated using bootstrapping analysis), as a function of setting and drug history (see text for details). The preference for one drug or the other was influenced in opposite directions by the context. At home, 57.7% rats preferred heroin to cocaine, whereas only 23.1% preferred cocaine to heroin. Outside the home, 60% rats preferred cocaine to heroin, whereas only 16.7% preferred heroin to cocaine. Some rats (19.2% at home and 23.3% outside the home) did not exhibit a significant preference for either drug. Modified from De Luca et al. (2019)Fig. 6Experimental design aimed at quantifying the decision utility of heroin seeking and cocaine seeking after a period of abstinence from the drug (Montanari et al. 2015). The rats were first trained to self-administer heroin and cocaine on alternate days (A–C) and then underwent an extinction procedure (D), during which lever pressing did not result in drug infusion even in the presence of drug-paired cues (e.g., lever extension, cue lights, infusion of vehicle). The rats were then tested in a reinstatement procedure (E), developed to model relapse into drug seeking after a period of abstinence. The ability of a single, noncontingent intravenous drug infusion (drug priming) to precipitate drug seeking was assessed by comparing lever pressing during the reinstatement session to lever pressing under extinction conditions (for results, see Fig. 7)Fig. 7Mean (±SEM) number of lever presses during the first hour of the last extinction session (white bars) versus the reinstatement session (black bars) for rats tested at home versus rats outside the home (see Fig. 6). At the beginning of the reinstatement session, independent groups of rats (N values are indicated by the numbers within the white bars) received noncontingent intravenous (i.v.) infusions of one of three doses of cocaine (top panels) or heroin (bottom panels). Significant (##p ≤ 0.01 and ####p ≤ 0.0001) main effect of priming. Data from Montanari et al. (2015)',\n", - " 'paragraph_id': 18,\n", - " 'tokenizer': 'a, series, of, experiments, (, cap, ##rio, ##li, et, al, ., 2007, ##a, ,, 2008, ,, 2009, ;, ce, ##lent, ##ano, et, al, ., 2009, ;, montana, ##ri, et, al, ., 2015, ;, av, ##vis, ##ati, et, al, ., 2016, ;, de, luca, et, al, ., 2019, ), were, conducted, in, male, sp, ##rag, ##ue, –, da, ##wley, rats, to, assess, the, decision, utility, of, heroin, versus, cocaine, (, or, amp, ##het, ##amine, ), ., also, in, these, experiments, ,, the, rats, were, tested, either, at, home, or, outside, the, home, ., decision, utility, was, assessed, using, different, procedures, ., between, -, subject, procedures, were, used, to, assess, the, rats, ’, willingness, to, pay, for, heroin, or, cocaine, ,, as, a, function, of, setting, ., in, some, experiments, (, cap, ##rio, ##li, et, al, ., 2007, ##a, ,, 2008, ), ,, the, rats, were, given, the, choice, between, a, lever, that, triggered, a, drug, in, ##fusion, and, a, control, lever, that, triggered, an, in, ##fusion, of, vehicle, ,, and, the, work, necessary, to, obtain, the, drug, was, increased, progressively, across, sessions, and, within, session, ,, using, a, break, -, point, procedure, ., the, rats, ’, decision, to, self, -, administer, heroin, or, cocaine, was, influenced, in, an, opposite, manner, by, the, setting, ., rats, tested, at, home, self, -, administered, more, heroin, at, home, than, rats, tested, outside, the, home, ., in, contrast, ,, the, rats, took, more, cocaine, (, and, amp, ##het, ##amine, ), outside, the, home, than, at, home, ., furthermore, ,, the, rats, worked, harder, for, heroin, at, home, than, outside, the, home, and, for, cocaine, (, or, amp, ##het, ##amine, ), outside, the, home, than, at, home, ., within, -, subject, procedures, were, used, to, compare, the, rats, ’, willingness, to, pay, for, heroin, versus, cocaine, ,, as, a, function, of, setting, ., in, these, experiments, (, cap, ##rio, ##li, et, al, ., 2009, ;, ce, ##lent, ##ano, et, al, ., 2009, ;, montana, ##ri, et, al, ., 2015, ;, av, ##vis, ##ati, et, al, ., 2016, ), ,, the, rats, were, trained, to, press, on, alternate, days, for, heroin, and, cocaine, ., one, lever, was, paired, with, heroin, and, the, other, with, cocaine, (, in, a, counter, ##balance, ##d, fashion, ), ,, and, the, work, necessary, to, obtain, each, drug, was, increased, progressively, across, sessions, ., also, ,, in, this, case, ,, the, rats, ’, decision, was, a, function, of, context, ,, which, influenced, in, an, opposite, manner, heroin, versus, cocaine, intake, ,, and, of, work, ##load, ., the, ratio, of, cocaine, to, heroin, in, ##fusion, ##s, was, greater, outside, the, home, than, at, home, (, indirectly, indicating, a, preference, ), and, became, progressively, larger, with, the, increase, in, work, ##load, ., within, -, subject, choice, procedures, were, used, in, some, studies, to, assess, the, rats, ’, preference, for, heroin, or, for, cocaine, ., to, the, best, of, our, knowledge, ,, these, are, the, first, and, only, studies, to, have, directly, compared, the, reward, ##ing, effects, of, heroin, and, cocaine, ., in, one, of, these, studies, (, cap, ##rio, ##li, et, al, ., 2009, ), ,, the, rats, were, first, trained, to, self, -, administer, heroin, and, cocaine, on, alternate, days, ,, as, previously, described, ., the, rats, were, then, given, the, opportunity, to, choose, between, heroin, and, cocaine, within, the, same, session, for, several, sessions, ., at, the, end, of, the, choice, sessions, ,, the, rats, were, classified, ,, using, a, straightforward, boots, ##tra, ##pping, procedure, (, wilson, 1927, ;, new, ##combe, 1988, ), ,, as, cocaine, -, preferring, ,, heroin, -, preferring, ,, or, non, ##pre, ##fer, ##ring, ., the, preference, for, one, drug, or, the, other, was, influenced, in, opposite, directions, by, the, context, ., at, home, ,, the, rats, tended, to, prefer, heroin, to, cocaine, ;, outside, the, home, ,, the, rats, tended, to, prefer, cocaine, to, heroin, ., striking, ##ly, ,, the, same, double, di, ##sso, ##ciation, in, decision, -, making, was, observed, when, we, used, an, experimental, design, (, see, fig, ., 3, ), in, which, rats, were, trained, to, receive, the, same, drug, (, heroin, for, some, ,, cocaine, for, other, rats, ,, fig, ##s, ., 3a, –, c, ,, 4, ), when, pressing, on, either, lever, (, de, luca, et, al, ., 2019, ), ., the, rats, were, then, offered, the, choice, between, heroin, and, cocaine, ,, as, described, above, (, fig, ., 3d, ), ., also, in, this, case, ,, the, rats, tested, at, home, tended, to, prefer, heroin, to, cocaine, ,, whereas, the, rats, tested, outside, the, home, tended, to, prefer, cocaine, to, heroin, (, fig, ., 5, ), ., in, summary, ,, drug, preference, appears, to, be, influenced, to, a, much, greater, extent, by, the, context, of, drug, use, than, by, the, history, of, drug, use, ., we, also, quan, ##ti, ##fied, the, decision, utility, of, heroin, seeking, and, cocaine, seeking, after, a, period, of, abs, ##tine, ##nce, from, the, drug, (, montana, ##ri, et, al, ., 2015, ), ., the, rats, were, first, trained, to, self, -, administer, heroin, and, cocaine, on, alternate, days, (, fig, ., 6, ##a, –, c, ), and, then, underwent, an, extinction, procedure, (, fig, ., 6, ##d, ), ,, during, which, lever, pressing, did, not, result, in, drug, in, ##fusion, even, in, the, presence, of, drug, -, paired, cues, (, e, ., g, ., ,, lever, extension, ,, cue, lights, ,, in, ##fusion, of, vehicle, ), ., the, rats, were, then, tested, in, a, reins, ##tate, ##ment, procedure, (, fig, ., 6, ##e, ), ,, developed, to, model, re, ##la, ##pse, into, drug, seeking, after, a, period, of, abs, ##tine, ##nce, (, de, wit, and, stewart, 1981, ;, shah, ##am, et, al, ., 2003, ), ., the, ability, of, a, single, ,, non, ##con, ##ting, ##ent, intra, ##ven, ##ous, drug, in, ##fusion, (, drug, pri, ##ming, ), to, pre, ##ci, ##pit, ##ate, drug, seeking, was, assessed, by, comparing, lever, pressing, during, the, reins, ##tate, ##ment, session, to, lever, pressing, under, extinction, conditions, ., heroin, pri, ##ming, pre, ##ci, ##pit, ##ated, heroin, seeking, in, rats, tested, at, home, but, not, in, rats, tested, outside, the, home, ,, whereas, the, opposite, was, observed, for, cocaine, :, cocaine, pri, ##ming, pre, ##ci, ##pit, ##ated, cocaine, seeking, outside, the, home, but, not, at, home, (, fig, ., 7, ), ., it, is, important, to, notice, that, rats, were, able, to, update, the, decision, utility, of, a, given, lever, when, one, drug, was, substituted, for, another, ., when, rats, that, had, worked, more, vigorously, for, heroin, at, home, than, outside, the, home, were, shifted, to, amp, ##het, ##amine, self, -, administration, (, after, a, period, of, wash, ##out, ), ,, the, opposite, pattern, was, observed, ,, as, they, took, more, amp, ##het, ##amine, outside, the, home, than, at, home, (, cap, ##rio, ##li, et, al, ., 2008, ), ., fig, ., 3, ##ex, ##per, ##ime, ##ntal, design, of, a, within, -, subject, study, concerned, with, heroin, versus, cocaine, choice, in, rats, ., a, -, c, the, rats, were, first, trained, to, self, -, administer, heroin, (, 25, μ, ##g, /, kg, per, in, ##fusion, ), and, cocaine, (, 400, μ, ##g, /, kg, per, in, ##fusion, ), ,, on, alternate, sessions, ,, either, at, home, or, outside, the, home, ., the, training, lasted, for, 12, sessions, (, see, fig, ., 4, for, results, ), ., d, the, rats, were, then, given, the, opportunity, to, choose, between, heroin, and, cocaine, for, seven, consecutive, sessions, ., at, the, end, of, the, choice, sessions, ,, the, rats, were, classified, as, cocaine, -, preferring, ,, heroin, -, preferring, ,, or, non, ##pre, ##fer, ##ring, (, see, fig, ., 5, for, results, ), ., modified, from, de, luca, et, al, ., (, 2019, ), fig, ., 4, ##rat, ##s, were, tested, as, described, in, fig, ., 3a, –, c, ., mean, (, ±, ##se, ##m, ), number, of, in, ##fusion, ##s, during, the, training, phase, for, the, heroin, -, and, cocaine, -, trained, groups, ,, as, a, function, of, setting, ,, time, -, out, (, to, ), period, ,, maximum, number, of, in, ##fusion, ##s, ,, and, fixed, ratio, (, fr, ), ., single, and, double, as, ##ter, ##isk, ##s, indicate, significant, effect, setting, (, p, <, 0, ., 05, and, p, <, 0, ., 01, ,, respectively, ), ., consistent, with, previous, findings, (, cap, ##rio, ##li, et, al, ., 2007, ##a, ,, 2008, ), and, despite, the, constraints, in, the, maximum, number, of, in, ##fusion, ##s, ,, rats, at, home, self, -, administered, more, heroin, than, rats, outside, the, home, ,, whereas, rats, outside, the, home, self, -, administered, more, cocaine, than, rats, at, home, ., modified, from, de, luca, et, al, ., (, 2019, ), fig, ., 5, ##rat, ##s, were, tested, as, described, in, fig, ., 3d, ., drug, preferences, in, individual, rats, (, calculated, using, boots, ##tra, ##pping, analysis, ), ,, as, a, function, of, setting, and, drug, history, (, see, text, for, details, ), ., the, preference, for, one, drug, or, the, other, was, influenced, in, opposite, directions, by, the, context, ., at, home, ,, 57, ., 7, %, rats, preferred, heroin, to, cocaine, ,, whereas, only, 23, ., 1, %, preferred, cocaine, to, heroin, ., outside, the, home, ,, 60, %, rats, preferred, cocaine, to, heroin, ,, whereas, only, 16, ., 7, %, preferred, heroin, to, cocaine, ., some, rats, (, 19, ., 2, %, at, home, and, 23, ., 3, %, outside, the, home, ), did, not, exhibit, a, significant, preference, for, either, drug, ., modified, from, de, luca, et, al, ., (, 2019, ), fig, ., 6, ##ex, ##per, ##ime, ##ntal, design, aimed, at, quan, ##tify, ##ing, the, decision, utility, of, heroin, seeking, and, cocaine, seeking, after, a, period, of, abs, ##tine, ##nce, from, the, drug, (, montana, ##ri, et, al, ., 2015, ), ., the, rats, were, first, trained, to, self, -, administer, heroin, and, cocaine, on, alternate, days, (, a, –, c, ), and, then, underwent, an, extinction, procedure, (, d, ), ,, during, which, lever, pressing, did, not, result, in, drug, in, ##fusion, even, in, the, presence, of, drug, -, paired, cues, (, e, ., g, ., ,, lever, extension, ,, cue, lights, ,, in, ##fusion, of, vehicle, ), ., the, rats, were, then, tested, in, a, reins, ##tate, ##ment, procedure, (, e, ), ,, developed, to, model, re, ##la, ##pse, into, drug, seeking, after, a, period, of, abs, ##tine, ##nce, ., the, ability, of, a, single, ,, non, ##con, ##ting, ##ent, intra, ##ven, ##ous, drug, in, ##fusion, (, drug, pri, ##ming, ), to, pre, ##ci, ##pit, ##ate, drug, seeking, was, assessed, by, comparing, lever, pressing, during, the, reins, ##tate, ##ment, session, to, lever, pressing, under, extinction, conditions, (, for, results, ,, see, fig, ., 7, ), fig, ., 7, ##me, ##an, (, ±, ##se, ##m, ), number, of, lever, presses, during, the, first, hour, of, the, last, extinction, session, (, white, bars, ), versus, the, reins, ##tate, ##ment, session, (, black, bars, ), for, rats, tested, at, home, versus, rats, outside, the, home, (, see, fig, ., 6, ), ., at, the, beginning, of, the, reins, ##tate, ##ment, session, ,, independent, groups, of, rats, (, n, values, are, indicated, by, the, numbers, within, the, white, bars, ), received, non, ##con, ##ting, ##ent, intra, ##ven, ##ous, (, i, ., v, ., ), in, ##fusion, ##s, of, one, of, three, doses, of, cocaine, (, top, panels, ), or, heroin, (, bottom, panels, ), ., significant, (, #, #, p, ≤, 0, ., 01, and, #, #, #, #, p, ≤, 0, ., 000, ##1, ), main, effect, of, pri, ##ming, ., data, from, montana, ##ri, et, al, ., (, 2015, )'},\n", - " {'article_id': '2afd98c52706b12bad139a461e64e517',\n", - " 'section_name': 'Functional characterization of NAP genes',\n", - " 'text': 'Sub-clustering of the 147 unique human orthologs within the PLN network reveals nine functionally distinct gene modules (Fig. 5a). Similar mouse modules were uncovered when grouping NAP genes based on gene expression dynamics across the developing mouse CNS (Supplementary Fig. 8), reinforcing the relevance of translational studies between human and mouse. The human module 2 was enriched for cell cycle-related GO annotations specifically the G2/M checkpoint (Fig. 5a; Supplementary Data 18), implicating these genes in early neurodevelopmental processes. By contrast, human modules 0 and 7 exhibit an excess of brain-specific (p = 0.002 and p = 0.045, respectively; right-tailed Fisher’s test) and human orthologs of FMRP target genes (p = 7.81E−04 and p = 0.030, respectively; Fig. 5b; right-tailed Fisher test). Moreover, module 0 is also enriched for human orthologs of mouse PSD and synaptosome genes (p = 7.81E−04 and p = 0.019, respectively; Fig. 5b; right-tailed Fisher’s test) and the associated genes are functionally annotated with the GO terms PSD (BH-p = 0.0015; right-tailed hypergeometric test), cell projection (BH-p = 0.040; right-tailed hypergeometric test), and cytoskeleton (BH-p = 0.026; right-tailed hypergeometric test) (Supplementary Data 18). While both modules possess neuronal functions, genes from module 0 are upregulated postnatally, while those in module 7 are upregulated in the fetal brain (Fig. 5c), suggesting that each module contributes to distinct neurodevelopmental and mature synaptic functions. Accordingly, modules 7 and 0 are enriched in different subsets of fetally and postnatally expressed FMRP target genes (p = 0.0038 and p = 0.0055, respectively; Fig. 5b; right-tailed Fisher test). In humans, disruptions of genes within the same neurodevelopmental pathway cause a similar pattern of pleiotropic phenotypes^33. Correspondingly, while no specific neuroanatomical abnormality was overrepresented among mouse models of orthologs belonging to the same human functional modules, an overall phenotypic convergence was observed for modules 2, 7, and 8 (Fig. 5d; Supplementary Notes) revealing neurodevelopmental pathway/phenotype relationships. Specifically, mouse orthologs of modules 2 and 7 yielded more similar brain abnormalities than other NAP genes across Bregma +0.98 mm but not Bregma −1.34 mm, while the opposite pattern was found for module 8 orthologs (Fig. 5d). Congruently, while genes from human modules 2 and 7 are more strongly expressed across tissues mapping to Bregma +0.98 mm than Bregma −1.34 mm, those from module 8 are more highly expressed across Bregma −1.34 mm tissues (Fig. 5c).Fig. 5Functional characterization of human gene modules. a The PLN (Phenotypic Linkage Network) identifies 381 functional links between 121 human orthologs of NeuroAnatomical Phenotype (NAP) genes, which partitioned into the 9 modules of closely related genes (illustrated by the color of the nodes). The thickness of each edge is proportional to the functional similarity score, as given by the PLN, and the color of each edge indicates the largest contributing information source. Red borders depict known ID-associated genes, whereas blue and green borders refer to the set of embryonically expressed and mature Fragile X Mental Retardation Protein (FMRP) target genes, respectively. Module descriptions were added, where clearly discernable. b Gene set enrichment analysis across the nine human modules. c Spatiotemporal expression dynamics of module genes compared to the remaining NAP orthologs. d The heat map depicts the similarity of brain abnormalities caused by module genes in the critical sections 1 and 2 (Bregma +0.98 mm and −1.34 mm, respectively). The color code corresponds to the adjusted p value with double S (§) referring to BH-p < 0.05 (c, d; permutation test). e New neuroanatomical study of Fmr1^−/Y in the coronal plane (n = 4 wild types (WTs) and n = 6 Fmr1^−/Y, male). Top: Schematic representation of the affected brain parameters at Bregma +0.98 mm and −1.34 mm. Numbers refer to the same brain parameters from Fig. 2b and Supplementary Fig. 2b, c. The color code indicates the unadjusted p value. Bottom: Histograms showing the percentage of increase/decrease of the brain parameters compared to WTs',\n", - " 'paragraph_id': 19,\n", - " 'tokenizer': 'sub, -, cluster, ##ing, of, the, 147, unique, human, or, ##th, ##olo, ##gs, within, the, pl, ##n, network, reveals, nine, functional, ##ly, distinct, gene, modules, (, fig, ., 5, ##a, ), ., similar, mouse, modules, were, uncovered, when, grouping, nap, genes, based, on, gene, expression, dynamics, across, the, developing, mouse, cn, ##s, (, supplementary, fig, ., 8, ), ,, rein, ##for, ##cing, the, relevance, of, translation, ##al, studies, between, human, and, mouse, ., the, human, module, 2, was, enriched, for, cell, cycle, -, related, go, ann, ##ota, ##tions, specifically, the, g, ##2, /, m, checkpoint, (, fig, ., 5, ##a, ;, supplementary, data, 18, ), ,, imp, ##lica, ##ting, these, genes, in, early, ne, ##uro, ##dev, ##elo, ##pment, ##al, processes, ., by, contrast, ,, human, modules, 0, and, 7, exhibit, an, excess, of, brain, -, specific, (, p, =, 0, ., 00, ##2, and, p, =, 0, ., 04, ##5, ,, respectively, ;, right, -, tailed, fisher, ’, s, test, ), and, human, or, ##th, ##olo, ##gs, of, fm, ##rp, target, genes, (, p, =, 7, ., 81, ##e, ##−, ##0, ##4, and, p, =, 0, ., 03, ##0, ,, respectively, ;, fig, ., 5, ##b, ;, right, -, tailed, fisher, test, ), ., moreover, ,, module, 0, is, also, enriched, for, human, or, ##th, ##olo, ##gs, of, mouse, ps, ##d, and, syn, ##ap, ##tos, ##ome, genes, (, p, =, 7, ., 81, ##e, ##−, ##0, ##4, and, p, =, 0, ., 01, ##9, ,, respectively, ;, fig, ., 5, ##b, ;, right, -, tailed, fisher, ’, s, test, ), and, the, associated, genes, are, functional, ##ly, ann, ##ota, ##ted, with, the, go, terms, ps, ##d, (, b, ##h, -, p, =, 0, ., 001, ##5, ;, right, -, tailed, hyper, ##ge, ##ometric, test, ), ,, cell, projection, (, b, ##h, -, p, =, 0, ., 04, ##0, ;, right, -, tailed, hyper, ##ge, ##ometric, test, ), ,, and, cy, ##tos, ##kel, ##eto, ##n, (, b, ##h, -, p, =, 0, ., 02, ##6, ;, right, -, tailed, hyper, ##ge, ##ometric, test, ), (, supplementary, data, 18, ), ., while, both, modules, possess, ne, ##uron, ##al, functions, ,, genes, from, module, 0, are, up, ##re, ##gul, ##ated, post, ##nat, ##ally, ,, while, those, in, module, 7, are, up, ##re, ##gul, ##ated, in, the, fetal, brain, (, fig, ., 5, ##c, ), ,, suggesting, that, each, module, contributes, to, distinct, ne, ##uro, ##dev, ##elo, ##pment, ##al, and, mature, syn, ##ap, ##tic, functions, ., accordingly, ,, modules, 7, and, 0, are, enriched, in, different, subset, ##s, of, fetal, ##ly, and, post, ##nat, ##ally, expressed, fm, ##rp, target, genes, (, p, =, 0, ., 00, ##38, and, p, =, 0, ., 00, ##55, ,, respectively, ;, fig, ., 5, ##b, ;, right, -, tailed, fisher, test, ), ., in, humans, ,, disruption, ##s, of, genes, within, the, same, ne, ##uro, ##dev, ##elo, ##pment, ##al, pathway, cause, a, similar, pattern, of, pl, ##ei, ##ot, ##rop, ##ic, ph, ##eno, ##type, ##s, ^, 33, ., corresponding, ##ly, ,, while, no, specific, ne, ##uro, ##ana, ##tom, ##ical, abnormal, ##ity, was, over, ##re, ##pres, ##ented, among, mouse, models, of, or, ##th, ##olo, ##gs, belonging, to, the, same, human, functional, modules, ,, an, overall, ph, ##eno, ##typic, convergence, was, observed, for, modules, 2, ,, 7, ,, and, 8, (, fig, ., 5, ##d, ;, supplementary, notes, ), revealing, ne, ##uro, ##dev, ##elo, ##pment, ##al, pathway, /, ph, ##eno, ##type, relationships, ., specifically, ,, mouse, or, ##th, ##olo, ##gs, of, modules, 2, and, 7, yielded, more, similar, brain, abnormalities, than, other, nap, genes, across, br, ##eg, ##ma, +, 0, ., 98, mm, but, not, br, ##eg, ##ma, −, ##1, ., 34, mm, ,, while, the, opposite, pattern, was, found, for, module, 8, or, ##th, ##olo, ##gs, (, fig, ., 5, ##d, ), ., cong, ##ru, ##ently, ,, while, genes, from, human, modules, 2, and, 7, are, more, strongly, expressed, across, tissues, mapping, to, br, ##eg, ##ma, +, 0, ., 98, mm, than, br, ##eg, ##ma, −, ##1, ., 34, mm, ,, those, from, module, 8, are, more, highly, expressed, across, br, ##eg, ##ma, −, ##1, ., 34, mm, tissues, (, fig, ., 5, ##c, ), ., fig, ., 5, ##fu, ##nction, ##al, characterization, of, human, gene, modules, ., a, the, pl, ##n, (, ph, ##eno, ##typic, link, ##age, network, ), identifies, 381, functional, links, between, 121, human, or, ##th, ##olo, ##gs, of, ne, ##uro, ##ana, ##tom, ##ical, ph, ##eno, ##type, (, nap, ), genes, ,, which, partition, ##ed, into, the, 9, modules, of, closely, related, genes, (, illustrated, by, the, color, of, the, nodes, ), ., the, thickness, of, each, edge, is, proportional, to, the, functional, similarity, score, ,, as, given, by, the, pl, ##n, ,, and, the, color, of, each, edge, indicates, the, largest, contributing, information, source, ., red, borders, depict, known, id, -, associated, genes, ,, whereas, blue, and, green, borders, refer, to, the, set, of, embryo, ##nical, ##ly, expressed, and, mature, fragile, x, mental, re, ##tar, ##dation, protein, (, fm, ##rp, ), target, genes, ,, respectively, ., module, descriptions, were, added, ,, where, clearly, disc, ##ern, ##able, ., b, gene, set, enrichment, analysis, across, the, nine, human, modules, ., c, spat, ##iot, ##em, ##por, ##al, expression, dynamics, of, module, genes, compared, to, the, remaining, nap, or, ##th, ##olo, ##gs, ., d, the, heat, map, depicts, the, similarity, of, brain, abnormalities, caused, by, module, genes, in, the, critical, sections, 1, and, 2, (, br, ##eg, ##ma, +, 0, ., 98, mm, and, −, ##1, ., 34, mm, ,, respectively, ), ., the, color, code, corresponds, to, the, adjusted, p, value, with, double, s, (, §, ), referring, to, b, ##h, -, p, <, 0, ., 05, (, c, ,, d, ;, per, ##mut, ##ation, test, ), ., e, new, ne, ##uro, ##ana, ##tom, ##ical, study, of, fm, ##r, ##1, ^, −, /, y, in, the, corona, ##l, plane, (, n, =, 4, wild, types, (, w, ##ts, ), and, n, =, 6, fm, ##r, ##1, ^, −, /, y, ,, male, ), ., top, :, sc, ##hema, ##tic, representation, of, the, affected, brain, parameters, at, br, ##eg, ##ma, +, 0, ., 98, mm, and, −, ##1, ., 34, mm, ., numbers, refer, to, the, same, brain, parameters, from, fig, ., 2, ##b, and, supplementary, fig, ., 2, ##b, ,, c, ., the, color, code, indicates, the, una, ##d, ##just, ##ed, p, value, ., bottom, :, his, ##to, ##gram, ##s, showing, the, percentage, of, increase, /, decrease, of, the, brain, parameters, compared, to, w, ##ts'},\n", - " {'article_id': '2fa692af7a18169772b20d2215d57106',\n", - " 'section_name': 'Atypical channel behavior of Q/R-edited GluA2',\n", - " 'text': 'When recording glutamate-evoked currents (10 mM,100 ms, –60 mV) in outside-out patches excised from HEK293 cells expressing homomeric GluA2 with and without γ-2, γ-8, or GSG1L, we observed unexpected differences in the behavior of the unedited (Q) and edited (R) forms (Fig. 1). Compared with that of the Q-forms, GluA2(R) desensitization was slower (Fig. 1a–c). The mean differences in the weighed time constants of desensitization (τ_w, des) between the R- and Q-forms were 4.53 ms (95% confidence interval, 3.71–5.35) for GluA2 alone, 2.13 ms (95% confidence interval, 0.49–3.90) for GluA2/γ-2, 6.36 ms (95% confidence interval, 2.91–9.65) for GluA2/γ-8, and 2.83 ms (95% confidence interval, 1.28–4.56) for GluA2/GSG1L. This slowing of desensitization by Q/R site editing was accompanied by a striking increase in fractional steady-state current for GluA2, GluA2/γ-2, and GluA2/γ-8 (Fig. 1a, b, d). The mean differences in I_SS (% peak) between the R- and Q-forms were 9.2 (95% confidence interval, 6.6–11.1) for GluA2 alone, 33.9 (95% confidence interval, 29.2–38.4) for GluA2/γ-2, and 24.2 (95% confidence interval, 18.5–30.1) for GluA2/γ-8. By contrast, I_SS was not increased in the case of GluA2/GSG1L (1.43; 95% confidence interval, –0.35; 3.25) (Fig. 1d). Of note (except for GluA2/GSG1L) Q/R site editing had a much more pronounced effect on the steady-state currents (~400–600% increase) than on the desensitization time course (~30–90% slowing).Fig. 1Q/R editing affects the kinetics and variance of GluA2 currents. a Representative outside-out patch response (10 mM glutamate, 100 ms, –60 mV; gray bar) from a HEK293 cell transfected with GluA2(Q)/γ-2 (average current, black; five individual responses, grays). Inset: current–variance relationship (dotted line indicates background variance and red circle indicates expected origin). b As a, but for GluA2(R)/γ-2. Note that the data cannot be fitted with a parabolic relationship passing through the origin. c Pooled τ_w,des data for GluA2 alone (n = 12 Q-form and 9 R-form), GluA2/γ-2 (n = 21 and 27), GluA2/γ-8 (n = 7 and 10), and GluA2/GSG1L (n = 6 and 13). Box-and-whisker plots indicate the median (black line), the 25–75th percentiles (box), and the 10–90th percentiles (whiskers); filled circles are data from individual patches and open circles indicate means. Two-way ANOVA revealed an effect of Q/R editing (F_1,97 = 111.34, P < 0.0001), an effect of auxiliary subunit type (F_3,97 = 32.3, P < 0.0001) and an interaction (F_3,97 = 2.84, P = 0.041). d Pooled data for I_ss. Box-and-whisker plots and n numbers as in c. Two-way ANOVA indicated an effect of Q/R editing (F_1,97 = 129.98, P < 0.0001), an effect of auxiliary subunit type (F_3,97 = 58.30, P < 0.0001), and an interaction (F_3,97 = 58.67, P < 0.0001). e Doubly normalized and averaged current–variance relationships (desensitizing current phase only) from GluA2(Q) and GluA2(R) expressed alone (n = 12 and 9), with γ-2 (n = 19 and 23), with γ-8 (n = 7 and 10), or with GSG1L (n = 6 and 13). Error bars are s.e.m.s. All Q-forms can be fitted with parabolic relationships passing through the origin, while R-forms cannot. f Pooled NSFA conductance estimates for GluA2(Q) alone, GluA2(Q)/γ-2, GluA2(Q)/γ-8, and GluA2(Q)/GSG1L (n = 12, 18, 7, and 6, respectively). Box-and-whisker plots as in c. Indicated P values are from Wilcoxon rank sum tests. Source data are provided as a Source Data file',\n", - " 'paragraph_id': 4,\n", - " 'tokenizer': 'when, recording, g, ##lu, ##tama, ##te, -, ev, ##oked, currents, (, 10, mm, ,, 100, ms, ,, –, 60, mv, ), in, outside, -, out, patches, ex, ##cise, ##d, from, he, ##k, ##29, ##3, cells, expressing, homo, ##meric, g, ##lu, ##a, ##2, with, and, without, γ, -, 2, ,, γ, -, 8, ,, or, gs, ##g, ##1, ##l, ,, we, observed, unexpected, differences, in, the, behavior, of, the, une, ##dit, ##ed, (, q, ), and, edited, (, r, ), forms, (, fig, ., 1, ), ., compared, with, that, of, the, q, -, forms, ,, g, ##lu, ##a, ##2, (, r, ), des, ##ens, ##iti, ##zation, was, slower, (, fig, ., 1a, –, c, ), ., the, mean, differences, in, the, weighed, time, constant, ##s, of, des, ##ens, ##iti, ##zation, (, τ, _, w, ,, des, ), between, the, r, -, and, q, -, forms, were, 4, ., 53, ms, (, 95, %, confidence, interval, ,, 3, ., 71, –, 5, ., 35, ), for, g, ##lu, ##a, ##2, alone, ,, 2, ., 13, ms, (, 95, %, confidence, interval, ,, 0, ., 49, –, 3, ., 90, ), for, g, ##lu, ##a, ##2, /, γ, -, 2, ,, 6, ., 36, ms, (, 95, %, confidence, interval, ,, 2, ., 91, –, 9, ., 65, ), for, g, ##lu, ##a, ##2, /, γ, -, 8, ,, and, 2, ., 83, ms, (, 95, %, confidence, interval, ,, 1, ., 28, –, 4, ., 56, ), for, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, ., this, slowing, of, des, ##ens, ##iti, ##zation, by, q, /, r, site, editing, was, accompanied, by, a, striking, increase, in, fraction, ##al, steady, -, state, current, for, g, ##lu, ##a, ##2, ,, g, ##lu, ##a, ##2, /, γ, -, 2, ,, and, g, ##lu, ##a, ##2, /, γ, -, 8, (, fig, ., 1a, ,, b, ,, d, ), ., the, mean, differences, in, i, _, ss, (, %, peak, ), between, the, r, -, and, q, -, forms, were, 9, ., 2, (, 95, %, confidence, interval, ,, 6, ., 6, –, 11, ., 1, ), for, g, ##lu, ##a, ##2, alone, ,, 33, ., 9, (, 95, %, confidence, interval, ,, 29, ., 2, –, 38, ., 4, ), for, g, ##lu, ##a, ##2, /, γ, -, 2, ,, and, 24, ., 2, (, 95, %, confidence, interval, ,, 18, ., 5, –, 30, ., 1, ), for, g, ##lu, ##a, ##2, /, γ, -, 8, ., by, contrast, ,, i, _, ss, was, not, increased, in, the, case, of, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, (, 1, ., 43, ;, 95, %, confidence, interval, ,, –, 0, ., 35, ;, 3, ., 25, ), (, fig, ., 1, ##d, ), ., of, note, (, except, for, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, ), q, /, r, site, editing, had, a, much, more, pronounced, effect, on, the, steady, -, state, currents, (, ~, 400, –, 600, %, increase, ), than, on, the, des, ##ens, ##iti, ##zation, time, course, (, ~, 30, –, 90, %, slowing, ), ., fig, ., 1, ##q, /, r, editing, affects, the, kinetic, ##s, and, variance, of, g, ##lu, ##a, ##2, currents, ., a, representative, outside, -, out, patch, response, (, 10, mm, g, ##lu, ##tama, ##te, ,, 100, ms, ,, –, 60, mv, ;, gray, bar, ), from, a, he, ##k, ##29, ##3, cell, trans, ##fect, ##ed, with, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, (, average, current, ,, black, ;, five, individual, responses, ,, gray, ##s, ), ., ins, ##et, :, current, –, variance, relationship, (, dotted, line, indicates, background, variance, and, red, circle, indicates, expected, origin, ), ., b, as, a, ,, but, for, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, ., note, that, the, data, cannot, be, fitted, with, a, para, ##bolic, relationship, passing, through, the, origin, ., c, poole, ##d, τ, _, w, ,, des, data, for, g, ##lu, ##a, ##2, alone, (, n, =, 12, q, -, form, and, 9, r, -, form, ), ,, g, ##lu, ##a, ##2, /, γ, -, 2, (, n, =, 21, and, 27, ), ,, g, ##lu, ##a, ##2, /, γ, -, 8, (, n, =, 7, and, 10, ), ,, and, g, ##lu, ##a, ##2, /, gs, ##g, ##1, ##l, (, n, =, 6, and, 13, ), ., box, -, and, -, w, ##his, ##ker, plots, indicate, the, median, (, black, line, ), ,, the, 25, –, 75th, percent, ##ile, ##s, (, box, ), ,, and, the, 10, –, 90, ##th, percent, ##ile, ##s, (, w, ##his, ##kers, ), ;, filled, circles, are, data, from, individual, patches, and, open, circles, indicate, means, ., two, -, way, an, ##ova, revealed, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 97, =, 111, ., 34, ,, p, <, 0, ., 000, ##1, ), ,, an, effect, of, auxiliary, subunit, type, (, f, _, 3, ,, 97, =, 32, ., 3, ,, p, <, 0, ., 000, ##1, ), and, an, interaction, (, f, _, 3, ,, 97, =, 2, ., 84, ,, p, =, 0, ., 04, ##1, ), ., d, poole, ##d, data, for, i, _, ss, ., box, -, and, -, w, ##his, ##ker, plots, and, n, numbers, as, in, c, ., two, -, way, an, ##ova, indicated, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 97, =, 129, ., 98, ,, p, <, 0, ., 000, ##1, ), ,, an, effect, of, auxiliary, subunit, type, (, f, _, 3, ,, 97, =, 58, ., 30, ,, p, <, 0, ., 000, ##1, ), ,, and, an, interaction, (, f, _, 3, ,, 97, =, 58, ., 67, ,, p, <, 0, ., 000, ##1, ), ., e, do, ##ub, ##ly, normal, ##ized, and, averaged, current, –, variance, relationships, (, des, ##ens, ##iti, ##zing, current, phase, only, ), from, g, ##lu, ##a, ##2, (, q, ), and, g, ##lu, ##a, ##2, (, r, ), expressed, alone, (, n, =, 12, and, 9, ), ,, with, γ, -, 2, (, n, =, 19, and, 23, ), ,, with, γ, -, 8, (, n, =, 7, and, 10, ), ,, or, with, gs, ##g, ##1, ##l, (, n, =, 6, and, 13, ), ., error, bars, are, s, ., e, ., m, ., s, ., all, q, -, forms, can, be, fitted, with, para, ##bolic, relationships, passing, through, the, origin, ,, while, r, -, forms, cannot, ., f, poole, ##d, ns, ##fa, conduct, ##ance, estimates, for, g, ##lu, ##a, ##2, (, q, ), alone, ,, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, ,, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 8, ,, and, g, ##lu, ##a, ##2, (, q, ), /, gs, ##g, ##1, ##l, (, n, =, 12, ,, 18, ,, 7, ,, and, 6, ,, respectively, ), ., box, -, and, -, w, ##his, ##ker, plots, as, in, c, ., indicated, p, values, are, from, wilcox, ##on, rank, sum, tests, ., source, data, are, provided, as, a, source, data, file'},\n", - " {'article_id': '2fa692af7a18169772b20d2215d57106',\n", - " 'section_name': 'Low conductance steady-state openings follow desensitization',\n", - " 'text': 'As conventional current–variance relationships could be produced only from GluA2(R)/γ-2 activation and not desensitization (nor indeed from deactivation, during which there is a degree of desensitization) we speculated that desensitization itself may provide the key to our unexpected results. We hypothesized that the conformational rearrangements of the LBDs which normally trigger desensitization might not fully close the ion channel, such that the GluA2(R)/γ-2 receptors could adopt a conducting desensitized state, giving rise to the large fractional steady-state current and the anomalous current–variance relationships. If this were the case, and the shift from large resolvable channel openings to smaller openings was linked to the process of desensitization, a decline in GluA2(R)/γ-2 single-channel conductance (and therefore macroscopic current) would not be expected if desensitization was blocked. In the presence of cyclothiazide, which inhibits desensitization by stabilizing the upper LBD dimer interface^14, we found that GluA2(R)/γ-2 macroscopic currents (10 mM glutamate, 1 s) did not decay (Fig. 4a). Likewise, if the low-noise steady-state current of GluA2(R)/γ-2 arose from conducting desensitized channels, then we would expect the steady-state current to remain when desensitization was enhanced. To test this idea, we used the point mutation S754D. This weakens the upper LBD dimer interface, accelerating desensitization and reducing steady-state currents of GluA2(Q)^14. For both GluA2(Q)/γ-2 and GluA2(R)/γ-2 the S754D mutation produced a near 20-fold acceleration of desensitization (Fig. 4b, c) and a greater than twofold slowing of recovery from desensitization (Fig. 4d). As anticipated, GluA2(Q) S754D/γ-2 produced a negligible steady-state current (Fig. 4b, e). In marked contrast, GluA2(R) S754D/γ-2 exhibited an appreciable steady-state current (Fig. 4b, e). The presence of a large steady-state current with GluA2(R)/γ-2 under conditions strongly favoring desensitization is consistent with the view that desensitized channels can conduct.Fig. 4Large steady-state GluA2(R)/γ-2 currents are observed even in conditions favoring desensitization. a Representative GluA2(R)/γ-2 current (–60 mV) evoked by 10 mM glutamate (gray bar) in the presence of 50 μM cyclothiazide (green bar). Note the minimal current decay when desensitization is inhibited (for pooled data I_SS/I_peak = 93.4 ± 1.6%, n = 6) (mean ± s.e.m. from n patches). b Representative glutamate-evoked currents from Q- and R-forms of GluA2 S754D/γ-2. Both forms exhibit very fast desensitization, but the R-form has an appreciable steady-state current. c Pooled data showing desensitization kinetics (τ_w,des) for wild-type (wt; n = 6 and 5) and mutant (S754D; n = 5 and 5) forms of GluA2(Q)/γ-2 and GluA2(R)/γ-2. Box-and-whisker plots as in Fig. 1c. Two-way ANOVA indicated an effect of Q/R editing (F_1, 17 = 10.56, P = 0.0047), an effect of the mutation (F_1, 17 = 43.19, P < 0.0001) but no interaction (F_1, 17 = 2.63, P = 0.12). The mean difference between S754D and wild type was –8.1 ms (95% confidence interval, –10.9 to –6.0) for Q and –14.1 ms (95% confidence interval, –20.0 to –9.3) for R. d Pooled data (as in c) for recovery kinetics (τ_w,recov). Two-way ANOVA indicated no effect of Q/R editing (F_1, 17 = 0.13, P = 0.72), an effect of the mutation (F_1, 17 = 31.67, P < 0.0001) but no interaction (F_1, 17 = 1.65, P = 0.22). The mean difference between S754D and wild type was 24.1 ms (95% confidence interval, 15.3 to 33.2) for Q and 38.7 ms (95% confidence interval, 23.7 to 53.9) for R. e Pooled data (as in c) for the fractional steady-state current (I_SS). Two-way ANOVA indicated an effect of Q/R editing (F_1, 17 = 65.37, P < 0.0001), an effect of the mutation (F_1, 17 = 28.37, P < 0.0001), and an interaction (F_1, 17 = 14.93, P = 0.0012). The mean difference in I_SS (% of peak) between S754D and wild type was –7.7 (95% confidence interval, –11.2 to –5.2) for Q and –37.9 (95% confidence interval, –49.2 to –25.8) for R. Indicated P values are from Welch t-tests. Source data are provided as a Source Data file',\n", - " 'paragraph_id': 11,\n", - " 'tokenizer': 'as, conventional, current, –, variance, relationships, could, be, produced, only, from, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, activation, and, not, des, ##ens, ##iti, ##zation, (, nor, indeed, from, dea, ##ct, ##ivation, ,, during, which, there, is, a, degree, of, des, ##ens, ##iti, ##zation, ), we, speculated, that, des, ##ens, ##iti, ##zation, itself, may, provide, the, key, to, our, unexpected, results, ., we, h, ##yp, ##oth, ##es, ##ized, that, the, conform, ##ation, ##al, rear, ##rang, ##ement, ##s, of, the, lb, ##ds, which, normally, trigger, des, ##ens, ##iti, ##zation, might, not, fully, close, the, ion, channel, ,, such, that, the, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, receptors, could, adopt, a, conducting, des, ##ens, ##iti, ##zed, state, ,, giving, rise, to, the, large, fraction, ##al, steady, -, state, current, and, the, an, ##oma, ##lous, current, –, variance, relationships, ., if, this, were, the, case, ,, and, the, shift, from, large, res, ##ol, ##vable, channel, openings, to, smaller, openings, was, linked, to, the, process, of, des, ##ens, ##iti, ##zation, ,, a, decline, in, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, single, -, channel, conduct, ##ance, (, and, therefore, macro, ##scopic, current, ), would, not, be, expected, if, des, ##ens, ##iti, ##zation, was, blocked, ., in, the, presence, of, cy, ##cloth, ##ia, ##zi, ##de, ,, which, inhibit, ##s, des, ##ens, ##iti, ##zation, by, stab, ##ili, ##zing, the, upper, lb, ##d, dime, ##r, interface, ^, 14, ,, we, found, that, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, macro, ##scopic, currents, (, 10, mm, g, ##lu, ##tama, ##te, ,, 1, s, ), did, not, decay, (, fig, ., 4a, ), ., likewise, ,, if, the, low, -, noise, steady, -, state, current, of, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, arose, from, conducting, des, ##ens, ##iti, ##zed, channels, ,, then, we, would, expect, the, steady, -, state, current, to, remain, when, des, ##ens, ##iti, ##zation, was, enhanced, ., to, test, this, idea, ,, we, used, the, point, mutation, s, ##75, ##4, ##d, ., this, weaken, ##s, the, upper, lb, ##d, dime, ##r, interface, ,, accelerating, des, ##ens, ##iti, ##zation, and, reducing, steady, -, state, currents, of, g, ##lu, ##a, ##2, (, q, ), ^, 14, ., for, both, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, and, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, the, s, ##75, ##4, ##d, mutation, produced, a, near, 20, -, fold, acceleration, of, des, ##ens, ##iti, ##zation, (, fig, ., 4, ##b, ,, c, ), and, a, greater, than, two, ##fold, slowing, of, recovery, from, des, ##ens, ##iti, ##zation, (, fig, ., 4, ##d, ), ., as, anticipated, ,, g, ##lu, ##a, ##2, (, q, ), s, ##75, ##4, ##d, /, γ, -, 2, produced, a, ne, ##gli, ##gible, steady, -, state, current, (, fig, ., 4, ##b, ,, e, ), ., in, marked, contrast, ,, g, ##lu, ##a, ##2, (, r, ), s, ##75, ##4, ##d, /, γ, -, 2, exhibited, an, app, ##re, ##cia, ##ble, steady, -, state, current, (, fig, ., 4, ##b, ,, e, ), ., the, presence, of, a, large, steady, -, state, current, with, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, under, conditions, strongly, favor, ##ing, des, ##ens, ##iti, ##zation, is, consistent, with, the, view, that, des, ##ens, ##iti, ##zed, channels, can, conduct, ., fig, ., 4, ##lar, ##ge, steady, -, state, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, currents, are, observed, even, in, conditions, favor, ##ing, des, ##ens, ##iti, ##zation, ., a, representative, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, current, (, –, 60, mv, ), ev, ##oked, by, 10, mm, g, ##lu, ##tama, ##te, (, gray, bar, ), in, the, presence, of, 50, μ, ##m, cy, ##cloth, ##ia, ##zi, ##de, (, green, bar, ), ., note, the, minimal, current, decay, when, des, ##ens, ##iti, ##zation, is, inhibit, ##ed, (, for, poole, ##d, data, i, _, ss, /, i, _, peak, =, 93, ., 4, ±, 1, ., 6, %, ,, n, =, 6, ), (, mean, ±, s, ., e, ., m, ., from, n, patches, ), ., b, representative, g, ##lu, ##tama, ##te, -, ev, ##oked, currents, from, q, -, and, r, -, forms, of, g, ##lu, ##a, ##2, s, ##75, ##4, ##d, /, γ, -, 2, ., both, forms, exhibit, very, fast, des, ##ens, ##iti, ##zation, ,, but, the, r, -, form, has, an, app, ##re, ##cia, ##ble, steady, -, state, current, ., c, poole, ##d, data, showing, des, ##ens, ##iti, ##zation, kinetic, ##s, (, τ, _, w, ,, des, ), for, wild, -, type, (, w, ##t, ;, n, =, 6, and, 5, ), and, mutant, (, s, ##75, ##4, ##d, ;, n, =, 5, and, 5, ), forms, of, g, ##lu, ##a, ##2, (, q, ), /, γ, -, 2, and, g, ##lu, ##a, ##2, (, r, ), /, γ, -, 2, ., box, -, and, -, w, ##his, ##ker, plots, as, in, fig, ., 1, ##c, ., two, -, way, an, ##ova, indicated, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 17, =, 10, ., 56, ,, p, =, 0, ., 00, ##47, ), ,, an, effect, of, the, mutation, (, f, _, 1, ,, 17, =, 43, ., 19, ,, p, <, 0, ., 000, ##1, ), but, no, interaction, (, f, _, 1, ,, 17, =, 2, ., 63, ,, p, =, 0, ., 12, ), ., the, mean, difference, between, s, ##75, ##4, ##d, and, wild, type, was, –, 8, ., 1, ms, (, 95, %, confidence, interval, ,, –, 10, ., 9, to, –, 6, ., 0, ), for, q, and, –, 14, ., 1, ms, (, 95, %, confidence, interval, ,, –, 20, ., 0, to, –, 9, ., 3, ), for, r, ., d, poole, ##d, data, (, as, in, c, ), for, recovery, kinetic, ##s, (, τ, _, w, ,, rec, ##ov, ), ., two, -, way, an, ##ova, indicated, no, effect, of, q, /, r, editing, (, f, _, 1, ,, 17, =, 0, ., 13, ,, p, =, 0, ., 72, ), ,, an, effect, of, the, mutation, (, f, _, 1, ,, 17, =, 31, ., 67, ,, p, <, 0, ., 000, ##1, ), but, no, interaction, (, f, _, 1, ,, 17, =, 1, ., 65, ,, p, =, 0, ., 22, ), ., the, mean, difference, between, s, ##75, ##4, ##d, and, wild, type, was, 24, ., 1, ms, (, 95, %, confidence, interval, ,, 15, ., 3, to, 33, ., 2, ), for, q, and, 38, ., 7, ms, (, 95, %, confidence, interval, ,, 23, ., 7, to, 53, ., 9, ), for, r, ., e, poole, ##d, data, (, as, in, c, ), for, the, fraction, ##al, steady, -, state, current, (, i, _, ss, ), ., two, -, way, an, ##ova, indicated, an, effect, of, q, /, r, editing, (, f, _, 1, ,, 17, =, 65, ., 37, ,, p, <, 0, ., 000, ##1, ), ,, an, effect, of, the, mutation, (, f, _, 1, ,, 17, =, 28, ., 37, ,, p, <, 0, ., 000, ##1, ), ,, and, an, interaction, (, f, _, 1, ,, 17, =, 14, ., 93, ,, p, =, 0, ., 001, ##2, ), ., the, mean, difference, in, i, _, ss, (, %, of, peak, ), between, s, ##75, ##4, ##d, and, wild, type, was, –, 7, ., 7, (, 95, %, confidence, interval, ,, –, 11, ., 2, to, –, 5, ., 2, ), for, q, and, –, 37, ., 9, (, 95, %, confidence, interval, ,, –, 49, ., 2, to, –, 25, ., 8, ), for, r, ., indicated, p, values, are, from, welch, t, -, tests, ., source, data, are, provided, as, a, source, data, file'},\n", - " {'article_id': 'a0f24e75876344036375246a431899e7',\n", - " 'section_name': 'Monomeric Olfm1^Olf',\n", - " 'text': 'We determined a high-resolution crystal structure of Endo-H-deglycosylated Olfm1^Olf (Fig. 4), which leaves a single acetylglucosamine (GlcNAc) attached to glycosylated asparagines. The deglycosylation step often aids crystallisation. Our best crystal diffracted to 1.25 Å resolution (Table 1), representing the highest resolution crystal structure of an Olfactomedin domain to date. The highly conserved monomeric Olf domain has a five-bladed β-propeller fold with a central metal ion binding site [29–34, 50]. The structure shows a high degree of similarity to the Olf-domain dimer in our previously-determined structure of a dimeric Olfm1^coil-Olf (PDB 5AMO) [6] (C_α RMSD of 0.55 Å, Fig. 5). A human Olfm1 Olf domain structure derived from bacterially-expressed protein [35] has a very similar structure to our mouse Olfm1^Olf (C_α RMSD of 0.44 Å, Fig. 6), other than it lacking N-linked glycosylation as a result of the expression system. Comparing the structures of mouse Olfm1^Olf and human Olfm1^Olf [35] with that of Olfm1^coil-Olf, reveals structural rearrangements arising from the coordination of the Ca^2+ and Na^+ ions, that are not present in our previously determined structure of Olfm1^coil-Olf [6].\\nFig. 4High-resolution crystal structure of Olfm1^Olf to 1.25 Å with bound Na^+ and Ca^2+ ions reveals a structured switch loop and a water tunnel running to the metal ion binding sites. a Overview of the Olfm1^Olf β-propeller domain with the bound Na^+ (purple) and Ca^2+ (green) ions. The switch loop is indicated in violet, the water tunnel in green, the hydrophobic plug residues closing the tunnel in dark red and individual water molecules in the tunnel are represented as red spheres. The intra-chain disulfide between Cys227 and Cys409 is shown in sticks representation. b Close-up of the metal ion binding site with 2F_o-F_c electron density contoured at 2.5 σ. Metal ion-coordinating interactions are shown as black dashes and the hydrogen bond of the coordinating carboxylic acid group of Asp356 with the hydroxyl group of Tyr347 in the switch loop is indicated in green. c Analysis of the tunnel radius by HOLE [48]\\nTable 1Data collection and processing statisticsData CollectionPDB ID6QHJ (Olfm1^Olf)6QM3 (Olfm1^coil-Olf)BeamlineESRF ID30A-3DLS I03Resolution range (Å)^a36.76–1.25 (1.29–1.25)75.99–1.89 (2.10–1.89)Wavelength (Å)0.96770.9762Space GroupI222C2Unit Cell Dimensionsa, b, c (Å)61.79, 79.63, 111.72160.7, 47.0, 105.0α, β, γ90.0, 90.0, 90.090.0, 117.4, 90.0Measured reflections416,91095,762Unique reflections72,02829,117Mean I/σ13.7 (1.0)10.3 (1.7)Completeness (%)94.6 (63.9)92.2 (77.2)Redundancy5.8 (2.4)3.3 (3.4)R_merge (%)8.4 (90.8)6.0 (75.1)CC_1/20.998 (0.445)0.998 (0.551)Data RefinementResolution Range (Å)33.75–1.2571.30–2.00Total reflections72,02728,629Test set36231459R_work0.1240.179R_free0.1410.216No. of protein atoms43744321No. of ligand atoms156133No. of water atoms29899RMSD from idealBonds (Å)0.0100.007Angles (°)1.1680.852Mean B factor (Å^2)17.2549.09RamachandranFavoured (%)96.896.4Outliers (%)0.40.0Clashscore^b1.113.58^aNumbers in parentheses correspond to values for the highest resolution shell^bValue calculated by MolProbity [49]\\nFig. 5Comparison of Olfm1^Olf domain in the Ca^2+- and Na^+-bound state in grey with the previously-published apo state in teal [6]. The switch loop (violet) is only resolved in the Ca^2+- and Na^+-bound state. In the apo state, the negatively-charged side chains of Asp356, Glu404 and Asp453 are pushed outward in the absence of compensating positive charges from the Na^+ and Ca^2+ ions (indicated by arrows in the right panel). This most likely destabilises the conformation of the switch loop (violet) via Tyr347, which consequently is unstructured (indicated by a dashed line in the left panel) and thus not observed in the electron density of the apo form [6]. The intra-chain disulfide between Cys227 and Cys409 is shown in stick representation\\nFig. 6Mouse Olfm1^Olf and human Olfm1^Olf are very similar. Structural comparison of mouse Olfm1^Olf produced in mammalian (HEK293) cell line (grey) with human Olfm1^Olf produced in a bacterial expression system (PDB 4XAT, yellow) [35], both with bound Na^+ and Ca^2+, shows a high degree of similarity (C_α RMSD of 0.44). The switch loop (violet) is stabilised by bound Ca^2+ and Na^+ ions in both structures',\n", - " 'paragraph_id': 19,\n", - " 'tokenizer': 'we, determined, a, high, -, resolution, crystal, structure, of, end, ##o, -, h, -, de, ##gly, ##cos, ##yla, ##ted, ol, ##fm, ##1, ^, ol, ##f, (, fig, ., 4, ), ,, which, leaves, a, single, ace, ##ty, ##l, ##gl, ##uc, ##osa, ##mine, (, g, ##lc, ##nac, ), attached, to, g, ##ly, ##cos, ##yla, ##ted, as, ##para, ##gin, ##es, ., the, de, ##gly, ##cos, ##yla, ##tion, step, often, aids, crystal, ##lis, ##ation, ., our, best, crystal, di, ##ff, ##rac, ##ted, to, 1, ., 25, a, resolution, (, table, 1, ), ,, representing, the, highest, resolution, crystal, structure, of, an, ol, ##fa, ##ct, ##ome, ##din, domain, to, date, ., the, highly, conserved, mono, ##meric, ol, ##f, domain, has, a, five, -, bladed, β, -, propeller, fold, with, a, central, metal, ion, binding, site, [, 29, –, 34, ,, 50, ], ., the, structure, shows, a, high, degree, of, similarity, to, the, ol, ##f, -, domain, dime, ##r, in, our, previously, -, determined, structure, of, a, dime, ##ric, ol, ##fm, ##1, ^, coil, -, ol, ##f, (, pd, ##b, 5, ##amo, ), [, 6, ], (, c, _, α, rms, ##d, of, 0, ., 55, a, ,, fig, ., 5, ), ., a, human, ol, ##fm, ##1, ol, ##f, domain, structure, derived, from, bacterial, ##ly, -, expressed, protein, [, 35, ], has, a, very, similar, structure, to, our, mouse, ol, ##fm, ##1, ^, ol, ##f, (, c, _, α, rms, ##d, of, 0, ., 44, a, ,, fig, ., 6, ), ,, other, than, it, lacking, n, -, linked, g, ##ly, ##cos, ##yla, ##tion, as, a, result, of, the, expression, system, ., comparing, the, structures, of, mouse, ol, ##fm, ##1, ^, ol, ##f, and, human, ol, ##fm, ##1, ^, ol, ##f, [, 35, ], with, that, of, ol, ##fm, ##1, ^, coil, -, ol, ##f, ,, reveals, structural, rear, ##rang, ##ement, ##s, arising, from, the, coordination, of, the, ca, ^, 2, +, and, na, ^, +, ions, ,, that, are, not, present, in, our, previously, determined, structure, of, ol, ##fm, ##1, ^, coil, -, ol, ##f, [, 6, ], ., fig, ., 4, ##hi, ##gh, -, resolution, crystal, structure, of, ol, ##fm, ##1, ^, ol, ##f, to, 1, ., 25, a, with, bound, na, ^, +, and, ca, ^, 2, +, ions, reveals, a, structured, switch, loop, and, a, water, tunnel, running, to, the, metal, ion, binding, sites, ., a, overview, of, the, ol, ##fm, ##1, ^, ol, ##f, β, -, propeller, domain, with, the, bound, na, ^, +, (, purple, ), and, ca, ^, 2, +, (, green, ), ions, ., the, switch, loop, is, indicated, in, violet, ,, the, water, tunnel, in, green, ,, the, hydro, ##phobic, plug, residues, closing, the, tunnel, in, dark, red, and, individual, water, molecules, in, the, tunnel, are, represented, as, red, spheres, ., the, intra, -, chain, di, ##sul, ##fide, between, cy, ##s, ##22, ##7, and, cy, ##s, ##40, ##9, is, shown, in, sticks, representation, ., b, close, -, up, of, the, metal, ion, binding, site, with, 2, ##f, _, o, -, f, _, c, electron, density, con, ##tour, ##ed, at, 2, ., 5, σ, ., metal, ion, -, coordinating, interactions, are, shown, as, black, dash, ##es, and, the, hydrogen, bond, of, the, coordinating, car, ##box, ##yl, ##ic, acid, group, of, as, ##p, ##35, ##6, with, the, hydro, ##xy, ##l, group, of, ty, ##r, ##34, ##7, in, the, switch, loop, is, indicated, in, green, ., c, analysis, of, the, tunnel, radius, by, hole, [, 48, ], table, 1, ##da, ##ta, collection, and, processing, statistics, ##da, ##ta, collection, ##pd, ##b, id, ##6, ##q, ##h, ##j, (, ol, ##fm, ##1, ^, ol, ##f, ), 6, ##q, ##m, ##3, (, ol, ##fm, ##1, ^, coil, -, ol, ##f, ), beam, ##line, ##es, ##rf, id, ##30, ##a, -, 3d, ##ls, i, ##0, ##3, ##res, ##ol, ##ution, range, (, a, ), ^, a, ##36, ., 76, –, 1, ., 25, (, 1, ., 29, –, 1, ., 25, ), 75, ., 99, –, 1, ., 89, (, 2, ., 10, –, 1, ., 89, ), wavelength, (, a, ), 0, ., 96, ##7, ##70, ., 97, ##6, ##2, ##space, group, ##i, ##22, ##2, ##c, ##2, ##uni, ##t, cell, dimensions, ##a, ,, b, ,, c, (, a, ), 61, ., 79, ,, 79, ., 63, ,, 111, ., 72, ##16, ##0, ., 7, ,, 47, ., 0, ,, 105, ., 0, ##α, ,, β, ,, γ, ##90, ., 0, ,, 90, ., 0, ,, 90, ., 09, ##0, ., 0, ,, 117, ., 4, ,, 90, ., 0, ##me, ##as, ##ured, reflections, ##41, ##6, ,, 910, ##9, ##5, ,, 76, ##2, ##uni, ##que, reflections, ##7, ##2, ,, 02, ##8, ##29, ,, 117, ##me, ##an, i, /, σ, ##13, ., 7, (, 1, ., 0, ), 10, ., 3, (, 1, ., 7, ), complete, ##ness, (, %, ), 94, ., 6, (, 63, ., 9, ), 92, ., 2, (, 77, ., 2, ), red, ##unda, ##ncy, ##5, ., 8, (, 2, ., 4, ), 3, ., 3, (, 3, ., 4, ), r, _, merge, (, %, ), 8, ., 4, (, 90, ., 8, ), 6, ., 0, (, 75, ., 1, ), cc, _, 1, /, 20, ., 99, ##8, (, 0, ., 44, ##5, ), 0, ., 99, ##8, (, 0, ., 55, ##1, ), data, ref, ##ine, ##ment, ##res, ##ol, ##ution, range, (, a, ), 33, ., 75, –, 1, ., 257, ##1, ., 30, –, 2, ., 00, ##to, ##tal, reflections, ##7, ##2, ,, 02, ##7, ##28, ,, 62, ##9, ##test, set, ##36, ##23, ##14, ##59, ##r, _, work, ##0, ., 124, ##0, ., 179, ##r, _, free, ##0, ., 141, ##0, ., 216, ##no, ., of, protein, atoms, ##43, ##7, ##44, ##32, ##1, ##no, ., of, ligand, atoms, ##15, ##6, ##13, ##3, ##no, ., of, water, atoms, ##29, ##8, ##9, ##9, ##rm, ##sd, from, ideal, ##bon, ##ds, (, a, ), 0, ., 01, ##00, ., 00, ##7, ##ang, ##les, (, °, ), 1, ., 1680, ., 85, ##2, ##me, ##an, b, factor, (, a, ^, 2, ), 17, ., 254, ##9, ., 09, ##rama, ##chan, ##dran, ##fa, ##vo, ##ured, (, %, ), 96, ., 89, ##6, ., 4, ##out, ##lier, ##s, (, %, ), 0, ., 40, ., 0, ##cl, ##ash, ##sco, ##re, ^, b1, ., 113, ., 58, ^, an, ##umber, ##s, in, parentheses, correspond, to, values, for, the, highest, resolution, shell, ^, b, ##val, ##ue, calculated, by, mo, ##lp, ##ro, ##bit, ##y, [, 49, ], fig, ., 5, ##com, ##par, ##ison, of, ol, ##fm, ##1, ^, ol, ##f, domain, in, the, ca, ^, 2, +, -, and, na, ^, +, -, bound, state, in, grey, with, the, previously, -, published, ap, ##o, state, in, tea, ##l, [, 6, ], ., the, switch, loop, (, violet, ), is, only, resolved, in, the, ca, ^, 2, +, -, and, na, ^, +, -, bound, state, ., in, the, ap, ##o, state, ,, the, negatively, -, charged, side, chains, of, as, ##p, ##35, ##6, ,, g, ##lu, ##40, ##4, and, as, ##p, ##45, ##3, are, pushed, outward, in, the, absence, of, com, ##pen, ##sat, ##ing, positive, charges, from, the, na, ^, +, and, ca, ^, 2, +, ions, (, indicated, by, arrows, in, the, right, panel, ), ., this, most, likely, des, ##ta, ##bilis, ##es, the, conform, ##ation, of, the, switch, loop, (, violet, ), via, ty, ##r, ##34, ##7, ,, which, consequently, is, un, ##st, ##ructured, (, indicated, by, a, dashed, line, in, the, left, panel, ), and, thus, not, observed, in, the, electron, density, of, the, ap, ##o, form, [, 6, ], ., the, intra, -, chain, di, ##sul, ##fide, between, cy, ##s, ##22, ##7, and, cy, ##s, ##40, ##9, is, shown, in, stick, representation, fig, ., 6, ##mous, ##e, ol, ##fm, ##1, ^, ol, ##f, and, human, ol, ##fm, ##1, ^, ol, ##f, are, very, similar, ., structural, comparison, of, mouse, ol, ##fm, ##1, ^, ol, ##f, produced, in, mammalian, (, he, ##k, ##29, ##3, ), cell, line, (, grey, ), with, human, ol, ##fm, ##1, ^, ol, ##f, produced, in, a, bacterial, expression, system, (, pd, ##b, 4, ##xa, ##t, ,, yellow, ), [, 35, ], ,, both, with, bound, na, ^, +, and, ca, ^, 2, +, ,, shows, a, high, degree, of, similarity, (, c, _, α, rms, ##d, of, 0, ., 44, ), ., the, switch, loop, (, violet, ), is, stab, ##ilised, by, bound, ca, ^, 2, +, and, na, ^, +, ions, in, both, structures'},\n", - " {'article_id': 'a0f24e75876344036375246a431899e7',\n", - " 'section_name': 'Monomeric Olfm1^Olf',\n", - " 'text': 'Because of the high resolution of our Olfm1^Olf diffraction data to 1.25 Å, we can unambiguously assign a Na^+ and a Ca^2+ ion bound in the central cavity of the β-propeller. Metal ion assignment was based on previous binding data [6, 35], coordination distances (Table 2) [51] and fit to the electron density. The Ca^2+ ion is coordinated by the negatively-charged carboxyl groups of the side chains of Asp356, Asp453 and Glu404, as well as by the backbone carbonyl groups of Ala405 and Leu452 and a single water molecule (Fig. 4b and Table 2 for coordination distances and angles). The Na^+ ion is also coordinated by the carboxylic acid groups of the side chains of both Asp356 and Asp453, as well as by the backbone carbonyl group of Leu357 and a different water molecule than the one coordinating the calcium ion (Fig. 4b, Table 2). In sum, three formal negative charges of the carboxylic acid groups of the side chains of Asp356, Asp453 and Glu404 are compensated by three formal positive charges of the bound Ca^2+ and Na^+ ions.\\nTable 2Distances and angles of metal ion coordination in the Olfm1^Olf crystal structureDistances:Angles:distance (Å)angle (°)CalciumASP356 O_(carboxylate)2.3ASP356 O_(carboxylate)CalciumGLU404 O_(carboxylate)86.7CalciumGLU404 O_(carboxylate)2.3ASP356 O_(carboxylate)CalciumALA405 O_(carbonyl)93.1CalciumALA405 O_(carbonyl)2.3ASP356 O_(carboxylate)CalciumASP453 O_(carboxylate)105.5CalciumLEU452 O_(carbonyl)2.3ASP356 O_(carboxylate)CalciumH_2O94.1CalciumASP453 O_(carboxylate)2.3GLU404 O_(carboxylate)CalciumALA405 O_(carbonyl)83.0CalciumH_2O2.4GLU404 O_(carboxylate)CalciumLEU452 O_(carbonyl)83.7GLU404 O_(carboxylate)CalciumH_2O82.7SodiumGLY302 O_(carbonyl)2.9ALA405 O_(carbonyl)CalciumLEU452 O_(carbonyl)89.2SodiumGLN303 O_(carbonyl)3.0ALA405 O_(carbonyl)CalciumASP453 O_(carboxylate)103.8SodiumASP356 O_(carboxylate)2.3LEU452 O_(carbonyl)CalciumH_2O81.4SodiumLEU357 O_(carbonyl)2.2LEU452 O_(carbonyl)CalciumASP453 O_(carboxylate)83.6SodiumASP453 O_(carboxylate)2.3ASP453 O_(carboxylate)CalciumH_2O88.4SodiumH_2O2.4GLY302 O_(carbonyl)SodiumGLN303 O_(carbonyl)66.6ASP356 O_(carboxylate)TYR347 O_(hydroxyl)2.7GLY302 O_(carbonyl)SodiumASP356 O_(carboxylate)88.5GLY302 O_(carbonyl)SodiumLEU357 O_(carbonyl)78.3GLY302 O_(carbonyl)SodiumH_2O98.6GLN303 O_(carbonyl)SodiumLEU357 O_(carbonyl)88.4GLN303 O (carbonyl)SodiumASP453 O_(carboxylate)95.8GLN303 O (carbonyl)SodiumH_2O71.0ASP356 O_(carboxylate)SodiumLEU357 O_(carbonyl)101.4ASP356 O_(carboxylate)SodiumASP453 O_(carboxylate)109.4ASP356 O_(carboxylate)SodiumH_2O99.9LEU357 O_(carbonyl)SodiumASP453 O_(carboxylate)98.5ASP453 O_(carboxylate)SodiumH_2O77.8',\n", - " 'paragraph_id': 20,\n", - " 'tokenizer': 'because, of, the, high, resolution, of, our, ol, ##fm, ##1, ^, ol, ##f, di, ##ff, ##raction, data, to, 1, ., 25, a, ,, we, can, una, ##mb, ##ig, ##uously, assign, a, na, ^, +, and, a, ca, ^, 2, +, ion, bound, in, the, central, cavity, of, the, β, -, propeller, ., metal, ion, assignment, was, based, on, previous, binding, data, [, 6, ,, 35, ], ,, coordination, distances, (, table, 2, ), [, 51, ], and, fit, to, the, electron, density, ., the, ca, ^, 2, +, ion, is, coordinated, by, the, negatively, -, charged, car, ##box, ##yl, groups, of, the, side, chains, of, as, ##p, ##35, ##6, ,, as, ##p, ##45, ##3, and, g, ##lu, ##40, ##4, ,, as, well, as, by, the, backbone, carbon, ##yl, groups, of, ala, ##40, ##5, and, le, ##u, ##45, ##2, and, a, single, water, molecule, (, fig, ., 4, ##b, and, table, 2, for, coordination, distances, and, angles, ), ., the, na, ^, +, ion, is, also, coordinated, by, the, car, ##box, ##yl, ##ic, acid, groups, of, the, side, chains, of, both, as, ##p, ##35, ##6, and, as, ##p, ##45, ##3, ,, as, well, as, by, the, backbone, carbon, ##yl, group, of, le, ##u, ##35, ##7, and, a, different, water, molecule, than, the, one, coordinating, the, calcium, ion, (, fig, ., 4, ##b, ,, table, 2, ), ., in, sum, ,, three, formal, negative, charges, of, the, car, ##box, ##yl, ##ic, acid, groups, of, the, side, chains, of, as, ##p, ##35, ##6, ,, as, ##p, ##45, ##3, and, g, ##lu, ##40, ##4, are, compensated, by, three, formal, positive, charges, of, the, bound, ca, ^, 2, +, and, na, ^, +, ions, ., table, 2d, ##istan, ##ces, and, angles, of, metal, ion, coordination, in, the, ol, ##fm, ##1, ^, ol, ##f, crystal, structured, ##istan, ##ces, :, angles, :, distance, (, a, ), angle, (, °, ), calcium, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), 86, ., 7, ##cal, ##ci, ##um, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), 93, ., 1, ##cal, ##ci, ##uma, ##la, ##40, ##5, o, _, (, carbon, ##yl, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 105, ., 5, ##cal, ##ci, ##um, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), 2, ., 3a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##h, _, 2, ##o, ##9, ##4, ., 1, ##cal, ##ci, ##uma, ##sp, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), 83, ., 0, ##cal, ##ci, ##um, ##h, _, 2, ##o, ##2, ., 4, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), 83, ., 7, ##gl, ##u, ##40, ##4, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##h, _, 2, ##o, ##8, ##2, ., 7, ##so, ##dium, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), 2, ., 9, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), calcium, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), 89, ., 2, ##so, ##dium, ##gl, ##n, ##30, ##3, o, _, (, carbon, ##yl, ), 3, ., 0, ##ala, ##40, ##5, o, _, (, carbon, ##yl, ), calcium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 103, ., 8, ##so, ##dium, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), calcium, ##h, _, 2, ##o, ##8, ##1, ., 4, ##so, ##dium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 2, ., 2, ##le, ##u, ##45, ##2, o, _, (, carbon, ##yl, ), calcium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 83, ., 6, ##so, ##dium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 2, ., 3a, ##sp, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), calcium, ##h, _, 2, ##o, ##8, ##8, ., 4, ##so, ##dium, ##h, _, 2, ##o, ##2, ., 4, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##gl, ##n, ##30, ##3, o, _, (, carbon, ##yl, ), 66, ., 6, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), ty, ##r, ##34, ##7, o, _, (, hydro, ##xy, ##l, ), 2, ., 7, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), 88, ., 5, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 78, ., 3, ##gly, ##30, ##2, o, _, (, carbon, ##yl, ), sodium, ##h, _, 2, ##o, ##9, ##8, ., 6, ##gl, ##n, ##30, ##3, o, _, (, carbon, ##yl, ), sodium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 88, ., 4, ##gl, ##n, ##30, ##3, o, (, carbon, ##yl, ), sodium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 95, ., 8, ##gl, ##n, ##30, ##3, o, (, carbon, ##yl, ), sodium, ##h, _, 2, ##o, ##7, ##1, ., 0, ##as, ##p, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), 101, ., 4a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 109, ., 4a, ##sp, ##35, ##6, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##h, _, 2, ##o, ##9, ##9, ., 9, ##le, ##u, ##35, ##7, o, _, (, carbon, ##yl, ), sodium, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), 98, ., 5, ##as, ##p, ##45, ##3, o, _, (, car, ##box, ##yla, ##te, ), sodium, ##h, _, 2, ##o, ##7, ##7, ., 8'},\n", - " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", - " 'section_name': 'Disruption of the EphB2–NMDAR interaction',\n", - " 'text': 'Phosphorylation of EphB2 Y504 and a negative charge at Y504 are required for interaction with the NMDAR^19. To test how the charge of Y504 affects the EphB2–NMDAR interaction, PLA was performed on HEK293T cells transfected with EphB2 WT, EphB2 Y504E, or EphB2 Y504F, and WT Myc-GluN1, GluN2B, and EGFP (Fig. 6a). As expected, cells transfected with the more positively charged EphB2 phospho-null mutant (Y405F) had significantly fewer PLA puncta than both WT EphB2 and the more negatively charged phosphomimetic (Y504E) EphB2 (Fig. 6b, ****p < 0.0001, ANOVA). To specifically test the role of a negative charge at EphB2 Y504 in relation to the GluN1 charge mutants, PLA was performed on HEK293T cells transfected with EphB2 Y504E, GluN2B, EGFP and Myc-GluN1 WT or GluN1 point mutants (Fig. 6c, e). Consistent with the model that the negative charge of phosphomimetic EphB2 Y504E interacts with the positive potential of the GluN1 NTD hinge region, mutations in GluN1 that result in larger negative shifts of surface potential interact with EphB2 Y504E less well than those with smaller differences (Fig. 6d, f, WT vs. N273A, *p < 0.05; WT vs. R337D, ***p < 0.005; WT vs. N273A/R337D, ****p < 0.0001; ANOVA). Unfortunately, mutations of Y504 to a positively charged amino acid failed to reach the cell surface. Together these results suggest that the positively charged hinge region of GluN1 interacts with the negatively charged phosphorylated Y504 of EphB2 and this interaction is disrupted when GluN1 is mutated to become more negatively charged.Fig. 6EphB2–GluN1 interaction in HEK293T cells is charge-dependent.a Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated FLAG-EphB2 single point mutants (WT, Y504E, or Y504F), together with Myc-GluN1 WT, GluN2B, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. b Quantification of the effects of EphB2 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition. (****p < 0.0001, ANOVA; n = 30 cells for each condition). c Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 single point mutants, together with GluN2B, FLAG-EphB2 Y504E, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. d Quantification of the effects of GluN1 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition. (*p < 0.05, ***p < 0.005, ANOVA; n = 30 cells for each condition). e Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 double point mutants, together with GluN2B, FLAG-EphB2 Y504E, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. f Quantification of the effects of GluN1 mutants on PLA puncta number (*p = 0.0219, ****p < 0.0001, ANOVA; green dots represent n = 30 cells for each condition).',\n", - " 'paragraph_id': 18,\n", - " 'tokenizer': 'ph, ##os, ##ph, ##ory, ##lation, of, ep, ##h, ##b, ##2, y, ##50, ##4, and, a, negative, charge, at, y, ##50, ##4, are, required, for, interaction, with, the, nm, ##dar, ^, 19, ., to, test, how, the, charge, of, y, ##50, ##4, affects, the, ep, ##h, ##b, ##2, –, nm, ##dar, interaction, ,, pl, ##a, was, performed, on, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, ep, ##h, ##b, ##2, w, ##t, ,, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, or, ep, ##h, ##b, ##2, y, ##50, ##4, ##f, ,, and, w, ##t, my, ##c, -, g, ##lun, ##1, ,, g, ##lun, ##2, ##b, ,, and, e, ##gf, ##p, (, fig, ., 6, ##a, ), ., as, expected, ,, cells, trans, ##fect, ##ed, with, the, more, positively, charged, ep, ##h, ##b, ##2, ph, ##os, ##ph, ##o, -, null, mutant, (, y, ##40, ##5, ##f, ), had, significantly, fewer, pl, ##a, pun, ##cta, than, both, w, ##t, ep, ##h, ##b, ##2, and, the, more, negatively, charged, ph, ##os, ##ph, ##omi, ##met, ##ic, (, y, ##50, ##4, ##e, ), ep, ##h, ##b, ##2, (, fig, ., 6, ##b, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ), ., to, specifically, test, the, role, of, a, negative, charge, at, ep, ##h, ##b, ##2, y, ##50, ##4, in, relation, to, the, g, ##lun, ##1, charge, mutants, ,, pl, ##a, was, performed, on, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, g, ##lun, ##2, ##b, ,, e, ##gf, ##p, and, my, ##c, -, g, ##lun, ##1, w, ##t, or, g, ##lun, ##1, point, mutants, (, fig, ., 6, ##c, ,, e, ), ., consistent, with, the, model, that, the, negative, charge, of, ph, ##os, ##ph, ##omi, ##met, ##ic, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, interact, ##s, with, the, positive, potential, of, the, g, ##lun, ##1, nt, ##d, hi, ##nge, region, ,, mutations, in, g, ##lun, ##1, that, result, in, larger, negative, shifts, of, surface, potential, interact, with, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, less, well, than, those, with, smaller, differences, (, fig, ., 6, ##d, ,, f, ,, w, ##t, vs, ., n, ##27, ##3, ##a, ,, *, p, <, 0, ., 05, ;, w, ##t, vs, ., r, ##33, ##7, ##d, ,, *, *, *, p, <, 0, ., 00, ##5, ;, w, ##t, vs, ., n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, ,, *, *, *, *, p, <, 0, ., 000, ##1, ;, an, ##ova, ), ., unfortunately, ,, mutations, of, y, ##50, ##4, to, a, positively, charged, amino, acid, failed, to, reach, the, cell, surface, ., together, these, results, suggest, that, the, positively, charged, hi, ##nge, region, of, g, ##lun, ##1, interact, ##s, with, the, negatively, charged, ph, ##os, ##ph, ##ory, ##lated, y, ##50, ##4, of, ep, ##h, ##b, ##2, and, this, interaction, is, disrupted, when, g, ##lun, ##1, is, mu, ##tated, to, become, more, negatively, charged, ., fig, ., 6, ##ep, ##h, ##b, ##2, –, g, ##lun, ##1, interaction, in, he, ##k, ##29, ##3, ##t, cells, is, charge, -, dependent, ., a, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, flag, -, ep, ##h, ##b, ##2, single, point, mutants, (, w, ##t, ,, y, ##50, ##4, ##e, ,, or, y, ##50, ##4, ##f, ), ,, together, with, my, ##c, -, g, ##lun, ##1, w, ##t, ,, g, ##lun, ##2, ##b, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., b, quan, ##ti, ##fication, of, the, effects, of, ep, ##h, ##b, ##2, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, ., (, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, n, =, 30, cells, for, each, condition, ), ., c, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, single, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., d, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, ., (, *, p, <, 0, ., 05, ,, *, *, *, p, <, 0, ., 00, ##5, ,, an, ##ova, ;, n, =, 30, cells, for, each, condition, ), ., e, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, double, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, y, ##50, ##4, ##e, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., f, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, (, *, p, =, 0, ., 02, ##19, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), .'},\n", - " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", - " 'section_name': 'Impact on synaptic stability of the NMDAR',\n", - " 'text': 'Disrupting the EphB2–NMDAR interaction by mutating the hinge region of GluN1 results in increased mobility of NMDARs found in dendritic spines. We next asked whether the GluN1 N273A/R337D charge mutant is sufficient to increase the mobility of the NMDAR in dendritic spines. To test this, neurons were transfected with either WT EGFP–GluN1, EGFP–GluN1 I272A, or EGFP–GluN1 N273A/R337D, and GluN2B, mCherry, and GluN1 CRISPR. No significant differences were found between levels of WT or mutant EGFP–GluN1 in the dendritic shaft (Supplementary Fig. 9c, d), but there was a decrease in spine density in N237A/R337D expressing neurons (Supplementary Fig. 9e, f). EGFP–GluN1 mobility in dendritic spines was examined by FRAP, and images of EGFP–GluN1 puncta were collected once every 10 s for 15 min after bleaching. Fluorescence recovery of both WT and I272A EGFP–GluN1 was indistinguishable (Fig. 8a, b). In contrast, EGFP–GluN1 N273A/R337D recovered significantly more than WT (Fig. 8b, ****p < 0.0001, KS test; 15 min time point, *p < 0.05, ANOVA). These results suggest converting the surface charge in the hinge region of the GluN1 NTD increases NMDAR mobility at spines.Fig. 8GluN1 charge mutants show increased mobility due to disrupted EphB–NMDAR interaction.a Representative FRAP images at different time points of DIV21–23 cortical neurons transfected with EGFP–GluN1 (WT, I272A, or N273A/R337D) together with GluN2B, CRISPR construct targeting endogenous GluN1, and mCherry. Recovery of bleached spine puncta (magenta circle) was monitored for 15 min at 10s intervals. Scale bar = 2 μm. b Quantification of the recovery curve of different GluN1 mutants in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit (****p < 0.0001, Kolmogorov–Smirnov (KS) nonparametric test). Inset: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min after photobleaching in EGFP–GluN1 mutant transfected cells compared to WT EGFP–GluN1 in DIV21–23 cortical neurons (*p < 0.05, ANOVA; green dots represent WT n = 33 puncta; I272A n = 12; N273A/R337D n = 12). Error bars show S.E.M. c Representative FRAP images at different time points of DIV21–23 cortical neurons transfected with EGFP–GluN1 (WT, WT+EphB2 knockdown, N273A/R337D + EphB2 knockdown, WT+EphB2 knockdown rescued by RNAi insensitive EphB2) together with GluN2B, CRISPR construct targeting endogenous GluN1, and mCherry. FRAP was conducted on serveral puncta in different dendritic branches. Recovery of bleached spine puncta (magenta circle) was monitored for 15 min at 10s intervals. Scale bar = 2 μm. d Quantification of the recovery curve of different GluN1 mutants in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit (****p < 0.0001, Kolmogorov–Smirnov (KS) nonparametric test). Inset: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min after bleaching in EGFP–GluN1 mutant transfected cells compared to WT EGFP–GluN1 in DIV21–23 cortical neurons (*p < 0.05, ANOVA; green dots represent WT n = 33 puncta; WT+EphB2 K.D. n = 12; N273A/R337D+EphB2 K.D. n = 21; rescue n = 22). Error bars show S.E.M.',\n", - " 'paragraph_id': 20,\n", - " 'tokenizer': 'disrupt, ##ing, the, ep, ##h, ##b, ##2, –, nm, ##dar, interaction, by, mu, ##tat, ##ing, the, hi, ##nge, region, of, g, ##lun, ##1, results, in, increased, mobility, of, nm, ##dar, ##s, found, in, den, ##dr, ##itic, spines, ., we, next, asked, whether, the, g, ##lun, ##1, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, charge, mutant, is, sufficient, to, increase, the, mobility, of, the, nm, ##dar, in, den, ##dr, ##itic, spines, ., to, test, this, ,, neurons, were, trans, ##fect, ##ed, with, either, w, ##t, e, ##gf, ##p, –, g, ##lun, ##1, ,, e, ##gf, ##p, –, g, ##lun, ##1, i, ##27, ##2, ##a, ,, or, e, ##gf, ##p, –, g, ##lun, ##1, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, ,, and, g, ##lun, ##2, ##b, ,, mc, ##her, ##ry, ,, and, g, ##lun, ##1, crisp, ##r, ., no, significant, differences, were, found, between, levels, of, w, ##t, or, mutant, e, ##gf, ##p, –, g, ##lun, ##1, in, the, den, ##dr, ##itic, shaft, (, supplementary, fig, ., 9, ##c, ,, d, ), ,, but, there, was, a, decrease, in, spine, density, in, n, ##23, ##7, ##a, /, r, ##33, ##7, ##d, expressing, neurons, (, supplementary, fig, ., 9, ##e, ,, f, ), ., e, ##gf, ##p, –, g, ##lun, ##1, mobility, in, den, ##dr, ##itic, spines, was, examined, by, fra, ##p, ,, and, images, of, e, ##gf, ##p, –, g, ##lun, ##1, pun, ##cta, were, collected, once, every, 10, s, for, 15, min, after, b, ##lea, ##ching, ., flu, ##orescence, recovery, of, both, w, ##t, and, i, ##27, ##2, ##a, e, ##gf, ##p, –, g, ##lun, ##1, was, ind, ##ist, ##ing, ##uis, ##hab, ##le, (, fig, ., 8, ##a, ,, b, ), ., in, contrast, ,, e, ##gf, ##p, –, g, ##lun, ##1, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, recovered, significantly, more, than, w, ##t, (, fig, ., 8, ##b, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, ks, test, ;, 15, min, time, point, ,, *, p, <, 0, ., 05, ,, an, ##ova, ), ., these, results, suggest, converting, the, surface, charge, in, the, hi, ##nge, region, of, the, g, ##lun, ##1, nt, ##d, increases, nm, ##dar, mobility, at, spines, ., fig, ., 8, ##gl, ##un, ##1, charge, mutants, show, increased, mobility, due, to, disrupted, ep, ##h, ##b, –, nm, ##dar, interaction, ., a, representative, fra, ##p, images, at, different, time, points, of, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, trans, ##fect, ##ed, with, e, ##gf, ##p, –, g, ##lun, ##1, (, w, ##t, ,, i, ##27, ##2, ##a, ,, or, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, ), together, with, g, ##lun, ##2, ##b, ,, crisp, ##r, construct, targeting, end, ##ogen, ##ous, g, ##lun, ##1, ,, and, mc, ##her, ##ry, ., recovery, of, b, ##lea, ##ched, spine, pun, ##cta, (, mage, ##nta, circle, ), was, monitored, for, 15, min, at, 10, ##s, intervals, ., scale, bar, =, 2, μ, ##m, ., b, quan, ##ti, ##fication, of, the, recovery, curve, of, different, g, ##lun, ##1, mutants, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., ins, ##et, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, after, photo, ##ble, ##achi, ##ng, in, e, ##gf, ##p, –, g, ##lun, ##1, mutant, trans, ##fect, ##ed, cells, compared, to, w, ##t, e, ##gf, ##p, –, g, ##lun, ##1, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, (, *, p, <, 0, ., 05, ,, an, ##ova, ;, green, dots, represent, w, ##t, n, =, 33, pun, ##cta, ;, i, ##27, ##2, ##a, n, =, 12, ;, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, n, =, 12, ), ., error, bars, show, s, ., e, ., m, ., c, representative, fra, ##p, images, at, different, time, points, of, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, trans, ##fect, ##ed, with, e, ##gf, ##p, –, g, ##lun, ##1, (, w, ##t, ,, w, ##t, +, ep, ##h, ##b, ##2, knock, ##down, ,, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, +, ep, ##h, ##b, ##2, knock, ##down, ,, w, ##t, +, ep, ##h, ##b, ##2, knock, ##down, rescued, by, rna, ##i, ins, ##ens, ##itive, ep, ##h, ##b, ##2, ), together, with, g, ##lun, ##2, ##b, ,, crisp, ##r, construct, targeting, end, ##ogen, ##ous, g, ##lun, ##1, ,, and, mc, ##her, ##ry, ., fra, ##p, was, conducted, on, server, ##al, pun, ##cta, in, different, den, ##dr, ##itic, branches, ., recovery, of, b, ##lea, ##ched, spine, pun, ##cta, (, mage, ##nta, circle, ), was, monitored, for, 15, min, at, 10, ##s, intervals, ., scale, bar, =, 2, μ, ##m, ., d, quan, ##ti, ##fication, of, the, recovery, curve, of, different, g, ##lun, ##1, mutants, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., ins, ##et, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, after, b, ##lea, ##ching, in, e, ##gf, ##p, –, g, ##lun, ##1, mutant, trans, ##fect, ##ed, cells, compared, to, w, ##t, e, ##gf, ##p, –, g, ##lun, ##1, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, (, *, p, <, 0, ., 05, ,, an, ##ova, ;, green, dots, represent, w, ##t, n, =, 33, pun, ##cta, ;, w, ##t, +, ep, ##h, ##b, ##2, k, ., d, ., n, =, 12, ;, n, ##27, ##3, ##a, /, r, ##33, ##7, ##d, +, ep, ##h, ##b, ##2, k, ., d, ., n, =, 21, ;, rescue, n, =, 22, ), ., error, bars, show, s, ., e, ., m, .'},\n", - " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", - " 'section_name': 'Antibodies',\n", - " 'text': 'The following primary antibodies and dilutions were used: mouse monoclonal (IgG1) anti-GluN1 (1:500 (WB), BioLegend, clone R1JHL, cat# 828201, lot# B212895), goat polyclonal anti-EphB2 (1:1200 (ICC, PLA), R&D Systems, cat# AF467, lot# CVT0315041), mouse monoclonal (IgG1) anti-EphB2 (1:500 (WB), Invitrogen, clone 1A6C9, cat# 37-1700, lot# RD215698), rabbit polyclonal anti-Myc (1:3000 (ICC, PLA), Abcam, Cambridge, MA, cat# ab9103, lot# 2932489), mouse monoclonal (IgG2b) anti-GluN2B (1:500 (WB), Neuromab, UC Davis, Davis, CA, clone N59/36, cat# 75-101, lot# 455-10JD-82), mouse monoclonal (IgG2A) anti-PSD-95 (1:2500 (WB), Neuromab, UC Davis, Davis, CA, clone 28/43, cat# 75-028, lot# 455.7JD.22f), mouse monoclonal (IgG1) anti-Synaptophysin-1 (1:5000 (WB), Synaptic Systems, Gottingen, Germany, clone 7.2, cat# 101 111, lot# 101011/1-43), guinea pig polyclonal anti-vesicular glutamate transporter 1 (vGlut1; 1:5000 (WB, ICC), EMD Millipore, Temecula, CA, cat# AB5905, lot# 2932489), rabbit polyclonal anti-GFP (1:3000 (ICC), Life Technologies, cat# A6455, lot# 1736965), mouse monoclonal (IgG1) anti-GAPDH (1:500 (WB), EMD Millipore, Temecula, CA, cat# MAB374, lot# 2910381), rabbit polyclonal anti-Tubulin (1:10,000 (WB), Abcam, Cambridge, MA, cat# ab18251, lot# GR235480-2), rabbit polyclonal anti-actin (1:2000 (ICC), Sigma, cat# A2103, lot# 115M4865V), rabbit polyclonal anti-FLAG (1:1000 (IP, WB), Sigma, Cat# F7425, lot# 097M4882V). The following secondary antibodies were used: Donkey anti-mouse-HRP (1:10,000 (WB), Jackson ImmunoResearch, cat# 715-035-151, lot# 128396), Donkey anti-rabbit-HRP (1:10,000 (WB), Jackson ImmunoResearch, cat# 711-035-152, lot# 132960), Donkey anti-goat-HRP (1:10,000 (WB), Jackson ImmunoResearch, cat# 705-035-147, lot# 112876), Donkey anti-rabbit unconjugated (1:100 (ICC), Jackson ImmunoResearch, cat# 711-005-152 lot# 125861), Donkey anti-mouse AlexaFluor-488 (1:500 (ICC), Jackson ImmunoResearch, cat# 715-545-150, lot# 11603), Donkey anti-rabbit AlexaFluor-488 (1:500 (ICC), Jackson ImmunoResearch, cat# 711-545-152, lot# 126601), Donkey anti-goat Cy3 (1:500 (ICC), Jackson ImmunoResearch, cat# 705-166-147, lot# 107019), Donkey anti-rabbit Cy3 (1:500 (ICC), Jackson ImmunoResearch, cat# 711-165-152, lot# 123091), Donkey anti-guinea pig AlexaFluor-647 (1:500 (ICC), Jackson ImmunoResearch, cat# 706-605-148, lot# 116734), Donkey anti-goat AlexaFluor-647 (1:500 (ICC), Jackson ImmunoResearch, cat# 706-606-147, lot# 124186).',\n", - " 'paragraph_id': 46,\n", - " 'tokenizer': 'the, following, primary, antibodies, and, dil, ##ution, ##s, were, used, :, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, g, ##lun, ##1, (, 1, :, 500, (, wb, ), ,, bio, ##leg, ##end, ,, clone, r, ##1, ##jhl, ,, cat, #, 82, ##8, ##20, ##1, ,, lot, #, b, ##21, ##28, ##9, ##5, ), ,, goat, poly, ##cl, ##onal, anti, -, ep, ##h, ##b, ##2, (, 1, :, 1200, (, icc, ,, pl, ##a, ), ,, r, &, d, systems, ,, cat, #, af, ##46, ##7, ,, lot, #, cv, ##t, ##0, ##31, ##50, ##41, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, ep, ##h, ##b, ##2, (, 1, :, 500, (, wb, ), ,, in, ##vi, ##tro, ##gen, ,, clone, 1a, ##6, ##c, ##9, ,, cat, #, 37, -, 1700, ,, lot, #, rd, ##21, ##56, ##9, ##8, ), ,, rabbit, poly, ##cl, ##onal, anti, -, my, ##c, (, 1, :, 3000, (, icc, ,, pl, ##a, ), ,, abc, ##am, ,, cambridge, ,, ma, ,, cat, #, ab, ##9, ##10, ##3, ,, lot, #, 293, ##24, ##8, ##9, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##2, ##b, ), anti, -, g, ##lun, ##2, ##b, (, 1, :, 500, (, wb, ), ,, ne, ##uro, ##ma, ##b, ,, uc, davis, ,, davis, ,, ca, ,, clone, n, ##59, /, 36, ,, cat, #, 75, -, 101, ,, lot, #, 45, ##5, -, 10, ##j, ##d, -, 82, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##2, ##a, ), anti, -, ps, ##d, -, 95, (, 1, :, 2500, (, wb, ), ,, ne, ##uro, ##ma, ##b, ,, uc, davis, ,, davis, ,, ca, ,, clone, 28, /, 43, ,, cat, #, 75, -, 02, ##8, ,, lot, #, 45, ##5, ., 7, ##j, ##d, ., 22, ##f, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, syn, ##ap, ##top, ##hy, ##sin, -, 1, (, 1, :, 5000, (, wb, ), ,, syn, ##ap, ##tic, systems, ,, gottingen, ,, germany, ,, clone, 7, ., 2, ,, cat, #, 101, 111, ,, lot, #, 101, ##01, ##1, /, 1, -, 43, ), ,, guinea, pig, poly, ##cl, ##onal, anti, -, ve, ##sic, ##ular, g, ##lu, ##tama, ##te, transport, ##er, 1, (, v, ##gl, ##ut, ##1, ;, 1, :, 5000, (, wb, ,, icc, ), ,, em, ##d, mill, ##ip, ##ore, ,, te, ##me, ##cula, ,, ca, ,, cat, #, ab, ##59, ##0, ##5, ,, lot, #, 293, ##24, ##8, ##9, ), ,, rabbit, poly, ##cl, ##onal, anti, -, g, ##fp, (, 1, :, 3000, (, icc, ), ,, life, technologies, ,, cat, #, a, ##64, ##55, ,, lot, #, 1736, ##9, ##65, ), ,, mouse, mono, ##cl, ##onal, (, i, ##gg, ##1, ), anti, -, gap, ##dh, (, 1, :, 500, (, wb, ), ,, em, ##d, mill, ##ip, ##ore, ,, te, ##me, ##cula, ,, ca, ,, cat, #, mab, ##37, ##4, ,, lot, #, 291, ##0, ##38, ##1, ), ,, rabbit, poly, ##cl, ##onal, anti, -, tub, ##ulin, (, 1, :, 10, ,, 000, (, wb, ), ,, abc, ##am, ,, cambridge, ,, ma, ,, cat, #, ab, ##18, ##25, ##1, ,, lot, #, gr, ##23, ##54, ##80, -, 2, ), ,, rabbit, poly, ##cl, ##onal, anti, -, act, ##in, (, 1, :, 2000, (, icc, ), ,, sigma, ,, cat, #, a2, ##10, ##3, ,, lot, #, 115, ##m, ##48, ##65, ##v, ), ,, rabbit, poly, ##cl, ##onal, anti, -, flag, (, 1, :, 1000, (, ip, ,, wb, ), ,, sigma, ,, cat, #, f, ##7, ##42, ##5, ,, lot, #, 09, ##7, ##m, ##48, ##8, ##2, ##v, ), ., the, following, secondary, antibodies, were, used, :, donkey, anti, -, mouse, -, hr, ##p, (, 1, :, 10, ,, 000, (, wb, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##5, -, 03, ##5, -, 151, ,, lot, #, 128, ##39, ##6, ), ,, donkey, anti, -, rabbit, -, hr, ##p, (, 1, :, 10, ,, 000, (, wb, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 03, ##5, -, 152, ,, lot, #, 132, ##9, ##60, ), ,, donkey, anti, -, goat, -, hr, ##p, (, 1, :, 10, ,, 000, (, wb, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##5, -, 03, ##5, -, 147, ,, lot, #, 112, ##8, ##7, ##6, ), ,, donkey, anti, -, rabbit, un, ##con, ##ju, ##gated, (, 1, :, 100, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 00, ##5, -, 152, lot, #, 125, ##86, ##1, ), ,, donkey, anti, -, mouse, alexa, ##fl, ##uo, ##r, -, 48, ##8, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##5, -, 54, ##5, -, 150, ,, lot, #, 116, ##0, ##3, ), ,, donkey, anti, -, rabbit, alexa, ##fl, ##uo, ##r, -, 48, ##8, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 54, ##5, -, 152, ,, lot, #, 126, ##60, ##1, ), ,, donkey, anti, -, goat, cy, ##3, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##5, -, 166, -, 147, ,, lot, #, 107, ##01, ##9, ), ,, donkey, anti, -, rabbit, cy, ##3, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 71, ##1, -, 165, -, 152, ,, lot, #, 123, ##0, ##9, ##1, ), ,, donkey, anti, -, guinea, pig, alexa, ##fl, ##uo, ##r, -, 64, ##7, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##6, -, 60, ##5, -, 148, ,, lot, #, 116, ##7, ##34, ), ,, donkey, anti, -, goat, alexa, ##fl, ##uo, ##r, -, 64, ##7, (, 1, :, 500, (, icc, ), ,, jackson, im, ##mun, ##ores, ##ear, ##ch, ,, cat, #, 70, ##6, -, 60, ##6, -, 147, ,, lot, #, 124, ##18, ##6, ), .'},\n", - " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", - " 'section_name': 'The amino acids required for the EphB2–GluN1 interaction',\n", - " 'text': 'To begin to determine which amino acids in the NTD hinge region might mediate the EphB–NMDAR interaction, we generated six individual point mutants to each of the amino acids that form the area of positive surface charge (I272A, N273A, T335A, G336A, R337A, R337D). These mutants were chosen because they affect surface charge and not the glycosylation state of the GluN1 subunit. Each of these mutants trafficked to the cell surface at similar levels and ran as expected on western blots (Supplementary Fig. 7a–d, 7c, p = 0.0613; 7d, p = 0.1349; ANOVA). APBS models showed that mutations to N273 and R337 had the largest impact on the surface potential (N273A, R337A, and R337D) (Fig. 5a). If the positive surface charge of the GluN1 NTD hinge region mediates the EphB–NMDAR interaction, then the three GluN1 mutants that affect surface potential the most should disrupt the EphB2–NMDAR interaction. To test whether those charge mutants affect the interaction, PLA was performed on HEK293T cells transfected with each of the GluN1 single mutants (I272A, N273A, T335A, G336A, R337A, R337D), together with GluN2B, EphB2, and EGFP (Fig. 5b). Consistent with the charge-based model for the EphB–NMDAR interaction, the GluN1 mutants with the largest apparent effect on surface charge, N273A, R337A, and R337D, had significantly fewer PLA puncta per cell than WT (Fig. 5c, ****p < 0.0001, ANOVA). Mutations that did not alter the surface charge did not impact the number of PLA puncta (Fig. 5c, I272A vs. WT, p = 1.000; T335A vs. WT, p = 0.999; G336A vs. WT, p = 0.1489; ANOVA). Similarly, Myc-GluN1 N273 and R337 mutants co-immunoprecipitated FLAG-EphB2 less well than WT Myc-GluN1 (Supplementary Fig. 8). These data suggest that a positive surface potential in the NTD hinge region is necessary for the EphB–NMDAR interaction.Fig. 5Specific hinge region amino acid residues are responsible for the EphB2–GluN1 interaction in HEK293T cells.a Surface charge maps of GluN1 NTD hinge region of the indicated GluN1 single point mutants in order of increasing negative charged in the hinge region (left (positive) to right (negative)), with blue representing positive charge and red representing negative charge. Yellow outline indicates the location of the six key hinge region amino acids in WT GluN1. b Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 single point mutants, together with GluN2B, FLAG-EphB2, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. c Quantification of the effects of GluN1 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition (****p < 0.0001, ANOVA; green dots represent n = 30 cells for each condition). d Surface charge maps of GluN1 NTD hinge region of the indicated GluN1 double point mutants as in a (left (positive) to right (negative)). Yellow outline indicates the location of the six key hinge region amino acids in WT GluN1. e Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 double point mutants, together with GluN2B, FLAG-EphB2, and EGFP. The upper panels show PLA signal alone. The lower panels are merged images of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. f Quantification of the effects of GluN1 mutants on PLA puncta number. PLA puncta number are quantified by counting the number of puncta per 100 μm^2 in EGFP^+ cells and normalizing to the WT condition (****p < 0.0001, ANOVA; green dots represent n = 30 cells for each condition).',\n", - " 'paragraph_id': 16,\n", - " 'tokenizer': 'to, begin, to, determine, which, amino, acids, in, the, nt, ##d, hi, ##nge, region, might, media, ##te, the, ep, ##h, ##b, –, nm, ##dar, interaction, ,, we, generated, six, individual, point, mutants, to, each, of, the, amino, acids, that, form, the, area, of, positive, surface, charge, (, i, ##27, ##2, ##a, ,, n, ##27, ##3, ##a, ,, t, ##33, ##5, ##a, ,, g, ##33, ##6, ##a, ,, r, ##33, ##7, ##a, ,, r, ##33, ##7, ##d, ), ., these, mutants, were, chosen, because, they, affect, surface, charge, and, not, the, g, ##ly, ##cos, ##yla, ##tion, state, of, the, g, ##lun, ##1, subunit, ., each, of, these, mutants, traffic, ##ked, to, the, cell, surface, at, similar, levels, and, ran, as, expected, on, western, b, ##lot, ##s, (, supplementary, fig, ., 7, ##a, –, d, ,, 7, ##c, ,, p, =, 0, ., 06, ##13, ;, 7, ##d, ,, p, =, 0, ., 134, ##9, ;, an, ##ova, ), ., ap, ##bs, models, showed, that, mutations, to, n, ##27, ##3, and, r, ##33, ##7, had, the, largest, impact, on, the, surface, potential, (, n, ##27, ##3, ##a, ,, r, ##33, ##7, ##a, ,, and, r, ##33, ##7, ##d, ), (, fig, ., 5, ##a, ), ., if, the, positive, surface, charge, of, the, g, ##lun, ##1, nt, ##d, hi, ##nge, region, media, ##tes, the, ep, ##h, ##b, –, nm, ##dar, interaction, ,, then, the, three, g, ##lun, ##1, mutants, that, affect, surface, potential, the, most, should, disrupt, the, ep, ##h, ##b, ##2, –, nm, ##dar, interaction, ., to, test, whether, those, charge, mutants, affect, the, interaction, ,, pl, ##a, was, performed, on, he, ##k, ##29, ##3, ##t, cells, trans, ##fect, ##ed, with, each, of, the, g, ##lun, ##1, single, mutants, (, i, ##27, ##2, ##a, ,, n, ##27, ##3, ##a, ,, t, ##33, ##5, ##a, ,, g, ##33, ##6, ##a, ,, r, ##33, ##7, ##a, ,, r, ##33, ##7, ##d, ), ,, together, with, g, ##lun, ##2, ##b, ,, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, (, fig, ., 5, ##b, ), ., consistent, with, the, charge, -, based, model, for, the, ep, ##h, ##b, –, nm, ##dar, interaction, ,, the, g, ##lun, ##1, mutants, with, the, largest, apparent, effect, on, surface, charge, ,, n, ##27, ##3, ##a, ,, r, ##33, ##7, ##a, ,, and, r, ##33, ##7, ##d, ,, had, significantly, fewer, pl, ##a, pun, ##cta, per, cell, than, w, ##t, (, fig, ., 5, ##c, ,, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ), ., mutations, that, did, not, alter, the, surface, charge, did, not, impact, the, number, of, pl, ##a, pun, ##cta, (, fig, ., 5, ##c, ,, i, ##27, ##2, ##a, vs, ., w, ##t, ,, p, =, 1, ., 000, ;, t, ##33, ##5, ##a, vs, ., w, ##t, ,, p, =, 0, ., 999, ;, g, ##33, ##6, ##a, vs, ., w, ##t, ,, p, =, 0, ., 148, ##9, ;, an, ##ova, ), ., similarly, ,, my, ##c, -, g, ##lun, ##1, n, ##27, ##3, and, r, ##33, ##7, mutants, co, -, im, ##mun, ##op, ##re, ##ci, ##pit, ##ated, flag, -, ep, ##h, ##b, ##2, less, well, than, w, ##t, my, ##c, -, g, ##lun, ##1, (, supplementary, fig, ., 8, ), ., these, data, suggest, that, a, positive, surface, potential, in, the, nt, ##d, hi, ##nge, region, is, necessary, for, the, ep, ##h, ##b, –, nm, ##dar, interaction, ., fig, ., 5, ##sp, ##ec, ##ific, hi, ##nge, region, amino, acid, residues, are, responsible, for, the, ep, ##h, ##b, ##2, –, g, ##lun, ##1, interaction, in, he, ##k, ##29, ##3, ##t, cells, ., a, surface, charge, maps, of, g, ##lun, ##1, nt, ##d, hi, ##nge, region, of, the, indicated, g, ##lun, ##1, single, point, mutants, in, order, of, increasing, negative, charged, in, the, hi, ##nge, region, (, left, (, positive, ), to, right, (, negative, ), ), ,, with, blue, representing, positive, charge, and, red, representing, negative, charge, ., yellow, outline, indicates, the, location, of, the, six, key, hi, ##nge, region, amino, acids, in, w, ##t, g, ##lun, ##1, ., b, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, single, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., c, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), ., d, surface, charge, maps, of, g, ##lun, ##1, nt, ##d, hi, ##nge, region, of, the, indicated, g, ##lun, ##1, double, point, mutants, as, in, a, (, left, (, positive, ), to, right, (, negative, ), ), ., yellow, outline, indicates, the, location, of, the, six, key, hi, ##nge, region, amino, acids, in, w, ##t, g, ##lun, ##1, ., e, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, double, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, ., the, upper, panels, show, pl, ##a, signal, alone, ., the, lower, panels, are, merged, images, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., f, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, on, pl, ##a, pun, ##cta, number, ., pl, ##a, pun, ##cta, number, are, quan, ##ti, ##fied, by, counting, the, number, of, pun, ##cta, per, 100, μ, ##m, ^, 2, in, e, ##gf, ##p, ^, +, cells, and, normal, ##izing, to, the, w, ##t, condition, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), .'},\n", - " {'article_id': 'fcb414e186cdd2223c6b41e42cefc5bb',\n", - " 'section_name': 'The EphB–NMDAR interaction is charge-dependent',\n", - " 'text': 'The predicted structure of the charged hinge domain indicates that mutation of R337 results in modification of a feature formed by the arginine side chain (Figs. 5a and 9c). To achieve a dynamically modifiable surface charge, we took advantage of the pK_a of the side chain of histidine (Fig. 9d). The pK_a of histidine is 6.0. At a pH of 7.3, the deprotonated form of histidine is dominant (95% deprotonated) and the charge of histidine is neutral. At a pH of 5.0, the imidazole group of histidine is protonated (91% protonated) and is positively charged. Substituting histidine at GluN1 hinge region residues should generate a pH-sensitive molecular switch for the EphB-NMDAR interaction^48–50. Because low pH (<6.0) would also alter the pK_a of any exposed histidine residues in the extracellular domain, and is known to result in rearrangements of the NMDAR ectodomain^51, we generated three histidine point mutants in the GluN1 hinge region: I272H, N273H, and R337H. We expect that the WT and I272H mutant GluN1 should interact at both pH 5 and pH 7.3, controlling for the effects of rearrangements. If the EphB–NMDAR interaction is mediated by a positive surface charge in the hinge region, N273H and R337H mutants should interact with EphB2 at pH 5.0 but not at the physiological histidine-neutral pH 7.3.Fig. 9pH-sensitive histidine mutants in the hinge region elucidate a charge-dependent mechanism.a Representative images of PLA results in HEK293T cells. HEK293T cells were transfected with the indicated Myc-GluN1 single point mutants, together with GluN2B, FLAG-EphB2, and EGFP. Cells were treated with media at either pH 5.0 or pH 7.3 for 30 min before PLA. Upper panels: PLA signal alone. Lower panels: merge of EGFP in green and PLA signal in magenta. Scale bar = 10 μm. b Quantification of the effects of GluN1 mutants and pH on PLA puncta number (****p < 0.0005, ANOVA; green dots represent n = 30 cells for each condition). c Surface representation models (top) and charge maps (bottom) of WT GluN1 and R337H GluN1 predicted at neutral pH. d Model of experimental design. The same neurons were imaged for both pH conditions. e Representative FRAP images at different time points of DIV21–23 cortical neurons transfected with EGFP–GluN1 (WT or R337H) together with GluN2B, CRISPR construct targeting endogenous GluN1, and mCherry. FRAP of GluN1 puncta was conducted in the same neurons at pH 5.0 (H-positive) and pH 7.3 (H-neutral) and the order of pH presentation varied. Recovery of bleached spine puncta (magenta circle) was monitored for 15 min at 10s intervals. Scale bar = 2 μm. f Left: Quantification of the recovery curve of GluN1 WT or R337H mutant in ACSF at pH 7.3 and pH 5.0 in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit (****p < 0.0001, Kolmogorov–Smirnov (KS) nonparametric test). Right: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min after photobleaching (*p = 0.0398, WT-pH7.3 vs. R337H-pH7.3; ANOVA; green dots represent WT-pH5.0 n = 26 puncta; R337H-pH5.0 n = 24; WT-pH7.3 n = 23; R337H-pH7.3 n = 35). Error bars show S.E.M. g Left: Quantification of the recovery curve of GluN1 WT or I272H mutant in ACSF at pH7.3 and pH5.0 in DIV21–23 cortical neurons. Graphs represent mean intensity and show fit. (p = 0.8148, WT-pH7.3 vs. I272H-pH7.3, Kolmogorov–Smirnov (KS) nonparametric test). Right: Quantification of the mobile fraction of EGFP–GluN1 spine puncta at 15 min of FRAP (p = 0.9839; WT-pH7.3 vs. I272H-pH7.3; ANOVA; green dots represent WT-pH5.0 n = 26 puncta; I272H-pH5.0 n = 22; WT-pH7.3 n = 23; I272H-pH7.3 n = 30). Error bars show S.E.M.',\n", - " 'paragraph_id': 23,\n", - " 'tokenizer': 'the, predicted, structure, of, the, charged, hi, ##nge, domain, indicates, that, mutation, of, r, ##33, ##7, results, in, modification, of, a, feature, formed, by, the, ar, ##gin, ##ine, side, chain, (, fig, ##s, ., 5, ##a, and, 9, ##c, ), ., to, achieve, a, dynamic, ##ally, mod, ##if, ##iable, surface, charge, ,, we, took, advantage, of, the, p, ##k, _, a, of, the, side, chain, of, his, ##ti, ##dine, (, fig, ., 9, ##d, ), ., the, p, ##k, _, a, of, his, ##ti, ##dine, is, 6, ., 0, ., at, a, ph, of, 7, ., 3, ,, the, de, ##pro, ##ton, ##ated, form, of, his, ##ti, ##dine, is, dominant, (, 95, %, de, ##pro, ##ton, ##ated, ), and, the, charge, of, his, ##ti, ##dine, is, neutral, ., at, a, ph, of, 5, ., 0, ,, the, im, ##ida, ##zo, ##le, group, of, his, ##ti, ##dine, is, proton, ##ated, (, 91, %, proton, ##ated, ), and, is, positively, charged, ., sub, ##stituting, his, ##ti, ##dine, at, g, ##lun, ##1, hi, ##nge, region, residues, should, generate, a, ph, -, sensitive, molecular, switch, for, the, ep, ##h, ##b, -, nm, ##dar, interaction, ^, 48, –, 50, ., because, low, ph, (, <, 6, ., 0, ), would, also, alter, the, p, ##k, _, a, of, any, exposed, his, ##ti, ##dine, residues, in, the, extra, ##cellular, domain, ,, and, is, known, to, result, in, rear, ##rang, ##ement, ##s, of, the, nm, ##dar, ec, ##to, ##dom, ##ain, ^, 51, ,, we, generated, three, his, ##ti, ##dine, point, mutants, in, the, g, ##lun, ##1, hi, ##nge, region, :, i, ##27, ##2, ##h, ,, n, ##27, ##3, ##h, ,, and, r, ##33, ##7, ##h, ., we, expect, that, the, w, ##t, and, i, ##27, ##2, ##h, mutant, g, ##lun, ##1, should, interact, at, both, ph, 5, and, ph, 7, ., 3, ,, controlling, for, the, effects, of, rear, ##rang, ##ement, ##s, ., if, the, ep, ##h, ##b, –, nm, ##dar, interaction, is, mediated, by, a, positive, surface, charge, in, the, hi, ##nge, region, ,, n, ##27, ##3, ##h, and, r, ##33, ##7, ##h, mutants, should, interact, with, ep, ##h, ##b, ##2, at, ph, 5, ., 0, but, not, at, the, physiological, his, ##ti, ##dine, -, neutral, ph, 7, ., 3, ., fig, ., 9, ##ph, -, sensitive, his, ##ti, ##dine, mutants, in, the, hi, ##nge, region, el, ##uc, ##ida, ##te, a, charge, -, dependent, mechanism, ., a, representative, images, of, pl, ##a, results, in, he, ##k, ##29, ##3, ##t, cells, ., he, ##k, ##29, ##3, ##t, cells, were, trans, ##fect, ##ed, with, the, indicated, my, ##c, -, g, ##lun, ##1, single, point, mutants, ,, together, with, g, ##lun, ##2, ##b, ,, flag, -, ep, ##h, ##b, ##2, ,, and, e, ##gf, ##p, ., cells, were, treated, with, media, at, either, ph, 5, ., 0, or, ph, 7, ., 3, for, 30, min, before, pl, ##a, ., upper, panels, :, pl, ##a, signal, alone, ., lower, panels, :, merge, of, e, ##gf, ##p, in, green, and, pl, ##a, signal, in, mage, ##nta, ., scale, bar, =, 10, μ, ##m, ., b, quan, ##ti, ##fication, of, the, effects, of, g, ##lun, ##1, mutants, and, ph, on, pl, ##a, pun, ##cta, number, (, *, *, *, *, p, <, 0, ., 000, ##5, ,, an, ##ova, ;, green, dots, represent, n, =, 30, cells, for, each, condition, ), ., c, surface, representation, models, (, top, ), and, charge, maps, (, bottom, ), of, w, ##t, g, ##lun, ##1, and, r, ##33, ##7, ##h, g, ##lun, ##1, predicted, at, neutral, ph, ., d, model, of, experimental, design, ., the, same, neurons, were, image, ##d, for, both, ph, conditions, ., e, representative, fra, ##p, images, at, different, time, points, of, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, trans, ##fect, ##ed, with, e, ##gf, ##p, –, g, ##lun, ##1, (, w, ##t, or, r, ##33, ##7, ##h, ), together, with, g, ##lun, ##2, ##b, ,, crisp, ##r, construct, targeting, end, ##ogen, ##ous, g, ##lun, ##1, ,, and, mc, ##her, ##ry, ., fra, ##p, of, g, ##lun, ##1, pun, ##cta, was, conducted, in, the, same, neurons, at, ph, 5, ., 0, (, h, -, positive, ), and, ph, 7, ., 3, (, h, -, neutral, ), and, the, order, of, ph, presentation, varied, ., recovery, of, b, ##lea, ##ched, spine, pun, ##cta, (, mage, ##nta, circle, ), was, monitored, for, 15, min, at, 10, ##s, intervals, ., scale, bar, =, 2, μ, ##m, ., f, left, :, quan, ##ti, ##fication, of, the, recovery, curve, of, g, ##lun, ##1, w, ##t, or, r, ##33, ##7, ##h, mutant, in, ac, ##sf, at, ph, 7, ., 3, and, ph, 5, ., 0, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, (, *, *, *, *, p, <, 0, ., 000, ##1, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., right, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, after, photo, ##ble, ##achi, ##ng, (, *, p, =, 0, ., 03, ##9, ##8, ,, w, ##t, -, ph, ##7, ., 3, vs, ., r, ##33, ##7, ##h, -, ph, ##7, ., 3, ;, an, ##ova, ;, green, dots, represent, w, ##t, -, ph, ##5, ., 0, n, =, 26, pun, ##cta, ;, r, ##33, ##7, ##h, -, ph, ##5, ., 0, n, =, 24, ;, w, ##t, -, ph, ##7, ., 3, n, =, 23, ;, r, ##33, ##7, ##h, -, ph, ##7, ., 3, n, =, 35, ), ., error, bars, show, s, ., e, ., m, ., g, left, :, quan, ##ti, ##fication, of, the, recovery, curve, of, g, ##lun, ##1, w, ##t, or, i, ##27, ##2, ##h, mutant, in, ac, ##sf, at, ph, ##7, ., 3, and, ph, ##5, ., 0, in, di, ##v, ##21, –, 23, co, ##rti, ##cal, neurons, ., graphs, represent, mean, intensity, and, show, fit, ., (, p, =, 0, ., 81, ##48, ,, w, ##t, -, ph, ##7, ., 3, vs, ., i, ##27, ##2, ##h, -, ph, ##7, ., 3, ,, ko, ##lm, ##ogo, ##rov, –, sm, ##ir, ##nov, (, ks, ), non, ##para, ##metric, test, ), ., right, :, quan, ##ti, ##fication, of, the, mobile, fraction, of, e, ##gf, ##p, –, g, ##lun, ##1, spine, pun, ##cta, at, 15, min, of, fra, ##p, (, p, =, 0, ., 98, ##39, ;, w, ##t, -, ph, ##7, ., 3, vs, ., i, ##27, ##2, ##h, -, ph, ##7, ., 3, ;, an, ##ova, ;, green, dots, represent, w, ##t, -, ph, ##5, ., 0, n, =, 26, pun, ##cta, ;, i, ##27, ##2, ##h, -, ph, ##5, ., 0, n, =, 22, ;, w, ##t, -, ph, ##7, ., 3, n, =, 23, ;, i, ##27, ##2, ##h, -, ph, ##7, ., 3, n, =, 30, ), ., error, bars, show, s, ., e, ., m, .'},\n", - " {'article_id': '72a6fa0f75cc78645fa609d5a4d17a5c',\n", - " 'section_name': 'Alzheimer’s dementia ORs',\n", - " 'text': 'Table 1 and Supplementary Table 3 show Alzheimer’s dementia ORs for each APOE genotype and allelic doses (i.e., the number of APOE2 alleles in APOE4 non-carriers and the number of APOE4 alleles in APOE2 non-carriers) before and after adjustment for age and sex in the neuropathologically confirmed and unconfirmed groups before and after adjustment for age and sex, compared to the common APOE3/3 genotype. ORs associated with APOE2 allelic dose in APOE4 non-carriers (APOE2/2 < 2/3 < 3/3) and APOE4 allelic dose in APOE2 non-carriers (APOE4/4 > 3/4 > 3/3) were generated using allelic association tests in an additive genetic model. As discussed below, APOE2/2, APOE2/3, and APOE2 allelic dose ORs were significantly lower, and APOE3/4, APOE4/4, and APOE4 allelic dose ORs were significantly higher, in the neuropathologically confirmed group than in the unconfirmed group. While ORs for the other APOE genotypes were similar to those that we had reported in a small number of cases and controls, the number of APOE2 homozygotes in the earlier study was too small to provide an accurate OR estimate^1,11. Table 2 shows Alzheimer’s dementia ORs for each APOE genotype compared to the relatively low-risk APOE2/3 and highest risk APOE4 genotypes in the neuropathologically confirmed cohort. As discussed below, these ORs permitted us to confirm our primary hypothesis that APOE2/2 is associated with a significantly lower OR compared to APOE3/3 and to demonstrate an exceptionally low OR compared to APOE4/4. Supplementary Table 4 shows Alzheimer’s dementia ORs for each APOE genotype in the combined group, compared to APOE3/3, and for APOE2 and APOE4 allelic dose before and after adjustment for age, sex, and autopsy/non-autopsy group.Table 1Association of APOE genotypes and allelic doses compared to the APOE3/3 genotype.APOENeuropathologically confirmed groupNeuropathologically unconfirmed groupOR95% CIPOR95% CIPGenotype2/20.130.05–0.366.3 × 10^−50.520.30–0.900.022/30.390.30–0.501.6 × 10^−120.630.53–0.752.2 × 10^−72/42.681.65–4.367.5 × 10^−52.472.02–3.015.7 × 10^−193/46.135.08–7.412.2 × 10^−753.553.17–3.982.3 × 10^−1054/431.2216.59–58.754.9 × 10^−2610.709.12–12.567.5 × 10^−186Allelic dose20.380.30–0.481.1 × 10^−150.640.58–0.722.2 × 10^−1646.005.06–7.123.4 × 10^−903.433.26–3.60<10^−300For genotypic association tests, odds ratio (OR), 95% confidence interval (CI), and P value (P) for each APOE genotype compared to the APOE3/3 genotype were calculated under a logistic regression model.For allelic association tests, OR, CI, and P associated with APOE2 allelic dose in APOE4 non-carriers (APOE2/2 < 2/3 < 3/3) and APOE4 allelic dose in APOE2 non-carriers (APOE4/4 > 3/4 > 3/3) in an additive genetic model were generated under a logistic regression model.Table 2Association of each APOE genotype in the neuropathologically confirmed group.APOECompared to APOE2/3Compared to APOE4/4OR95% CIPOR95% CIP2/20.340.12–0.950.040.0040.001–0.0146.0 × 10^−192/3Ref.Ref.Ref.0.0120.006–0.0241.2 × 10^−343/32.602.00–3.381.6 × 10^−120.0320.017–0.0604.9 × 10^−262/46.964.06–11.927.5 × 10^−120.0860.039–0.1891.6 × 10^−93/415.9211.85–21.381.4 × 10^−700.1960.103–0.3758.4 × 10^−74/481.0541.39–158.681.2 × 10^−34Ref.Ref.Ref.Alzheimer’s dementia odds ratios (ORs), 95% confidence intervals (CIs), and P value (P) for each APOE genotype compared to the APOE2/3 or 4/4 genotype as a reference (Ref.) in the neuropathologically confirmed group were calculated under a logistic regression model.',\n", - " 'paragraph_id': 5,\n", - " 'tokenizer': 'table, 1, and, supplementary, table, 3, show, alzheimer, ’, s, dementia, or, ##s, for, each, ap, ##oe, gen, ##otype, and, all, ##eli, ##c, doses, (, i, ., e, ., ,, the, number, of, ap, ##oe, ##2, all, ##eles, in, ap, ##oe, ##4, non, -, carriers, and, the, number, of, ap, ##oe, ##4, all, ##eles, in, ap, ##oe, ##2, non, -, carriers, ), before, and, after, adjustment, for, age, and, sex, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, and, un, ##con, ##firmed, groups, before, and, after, adjustment, for, age, and, sex, ,, compared, to, the, common, ap, ##oe, ##3, /, 3, gen, ##otype, ., or, ##s, associated, with, ap, ##oe, ##2, all, ##eli, ##c, dose, in, ap, ##oe, ##4, non, -, carriers, (, ap, ##oe, ##2, /, 2, <, 2, /, 3, <, 3, /, 3, ), and, ap, ##oe, ##4, all, ##eli, ##c, dose, in, ap, ##oe, ##2, non, -, carriers, (, ap, ##oe, ##4, /, 4, >, 3, /, 4, >, 3, /, 3, ), were, generated, using, all, ##eli, ##c, association, tests, in, an, additive, genetic, model, ., as, discussed, below, ,, ap, ##oe, ##2, /, 2, ,, ap, ##oe, ##2, /, 3, ,, and, ap, ##oe, ##2, all, ##eli, ##c, dose, or, ##s, were, significantly, lower, ,, and, ap, ##oe, ##3, /, 4, ,, ap, ##oe, ##4, /, 4, ,, and, ap, ##oe, ##4, all, ##eli, ##c, dose, or, ##s, were, significantly, higher, ,, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, group, than, in, the, un, ##con, ##firmed, group, ., while, or, ##s, for, the, other, ap, ##oe, gen, ##otype, ##s, were, similar, to, those, that, we, had, reported, in, a, small, number, of, cases, and, controls, ,, the, number, of, ap, ##oe, ##2, homo, ##zy, ##go, ##tes, in, the, earlier, study, was, too, small, to, provide, an, accurate, or, estimate, ^, 1, ,, 11, ., table, 2, shows, alzheimer, ’, s, dementia, or, ##s, for, each, ap, ##oe, gen, ##otype, compared, to, the, relatively, low, -, risk, ap, ##oe, ##2, /, 3, and, highest, risk, ap, ##oe, ##4, gen, ##otype, ##s, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, co, ##hort, ., as, discussed, below, ,, these, or, ##s, permitted, us, to, confirm, our, primary, hypothesis, that, ap, ##oe, ##2, /, 2, is, associated, with, a, significantly, lower, or, compared, to, ap, ##oe, ##3, /, 3, and, to, demonstrate, an, exceptionally, low, or, compared, to, ap, ##oe, ##4, /, 4, ., supplementary, table, 4, shows, alzheimer, ’, s, dementia, or, ##s, for, each, ap, ##oe, gen, ##otype, in, the, combined, group, ,, compared, to, ap, ##oe, ##3, /, 3, ,, and, for, ap, ##oe, ##2, and, ap, ##oe, ##4, all, ##eli, ##c, dose, before, and, after, adjustment, for, age, ,, sex, ,, and, autopsy, /, non, -, autopsy, group, ., table, 1a, ##sso, ##ciation, of, ap, ##oe, gen, ##otype, ##s, and, all, ##eli, ##c, doses, compared, to, the, ap, ##oe, ##3, /, 3, gen, ##otype, ., ap, ##oe, ##ne, ##uro, ##path, ##ological, ##ly, confirmed, group, ##ne, ##uro, ##path, ##ological, ##ly, un, ##con, ##firmed, group, ##or, ##9, ##5, %, ci, ##por, ##9, ##5, %, ci, ##pg, ##eno, ##type, ##2, /, 20, ., 130, ., 05, –, 0, ., 36, ##6, ., 3, ×, 10, ^, −, ##50, ., 520, ., 30, –, 0, ., 900, ., 02, ##2, /, 30, ., 390, ., 30, –, 0, ., 501, ., 6, ×, 10, ^, −, ##12, ##0, ., 630, ., 53, –, 0, ., 75, ##2, ., 2, ×, 10, ^, −, ##7, ##2, /, 42, ., 68, ##1, ., 65, –, 4, ., 36, ##7, ., 5, ×, 10, ^, −, ##52, ., 47, ##2, ., 02, –, 3, ., 01, ##5, ., 7, ×, 10, ^, −, ##19, ##3, /, 46, ., 135, ., 08, –, 7, ., 412, ., 2, ×, 10, ^, −, ##75, ##3, ., 55, ##3, ., 17, –, 3, ., 98, ##2, ., 3, ×, 10, ^, −, ##10, ##54, /, 43, ##1, ., 221, ##6, ., 59, –, 58, ., 75, ##4, ., 9, ×, 10, ^, −, ##26, ##10, ., 70, ##9, ., 12, –, 12, ., 56, ##7, ., 5, ×, 10, ^, −, ##18, ##6, ##alle, ##lic, dose, ##20, ., 380, ., 30, –, 0, ., 48, ##1, ., 1, ×, 10, ^, −, ##15, ##0, ., 640, ., 58, –, 0, ., 72, ##2, ., 2, ×, 10, ^, −, ##16, ##46, ., 00, ##5, ., 06, –, 7, ., 123, ., 4, ×, 10, ^, −, ##90, ##3, ., 43, ##3, ., 26, –, 3, ., 60, <, 10, ^, −, ##30, ##0, ##for, gen, ##ot, ##yp, ##ic, association, tests, ,, odds, ratio, (, or, ), ,, 95, %, confidence, interval, (, ci, ), ,, and, p, value, (, p, ), for, each, ap, ##oe, gen, ##otype, compared, to, the, ap, ##oe, ##3, /, 3, gen, ##otype, were, calculated, under, a, log, ##istic, regression, model, ., for, all, ##eli, ##c, association, tests, ,, or, ,, ci, ,, and, p, associated, with, ap, ##oe, ##2, all, ##eli, ##c, dose, in, ap, ##oe, ##4, non, -, carriers, (, ap, ##oe, ##2, /, 2, <, 2, /, 3, <, 3, /, 3, ), and, ap, ##oe, ##4, all, ##eli, ##c, dose, in, ap, ##oe, ##2, non, -, carriers, (, ap, ##oe, ##4, /, 4, >, 3, /, 4, >, 3, /, 3, ), in, an, additive, genetic, model, were, generated, under, a, log, ##istic, regression, model, ., table, 2a, ##sso, ##ciation, of, each, ap, ##oe, gen, ##otype, in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, group, ., ap, ##oe, ##com, ##par, ##ed, to, ap, ##oe, ##2, /, 3, ##com, ##par, ##ed, to, ap, ##oe, ##4, /, 4, ##or, ##9, ##5, %, ci, ##por, ##9, ##5, %, ci, ##p, ##2, /, 20, ., 340, ., 12, –, 0, ., 950, ., 04, ##0, ., 00, ##40, ., 001, –, 0, ., 01, ##46, ., 0, ×, 10, ^, −, ##19, ##2, /, 3, ##re, ##f, ., ref, ., ref, ., 0, ., 01, ##20, ., 00, ##6, –, 0, ., 02, ##41, ., 2, ×, 10, ^, −, ##34, ##3, /, 32, ., 60, ##2, ., 00, –, 3, ., 381, ., 6, ×, 10, ^, −, ##12, ##0, ., 03, ##20, ., 01, ##7, –, 0, ., 06, ##0, ##4, ., 9, ×, 10, ^, −, ##26, ##2, /, 46, ., 96, ##4, ., 06, –, 11, ., 92, ##7, ., 5, ×, 10, ^, −, ##12, ##0, ., 08, ##60, ., 03, ##9, –, 0, ., 1891, ., 6, ×, 10, ^, −, ##9, ##3, /, 415, ., 92, ##11, ., 85, –, 21, ., 381, ., 4, ×, 10, ^, −, ##70, ##0, ., 1960, ., 103, –, 0, ., 375, ##8, ., 4, ×, 10, ^, −, ##7, ##4, /, 48, ##1, ., 05, ##41, ., 39, –, 158, ., 68, ##1, ., 2, ×, 10, ^, −, ##34, ##re, ##f, ., ref, ., ref, ., alzheimer, ’, s, dementia, odds, ratios, (, or, ##s, ), ,, 95, %, confidence, intervals, (, cis, ), ,, and, p, value, (, p, ), for, each, ap, ##oe, gen, ##otype, compared, to, the, ap, ##oe, ##2, /, 3, or, 4, /, 4, gen, ##otype, as, a, reference, (, ref, ., ), in, the, ne, ##uro, ##path, ##ological, ##ly, confirmed, group, were, calculated, under, a, log, ##istic, regression, model, .'},\n", - " {'article_id': '8ac4fbd9ed9f0baa294353544aae74fc',\n", - " 'section_name': 'Metabolic defects in ob/ob; Pomc-Cre; Atg7^loxP/loxP mice',\n", - " 'text': 'To further investigate the relationship between leptin deficiency, ER stress and autophagy in vivo, we generated ob/ob mice that lack the autophagy gene Atg7 in POMC neurons (ob/ob; Pomc-Cre; Atg7^loxP/loxP mice). The rationale for focusing on POMC neurons, specifically, is because we found that TUDCA treatment only rescues POMC projections in ob/ob mice (see results above), and we previously reported that Atg7 in POMC neurons is required for normal metabolic regulation and neuronal development^24. We confirmed that these mice are indeed autophagy-defective by analyzing the expression of the polyubiquitin-binding protein p62, which links ubiquitinated proteins to the autophagy apparatus^25. We found that ob/ob; Pomc-Cre; Atg7^loxP/loxP mice displayed higher levels of p62-IR in the ARH compared to WT and ob/ob mice (Fig. 6a). The ob/ob; Pomc-Cre; Atg7^loxP/loxP mice were born normal and survived to adulthood. In addition, these mutant mice had body weights indistinguishable from those of their ob/ob control littermates during the preweaning period and in adulthood (Fig. 6b, c). However, when exposed to a glucose challenge, ob/ob; Pomc-Cre; Atg7^loxP/loxP mice displayed impaired glucose tolerance compared to ob/ob mice (Fig. 6d). Serum insulin levels appeared normal in fed ob/ob; Pomc-Cre; Atg7^loxP/loxP mice (Fig. 6e). In addition, food intake and fat mass were increased in 10-week-old and 4-week-old, ob/ob; Pomc-Cre; Atg7^loxP/loxP mice (Fig. 6f, g), but the body composition became normal in 10-week-old mice (Fig. 6g). We also treated ob/ob; Pomc-Cre; Atg7^loxP/loxP mice with TUDCA daily from P4 to P16 and found that neonatal TUDCA treatment reduced arcuate p62-IR, body weight, serum insulin levels, food intake, and body composition and improved glucose tolerance (Fig. 6a–g).Fig. 6Neonatal tauroursodeoxycholic acid treatment ameliorates metabolic defects inob/ob;Pomc-Cre;Atg7^loxP/loxPmice.a Representative images and quantification of ubiquitin-binding protein (p62) immunoreactivity (red) in the arcuate nucleus (ARH) of 10-week-old wild-type (WT) mice, leptin-deficient (ob/ob) mice treated neonatally with vehicle or tauroursodeoxycholic acid (TUDCA), and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 5–7 per group). b Pre- (ob/ob, ob/ob; Pomc-Cre; Atg7^loxP/loxP + Vehicle: n = 9, ob/ob; Pomc-Cre; Atg7^loxP/loxP + TUDCA: n = 8 per group) and (c) post-weaning growth curves of ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (ob/ob, ob/ob; Pomc-Cre; Atg7^loxP/loxP + Vehicle: n = 7, ob/ob; Pomc-Cre; Atg7^loxP/loxP + TUDCA: n = 6 per group). d Blood glucose concentration after intraperitoneal injection of glucose and area under the glucose tolerance test (GTT) curve (AUC) (ob/ob, ob/ob; Pomc-Cre; Atg7^loxP/loxP + TUDCA: n = 6, ob/ob; Pomc-Cre; Atg7^loxP/loxP + Vehicle: n = 10 per group) and e serum insulin levels of 8-week-old fed ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 7 per group). f Food intake of 10-week-old ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 3–5 per group). g Body composition of 4- (n = 3 per group) and 10-week-old ob/ob mice and ob/ob; Pomc-Cre; Atg7^loxP/loxP mice treated neonatally with vehicle or TUDCA (n = 4–5 per group). Error bars represent the SEM. *P ≤ 0.05, and **P < 0.01 versus all groups (a), *P ≤ 0.05, **P < 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 versus vehicle-treated ob/ob; Pomc-Cre; Atg7^loxP/loxP mice (b–g), ^#P < 0.05, ^##P ≤ 0.01, ^###P ≤ 0.001, and ^####P ≤ 0.0001 versus WT mice (d). Statistical significance between groups was determined using one-way ANOVA (a, AUC in d, e–g) and two-way ANOVA (b–d) followed by Tukey’s multiple comparison test. ARH, arcuate nucleus of the hypothalamus; me, median eminence; V3, third ventricle. Scale bar, 50 μm (a). Source data are provided as a Source Data file.',\n", - " 'paragraph_id': 14,\n", - " 'tokenizer': 'to, further, investigate, the, relationship, between, le, ##pt, ##in, deficiency, ,, er, stress, and, auto, ##pha, ##gy, in, vivo, ,, we, generated, ob, /, ob, mice, that, lack, the, auto, ##pha, ##gy, gene, at, ##g, ##7, in, po, ##mc, neurons, (, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, ), ., the, rational, ##e, for, focusing, on, po, ##mc, neurons, ,, specifically, ,, is, because, we, found, that, tu, ##dc, ##a, treatment, only, rescues, po, ##mc, projections, in, ob, /, ob, mice, (, see, results, above, ), ,, and, we, previously, reported, that, at, ##g, ##7, in, po, ##mc, neurons, is, required, for, normal, metabolic, regulation, and, ne, ##uron, ##al, development, ^, 24, ., we, confirmed, that, these, mice, are, indeed, auto, ##pha, ##gy, -, defective, by, analyzing, the, expression, of, the, poly, ##ub, ##iq, ##uit, ##in, -, binding, protein, p, ##6, ##2, ,, which, links, u, ##bi, ##qui, ##tina, ##ted, proteins, to, the, auto, ##pha, ##gy, apparatus, ^, 25, ., we, found, that, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, displayed, higher, levels, of, p, ##6, ##2, -, ir, in, the, ar, ##h, compared, to, w, ##t, and, ob, /, ob, mice, (, fig, ., 6, ##a, ), ., the, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, were, born, normal, and, survived, to, adulthood, ., in, addition, ,, these, mutant, mice, had, body, weights, ind, ##ist, ##ing, ##uis, ##hab, ##le, from, those, of, their, ob, /, ob, control, litter, ##mates, during, the, pre, ##we, ##ani, ##ng, period, and, in, adulthood, (, fig, ., 6, ##b, ,, c, ), ., however, ,, when, exposed, to, a, glucose, challenge, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, displayed, impaired, glucose, tolerance, compared, to, ob, /, ob, mice, (, fig, ., 6, ##d, ), ., serum, insulin, levels, appeared, normal, in, fed, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, (, fig, ., 6, ##e, ), ., in, addition, ,, food, intake, and, fat, mass, were, increased, in, 10, -, week, -, old, and, 4, -, week, -, old, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, (, fig, ., 6, ##f, ,, g, ), ,, but, the, body, composition, became, normal, in, 10, -, week, -, old, mice, (, fig, ., 6, ##g, ), ., we, also, treated, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, with, tu, ##dc, ##a, daily, from, p, ##4, to, p, ##16, and, found, that, neon, ##atal, tu, ##dc, ##a, treatment, reduced, arc, ##uate, p, ##6, ##2, -, ir, ,, body, weight, ,, serum, insulin, levels, ,, food, intake, ,, and, body, composition, and, improved, glucose, tolerance, (, fig, ., 6, ##a, –, g, ), ., fig, ., 6, ##neo, ##nat, ##al, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, treatment, am, ##eli, ##ora, ##tes, metabolic, defects, in, ##ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##pm, ##ice, ., a, representative, images, and, quan, ##ti, ##fication, of, u, ##bi, ##qui, ##tin, -, binding, protein, (, p, ##6, ##2, ), im, ##mun, ##ore, ##act, ##ivity, (, red, ), in, the, arc, ##uate, nucleus, (, ar, ##h, ), of, 10, -, week, -, old, wild, -, type, (, w, ##t, ), mice, ,, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), mice, treated, neon, ##atal, ##ly, with, vehicle, or, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, (, tu, ##dc, ##a, ), ,, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 5, –, 7, per, group, ), ., b, pre, -, (, ob, /, ob, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, vehicle, :, n, =, 9, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, tu, ##dc, ##a, :, n, =, 8, per, group, ), and, (, c, ), post, -, we, ##ani, ##ng, growth, curves, of, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, ob, /, ob, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, vehicle, :, n, =, 7, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, tu, ##dc, ##a, :, n, =, 6, per, group, ), ., d, blood, glucose, concentration, after, intra, ##per, ##ito, ##nea, ##l, injection, of, glucose, and, area, under, the, glucose, tolerance, test, (, gt, ##t, ), curve, (, au, ##c, ), (, ob, /, ob, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, tu, ##dc, ##a, :, n, =, 6, ,, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, +, vehicle, :, n, =, 10, per, group, ), and, e, serum, insulin, levels, of, 8, -, week, -, old, fed, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 7, per, group, ), ., f, food, intake, of, 10, -, week, -, old, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 3, –, 5, per, group, ), ., g, body, composition, of, 4, -, (, n, =, 3, per, group, ), and, 10, -, week, -, old, ob, /, ob, mice, and, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 4, –, 5, per, group, ), ., error, bars, represent, the, se, ##m, ., *, p, ≤, 0, ., 05, ,, and, *, *, p, <, 0, ., 01, versus, all, groups, (, a, ), ,, *, p, ≤, 0, ., 05, ,, *, *, p, <, 0, ., 01, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, treated, ob, /, ob, ;, po, ##mc, -, cr, ##e, ;, at, ##g, ##7, ^, lo, ##x, ##p, /, lo, ##x, ##p, mice, (, b, –, g, ), ,, ^, #, p, <, 0, ., 05, ,, ^, #, #, p, ≤, 0, ., 01, ,, ^, #, #, #, p, ≤, 0, ., 001, ,, and, ^, #, #, #, #, p, ≤, 0, ., 000, ##1, versus, w, ##t, mice, (, d, ), ., statistical, significance, between, groups, was, determined, using, one, -, way, an, ##ova, (, a, ,, au, ##c, in, d, ,, e, –, g, ), and, two, -, way, an, ##ova, (, b, –, d, ), followed, by, tu, ##key, ’, s, multiple, comparison, test, ., ar, ##h, ,, arc, ##uate, nucleus, of, the, h, ##yp, ##oth, ##ala, ##mus, ;, me, ,, median, emi, ##nen, ##ce, ;, v, ##3, ,, third, vent, ##ric, ##le, ., scale, bar, ,, 50, μ, ##m, (, a, ), ., source, data, are, provided, as, a, source, data, file, .'},\n", - " {'article_id': '8ac4fbd9ed9f0baa294353544aae74fc',\n", - " 'section_name': 'Leptin deficiency induces early life ER stress',\n", - " 'text': 'To examine whether leptin deficiency causes ER stress during critical periods of development, we measured the expression levels of the following ER stress markers: activating transcription factor 4 (Atf4), 6 (Atf6), X-box binding protein (Xbp1), glucose regulated protein GRP78 (referred to as Bip), and CCAAT-enhancer-binding protein homologous protein (Chop), in the embryonic, postnatal and adult hypothalamus of leptin-deficient (ob/ob) and wild-type (WT) mice. The levels of ER stress gene expression were not significantly changed in the hypothalamus of E14.5 ob/ob embryos (Fig. 1a) or in the arcuate nucleus of the hypothalamus (ARH) of postnatal day (P) 0 ob/ob mice (Fig. 1b). In contrast, all ER stress markers examined were significantly elevated in the ARH of P10 ob/ob mice (Fig. 1c). We next assessed ER stress marker expression specifically in arcuate Pomc and Agrp neurons and found that the levels of Atf4, Atf6, Xbp1, and Bip mRNAs were higher in these two neuronal populations in P10 ob/ob mice (Fig. 1d). During adulthood, leptin deficiency only caused an increase in Xbp1 and Bip mRNA expression in the ARH (Fig. 1e). In addition, Xbp1 mRNA levels were significantly higher in the paraventricular nucleus of the hypothalamus (PVH) of P0 (Fig. 1f) and P10 ob/ob mice (Fig. 1g), but none of the ER stress markers studied were significantly elevated in the PVH of adult ob/ob mice (Fig. 1h). We also examined ER stress markers in metabolically relevant peripheral tissues and found that Xbp1 gene expression was upregulated in the liver and adipose tissue of P10 ob/ob mice and that Atf4 mRNA levels were increased in the livers of P10 ob/ob mice (Supplementary Fig. 1a, b). In contrast, most of the ER stress markers studied were downregulated in the liver and adipose tissue of adult ob/ob mice (Supplementary Fig. 1c, d).Fig. 1Leptin deficiency increases endoplasmic reticulum stress markers in the developing hypothalamus.Relative expression of activating transcription factor 4 (Atf4), 6 (Atf6), X-box binding protein (Xbp1), glucose regulated protein GRP78 (referred to as Bip), and CCAAT-enhancer-binding protein homologous protein (Chop) mRNA a in the hypothalamus of embryonic day (E)14.5 mice (n = 4–5 per group) and b in the arcuate nucleus (ARH) of postnatal day (P) 0 wild-type (WT) and leptin-deficient (ob/ob) mice (n = 5–6 per group). c Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in the ARH of P10 WT mice and ob/ob mice treated neonatally either vehicle or tauroursodeoxycholic acid (TUDCA) or leptin (WT, ob/ob + Vehicle, ob/ob + TUDCA n = 4, ob/ob + Leptin: n = 5 per group). d Representative images and quantification of Atf4, Atf6, Xbp1, Bip, and Chop mRNA (green) in arcuate pro-opiomelanocortin (Pomc)- (white) and agouti-related peptide (Agrp) (red) mRNA-expressing cells of WT and ob/ob mice at P10 (n = 3–4 per group). e Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in the ARH of 10-week-old adult WT mice and ob/ob mice treated neonatally either vehicle or TUDCA (n = 6 per group). Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in the paraventricular nucleus (PVH) of f P0 (n = 4 per group), g P10 (n = 6 per group), and h 10-week-old adult WT mice and ob/ob mice treated neonatally either vehicle or TUDCA (n = 6 per group). i Relative expression of Atf4, Atf6, Xbp1, Bip, and Chop mRNA in hypothalamic mHypoE-N43/5 cell lysates treated with dimethyl sulfoxide (DMSO, control) or leptin (LEP, 100 ng/ml) or tunicamycin (TUN, 0.1 μg/ml) or TUN + LEP for 5 h (n = 4 per group). Error bars represent the SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 versus ob/ob mice (d, f), *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001 versus vehicle-injected ob/ob mice (c, e, g, h). **P ≤ 0.01 and ****P ≤ 0.0001 versus tunicamycin treated group (i). Statistical significance was determined using two-way ANOVA followed by Tukey’s Multiple Comparison test (a–i). Scale bar, 5 μm (d). Source data are provided as a Source Data file.',\n", - " 'paragraph_id': 4,\n", - " 'tokenizer': 'to, examine, whether, le, ##pt, ##in, deficiency, causes, er, stress, during, critical, periods, of, development, ,, we, measured, the, expression, levels, of, the, following, er, stress, markers, :, act, ##ivating, transcription, factor, 4, (, at, ##f, ##4, ), ,, 6, (, at, ##f, ##6, ), ,, x, -, box, binding, protein, (, x, ##b, ##p, ##1, ), ,, glucose, regulated, protein, gr, ##p, ##7, ##8, (, referred, to, as, bi, ##p, ), ,, and, cc, ##aa, ##t, -, enhance, ##r, -, binding, protein, homo, ##log, ##ous, protein, (, chop, ), ,, in, the, embryo, ##nic, ,, post, ##nat, ##al, and, adult, h, ##yp, ##oth, ##ala, ##mus, of, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), and, wild, -, type, (, w, ##t, ), mice, ., the, levels, of, er, stress, gene, expression, were, not, significantly, changed, in, the, h, ##yp, ##oth, ##ala, ##mus, of, e, ##14, ., 5, ob, /, ob, embryo, ##s, (, fig, ., 1a, ), or, in, the, arc, ##uate, nucleus, of, the, h, ##yp, ##oth, ##ala, ##mus, (, ar, ##h, ), of, post, ##nat, ##al, day, (, p, ), 0, ob, /, ob, mice, (, fig, ., 1b, ), ., in, contrast, ,, all, er, stress, markers, examined, were, significantly, elevated, in, the, ar, ##h, of, p, ##10, ob, /, ob, mice, (, fig, ., 1, ##c, ), ., we, next, assessed, er, stress, marker, expression, specifically, in, arc, ##uate, po, ##mc, and, ag, ##rp, neurons, and, found, that, the, levels, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, and, bi, ##p, mrna, ##s, were, higher, in, these, two, ne, ##uron, ##al, populations, in, p, ##10, ob, /, ob, mice, (, fig, ., 1, ##d, ), ., during, adulthood, ,, le, ##pt, ##in, deficiency, only, caused, an, increase, in, x, ##b, ##p, ##1, and, bi, ##p, mrna, expression, in, the, ar, ##h, (, fig, ., 1, ##e, ), ., in, addition, ,, x, ##b, ##p, ##1, mrna, levels, were, significantly, higher, in, the, para, ##vent, ##ric, ##ular, nucleus, of, the, h, ##yp, ##oth, ##ala, ##mus, (, pv, ##h, ), of, p, ##0, (, fig, ., 1, ##f, ), and, p, ##10, ob, /, ob, mice, (, fig, ., 1, ##g, ), ,, but, none, of, the, er, stress, markers, studied, were, significantly, elevated, in, the, pv, ##h, of, adult, ob, /, ob, mice, (, fig, ., 1, ##h, ), ., we, also, examined, er, stress, markers, in, metabolic, ##ally, relevant, peripheral, tissues, and, found, that, x, ##b, ##p, ##1, gene, expression, was, up, ##re, ##gul, ##ated, in, the, liver, and, adi, ##pose, tissue, of, p, ##10, ob, /, ob, mice, and, that, at, ##f, ##4, mrna, levels, were, increased, in, the, liver, ##s, of, p, ##10, ob, /, ob, mice, (, supplementary, fig, ., 1a, ,, b, ), ., in, contrast, ,, most, of, the, er, stress, markers, studied, were, down, ##re, ##gul, ##ated, in, the, liver, and, adi, ##pose, tissue, of, adult, ob, /, ob, mice, (, supplementary, fig, ., 1, ##c, ,, d, ), ., fig, ., 1, ##le, ##pt, ##in, deficiency, increases, end, ##op, ##las, ##mic, re, ##tic, ##ulum, stress, markers, in, the, developing, h, ##yp, ##oth, ##ala, ##mus, ., relative, expression, of, act, ##ivating, transcription, factor, 4, (, at, ##f, ##4, ), ,, 6, (, at, ##f, ##6, ), ,, x, -, box, binding, protein, (, x, ##b, ##p, ##1, ), ,, glucose, regulated, protein, gr, ##p, ##7, ##8, (, referred, to, as, bi, ##p, ), ,, and, cc, ##aa, ##t, -, enhance, ##r, -, binding, protein, homo, ##log, ##ous, protein, (, chop, ), mrna, a, in, the, h, ##yp, ##oth, ##ala, ##mus, of, embryo, ##nic, day, (, e, ), 14, ., 5, mice, (, n, =, 4, –, 5, per, group, ), and, b, in, the, arc, ##uate, nucleus, (, ar, ##h, ), of, post, ##nat, ##al, day, (, p, ), 0, wild, -, type, (, w, ##t, ), and, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), mice, (, n, =, 5, –, 6, per, group, ), ., c, relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, the, ar, ##h, of, p, ##10, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, either, vehicle, or, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, (, tu, ##dc, ##a, ), or, le, ##pt, ##in, (, w, ##t, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, n, =, 4, ,, ob, /, ob, +, le, ##pt, ##in, :, n, =, 5, per, group, ), ., d, representative, images, and, quan, ##ti, ##fication, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, (, green, ), in, arc, ##uate, pro, -, op, ##iom, ##ela, ##no, ##cor, ##tin, (, po, ##mc, ), -, (, white, ), and, ago, ##uti, -, related, peptide, (, ag, ##rp, ), (, red, ), mrna, -, expressing, cells, of, w, ##t, and, ob, /, ob, mice, at, p, ##10, (, n, =, 3, –, 4, per, group, ), ., e, relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, the, ar, ##h, of, 10, -, week, -, old, adult, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, either, vehicle, or, tu, ##dc, ##a, (, n, =, 6, per, group, ), ., relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, the, para, ##vent, ##ric, ##ular, nucleus, (, pv, ##h, ), of, f, p, ##0, (, n, =, 4, per, group, ), ,, g, p, ##10, (, n, =, 6, per, group, ), ,, and, h, 10, -, week, -, old, adult, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, either, vehicle, or, tu, ##dc, ##a, (, n, =, 6, per, group, ), ., i, relative, expression, of, at, ##f, ##4, ,, at, ##f, ##6, ,, x, ##b, ##p, ##1, ,, bi, ##p, ,, and, chop, mrna, in, h, ##yp, ##oth, ##ala, ##mic, m, ##hy, ##po, ##e, -, n, ##43, /, 5, cell, l, ##ys, ##ates, treated, with, dime, ##thy, ##l, sul, ##fo, ##xide, (, d, ##ms, ##o, ,, control, ), or, le, ##pt, ##in, (, le, ##p, ,, 100, ng, /, ml, ), or, tunic, ##amy, ##cin, (, tun, ,, 0, ., 1, μ, ##g, /, ml, ), or, tun, +, le, ##p, for, 5, h, (, n, =, 4, per, group, ), ., error, bars, represent, the, se, ##m, ., *, p, ≤, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, ob, /, ob, mice, (, d, ,, f, ), ,, *, p, ≤, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, injected, ob, /, ob, mice, (, c, ,, e, ,, g, ,, h, ), ., *, *, p, ≤, 0, ., 01, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, tunic, ##amy, ##cin, treated, group, (, i, ), ., statistical, significance, was, determined, using, two, -, way, an, ##ova, followed, by, tu, ##key, ’, s, multiple, comparison, test, (, a, –, i, ), ., scale, bar, ,, 5, μ, ##m, (, d, ), ., source, data, are, provided, as, a, source, data, file, .'},\n", - " {'article_id': '8ac4fbd9ed9f0baa294353544aae74fc',\n", - " 'section_name': 'Neonatal TUDCA treatment improves energy balance',\n", - " 'text': 'Beginning at 3 weeks of age, the TUDCA-treated ob/ob neonates had significantly lower body weights than the control ob/ob mice, and this reduction in body weight persisted until 6 weeks of age (Fig. 2a). Neonatal TUDCA treatment also reduced the daily food intake in 10-week-old ob/ob mice (Fig. 2b). Moreover, 4-week-old ob/ob mice treated with TUDCA neonatally displayed a reduction in fat mass, but this effect was not observed in 10-week-old animals (Fig. 2c). Similarly, respiratory quotient, energy expenditure, and locomotor activity during the light phase appeared comparable between control and TUDCA-treated ob/ob mice (Fig. 2d–f). However, locomotor activity during the dark phase was slightly reduced in TUDCA-treated mice (Fig. 2f). To examine whether relieving ER stress neonatally also had consequences on glucose homeostasis, we performed glucose- and insulin-tolerance tests. When exposed to a glucose or an insulin challenge, adult ob/ob mice neonatally treated with TUDCA displayed improved glucose and insulin tolerance, respectively, compared to control ob/ob mice (Fig. 2g–i). In addition, neonatal TUDCA treatment reduced insulin levels in adult fed ob/ob mice (Fig. 2j).Fig. 2Neonatal TUDCA treatment causes long-term beneficial metabolic effects inob/obmice.a Growth curves of wild-type (WT) mice and leptin-deficient (ob/ob) mice treated neonatally with vehicle or tauroursodeoxycholic acid (TUDCA) (n = 8 per group). b Food intake (WT: n = 5, ob/ob + Vehicle, ob/ob + TUDCA: n = 4 per group) and c body composition of 4- (n = 3 per group) and 10-week-old (n = 4–5 per group) WT mice and ob/ob mice treated neonatally with vehicle or TUDCA. d Respiratory exchange ratio (WT: n = 5, ob/ob + Vehicle, ob/ob + TUDCA: n = 4 per group), e energy expenditure (WT: n = 7, ob/ob + Vehicle, ob/ob + TUDCA: n = 3 per group), and f locomotor activity of 6-week-old WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (WT: n = 7, ob/ob + Vehicle, ob/ob + TUDCA: n = 3 per group). g, h Glucose tolerance tests (GTT) and area under the curve (AUC) quantification of 4-week-old (WT: n = 5, ob/ob + Vehicle, ob/ob + TUDCA: n = 8 per group) (g) and 8-week-old (WT: n = 5, ob/ob + Vehicle: n = 6, ob/ob + TUDCA: n = 10 per group) (h) WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (n = 5–10 per group). i Insulin tolerance test (ITT) and area under the ITT curve (AUC) of 9-week-old WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (WT, ob/ob + Vehicle: n = 5, ob/ob + TUDCA: n = 9 per group). j Serum insulin levels of 10- to 12-week-old fed WT mice and ob/ob mice treated neonatally with vehicle or TUDCA (n = 7 per group). Error bars represent the SEM. *P < 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 versus vehicle-injected ob/ob mice (a, g–i), ^#P < 0.05, ^##P ≤ 0.01, ^###P ≤ 0.001, and ^####P ≤ 0.0001 versus WT mice (a, g–i). *P < 0.05, ***P ≤ 0.001, and ****P ≤ 0.0001 versus WT mice and *P < 0.05, **P ≤ 0.01, and ****P ≤ 0.0001 versus vehicle-injected ob/ob mice (b–f, j). Statistical significance between groups was determined using two-tailed Student’s t test (f), one-way ANOVA (b, c, e, f, j) and AUCs in g–j and two-way ANOVA (a, d, g–i) followed by Tukey’s multiple comparison test. Source data are provided as a Source Data file.',\n", - " 'paragraph_id': 7,\n", - " 'tokenizer': 'beginning, at, 3, weeks, of, age, ,, the, tu, ##dc, ##a, -, treated, ob, /, ob, neon, ##ates, had, significantly, lower, body, weights, than, the, control, ob, /, ob, mice, ,, and, this, reduction, in, body, weight, persisted, until, 6, weeks, of, age, (, fig, ., 2a, ), ., neon, ##atal, tu, ##dc, ##a, treatment, also, reduced, the, daily, food, intake, in, 10, -, week, -, old, ob, /, ob, mice, (, fig, ., 2, ##b, ), ., moreover, ,, 4, -, week, -, old, ob, /, ob, mice, treated, with, tu, ##dc, ##a, neon, ##atal, ##ly, displayed, a, reduction, in, fat, mass, ,, but, this, effect, was, not, observed, in, 10, -, week, -, old, animals, (, fig, ., 2, ##c, ), ., similarly, ,, respiratory, quo, ##tie, ##nt, ,, energy, expenditure, ,, and, loco, ##moto, ##r, activity, during, the, light, phase, appeared, comparable, between, control, and, tu, ##dc, ##a, -, treated, ob, /, ob, mice, (, fig, ., 2d, –, f, ), ., however, ,, loco, ##moto, ##r, activity, during, the, dark, phase, was, slightly, reduced, in, tu, ##dc, ##a, -, treated, mice, (, fig, ., 2, ##f, ), ., to, examine, whether, re, ##lie, ##ving, er, stress, neon, ##atal, ##ly, also, had, consequences, on, glucose, home, ##osta, ##sis, ,, we, performed, glucose, -, and, insulin, -, tolerance, tests, ., when, exposed, to, a, glucose, or, an, insulin, challenge, ,, adult, ob, /, ob, mice, neon, ##atal, ##ly, treated, with, tu, ##dc, ##a, displayed, improved, glucose, and, insulin, tolerance, ,, respectively, ,, compared, to, control, ob, /, ob, mice, (, fig, ., 2, ##g, –, i, ), ., in, addition, ,, neon, ##atal, tu, ##dc, ##a, treatment, reduced, insulin, levels, in, adult, fed, ob, /, ob, mice, (, fig, ., 2, ##j, ), ., fig, ., 2, ##neo, ##nat, ##al, tu, ##dc, ##a, treatment, causes, long, -, term, beneficial, metabolic, effects, in, ##ob, /, ob, ##mic, ##e, ., a, growth, curves, of, wild, -, type, (, w, ##t, ), mice, and, le, ##pt, ##in, -, def, ##icient, (, ob, /, ob, ), mice, treated, neon, ##atal, ##ly, with, vehicle, or, tau, ##rou, ##rso, ##de, ##ox, ##ych, ##olic, acid, (, tu, ##dc, ##a, ), (, n, =, 8, per, group, ), ., b, food, intake, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 4, per, group, ), and, c, body, composition, of, 4, -, (, n, =, 3, per, group, ), and, 10, -, week, -, old, (, n, =, 4, –, 5, per, group, ), w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, ., d, respiratory, exchange, ratio, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 4, per, group, ), ,, e, energy, expenditure, (, w, ##t, :, n, =, 7, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 3, per, group, ), ,, and, f, loco, ##moto, ##r, activity, of, 6, -, week, -, old, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, w, ##t, :, n, =, 7, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 3, per, group, ), ., g, ,, h, glucose, tolerance, tests, (, gt, ##t, ), and, area, under, the, curve, (, au, ##c, ), quan, ##ti, ##fication, of, 4, -, week, -, old, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 8, per, group, ), (, g, ), and, 8, -, week, -, old, (, w, ##t, :, n, =, 5, ,, ob, /, ob, +, vehicle, :, n, =, 6, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 10, per, group, ), (, h, ), w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 5, –, 10, per, group, ), ., i, insulin, tolerance, test, (, it, ##t, ), and, area, under, the, it, ##t, curve, (, au, ##c, ), of, 9, -, week, -, old, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, w, ##t, ,, ob, /, ob, +, vehicle, :, n, =, 5, ,, ob, /, ob, +, tu, ##dc, ##a, :, n, =, 9, per, group, ), ., j, serum, insulin, levels, of, 10, -, to, 12, -, week, -, old, fed, w, ##t, mice, and, ob, /, ob, mice, treated, neon, ##atal, ##ly, with, vehicle, or, tu, ##dc, ##a, (, n, =, 7, per, group, ), ., error, bars, represent, the, se, ##m, ., *, p, <, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, injected, ob, /, ob, mice, (, a, ,, g, –, i, ), ,, ^, #, p, <, 0, ., 05, ,, ^, #, #, p, ≤, 0, ., 01, ,, ^, #, #, #, p, ≤, 0, ., 001, ,, and, ^, #, #, #, #, p, ≤, 0, ., 000, ##1, versus, w, ##t, mice, (, a, ,, g, –, i, ), ., *, p, <, 0, ., 05, ,, *, *, *, p, ≤, 0, ., 001, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, w, ##t, mice, and, *, p, <, 0, ., 05, ,, *, *, p, ≤, 0, ., 01, ,, and, *, *, *, *, p, ≤, 0, ., 000, ##1, versus, vehicle, -, injected, ob, /, ob, mice, (, b, –, f, ,, j, ), ., statistical, significance, between, groups, was, determined, using, two, -, tailed, student, ’, s, t, test, (, f, ), ,, one, -, way, an, ##ova, (, b, ,, c, ,, e, ,, f, ,, j, ), and, au, ##cs, in, g, –, j, and, two, -, way, an, ##ova, (, a, ,, d, ,, g, –, i, ), followed, by, tu, ##key, ’, s, multiple, comparison, test, ., source, data, are, provided, as, a, source, data, file, .'},\n", - " {'article_id': 'b7bfa0c785ac14cbcc984dd2d223647c',\n", - " 'section_name': 'Protein Delivery to the Cytosol or Nucleus',\n", - " 'text': 'Methods for protein delivery include approaches based on physical membrane disruption and approaches that rely on the endocytotic uptake of cargo with subsequent endosomal release [100]. For the latter class, endosomal entrapment has in the past been found to pose a major block to delivery efficiency [101, 102]. Further delivery methods include approaches that combine physical methods with chemicals, such as the application of graphene quantum dots to cells and laser irradiation [103], or use microorganisms to deliver cargoes [104]. Among the many proposed approaches to the cytosolic delivery of proteins, disruption of the membrane has proven particularly efficient for the delivery of proteins into cells [3, 105, 106]. With an efficiency of up to 90–99%, high cell viability of 80–90% [107, 108] and validation in many cell types over the last 20 years (Table 3), electroporation is a robust approach for delivering antibodies into the cytosol. Further physical methods include microinjection or microfluidic cell squeezing, which are either applicable to lower cell numbers or require special equipment [106]. Delivered antibodies remain functional in the cytosol in spite of the reducing environment. The half-life of antibodies in the cytosol is long and they bind to their targets even 3–4 days after electroporation [3, 105]. This suggests that degradation might be even slower than dilution of the antibody by cell division. Compared with DNA that has integrated into the genome, protein delivery is not permanent but transient and depends on the half-life of the delivered protein. The time-limited activity of a protein drug offers the opportunity for better control over therapy and thus higher safety.Table 3Antibodies or proteins delivered by electroporationDelivered proteinCell typeReferencesAsparagine synthetase antibodyHeLa, HT-5, and L5178Y DlO/R[107]p21^ras antibodyB16BL6 mouse melanoma cells[322]Various antibodiesHuman cells[323]MLCK antibody, constitutively active form of MLCKMacrophages[324]Various antibodies and proteinsPheochromocytoma, other cultured cells[325]p21^ras antibodyB16BL6 mouse melanoma cells[326]Tubulin antibodyCHO cells[327]TK enzymeTK-deficient mammalian cell line[328]Lipoxygenase antibodyLentil protoplasts[329]Vimentin antibody, RNAse AFibroblasts[330]Lipoxygenase antibodyLentil protoplasts[331]Cyclin D1 antibodyMouse embryo and SKUT1B cells[332]TGN38-, p200- and VSV-G antibodiesNRK-6G cells[333]Tropomodulin, antibodies specific to: tropomodulin, talin, vinculin and a-actininFibroblasts[334]Lucifer yellow, IgGSW 3T3, NIH 3T3, dHL60, A7r5, BASM[335]MAP kinase antibodyMDCK cells[336]Anti-M-line protein, titin antibodiesChicken cardiomyocytes[337]Various antibodiesChicken cardiomyocytes[338]Wild-type STAT1, mutated STAT1, STAT1 antibodyRat mesangial cells[339]DNase I, restriction enzymesJurkat cells[340]c-Src antibodyHuman vascular smooth muscle cells[341]TFAR19 antibodyHeLa[342]c-Fos antibodySpinal neuronal cells[37]STIM1 antibodyPlatelets[343]Orai1 antibodyPlatelets[344]EGFPHeLa[345]Orai1 antibodyPlatelets[346]HPV16 E6 oncoprotein, PCNA, RNA polymerase II largest subunitHeLa, CaSki, H1299, MEL501 and U2OS[105]Fc-Cre, tubulin antibody, myosin antibodySC1 REW22, HeLa[3]PCNA, DNA polymerase alphaHeLa, US2-OS[317]Pericentrin, mTOR, IκBα, NLRP3, anti-IKKα antibodiesNIH3T3, HEK293T, human monocyte-derived macrophages[8]RBP1, TBP and TAF10 antibodiesVarious mammalian or Drosophila melanogaster cell types[108]γ H2AX antibodyU2-OS[347]Various recombinant proteinsVarious cell lines[348]BASM bovine aortic smooth muscle, CHO Chinese hamster ovary, c-Src cellular Src, EGFP enhanced green fluorescent protein, H2AX H2A.X variant histone, HPV16 human papillomavirus 16, IKKα IκB kinase α, MAP mitogen-activated protein, MDCK Madin-Darby canine kidney, MLCK myosin light chain kinase, mTOR mammalian target of rapamycin, NLRP3 NLR family pyrin domain containing 3, NRK normal rat kidney, Orai1 ORAI calcium release-activated calcium modulator 1, PCNA proliferating cell nuclear antigen, RBP1 retinol binding protein 1, STAT signal transducer and activator of transcription, STIM1 stromal interaction molecule 1, TAF10 TATA-box binding protein associated factor 10, TBP TATA box binding protein, TFAR19 TF-1 apoptosis-related gene 19, TK thymidine kinase',\n", - " 'paragraph_id': 17,\n", - " 'tokenizer': 'methods, for, protein, delivery, include, approaches, based, on, physical, membrane, disruption, and, approaches, that, rely, on, the, end, ##oc, ##yt, ##otic, up, ##take, of, cargo, with, subsequent, end, ##osomal, release, [, 100, ], ., for, the, latter, class, ,, end, ##osomal, en, ##tra, ##pment, has, in, the, past, been, found, to, pose, a, major, block, to, delivery, efficiency, [, 101, ,, 102, ], ., further, delivery, methods, include, approaches, that, combine, physical, methods, with, chemicals, ,, such, as, the, application, of, graph, ##ene, quantum, dots, to, cells, and, laser, ir, ##rad, ##iation, [, 103, ], ,, or, use, micro, ##org, ##ani, ##sms, to, deliver, cargo, ##es, [, 104, ], ., among, the, many, proposed, approaches, to, the, cy, ##tos, ##olic, delivery, of, proteins, ,, disruption, of, the, membrane, has, proven, particularly, efficient, for, the, delivery, of, proteins, into, cells, [, 3, ,, 105, ,, 106, ], ., with, an, efficiency, of, up, to, 90, –, 99, %, ,, high, cell, via, ##bility, of, 80, –, 90, %, [, 107, ,, 108, ], and, validation, in, many, cell, types, over, the, last, 20, years, (, table, 3, ), ,, electro, ##por, ##ation, is, a, robust, approach, for, delivering, antibodies, into, the, cy, ##tos, ##ol, ., further, physical, methods, include, micro, ##in, ##ject, ##ion, or, micro, ##fl, ##uid, ##ic, cell, squeezing, ,, which, are, either, applicable, to, lower, cell, numbers, or, require, special, equipment, [, 106, ], ., delivered, antibodies, remain, functional, in, the, cy, ##tos, ##ol, in, spite, of, the, reducing, environment, ., the, half, -, life, of, antibodies, in, the, cy, ##tos, ##ol, is, long, and, they, bind, to, their, targets, even, 3, –, 4, days, after, electro, ##por, ##ation, [, 3, ,, 105, ], ., this, suggests, that, degradation, might, be, even, slower, than, dil, ##ution, of, the, antibody, by, cell, division, ., compared, with, dna, that, has, integrated, into, the, genome, ,, protein, delivery, is, not, permanent, but, transient, and, depends, on, the, half, -, life, of, the, delivered, protein, ., the, time, -, limited, activity, of, a, protein, drug, offers, the, opportunity, for, better, control, over, therapy, and, thus, higher, safety, ., table, 3a, ##nti, ##bo, ##dies, or, proteins, delivered, by, electro, ##por, ##ation, ##del, ##iver, ##ed, protein, ##cel, ##l, type, ##re, ##ference, ##sas, ##para, ##gin, ##e, synth, ##eta, ##se, antibody, ##hel, ##a, ,, h, ##t, -, 5, ,, and, l, ##51, ##7, ##8, ##y, dl, ##o, /, r, [, 107, ], p, ##21, ^, ras, antibody, ##b, ##16, ##bl, ##6, mouse, mel, ##ano, ##ma, cells, [, 322, ], various, antibodies, ##hum, ##an, cells, [, 323, ], ml, ##ck, antibody, ,, con, ##sti, ##tu, ##tively, active, form, of, ml, ##ck, ##mac, ##rop, ##ha, ##ges, [, 324, ], various, antibodies, and, proteins, ##ph, ##eo, ##ch, ##rom, ##oc, ##yt, ##oma, ,, other, culture, ##d, cells, [, 325, ], p, ##21, ^, ras, antibody, ##b, ##16, ##bl, ##6, mouse, mel, ##ano, ##ma, cells, [, 326, ], tub, ##ulin, antibody, ##cho, cells, [, 327, ], t, ##k, enzyme, ##t, ##k, -, def, ##icient, mammalian, cell, line, [, 328, ], lip, ##ox, ##y, ##genase, antibody, ##lent, ##il, proto, ##pl, ##ast, ##s, [, 329, ], vi, ##ment, ##in, antibody, ,, rna, ##se, afi, ##bro, ##bla, ##sts, [, 330, ], lip, ##ox, ##y, ##genase, antibody, ##lent, ##il, proto, ##pl, ##ast, ##s, [, 331, ], cy, ##cl, ##in, d, ##1, antibody, ##mous, ##e, embryo, and, sk, ##ut, ##1, ##b, cells, [, 332, ], t, ##gn, ##38, -, ,, p, ##200, -, and, vs, ##v, -, g, antibodies, ##nr, ##k, -, 6, ##g, cells, [, 333, ], tr, ##op, ##omo, ##du, ##lin, ,, antibodies, specific, to, :, tr, ##op, ##omo, ##du, ##lin, ,, tal, ##in, ,, vin, ##cu, ##lin, and, a, -, act, ##ini, ##n, ##fi, ##bro, ##bla, ##sts, [, 334, ], lucifer, yellow, ,, i, ##ggs, ##w, 3, ##t, ##3, ,, ni, ##h, 3, ##t, ##3, ,, dh, ##l, ##60, ,, a, ##7, ##r, ##5, ,, bas, ##m, [, 335, ], map, kinase, antibody, ##md, ##ck, cells, [, 336, ], anti, -, m, -, line, protein, ,, ti, ##tin, antibodies, ##chi, ##cken, card, ##iom, ##yo, ##cytes, [, 337, ], various, antibodies, ##chi, ##cken, card, ##iom, ##yo, ##cytes, [, 338, ], wild, -, type, stat, ##1, ,, mu, ##tated, stat, ##1, ,, stat, ##1, antibody, ##rat, mesa, ##ng, ##ial, cells, [, 339, ], dna, ##se, i, ,, restriction, enzymes, ##ju, ##rka, ##t, cells, [, 340, ], c, -, sr, ##c, antibody, ##hum, ##an, vascular, smooth, muscle, cells, [, 341, ], t, ##far, ##19, antibody, ##hel, ##a, [, 34, ##2, ], c, -, f, ##os, antibody, ##sp, ##inal, ne, ##uron, ##al, cells, [, 37, ], st, ##im, ##1, antibody, ##plate, ##lets, [, 343, ], or, ##ai, ##1, antibody, ##plate, ##lets, [, 344, ], e, ##gf, ##ph, ##ela, [, 345, ], or, ##ai, ##1, antibody, ##plate, ##lets, [, 34, ##6, ], hp, ##v, ##16, e, ##6, on, ##co, ##pro, ##tein, ,, pc, ##na, ,, rna, polymer, ##ase, ii, largest, subunit, ##hel, ##a, ,, cas, ##ki, ,, h, ##12, ##9, ##9, ,, mel, ##50, ##1, and, u2, ##os, [, 105, ], fc, -, cr, ##e, ,, tub, ##ulin, antibody, ,, my, ##osi, ##n, antibody, ##sc, ##1, re, ##w, ##22, ,, he, ##la, [, 3, ], pc, ##na, ,, dna, polymer, ##ase, alpha, ##hel, ##a, ,, us, ##2, -, os, [, 317, ], per, ##ice, ##nt, ##rin, ,, mt, ##or, ,, i, ##κ, ##b, ##α, ,, nl, ##rp, ##3, ,, anti, -, ik, ##k, ##α, antibodies, ##ni, ##h, ##3, ##t, ##3, ,, he, ##k, ##29, ##3, ##t, ,, human, mono, ##cy, ##te, -, derived, macro, ##pha, ##ges, [, 8, ], rb, ##p, ##1, ,, tb, ##p, and, ta, ##f, ##10, antibodies, ##var, ##ious, mammalian, or, dr, ##oso, ##phila, mel, ##ano, ##gas, ##ter, cell, types, [, 108, ], γ, h, ##2, ##ax, antibody, ##u, ##2, -, os, [, 34, ##7, ], various, rec, ##om, ##bina, ##nt, proteins, ##var, ##ious, cell, lines, [, 34, ##8, ], bas, ##m, bo, ##vine, ao, ##rti, ##c, smooth, muscle, ,, cho, chinese, ham, ##ster, o, ##vary, ,, c, -, sr, ##c, cellular, sr, ##c, ,, e, ##gf, ##p, enhanced, green, fluorescent, protein, ,, h, ##2, ##ax, h, ##2, ##a, ., x, variant, his, ##tone, ,, hp, ##v, ##16, human, pa, ##pi, ##llo, ##ma, ##virus, 16, ,, ik, ##k, ##α, i, ##κ, ##b, kinase, α, ,, map, mit, ##ogen, -, activated, protein, ,, md, ##ck, mad, ##in, -, darby, canine, kidney, ,, ml, ##ck, my, ##osi, ##n, light, chain, kinase, ,, mt, ##or, mammalian, target, of, rap, ##amy, ##cin, ,, nl, ##rp, ##3, nl, ##r, family, p, ##yr, ##in, domain, containing, 3, ,, nr, ##k, normal, rat, kidney, ,, or, ##ai, ##1, or, ##ai, calcium, release, -, activated, calcium, mod, ##ulator, 1, ,, pc, ##na, pro, ##life, ##rating, cell, nuclear, antigen, ,, rb, ##p, ##1, re, ##tino, ##l, binding, protein, 1, ,, stat, signal, trans, ##du, ##cer, and, act, ##iva, ##tor, of, transcription, ,, st, ##im, ##1, st, ##rom, ##al, interaction, molecule, 1, ,, ta, ##f, ##10, tata, -, box, binding, protein, associated, factor, 10, ,, tb, ##p, tata, box, binding, protein, ,, t, ##far, ##19, t, ##f, -, 1, ap, ##op, ##tosis, -, related, gene, 19, ,, t, ##k, thy, ##mi, ##dine, kinase'},\n", - " {'article_id': '0f95431b101de7554500eebfc9ad3378',\n", - " 'section_name': 'Results',\n", - " 'text': \"The median age of the 43 patients was 76 years (IQR 70–86; range 51–94), 16 (37%) patients were women and 27 (63%) were men. 40 (93%) had relevant pre-existing chronic medical conditions (mainly cardiorespiratory problems), and 13 (30%) had pre-existing neurological diseases, such as neurodegenerative disease or epilepsy (table\\n). 11 patients (26%) died outside of a hospital (five at home and six in a nursing facility) and 32 (74%) died in a hospital. 12 (28%) patients who died in hospital were treated in intensive care units (ICUs). Cause of death was mainly attributed to the respiratory system, with viral pneumonia as the underlying condition in most cases (table).TableSummary of cases and brain autopsy findingsSexAge, yearsPlace of deathPost-mortem interval, daysCause of deathComorbiditiesBrain weight, gBrain oedemaBrain atrophyArteriosclerosisMacroscopic findingsCase 1Female87Nursing home0PneumoniaCOPD, dementia, IHD, renal insufficiency1215NoneMildModerateNoneCase 2Female85Hospital ward0PneumoniaAtrial fibrillation, cardiac insufficiency, IHD, myelofibrosis, renal insufficiency1240NoneMildModerateFresh infarction in territory of PCACase 3Male88Hospital ward5PneumoniaEmphysema, IHD, renal insufficiency1490ModerateNoneModerateFresh infarction in territory of MCACase 4Male75ICU4Pulmonary arterial embolism, pneumoniaAtrial fibrillation, emphysema, hypertension, renal insufficiency1475MildNoneModerateFresh infarction in territory of PCACase 5Female86Nursing home0PneumoniaCOPD, dementia, IHD1250NoneMildSevereFresh infarction in territory of PCACase 6Male90Nursing home2PneumoniaAtrial fibrillation, dementia, diabetes, history of stroke1015NoneModerateSevereOld infarctions in territory of PCACase 7Male90Hospital ward3Emphysema with respiratory decompensationCardiac insufficiency, COPD1440NoneMildModerateNoneCase 8Male77Hospital ward2PneumoniaAortic aneurysm, atrial flutter, cardiac hypertrophy, emphysema, renal insufficiency1590ModerateNoneModerateNoneCase 9Male76ICU3Pulmonary arterial embolism, respiratory tract infectionCardiac insufficiency, COPD1460MildNoneModerateNoneCase 10Male76ICU3Sepsis, aortic valve endocarditis, pneumoniaAML, cardiomyopathy, thyroid cancer1270NoneMildMildNoneCase 11Male70Hospital ward1Pneumonia (aspiration)Cardiac insufficiency, COPD, IHD, Parkinson's disease1430MildNoneSevereNoneCase 12Male93Hospital ward3PneumoniaDiabetes, hypertension1400MildNoneModerateNoneCase 13Male66Emergency room2PneumoniaDiabetes, IHD1450MildNoneSevereNoneCase 14Female54Hospital ward1PneumoniaTrisomy 21, epilepsy950NoneSevereMildGrey matter heterotopiaCase 15Male82Hospital ward1PneumoniaDiabetes, IHD, Parkinson's disease1170NoneMildModerateOld infarctions in territory of PCACase 16Male86Nursing home2Sepsis, pneumoniaEmphysema, epilepsy, hypoxic brain damage, IHD, renal insufficiency1210NoneMildModerateNoneCase 17Female87Home1PneumoniaCardiac insufficiency, COPD1180NoneMildSevereNoneCase 18Female70ICU3PneumoniaCardiac insufficiency1150NoneMildModerateNoneCase 19Female75ICU4PneumoniaCardiac arrythmia, IHD1210NoneMildSevereNoneCase 20Male93Hospital ward2PneumoniaAtrial fibrillation, cardiac insufficiency, diabetes, IHD, obstructive sleep apnoea syndrome1000NoneModerateModerateOld cerebellar infarctionCase 21Female82Hospital ward4Purulent bronchitisCOPD, history of pulmonary embolism, renal insufficiency1080NoneModerateModerateNoneCase 22Male63ICU1Pulmonary arterial embolism, pneumoniaCardiac insufficiency1435MildNoneMildFresh infarction in territory of ACACase 23Male84Hospital ward5Pneumonia, septic encephalopathyDiabetes, history of stroke, hypertension, IHD, ulcerative colitis1350MildNoneSevereNoneCase 24Male71ICU2Pulmonary arterial embolism, pneumoniaCardiac insufficiency, diabetes, lung granuloma1665ModerateNoneMildNoneCase 25Male75Nursing home3Sudden cardiac deathParkinson's disease1110MildNoneModerateNoneCase 26Male52Home1Pulmonary arterial embolism, pneumoniaCardiac insufficiency1520ModerateNoneSevereNoneCase 27Male85ICU2PneumoniaCOPD, aortic valve replacement, hypertension, IHD1400MildNoneModerateNoneCase 28Female75Home2Pulmonary arterial embolismHypertension, IHD1095NoneModerateModerateNoneCase 29Male59Hospital ward12PneumoniaCardiomyopathy1575ModerateNoneMildNoneCase 30Male85Hospital ward15PneumoniaAtrial fibrillation, COPD, hypothyroidism, lung cancer, renal insufficiency1540ModerateNoneModerateCerebellar metastasis of non-small cell lung cancerCase 31Female76Hospital ward2PneumoniaBreast cancer, hypertension1180NoneMildModerateNoneCase 32Male73Home9Sudden cardiac deathCardiomyopathy, emphysema, IHD1430MildNoneSevereNoneCase 33Male70ICU9PneumoniaDementia, IHD, hypertension1370NoneNoneModerateNoneCase 34Female90Nursing home3PneumoniaCardiomyopathy, dementia, emphysema, renal insufficiency1090NoneSevereModerateNoneCase 35Female94Hospital ward2SepsisAtrial fibrillation, cardiac insufficiency, dementia, history of stroke, IHD, renal insufficiency1220MildMildModerateOld infarction in territory of PCACase 36Female87Hospital ward3Sepsis, pneumoniaColon cancer, emphysema, paranoid schizophrenia1310NoneNoneMildNoneCase 37Female54ICU1PneumoniaMild cardiomyopathy1470MildNoneMildNoneCase 38Female79Hospital ward5PneumoniaCOPD, myelodysplastic syndrome, IHD1290NoneMildMildNoneCase 39Male51Home8PneumoniaLiver cirrhosis1255MildMildMildNoneCase 40Male85Hospital ward3PneumoniaAtrial fibrillation, cardiac insufficiency, dysphagia, emphysema, hypertension, IHD1290MildNoneModerateNoneCase 41Male56Hospital ward3PneumoniaCardiac insufficiency, COPD, diabetes, IHD, renal insufficiency1230MildNoneMildOld infarctions in territory of PCA and lenticulostriate arteriesCase 42Male76ICU3Aortic valve endocarditis, pneumoniaAML, cardiomyopathy, thyroid cancer1270MildNoneMildNoneCase 43Female59ICU1PneumoniaMultiple myeloma1220MildNoneMildFresh infarction in territory of MCACOPD=chronic obstructive pulmonary disease. IHD=ischaemic heart disease. PCA=posterior cerebral artery. MCA=middle cerebral artery. ICU=intensive care unit. AML=acute myeloid leukaemia. ACA=anterior cerebral artery.\",\n", - " 'paragraph_id': 18,\n", - " 'tokenizer': \"the, median, age, of, the, 43, patients, was, 76, years, (, iq, ##r, 70, –, 86, ;, range, 51, –, 94, ), ,, 16, (, 37, %, ), patients, were, women, and, 27, (, 63, %, ), were, men, ., 40, (, 93, %, ), had, relevant, pre, -, existing, chronic, medical, conditions, (, mainly, card, ##ior, ##es, ##pi, ##rator, ##y, problems, ), ,, and, 13, (, 30, %, ), had, pre, -, existing, neurological, diseases, ,, such, as, ne, ##uro, ##de, ##gen, ##erative, disease, or, ep, ##ile, ##psy, (, table, ), ., 11, patients, (, 26, %, ), died, outside, of, a, hospital, (, five, at, home, and, six, in, a, nursing, facility, ), and, 32, (, 74, %, ), died, in, a, hospital, ., 12, (, 28, %, ), patients, who, died, in, hospital, were, treated, in, intensive, care, units, (, ic, ##us, ), ., cause, of, death, was, mainly, attributed, to, the, respiratory, system, ,, with, viral, pneumonia, as, the, underlying, condition, in, most, cases, (, table, ), ., tables, ##um, ##mar, ##y, of, cases, and, brain, autopsy, findings, ##se, ##xa, ##ge, ,, years, ##pl, ##ace, of, death, ##post, -, mort, ##em, interval, ,, days, ##ca, ##use, of, death, ##com, ##or, ##bid, ##ities, ##bra, ##in, weight, ,, gb, ##rain, o, ##ede, ##ma, ##bra, ##in, at, ##rop, ##hya, ##rter, ##ios, ##cle, ##rosis, ##mac, ##ros, ##copic, findings, ##case, 1, ##fe, ##mal, ##e, ##8, ##7, ##nu, ##rs, ##ing, home, ##0, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, dementia, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##15, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 2, ##fe, ##mal, ##e, ##85, ##hos, ##pit, ##al, ward, ##0, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, i, ##hd, ,, my, ##elo, ##fi, ##bro, ##sis, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##40, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##fr, ##esh, in, ##far, ##ction, in, territory, of, pc, ##aca, ##se, 3, ##mal, ##e, ##8, ##8, ##hos, ##pit, ##al, ward, ##5, ##p, ##ne, ##um, ##onia, ##em, ##phy, ##se, ##ma, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##14, ##90, ##mo, ##der, ##ate, ##non, ##em, ##oder, ##ate, ##fr, ##esh, in, ##far, ##ction, in, territory, of, mca, ##case, 4, ##mal, ##e, ##75, ##ic, ##u, ##4, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, pneumonia, ##at, ##rial, fi, ##bri, ##llation, ,, em, ##phy, ##se, ##ma, ,, hyper, ##tension, ,, renal, ins, ##uf, ##fi, ##ciency, ##14, ##75, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##fr, ##esh, in, ##far, ##ction, in, territory, of, pc, ##aca, ##se, 5, ##fe, ##mal, ##e, ##86, ##nu, ##rs, ##ing, home, ##0, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, dementia, ,, i, ##hd, ##12, ##50, ##non, ##emi, ##ld, ##se, ##vere, ##fr, ##esh, in, ##far, ##ction, in, territory, of, pc, ##aca, ##se, 6, ##mal, ##e, ##90, ##nu, ##rs, ##ing, home, ##2, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, dementia, ,, diabetes, ,, history, of, stroke, ##10, ##15, ##non, ##em, ##oder, ##ates, ##ever, ##eo, ##ld, in, ##far, ##ctions, in, territory, of, pc, ##aca, ##se, 7, ##mal, ##e, ##90, ##hos, ##pit, ##al, ward, ##3, ##em, ##phy, ##se, ##ma, with, respiratory, deco, ##mp, ##ens, ##ation, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ##14, ##40, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 8, ##mal, ##e, ##7, ##7, ##hos, ##pit, ##al, ward, ##2, ##p, ##ne, ##um, ##onia, ##ao, ##rti, ##c, an, ##eur, ##ys, ##m, ,, at, ##rial, flutter, ,, cardiac, hyper, ##tro, ##phy, ,, em, ##phy, ##se, ##ma, ,, renal, ins, ##uf, ##fi, ##ciency, ##15, ##90, ##mo, ##der, ##ate, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 9, ##mal, ##e, ##7, ##6, ##ic, ##u, ##3, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, respiratory, tract, infection, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ##14, ##60, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 10, ##mal, ##e, ##7, ##6, ##ic, ##u, ##3, ##se, ##psis, ,, ao, ##rti, ##c, valve, end, ##oca, ##rdi, ##tis, ,, pneumonia, ##am, ##l, ,, card, ##iom, ##yo, ##pathy, ,, thyroid, cancer, ##12, ##70, ##non, ##emi, ##ld, ##mi, ##ld, ##non, ##eca, ##se, 11, ##mal, ##e, ##70, ##hos, ##pit, ##al, ward, ##1, ##p, ##ne, ##um, ##onia, (, as, ##piration, ), cardiac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ,, i, ##hd, ,, parkinson, ', s, disease, ##14, ##30, ##mi, ##ld, ##non, ##ese, ##vere, ##non, ##eca, ##se, 12, ##mal, ##e, ##9, ##3, ##hos, ##pit, ##al, ward, ##3, ##p, ##ne, ##um, ##onia, ##dia, ##bet, ##es, ,, hyper, ##tension, ##14, ##00, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 13, ##mal, ##e, ##66, ##eme, ##rgen, ##cy, room, ##2, ##p, ##ne, ##um, ##onia, ##dia, ##bet, ##es, ,, i, ##hd, ##14, ##50, ##mi, ##ld, ##non, ##ese, ##vere, ##non, ##eca, ##se, 14, ##fe, ##mal, ##e, ##54, ##hos, ##pit, ##al, ward, ##1, ##p, ##ne, ##um, ##onia, ##tri, ##som, ##y, 21, ,, ep, ##ile, ##psy, ##9, ##50, ##non, ##ese, ##vere, ##mi, ##ld, ##gre, ##y, matter, het, ##ero, ##top, ##iac, ##ase, 15, ##mal, ##e, ##8, ##2, ##hos, ##pit, ##al, ward, ##1, ##p, ##ne, ##um, ##onia, ##dia, ##bet, ##es, ,, i, ##hd, ,, parkinson, ', s, disease, ##11, ##70, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##old, in, ##far, ##ctions, in, territory, of, pc, ##aca, ##se, 16, ##mal, ##e, ##86, ##nu, ##rs, ##ing, home, ##2, ##se, ##psis, ,, pneumonia, ##em, ##phy, ##se, ##ma, ,, ep, ##ile, ##psy, ,, h, ##yp, ##ox, ##ic, brain, damage, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##10, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 17, ##fe, ##mal, ##e, ##8, ##7, ##hom, ##e, ##1, ##p, ##ne, ##um, ##onia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ##11, ##80, ##non, ##emi, ##ld, ##se, ##vere, ##non, ##eca, ##se, 18, ##fe, ##mal, ##e, ##70, ##ic, ##u, ##3, ##p, ##ne, ##um, ##onia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ##11, ##50, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 19, ##fe, ##mal, ##e, ##75, ##ic, ##u, ##4, ##p, ##ne, ##um, ##onia, ##card, ##iac, ar, ##ry, ##th, ##mia, ,, i, ##hd, ##12, ##10, ##non, ##emi, ##ld, ##se, ##vere, ##non, ##eca, ##se, 20, ##mal, ##e, ##9, ##3, ##hos, ##pit, ##al, ward, ##2, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, diabetes, ,, i, ##hd, ,, ob, ##st, ##ru, ##ctive, sleep, ap, ##no, ##ea, syndrome, ##100, ##0, ##non, ##em, ##oder, ##ate, ##mo, ##der, ##ate, ##old, ce, ##re, ##bella, ##r, in, ##far, ##ction, ##case, 21, ##fe, ##mal, ##e, ##8, ##2, ##hos, ##pit, ##al, ward, ##4, ##pur, ##ulent, bro, ##nch, ##itis, ##co, ##pd, ,, history, of, pulmonary, em, ##bol, ##ism, ,, renal, ins, ##uf, ##fi, ##ciency, ##10, ##80, ##non, ##em, ##oder, ##ate, ##mo, ##der, ##ate, ##non, ##eca, ##se, 22, ##mal, ##e, ##6, ##3, ##ic, ##u, ##1, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, pneumonia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ##14, ##35, ##mi, ##ld, ##non, ##emi, ##ld, ##fr, ##esh, in, ##far, ##ction, in, territory, of, ac, ##aca, ##se, 23, ##mal, ##e, ##8, ##4, ##hos, ##pit, ##al, ward, ##5, ##p, ##ne, ##um, ##onia, ,, sept, ##ic, en, ##ce, ##pha, ##lo, ##pathy, ##dia, ##bet, ##es, ,, history, of, stroke, ,, hyper, ##tension, ,, i, ##hd, ,, ul, ##cera, ##tive, coli, ##tis, ##13, ##50, ##mi, ##ld, ##non, ##ese, ##vere, ##non, ##eca, ##se, 24, ##mal, ##e, ##7, ##1, ##ic, ##u, ##2, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, pneumonia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, diabetes, ,, lung, gran, ##ulo, ##ma, ##16, ##65, ##mo, ##der, ##ate, ##non, ##emi, ##ld, ##non, ##eca, ##se, 25, ##mal, ##e, ##75, ##nu, ##rs, ##ing, home, ##3, ##su, ##dden, cardiac, death, ##park, ##ins, ##on, ', s, disease, ##11, ##10, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 26, ##mal, ##e, ##52, ##hom, ##e, ##1, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ,, pneumonia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ##15, ##20, ##mo, ##der, ##ate, ##non, ##ese, ##vere, ##non, ##eca, ##se, 27, ##mal, ##e, ##85, ##ic, ##u, ##2, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, ao, ##rti, ##c, valve, replacement, ,, hyper, ##tension, ,, i, ##hd, ##14, ##00, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 28, ##fe, ##mal, ##e, ##75, ##hom, ##e, ##2, ##pu, ##lm, ##ona, ##ry, arterial, em, ##bol, ##ism, ##hy, ##per, ##tension, ,, i, ##hd, ##10, ##9, ##5, ##non, ##em, ##oder, ##ate, ##mo, ##der, ##ate, ##non, ##eca, ##se, 29, ##mal, ##e, ##59, ##hos, ##pit, ##al, ward, ##12, ##p, ##ne, ##um, ##onia, ##card, ##iom, ##yo, ##pathy, ##15, ##75, ##mo, ##der, ##ate, ##non, ##emi, ##ld, ##non, ##eca, ##se, 30, ##mal, ##e, ##85, ##hos, ##pit, ##al, ward, ##15, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cop, ##d, ,, h, ##yp, ##oth, ##yr, ##oid, ##ism, ,, lung, cancer, ,, renal, ins, ##uf, ##fi, ##ciency, ##15, ##40, ##mo, ##der, ##ate, ##non, ##em, ##oder, ##ate, ##cer, ##eb, ##ella, ##r, meta, ##sta, ##sis, of, non, -, small, cell, lung, cancer, ##case, 31, ##fe, ##mal, ##e, ##7, ##6, ##hos, ##pit, ##al, ward, ##2, ##p, ##ne, ##um, ##onia, ##bre, ##ast, cancer, ,, hyper, ##tension, ##11, ##80, ##non, ##emi, ##ld, ##mo, ##der, ##ate, ##non, ##eca, ##se, 32, ##mal, ##e, ##7, ##3, ##hom, ##e, ##9, ##su, ##dden, cardiac, death, ##card, ##iom, ##yo, ##pathy, ,, em, ##phy, ##se, ##ma, ,, i, ##hd, ##14, ##30, ##mi, ##ld, ##non, ##ese, ##vere, ##non, ##eca, ##se, 33, ##mal, ##e, ##70, ##ic, ##u, ##9, ##p, ##ne, ##um, ##onia, ##de, ##ment, ##ia, ,, i, ##hd, ,, hyper, ##tension, ##13, ##70, ##non, ##eno, ##nem, ##oder, ##ate, ##non, ##eca, ##se, 34, ##fe, ##mal, ##e, ##90, ##nu, ##rs, ##ing, home, ##3, ##p, ##ne, ##um, ##onia, ##card, ##iom, ##yo, ##pathy, ,, dementia, ,, em, ##phy, ##se, ##ma, ,, renal, ins, ##uf, ##fi, ##ciency, ##10, ##90, ##non, ##ese, ##vere, ##mo, ##der, ##ate, ##non, ##eca, ##se, 35, ##fe, ##mal, ##e, ##9, ##4, ##hos, ##pit, ##al, ward, ##2, ##se, ##psis, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, dementia, ,, history, of, stroke, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##20, ##mi, ##ld, ##mi, ##ld, ##mo, ##der, ##ate, ##old, in, ##far, ##ction, in, territory, of, pc, ##aca, ##se, 36, ##fe, ##mal, ##e, ##8, ##7, ##hos, ##pit, ##al, ward, ##3, ##se, ##psis, ,, pneumonia, ##col, ##on, cancer, ,, em, ##phy, ##se, ##ma, ,, paranoid, schizophrenia, ##13, ##10, ##non, ##eno, ##nem, ##il, ##d, ##non, ##eca, ##se, 37, ##fe, ##mal, ##e, ##54, ##ic, ##u, ##1, ##p, ##ne, ##um, ##onia, ##mi, ##ld, card, ##iom, ##yo, ##pathy, ##14, ##70, ##mi, ##ld, ##non, ##emi, ##ld, ##non, ##eca, ##se, 38, ##fe, ##mal, ##e, ##7, ##9, ##hos, ##pit, ##al, ward, ##5, ##p, ##ne, ##um, ##onia, ##co, ##pd, ,, my, ##elo, ##dy, ##sp, ##lastic, syndrome, ,, i, ##hd, ##12, ##90, ##non, ##emi, ##ld, ##mi, ##ld, ##non, ##eca, ##se, 39, ##mal, ##e, ##51, ##hom, ##e, ##8, ##p, ##ne, ##um, ##onia, ##li, ##ver, ci, ##rr, ##hosis, ##12, ##55, ##mi, ##ld, ##mi, ##ld, ##mi, ##ld, ##non, ##eca, ##se, 40, ##mal, ##e, ##85, ##hos, ##pit, ##al, ward, ##3, ##p, ##ne, ##um, ##onia, ##at, ##rial, fi, ##bri, ##llation, ,, cardiac, ins, ##uf, ##fi, ##ciency, ,, d, ##ys, ##pha, ##gia, ,, em, ##phy, ##se, ##ma, ,, hyper, ##tension, ,, i, ##hd, ##12, ##90, ##mi, ##ld, ##non, ##em, ##oder, ##ate, ##non, ##eca, ##se, 41, ##mal, ##e, ##56, ##hos, ##pit, ##al, ward, ##3, ##p, ##ne, ##um, ##onia, ##card, ##iac, ins, ##uf, ##fi, ##ciency, ,, cop, ##d, ,, diabetes, ,, i, ##hd, ,, renal, ins, ##uf, ##fi, ##ciency, ##12, ##30, ##mi, ##ld, ##non, ##emi, ##ld, ##old, in, ##far, ##ctions, in, territory, of, pc, ##a, and, lent, ##ic, ##ulo, ##st, ##ria, ##te, arteries, ##case, 42, ##mal, ##e, ##7, ##6, ##ic, ##u, ##3, ##ao, ##rti, ##c, valve, end, ##oca, ##rdi, ##tis, ,, pneumonia, ##am, ##l, ,, card, ##iom, ##yo, ##pathy, ,, thyroid, cancer, ##12, ##70, ##mi, ##ld, ##non, ##emi, ##ld, ##non, ##eca, ##se, 43, ##fe, ##mal, ##e, ##59, ##ic, ##u, ##1, ##p, ##ne, ##um, ##onia, ##mu, ##lt, ##ip, ##le, my, ##elo, ##ma, ##12, ##20, ##mi, ##ld, ##non, ##emi, ##ld, ##fr, ##esh, in, ##far, ##ction, in, territory, of, mca, ##co, ##pd, =, chronic, ob, ##st, ##ru, ##ctive, pulmonary, disease, ., i, ##hd, =, is, ##cha, ##emi, ##c, heart, disease, ., pc, ##a, =, posterior, cerebral, artery, ., mca, =, middle, cerebral, artery, ., ic, ##u, =, intensive, care, unit, ., am, ##l, =, acute, my, ##elo, ##id, le, ##uka, ##emia, ., ac, ##a, =, anterior, cerebral, artery, .\"}]" - ] - }, - "execution_count": 48, - "metadata": {}, - "output_type": "execute_result" - }, - { - "name": "stderr", - "output_type": "stream", - "text": [ - "Scanning paragraphs: 16199 Docs [00:16, 2773.05 Docs/s]" - ] - } - ], - "source": [ - "paragraphs" - ] - } - ], - "metadata": { - "kernelspec": { - "display_name": "Python 3.10.5 ('py10')", - "language": "python", - "name": "python3" - }, - "language_info": { - "codemirror_mode": { - "name": "ipython", - "version": 3 - }, - "file_extension": ".py", - "mimetype": "text/x-python", - "name": "python", - "nbconvert_exporter": "python", - "pygments_lexer": "ipython3", - "version": "3.10.5" - }, - "orig_nbformat": 4, - "vscode": { - "interpreter": { - "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" - } - } - }, - "nbformat": 4, - "nbformat_minor": 2 -} diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb deleted file mode 100644 index 6fe65fc12..000000000 --- a/src/bluesearch/k8s/create_indices.ipynb +++ /dev/null @@ -1,283 +0,0 @@ -{ - "cells": [ - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# Connect to ES" - ] - }, - { - "cell_type": "code", - "execution_count": 1, - "metadata": {}, - "outputs": [], - "source": [ - "import elasticsearch\n", - "from elasticsearch import Elasticsearch\n", - "from decouple import config" - ] - }, - { - "cell_type": "code", - "execution_count": 2, - "metadata": {}, - "outputs": [], - "source": [ - "import urllib3\n", - "urllib3.disable_warnings()" - ] - }, - { - "cell_type": "code", - "execution_count": 3, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "(8, 3, 3)" - ] - }, - "execution_count": 3, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "elasticsearch.__version__" - ] - }, - { - "cell_type": "code", - "execution_count": 4, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/elasticsearch/_sync/client/__init__.py:395: SecurityWarning: Connecting to 'https://ml-elasticsearch.kcp.bbp.epfl.ch:443' using TLS with verify_certs=False is insecure\n", - " _transport = transport_class(\n" - ] - } - ], - "source": [ - "client = Elasticsearch(\n", - " \"https://ml-elasticsearch.kcp.bbp.epfl.ch:443\",\n", - " basic_auth=(\"elastic\", config('ES_PASS')),\n", - " verify_certs=False,\n", - ")" - ] - }, - { - "cell_type": "code", - "execution_count": 5, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "ObjectApiResponse({'name': 'elasticsearch-coordinating-0', 'cluster_name': 'elastic', 'cluster_uuid': 'dv5oiXnCRJiB8nhV7a81RA', 'version': {'number': '8.3.3', 'build_flavor': 'default', 'build_type': 'tar', 'build_hash': '801fed82df74dbe537f89b71b098ccaff88d2c56', 'build_date': '2022-07-23T19:30:09.227964828Z', 'build_snapshot': False, 'lucene_version': '9.2.0', 'minimum_wire_compatibility_version': '7.17.0', 'minimum_index_compatibility_version': '7.0.0'}, 'tagline': 'You Know, for Search'})" - ] - }, - "execution_count": 5, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "client.info()" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# Create indices" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## mapping articles" - ] - }, - { - "cell_type": "code", - "execution_count": 10, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/tmp/ipykernel_1937749/4048237628.py:1: DeprecationWarning: The 'body' parameter is deprecated and will be removed in a future version. Instead use individual parameters.\n", - " client.indices.create(\n", - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, - { - "data": { - "text/plain": [ - "ObjectApiResponse({'acknowledged': True, 'shards_acknowledged': True, 'index': 'articles'})" - ] - }, - "execution_count": 10, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "client.indices.create(\n", - " index=\"articles\",\n", - " body={\n", - " \"settings\": {\"number_of_shards\": 2,\n", - " \"number_of_replicas\": 1},\n", - " \"mappings\": {\n", - " \"dynamic\": \"strict\",\n", - " \"properties\": {\n", - " \"article_id\": {\"type\": \"keyword\"},\n", - " \"doi\": {\"type\": \"keyword\"},\n", - " \"pmc_id\": {\"type\": \"keyword\"},\n", - " \"pubmed_id\": {\"type\": \"keyword\"},\n", - " \"arxiv_id\": {\"type\": \"keyword\"},\n", - " \"title\": {\"type\": \"text\"},\n", - " \"authors\": {\"type\": \"text\"},\n", - " \"abstract\": {\"type\": \"text\"},\n", - " \"journal\": {\"type\": \"keyword\"},\n", - " \"publish_time\": {\"type\": \"date\", \"format\": \"yyyy-MM-dd\"},\n", - " \"license\": {\"type\": \"keyword\"},\n", - " \"is_english\": {\"type\": \"boolean\"},\n", - " }\n", - " },\n", - " }\n", - ")" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## mapping paragraphs" - ] - }, - { - "cell_type": "code", - "execution_count": 11, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/tmp/ipykernel_1937749/3760375478.py:1: DeprecationWarning: The 'body' parameter is deprecated and will be removed in a future version. Instead use individual parameters.\n", - " client.indices.create(\n", - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, - { - "data": { - "text/plain": [ - "ObjectApiResponse({'acknowledged': True, 'shards_acknowledged': True, 'index': 'paragraphs'})" - ] - }, - "execution_count": 11, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "client.indices.create(\n", - " index=\"paragraphs\",\n", - " body={\n", - " \"settings\": {\"number_of_shards\": 2,\n", - " \"number_of_replicas\": 1},\n", - " \"mappings\": {\n", - " \"dynamic\": \"strict\",\n", - " \"properties\": {\n", - " \"article_id\": {\"type\": \"keyword\"},\n", - " \"section_name\": {\"type\": \"keyword\"},\n", - " \"paragraph_id\": {\"type\": \"short\"},\n", - " \"text\": {\"type\": \"text\"},\n", - " \"is_bad\": {\"type\": \"boolean\"},\n", - " \"embedding\": {\n", - " \"type\": \"dense_vector\",\n", - " \"dims\": 384,\n", - " \"index\": True,\n", - " \"similarity\": \"dot_product\"\n", - " }\n", - " }\n", - " },\n", - " }\n", - ")" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## check indices" - ] - }, - { - "cell_type": "code", - "execution_count": 12, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, - { - "data": { - "text/plain": [ - "['articles', 'arxiv_dense', 'paragraphs']" - ] - }, - "execution_count": 12, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "indices = client.indices.get_alias().keys()\n", - "sorted(indices)" - ] - } - ], - "metadata": { - "kernelspec": { - "display_name": "Python 3.10.5 ('py10')", - "language": "python", - "name": "python3" - }, - "language_info": { - "codemirror_mode": { - "name": "ipython", - "version": 3 - }, - "file_extension": ".py", - "mimetype": "text/x-python", - "name": "python", - "nbconvert_exporter": "python", - "pygments_lexer": "ipython3", - "version": "3.10.5" - }, - "orig_nbformat": 4, - "vscode": { - "interpreter": { - "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" - } - } - }, - "nbformat": 4, - "nbformat_minor": 2 -} diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embedings.py index 8984dc178..66f098689 100644 --- a/src/bluesearch/k8s/embedings.py +++ b/src/bluesearch/k8s/embedings.py @@ -1,3 +1,5 @@ +from __future__ import annotations + import logging import elasticsearch @@ -19,10 +21,8 @@ def embed_locally( model = SentTransformer(model_name) # get paragraphs without embeddings - query = {"query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}}} - paragraph_count = client.count(index="paragraphs", body=query)[ # type: ignore - "count" - ] + query = {"bool": {"must_not": {"exists": {"field": "embedding"}}}} + paragraph_count = client.count(index="paragraphs", query=query)["count"] logger.info("There are {paragraph_count} paragraphs without embeddings") # creates embeddings for all the documents withouts embeddings and updates them From bf93692d9521492dd8158e3264c5e81dd7296d50 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 20 Sep 2022 16:56:23 +0200 Subject: [PATCH 17/99] adjustments after PR review --- tox.ini | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/tox.ini b/tox.ini index c98861396..7870fea80 100644 --- a/tox.ini +++ b/tox.ini @@ -176,7 +176,7 @@ source = bluesearch branch = True [coverage:report] -#fail_under = 80 +fail_under = 80 skip_covered = False show_missing = False From c5d146d8cbe7d882493d396c638b9736b6a35f6a Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 20 Sep 2022 17:10:46 +0200 Subject: [PATCH 18/99] changes after PR review --- .gitignore | 8 +- src/bluesearch/database/article.py | 12 +- src/bluesearch/k8s/create_indices.ipynb | 293 ------------------------ tox.ini | 2 +- 4 files changed, 8 insertions(+), 307 deletions(-) delete mode 100644 src/bluesearch/k8s/create_indices.ipynb diff --git a/.gitignore b/.gitignore index e2a6e5b12..79b339240 100644 --- a/.gitignore +++ b/.gitignore @@ -151,9 +151,6 @@ venv.bak/ # mkdocs documentation /site -# trunk -.trunk - # mypy .mypy_cache/ .dmypy.json @@ -170,7 +167,4 @@ cython_debug/ # static files generated from Django application using `collectstatic` media -static - -#IDE -launch.json \ No newline at end of file +static \ No newline at end of file diff --git a/src/bluesearch/database/article.py b/src/bluesearch/database/article.py index 78e1f0ba8..b5c47ba1b 100644 --- a/src/bluesearch/database/article.py +++ b/src/bluesearch/database/article.py @@ -28,7 +28,7 @@ from dataclasses import dataclass from io import StringIO from pathlib import Path -from typing import IO, Generator, Iterable, Optional, Sequence, Tuple, Any +from typing import IO, Generator, Iterable, Sequence, Tuple, Any from xml.etree.ElementTree import Element # nosec from zipfile import ZipFile @@ -1066,11 +1066,11 @@ class Article(DataClassJSONMixin): authors: Sequence[str] abstract: Sequence[str] section_paragraphs: Sequence[Tuple[str, str]] - pubmed_id: Optional[str] = None - pmc_id: Optional[str] = None - arxiv_id: Optional[str] = None - doi: Optional[str] = None - uid: Optional[str] = None + pubmed_id: str | None = None + pmc_id: str | None = None + arxiv_id: str | None = None + doi: str | None = None + uid: str | None = None @classmethod def parse(cls, parser: ArticleParser) -> Article: diff --git a/src/bluesearch/k8s/create_indices.ipynb b/src/bluesearch/k8s/create_indices.ipynb deleted file mode 100644 index f0624f640..000000000 --- a/src/bluesearch/k8s/create_indices.ipynb +++ /dev/null @@ -1,293 +0,0 @@ -{ - "cells": [ - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# Connect to ES" - ] - }, - { - "cell_type": "code", - "execution_count": 1, - "metadata": {}, - "outputs": [], - "source": [ - "import elasticsearch\n", - "from elasticsearch import Elasticsearch\n", - "from decouple import config" - ] - }, - { - "cell_type": "code", - "execution_count": 2, - "metadata": {}, - "outputs": [], - "source": [ - "import urllib3\n", - "urllib3.disable_warnings()" - ] - }, - { - "cell_type": "code", - "execution_count": 3, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "(8, 3, 3)" - ] - }, - "execution_count": 3, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "elasticsearch.__version__" - ] - }, - { - "cell_type": "code", - "execution_count": 4, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/elasticsearch/_sync/client/__init__.py:395: SecurityWarning: Connecting to 'https://ml-elasticsearch.kcp.bbp.epfl.ch:443' using TLS with verify_certs=False is insecure\n", - " _transport = transport_class(\n" - ] - } - ], - "source": [ - "client = Elasticsearch(\n", - " \"https://ml-elasticsearch.kcp.bbp.epfl.ch:443\",\n", - " basic_auth=(\"elastic\", config('ES_PASS')),\n", - " verify_certs=False,\n", - ")" - ] - }, - { - "cell_type": "code", - "execution_count": 5, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "ObjectApiResponse({'name': 'elasticsearch-coordinating-1', 'cluster_name': 'elastic', 'cluster_uuid': 'dv5oiXnCRJiB8nhV7a81RA', 'version': {'number': '8.3.3', 'build_flavor': 'default', 'build_type': 'tar', 'build_hash': '801fed82df74dbe537f89b71b098ccaff88d2c56', 'build_date': '2022-07-23T19:30:09.227964828Z', 'build_snapshot': False, 'lucene_version': '9.2.0', 'minimum_wire_compatibility_version': '7.17.0', 'minimum_index_compatibility_version': '7.0.0'}, 'tagline': 'You Know, for Search'})" - ] - }, - "execution_count": 5, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "client.info()" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "# Create indices" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## mapping articles" - ] - }, - { - "cell_type": "code", - "execution_count": 10, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/tmp/ipykernel_1937749/4048237628.py:1: DeprecationWarning: The 'body' parameter is deprecated and will be removed in a future version. Instead use individual parameters.\n", - " client.indices.create(\n", - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, - { - "data": { - "text/plain": [ - "ObjectApiResponse({'acknowledged': True, 'shards_acknowledged': True, 'index': 'articles'})" - ] - }, - "execution_count": 10, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "client.indices.create(\n", - " index=\"articles\",\n", - " body={\n", - " \"settings\": {\"number_of_shards\": 2,\n", - " \"number_of_replicas\": 1},\n", - " \"mappings\": {\n", - " \"dynamic\": \"strict\",\n", - " \"properties\": {\n", - " \"article_id\": {\"type\": \"keyword\"},\n", - " \"doi\": {\"type\": \"keyword\"},\n", - " \"pmc_id\": {\"type\": \"keyword\"},\n", - " \"pubmed_id\": {\"type\": \"keyword\"},\n", - " \"title\": {\"type\": \"text\"},\n", - " \"authors\": {\"type\": \"text\"},\n", - " \"abstract\": {\"type\": \"text\"},\n", - " \"journal\": {\"type\": \"keyword\"},\n", - " \"publish_time\": {\"type\": \"date\", \"format\": \"yyyy-MM-dd\"},\n", - " \"license\": {\"type\": \"keyword\"},\n", - " \"is_english\": {\"type\": \"boolean\"},\n", - " }\n", - " },\n", - " }\n", - ")" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## mapping paragraphs" - ] - }, - { - "cell_type": "code", - "execution_count": 11, - "metadata": {}, - "outputs": [ - { - "name": "stderr", - "output_type": "stream", - "text": [ - "/tmp/ipykernel_1937749/3760375478.py:1: DeprecationWarning: The 'body' parameter is deprecated and will be removed in a future version. Instead use individual parameters.\n", - " client.indices.create(\n", - "/home/reissant/miniforge3/envs/py10/lib/python3.10/site-packages/urllib3/connectionpool.py:1013: InsecureRequestWarning: Unverified HTTPS request is being made to host 'ml-elasticsearch.kcp.bbp.epfl.ch'. Adding certificate verification is strongly advised. See: https://urllib3.readthedocs.io/en/latest/advanced-usage.html#ssl-warnings\n", - " warnings.warn(\n" - ] - }, - { - "data": { - "text/plain": [ - "ObjectApiResponse({'acknowledged': True, 'shards_acknowledged': True, 'index': 'paragraphs'})" - ] - }, - "execution_count": 11, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "client.indices.create(\n", - " index=\"paragraphs\",\n", - " body={\n", - " \"settings\": {\"number_of_shards\": 2,\n", - " \"number_of_replicas\": 1},\n", - " \"mappings\": {\n", - " \"dynamic\": \"strict\",\n", - " \"properties\": {\n", - " \"article_id\": {\"type\": \"keyword\"},\n", - " \"section_name\": {\"type\": \"keyword\"},\n", - " \"paragraph_id\": {\"type\": \"short\"},\n", - " \"text\": {\"type\": \"text\"},\n", - " \"is_bad\": {\"type\": \"boolean\"},\n", - " \"embedding\": {\n", - " \"type\": \"dense_vector\",\n", - " \"dims\": 384,\n", - " \"index\": True,\n", - " \"similarity\": \"dot_product\"\n", - " }\n", - " }\n", - " },\n", - " }\n", - ")" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## check indices" - ] - }, - { - "cell_type": "code", - "execution_count": 6, - "metadata": {}, - "outputs": [ - { - "data": { - "text/plain": [ - "['articles', 'arxiv_dense', 'arxiv_meta', 'paragraphs']" - ] - }, - "execution_count": 6, - "metadata": {}, - "output_type": "execute_result" - } - ], - "source": [ - "indices = client.indices.get_alias().keys()\n", - "sorted(indices)" - ] - }, - { - "cell_type": "markdown", - "metadata": {}, - "source": [ - "## check data on index" - ] - }, - { - "cell_type": "code", - "execution_count": 11, - "metadata": {}, - "outputs": [], - "source": [ - "resp = client.search(index=\"paragraphs\", query={\"match_all\": {}})\n", - "print(\"Got %d Hits:\" % resp['hits']['total']['value'])\n", - "for hit in resp['hits']['hits']:\n", - " print(hit[\"_source\"])" - ] - } - ], - "metadata": { - "kernelspec": { - "display_name": "Python 3.10.5 ('py10')", - "language": "python", - "name": "python3" - }, - "language_info": { - "codemirror_mode": { - "name": "ipython", - "version": 3 - }, - "file_extension": ".py", - "mimetype": "text/x-python", - "name": "python", - "nbconvert_exporter": "python", - "pygments_lexer": "ipython3", - "version": "3.10.5" - }, - "orig_nbformat": 4, - "vscode": { - "interpreter": { - "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" - } - } - }, - "nbformat": 4, - "nbformat_minor": 2 -} diff --git a/tox.ini b/tox.ini index c98861396..7870fea80 100644 --- a/tox.ini +++ b/tox.ini @@ -176,7 +176,7 @@ source = bluesearch branch = True [coverage:report] -#fail_under = 80 +fail_under = 80 skip_covered = False show_missing = False From cd872367cb34827793d74f616c1b0d96f42d784b Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 20 Sep 2022 17:11:34 +0200 Subject: [PATCH 19/99] changes after PR review --- .gitignore | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/.gitignore b/.gitignore index 79b339240..6301e8019 100644 --- a/.gitignore +++ b/.gitignore @@ -167,4 +167,4 @@ cython_debug/ # static files generated from Django application using `collectstatic` media -static \ No newline at end of file +static From 7b508cd4f77c54acaaab3f6be5457d6edb0374ba Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 11:23:40 +0200 Subject: [PATCH 20/99] remove outdated test --- tests/unit/test_decouple.py | 5 ----- 1 file changed, 5 deletions(-) delete mode 100644 tests/unit/test_decouple.py diff --git a/tests/unit/test_decouple.py b/tests/unit/test_decouple.py deleted file mode 100644 index 6b9f39674..000000000 --- a/tests/unit/test_decouple.py +++ /dev/null @@ -1,5 +0,0 @@ -from decouple import config - - -def test_es_url(): - assert config("ES_URL")[:4] == "http" From b5e883f8e71495967a4b510ee1758f3d893201ce Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 11:26:55 +0200 Subject: [PATCH 21/99] remove .env file from tox --- tox.ini | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/tox.ini b/tox.ini index 7870fea80..daf24c43a 100644 --- a/tox.ini +++ b/tox.ini @@ -18,7 +18,7 @@ [tox] minversion = 3.1.0 requires = virtualenv >= 20.0.0 -sources = setup.py .env src/bluesearch tests benchmarks data_and_models +sources = setup.py src/bluesearch tests benchmarks data_and_models envlist = lint, type, py{37, 38, 39}, docs, check-apidoc, check-packaging ; Enable PEP-517/518, https://tox.wiki/en/latest/config.html#conf-isolated_build isolated_build = true From fc7c2e6f5d6ab527eaede6770c5b3a0eaf248306 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 12:08:22 +0200 Subject: [PATCH 22/99] flake8 fixes --- src/bluesearch/k8s/connect.py | 19 ++++++++++++++++++- src/bluesearch/k8s/create_indices.py | 19 +++++++++++++++++++ 2 files changed, 37 insertions(+), 1 deletion(-) diff --git a/src/bluesearch/k8s/connect.py b/src/bluesearch/k8s/connect.py index ba9f16689..f8b37de54 100644 --- a/src/bluesearch/k8s/connect.py +++ b/src/bluesearch/k8s/connect.py @@ -1,3 +1,20 @@ +# Blue Brain Search is a text mining toolbox focused on scientific use cases. +# +# Copyright (C) 2020 Blue Brain Project, EPFL. +# +# This program is free software: you can redistribute it and/or modify +# it under the terms of the GNU Lesser General Public License as published by +# the Free Software Foundation, either version 3 of the License, or +# (at your option) any later version. +# +# This program is distributed in the hope that it will be useful, +# but WITHOUT ANY WARRANTY; without even the implied warranty of +# MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the +# GNU Lesser General Public License for more details. +# +# You should have received a copy of the GNU Lesser General Public License +# along with this program. If not, see . +"""connects to ES.""" import logging import os @@ -12,7 +29,7 @@ def connect() -> Elasticsearch: - """return a client connect to BBP K8S""" + """Return a client connect to BBP K8S.""" client = Elasticsearch( os.environ["ES_URL"], basic_auth=("elastic", os.environ["ES_PASS"]), diff --git a/src/bluesearch/k8s/create_indices.py b/src/bluesearch/k8s/create_indices.py index bc0c6589a..60fbf7cae 100644 --- a/src/bluesearch/k8s/create_indices.py +++ b/src/bluesearch/k8s/create_indices.py @@ -1,3 +1,20 @@ +# Blue Brain Search is a text mining toolbox focused on scientific use cases. +# +# Copyright (C) 2020 Blue Brain Project, EPFL. +# +# This program is free software: you can redistribute it and/or modify +# it under the terms of the GNU Lesser General Public License as published by +# the Free Software Foundation, either version 3 of the License, or +# (at your option) any later version. +# +# This program is distributed in the hope that it will be useful, +# but WITHOUT ANY WARRANTY; without even the implied warranty of +# MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the +# GNU Lesser General Public License for more details. +# +# You should have received a copy of the GNU Lesser General Public License +# along with this program. If not, see . +"""creates an index on ES with the provided name, settings and mappings.""" from __future__ import annotations import logging @@ -51,6 +68,7 @@ def add_index( settings: dict[str, Any] | None = None, mappings: dict[str, Any] | None = None, ) -> None: + """Add the index to ES.""" client = connect() if index in client.indices.get_alias().keys(): @@ -64,6 +82,7 @@ def add_index( def remove_index(index: str | list[str]) -> None: + """Remove the index from ES.""" client = connect() if index not in client.indices.get_alias().keys(): From 9988843fbde139ea9986fc276d3d273ff2834293 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 13:48:20 +0200 Subject: [PATCH 23/99] add __init__.py --- src/bluesearch/k8s/__init__.py | 0 1 file changed, 0 insertions(+), 0 deletions(-) create mode 100644 src/bluesearch/k8s/__init__.py diff --git a/src/bluesearch/k8s/__init__.py b/src/bluesearch/k8s/__init__.py new file mode 100644 index 000000000..e69de29bb From 788854bf9f8069f2e8871c9508678f8f7731b027 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 13:53:19 +0200 Subject: [PATCH 24/99] add docstring to init --- src/bluesearch/k8s/__init__.py | 1 + 1 file changed, 1 insertion(+) diff --git a/src/bluesearch/k8s/__init__.py b/src/bluesearch/k8s/__init__.py index e69de29bb..8f67f6b07 100644 --- a/src/bluesearch/k8s/__init__.py +++ b/src/bluesearch/k8s/__init__.py @@ -0,0 +1 @@ +"""Subpackage for Kubernetes related code.""" \ No newline at end of file From 1206ee36d4f82de1fd656b425b2033c53af41a5a Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 13:54:18 +0200 Subject: [PATCH 25/99] add docstring to init --- src/bluesearch/k8s/__init__.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/k8s/__init__.py b/src/bluesearch/k8s/__init__.py index 8f67f6b07..744e2d716 100644 --- a/src/bluesearch/k8s/__init__.py +++ b/src/bluesearch/k8s/__init__.py @@ -1 +1 @@ -"""Subpackage for Kubernetes related code.""" \ No newline at end of file +"""Subpackage for Kubernetes related code.""" From 6bc72b80ee10529a63ec627f3f14bca5fa605fc1 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 16:26:26 +0200 Subject: [PATCH 26/99] update docs --- docs/source/api/bluesearch.k8s.connect.rst | 7 +++++++ .../api/bluesearch.k8s.create_indices.rst | 7 +++++++ docs/source/api/bluesearch.k8s.rst | 19 +++++++++++++++++++ docs/source/api/bluesearch.rst | 1 + 4 files changed, 34 insertions(+) create mode 100644 docs/source/api/bluesearch.k8s.connect.rst create mode 100644 docs/source/api/bluesearch.k8s.create_indices.rst create mode 100644 docs/source/api/bluesearch.k8s.rst diff --git a/docs/source/api/bluesearch.k8s.connect.rst b/docs/source/api/bluesearch.k8s.connect.rst new file mode 100644 index 000000000..acb5ade19 --- /dev/null +++ b/docs/source/api/bluesearch.k8s.connect.rst @@ -0,0 +1,7 @@ +bluesearch.k8s.connect module +============================= + +.. automodule:: bluesearch.k8s.connect + :members: + :undoc-members: + :show-inheritance: diff --git a/docs/source/api/bluesearch.k8s.create_indices.rst b/docs/source/api/bluesearch.k8s.create_indices.rst new file mode 100644 index 000000000..dd5ecb024 --- /dev/null +++ b/docs/source/api/bluesearch.k8s.create_indices.rst @@ -0,0 +1,7 @@ +bluesearch.k8s.create\_indices module +===================================== + +.. automodule:: bluesearch.k8s.create_indices + :members: + :undoc-members: + :show-inheritance: diff --git a/docs/source/api/bluesearch.k8s.rst b/docs/source/api/bluesearch.k8s.rst new file mode 100644 index 000000000..a76de5009 --- /dev/null +++ b/docs/source/api/bluesearch.k8s.rst @@ -0,0 +1,19 @@ +bluesearch.k8s package +====================== + +Submodules +---------- + +.. toctree:: + :maxdepth: 4 + + bluesearch.k8s.connect + bluesearch.k8s.create_indices + +Module contents +--------------- + +.. automodule:: bluesearch.k8s + :members: + :undoc-members: + :show-inheritance: diff --git a/docs/source/api/bluesearch.rst b/docs/source/api/bluesearch.rst index 2c8f4d738..03db410f7 100644 --- a/docs/source/api/bluesearch.rst +++ b/docs/source/api/bluesearch.rst @@ -9,6 +9,7 @@ Subpackages bluesearch.database bluesearch.entrypoint + bluesearch.k8s bluesearch.mining bluesearch.server bluesearch.widgets From 370e14b9c582b17512bd5f5d5c23157b9391f50a Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 16:49:03 +0200 Subject: [PATCH 27/99] add elasticsearch to ci --- .github/workflows/ci.yaml | 6 ++++++ 1 file changed, 6 insertions(+) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 4cd2594f6..5e2981a45 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -11,6 +11,12 @@ on: jobs: tox: runs-on: ubuntu-latest + services: + elasticsearch: + image: elasticsearch:8.3.3 + ports: + - 9200/tcp + options: -e="discovery.type=single-node" --health-cmd="curl http://localhost:9200/_cluster/health" --health-interval=10s --health-timeout=5s --health-retries=10 strategy: matrix: tox-env: [lint, type, docs, check-apidoc, check-packaging] From 7022102b91a620e25605ef8920d8468007b3e942 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 17:10:00 +0200 Subject: [PATCH 28/99] update ci --- .github/workflows/ci.yaml | 13 ++++++++++--- 1 file changed, 10 insertions(+), 3 deletions(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 5e2981a45..6863e5ce9 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -13,10 +13,17 @@ jobs: runs-on: ubuntu-latest services: elasticsearch: - image: elasticsearch:8.3.3 + image: docker.elastic.co/elasticsearch/elasticsearch:7.9.2 + env: + discovery.type: single-node + options: >- + --health-cmd "curl http://localhost:9200/_cluster/health" + --health-interval 10s + --health-timeout 5s + --health-retries 10 ports: - - 9200/tcp - options: -e="discovery.type=single-node" --health-cmd="curl http://localhost:9200/_cluster/health" --health-interval=10s --health-timeout=5s --health-retries=10 + # : + - 9200:9200 strategy: matrix: tox-env: [lint, type, docs, check-apidoc, check-packaging] From e4405078962a9de36e874c557ec0db9fe924ae19 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 17:45:57 +0200 Subject: [PATCH 29/99] update ci --- .github/workflows/ci.yaml | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 6863e5ce9..9a0771160 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -13,7 +13,7 @@ jobs: runs-on: ubuntu-latest services: elasticsearch: - image: docker.elastic.co/elasticsearch/elasticsearch:7.9.2 + image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 env: discovery.type: single-node options: >- From 20bd85b9a334446c69b814e17e88e01a2735f1cd Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 17:49:54 +0200 Subject: [PATCH 30/99] update ci --- .github/workflows/ci.yaml | 1 + 1 file changed, 1 insertion(+) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 9a0771160..2f25beb19 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -21,6 +21,7 @@ jobs: --health-interval 10s --health-timeout 5s --health-retries 10 + - xpack.security.enabled=false ports: # : - 9200:9200 From a10e5bc53fa3d0b008977e4b55d08599201ad19c Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 21 Sep 2022 17:53:35 +0200 Subject: [PATCH 31/99] update ci --- .github/workflows/ci.yaml | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 2f25beb19..ff2df7b85 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -16,12 +16,12 @@ jobs: image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 env: discovery.type: single-node + xpack.security.enabled: false options: >- --health-cmd "curl http://localhost:9200/_cluster/health" --health-interval 10s --health-timeout 5s --health-retries 10 - - xpack.security.enabled=false ports: # : - 9200:9200 From d31a2a8535ea53e70cc695e311092f0ba6d9ae48 Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Thu, 22 Sep 2022 10:55:56 +0200 Subject: [PATCH 32/99] Modify test and the design --- src/bluesearch/k8s/connect.py | 6 +++--- src/bluesearch/k8s/create_indices.py | 11 +++++----- tests/unit/k8s/test_create_indices.py | 29 ++++++++++++++++++++++++--- 3 files changed, 34 insertions(+), 12 deletions(-) diff --git a/src/bluesearch/k8s/connect.py b/src/bluesearch/k8s/connect.py index f8b37de54..92a1c8a03 100644 --- a/src/bluesearch/k8s/connect.py +++ b/src/bluesearch/k8s/connect.py @@ -29,7 +29,7 @@ def connect() -> Elasticsearch: - """Return a client connect to BBP K8S.""" + """Return a client connect ES.""" client = Elasticsearch( os.environ["ES_URL"], basic_auth=("elastic", os.environ["ES_PASS"]), @@ -37,9 +37,9 @@ def connect() -> Elasticsearch: ) if not client.ping(): - raise RuntimeError(f"Cannot connect to BBP K8S: {client.info()}") + raise RuntimeError(f"Cannot connect to ES: {os.environ['ES_URL']}") - logger.info("Connected to BBP K8S") + logger.info("Connected to ES") return client diff --git a/src/bluesearch/k8s/create_indices.py b/src/bluesearch/k8s/create_indices.py index 60fbf7cae..c834d2770 100644 --- a/src/bluesearch/k8s/create_indices.py +++ b/src/bluesearch/k8s/create_indices.py @@ -20,7 +20,7 @@ import logging from typing import Any -from bluesearch.k8s.connect import connect +from elasticsearch import Elasticsearch logger = logging.getLogger(__name__) @@ -64,13 +64,12 @@ def add_index( + client: Elasticsearch, index: str, settings: dict[str, Any] | None = None, mappings: dict[str, Any] | None = None, ) -> None: """Add the index to ES.""" - client = connect() - if index in client.indices.get_alias().keys(): raise RuntimeError("Index already in ES") @@ -81,10 +80,10 @@ def add_index( print("Elasticsearch add_index ERROR:", err) -def remove_index(index: str | list[str]) -> None: +def remove_index( + client: Elasticsearch, + index: str | list[str]) -> None: """Remove the index from ES.""" - client = connect() - if index not in client.indices.get_alias().keys(): raise RuntimeError("Index not in ES") diff --git a/tests/unit/k8s/test_create_indices.py b/tests/unit/k8s/test_create_indices.py index ae2f6b37e..c959712bc 100644 --- a/tests/unit/k8s/test_create_indices.py +++ b/tests/unit/k8s/test_create_indices.py @@ -1,8 +1,31 @@ +import pytest + +from bluesearch.k8s.connect import connect from bluesearch.k8s.create_indices import add_index, remove_index +ES_URL="http://localhost:9200" +ES_PASS="" + + +@pytest.fixture() +def get_es_client(monkeypatch): + monkeypatch.setenv("ES_URL", ES_URL) + monkeypatch.setenv("ES_PASS", ES_PASS) + + try: + client = connect() + except RuntimeError: + client = None + + yield client + +def test_create_and_remove_index(get_es_client): + client = get_es_client -def test_create_and_remove_index(index="test_index"): + if client is None: + pytest.skip("Elastic search is not available") - add_index(index) + index="test_index" - remove_index(index) + add_index(client, index) + remove_index(client, index) From f73a8a52582b04ff2f89ba8a8e68145bc99128c4 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Thu, 22 Sep 2022 11:08:30 +0200 Subject: [PATCH 33/99] linters --- src/bluesearch/k8s/create_indices.py | 4 +--- 1 file changed, 1 insertion(+), 3 deletions(-) diff --git a/src/bluesearch/k8s/create_indices.py b/src/bluesearch/k8s/create_indices.py index c834d2770..898682179 100644 --- a/src/bluesearch/k8s/create_indices.py +++ b/src/bluesearch/k8s/create_indices.py @@ -80,9 +80,7 @@ def add_index( print("Elasticsearch add_index ERROR:", err) -def remove_index( - client: Elasticsearch, - index: str | list[str]) -> None: +def remove_index(client: Elasticsearch, index: str | list[str]) -> None: """Remove the index from ES.""" if index not in client.indices.get_alias().keys(): raise RuntimeError("Index not in ES") From 17b56d7322fbf0e45b5119d0cafc91b2745c9d30 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Thu, 22 Sep 2022 11:13:48 +0200 Subject: [PATCH 34/99] linters --- tests/unit/k8s/test_create_indices.py | 7 ++++--- 1 file changed, 4 insertions(+), 3 deletions(-) diff --git a/tests/unit/k8s/test_create_indices.py b/tests/unit/k8s/test_create_indices.py index c959712bc..bd668b86d 100644 --- a/tests/unit/k8s/test_create_indices.py +++ b/tests/unit/k8s/test_create_indices.py @@ -3,8 +3,8 @@ from bluesearch.k8s.connect import connect from bluesearch.k8s.create_indices import add_index, remove_index -ES_URL="http://localhost:9200" -ES_PASS="" +ES_URL = "http://localhost:9200" +ES_PASS = "" @pytest.fixture() @@ -19,13 +19,14 @@ def get_es_client(monkeypatch): yield client + def test_create_and_remove_index(get_es_client): client = get_es_client if client is None: pytest.skip("Elastic search is not available") - index="test_index" + index = "test_index" add_index(client, index) remove_index(client, index) From f5bdfb68f181f9a87a09c9a72ca2fa4b4a2de1ae Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Thu, 22 Sep 2022 14:31:44 +0200 Subject: [PATCH 35/99] Fix random pandas issue --- src/bluesearch/sql.py | 4 +++- 1 file changed, 3 insertions(+), 1 deletion(-) diff --git a/src/bluesearch/sql.py b/src/bluesearch/sql.py index 6b32018be..50e3e8574 100644 --- a/src/bluesearch/sql.py +++ b/src/bluesearch/sql.py @@ -278,7 +278,9 @@ def retrieve_articles(article_ids, engine): sql_query = sql_query.bindparams(sql.bindparam("articles_ids", expanding=True)) all_sentences = pd.read_sql(sql_query, engine, params={"articles_ids": article_ids}) - groupby_var = all_sentences.groupby(by=["article_id", "paragraph_pos_in_article"]) + groupby_var = all_sentences.groupby( + by=["article_id", "paragraph_pos_in_article"], group_keys=False + ) paragraphs = groupby_var["text"].apply(lambda x: " ".join(x)) section_name = groupby_var["section_name"].unique().apply(lambda x: x[0]) From fd797725bafeb4b24439d1a1a04d849e8b2f3f82 Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Thu, 22 Sep 2022 15:25:07 +0200 Subject: [PATCH 36/99] Temp removal of tox dependencies --- tox.ini | 3 --- 1 file changed, 3 deletions(-) diff --git a/tox.ini b/tox.ini index daf24c43a..2ba019b49 100644 --- a/tox.ini +++ b/tox.ini @@ -26,9 +26,6 @@ isolated_build = true [testenv] description = Run pytest download = true -deps = - en-core-web-sm @ https://github.com/explosion/spacy-models/releases/download/en_core_web_sm-3.0.0/en_core_web_sm-3.0.0.tar.gz - en-core-sci-lg @ https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.4.0/en_core_sci_lg-0.4.0.tar.gz extras = dev allowlist_externals = docker commands = pytest -m "" {posargs:tests} From d7294a7476a8a0b3ae17709b036b0cee1c7ed63e Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Thu, 22 Sep 2022 16:11:26 +0200 Subject: [PATCH 37/99] Completely get rid of en-core-sci-lg --- requirements.txt | 1 - src/bluesearch/database/cord_19.py | 2 +- src/bluesearch/entrypoint/database/add.py | 2 +- 3 files changed, 2 insertions(+), 3 deletions(-) diff --git a/requirements.txt b/requirements.txt index 998408697..bcdccb204 100644 --- a/requirements.txt +++ b/requirements.txt @@ -21,7 +21,6 @@ boto3==1.20.16 catalogue==2.0.4 cryptography==3.4.7 defusedxml==0.6.0 -en-core-sci-lg @ https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.4.0/en_core_sci_lg-0.4.0.tar.gz google-cloud-storage==1.43.0 h5py==3.3.0 ipython==7.31.1 diff --git a/src/bluesearch/database/cord_19.py b/src/bluesearch/database/cord_19.py index 73dcb6402..1f338b972 100644 --- a/src/bluesearch/database/cord_19.py +++ b/src/bluesearch/database/cord_19.py @@ -332,7 +332,7 @@ def _process_article_sentences(self, article, nlp): return pmc_json, pdf_json - def _sentences_table(self, model_name="en_core_sci_lg"): + def _sentences_table(self, model_name="en_core_web_sm"): """Fill the sentences table thanks to all the json files. For each paragraph, all sentences are extracted and populate diff --git a/src/bluesearch/entrypoint/database/add.py b/src/bluesearch/entrypoint/database/add.py index b9f9814b6..dd2dd8104 100644 --- a/src/bluesearch/entrypoint/database/add.py +++ b/src/bluesearch/entrypoint/database/add.py @@ -117,7 +117,7 @@ def run( raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") logger.info("Loading spacy model") - nlp = load_spacy_model("en_core_sci_lg", disable=["ner"]) + nlp = load_spacy_model("en_core_web_sm", disable=["ner"]) logger.info("Splitting text into sentences") article_mappings = [] From 6969c50d1c3995062c4345de0a9d1f852809babc Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Thu, 22 Sep 2022 16:13:44 +0200 Subject: [PATCH 38/99] Download spacy model just before unit tests --- tox.ini | 4 +++- 1 file changed, 3 insertions(+), 1 deletion(-) diff --git a/tox.ini b/tox.ini index 2ba019b49..2af165d40 100644 --- a/tox.ini +++ b/tox.ini @@ -28,7 +28,9 @@ description = Run pytest download = true extras = dev allowlist_externals = docker -commands = pytest -m "" {posargs:tests} +commands = + python -m spacy download en-core-web-sm + pytest -m "" {posargs:tests} [testenv:lint] description = Lint using flake8, black, isort and bandit From 12de5a022f42ef8798c49dec2cf6c46efd70cfa1 Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Thu, 22 Sep 2022 16:18:23 +0200 Subject: [PATCH 39/99] Use underscores instead --- tox.ini | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/tox.ini b/tox.ini index 2af165d40..09c5fabad 100644 --- a/tox.ini +++ b/tox.ini @@ -29,7 +29,7 @@ download = true extras = dev allowlist_externals = docker commands = - python -m spacy download en-core-web-sm + python -m spacy download en_core_web_sm pytest -m "" {posargs:tests} [testenv:lint] From f3d8be0eb3ddaa5af9e0e61530bf7db8307942c1 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 10:10:03 +0200 Subject: [PATCH 40/99] update docstrings --- src/bluesearch/k8s/create_indices.py | 32 ++++++++++++++++++++++++++-- 1 file changed, 30 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/k8s/create_indices.py b/src/bluesearch/k8s/create_indices.py index 898682179..00db98efe 100644 --- a/src/bluesearch/k8s/create_indices.py +++ b/src/bluesearch/k8s/create_indices.py @@ -69,7 +69,23 @@ def add_index( settings: dict[str, Any] | None = None, mappings: dict[str, Any] | None = None, ) -> None: - """Add the index to ES.""" + """Add an index to ES. + + Parameters + ---------- + client: Elasticsearch + Elasticsearch client. + index: str + Name of the index. + settings: dict[str, Any] | None + Settings of the index. + mappings: dict[str, Any] | None + Mappings of the index. + + Returns + ------- + None + """ if index in client.indices.get_alias().keys(): raise RuntimeError("Index already in ES") @@ -81,7 +97,19 @@ def add_index( def remove_index(client: Elasticsearch, index: str | list[str]) -> None: - """Remove the index from ES.""" + """Remove an index from ES. + + Parameters + ---------- + client: Elasticsearch + Elasticsearch client. + index: str | list[str] + Name of the index. + + Returns + ------- + None + """ if index not in client.indices.get_alias().keys(): raise RuntimeError("Index not in ES") From cfbfcb1b70c84d795ea6bace7e7dcd47887bafd4 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 10:51:01 +0200 Subject: [PATCH 41/99] update docstrings --- src/bluesearch/entrypoint/database/add.py | 46 +++++++++++++++++++++++ 1 file changed, 46 insertions(+) diff --git a/src/bluesearch/entrypoint/database/add.py b/src/bluesearch/entrypoint/database/add.py index 4fc41db44..d0a5db7b1 100644 --- a/src/bluesearch/entrypoint/database/add.py +++ b/src/bluesearch/entrypoint/database/add.py @@ -15,6 +15,8 @@ # You should have received a copy of the GNU Lesser General Public License # along with this program. If not, see . """Adding articles to the database.""" +from __future__ import annotations + import argparse import logging from pathlib import Path @@ -73,6 +75,23 @@ def _upload_sql( article_mappings: list[dict[str, Any]], paragraph_mappings: list[dict[str, Any]], ) -> None: + """Upload the mappings to a SQL database. + + Parameters + ---------- + db_url + The location of the database. + db_type + Type of the database. + article_mappings + The mappings of the articles to upload. + paragraph_mappings + The mappings of the paragraphs to upload. + + Returns + ------- + None + """ import sqlalchemy @@ -127,6 +146,21 @@ def _upload_es( article_mappings: list[dict[str, Any]], paragraph_mappings: list[dict[str, Any]], ) -> None: + """Upload the mappings to an Elasticsearch database. + + Parameters + ---------- + db_url + The location of the database. + article_mappings + The mappings of the articles to upload. + paragraph_mappings + The mappings of the paragraphs to upload. + + Returns + ------- + None + """ import tqdm import urllib3 @@ -177,6 +211,18 @@ def bulk_articles( def bulk_paragraphs( paragraph_mappings: list[dict[str, Any]], progress: Any = None ) -> Iterable[dict[str, Any]]: + """Yield a paragraph mapping as a document to upload to Elasticsearch. + + Parameters + ---------- + paragraph_mappings + The mappings of the paragraphs to upload. + + Returns + ------- + Iterable[dict[str, Any]] + A generator of documents to upload to Elasticsearch. + """ for paragraph in paragraph_mappings: doc = { "_index": "paragraphs", From 7b9bdb288db6e44a165b14cf3446b09b8cf6f54d Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 13:14:25 +0200 Subject: [PATCH 42/99] revert mypy changes --- .mypy.ini | 3 --- src/bluesearch/entrypoint/database/add.py | 4 +--- 2 files changed, 1 insertion(+), 6 deletions(-) diff --git a/.mypy.ini b/.mypy.ini index 340e80086..bc99f1f8f 100644 --- a/.mypy.ini +++ b/.mypy.ini @@ -25,6 +25,3 @@ warn_unused_ignores = True show_error_codes = True plugins = sqlmypy exclude = benchmarks/conftest.py|data_and_models/pipelines/ner/transformers_vs_spacy/transformers/|data_and_models/pipelines/sentence_embedding/training_transformers/ -disallow_any_generics = True -disallow_incomplete_defs = True -disallow_untyped_defs = True diff --git a/src/bluesearch/entrypoint/database/add.py b/src/bluesearch/entrypoint/database/add.py index d0a5db7b1..0608bc781 100644 --- a/src/bluesearch/entrypoint/database/add.py +++ b/src/bluesearch/entrypoint/database/add.py @@ -92,7 +92,6 @@ def _upload_sql( ------- None """ - import sqlalchemy if db_type == "sqlite": @@ -156,12 +155,11 @@ def _upload_es( The mappings of the articles to upload. paragraph_mappings The mappings of the paragraphs to upload. - + Returns ------- None """ - import tqdm import urllib3 from decouple import config From 687acb30b1fea4da3b4b3159946c6cc2c2f72098 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 13:21:26 +0200 Subject: [PATCH 43/99] isort --- src/bluesearch/database/article.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/database/article.py b/src/bluesearch/database/article.py index b5c47ba1b..bc7fd4bfa 100644 --- a/src/bluesearch/database/article.py +++ b/src/bluesearch/database/article.py @@ -28,7 +28,7 @@ from dataclasses import dataclass from io import StringIO from pathlib import Path -from typing import IO, Generator, Iterable, Sequence, Tuple, Any +from typing import IO, Any, Generator, Iterable, Sequence, Tuple from xml.etree.ElementTree import Element # nosec from zipfile import ZipFile From e33ba1b4af0285b6ed2f7214cac30cba7bbaed7e Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 13:36:59 +0200 Subject: [PATCH 44/99] from __future__ import annotations --- tests/integration/test_bbs_database.py | 2 ++ 1 file changed, 2 insertions(+) diff --git a/tests/integration/test_bbs_database.py b/tests/integration/test_bbs_database.py index 3008b6d2d..45934f525 100644 --- a/tests/integration/test_bbs_database.py +++ b/tests/integration/test_bbs_database.py @@ -1,3 +1,5 @@ +from __future__ import annotations + import subprocess import time From e5ab4674dd717de040d3ed85037d3eff7edeebe1 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 16:17:09 +0200 Subject: [PATCH 45/99] separate add es and sql --- src/bluesearch/entrypoint/database/add_es.py | 211 ++++++++++++++++++ src/bluesearch/entrypoint/database/parent.py | 6 + tests/conftest.py | 24 ++ tests/unit/entrypoint/database/test_add_es.py | 38 ++++ tests/unit/k8s/test_create_indices.py | 17 -- 5 files changed, 279 insertions(+), 17 deletions(-) create mode 100644 src/bluesearch/entrypoint/database/add_es.py create mode 100644 tests/unit/entrypoint/database/test_add_es.py diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py new file mode 100644 index 000000000..ffc2ad87f --- /dev/null +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -0,0 +1,211 @@ +# Blue Brain Search is a text mining toolbox focused on scientific use cases. +# +# Copyright (C) 2020 Blue Brain Project, EPFL. +# +# This program is free software: you can redistribute it and/or modify +# it under the terms of the GNU Lesser General Public License as published by +# the Free Software Foundation, either version 3 of the License, or +# (at your option) any later version. +# +# This program is distributed in the hope that it will be useful, +# but WITHOUT ANY WARRANTY; without even the implied warranty of +# MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the +# GNU Lesser General Public License for more details. +# +# You should have received a copy of the GNU Lesser General Public License +# along with this program. If not, see . +"""Adding articles to the database.""" +from __future__ import annotations + +import argparse +import logging +from pathlib import Path +from typing import Any, Iterable + +logger = logging.getLogger(__name__) + + +def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: + """Initialise the argument parser for the add subcommand. + + Parameters + ---------- + parser + The argument parser to initialise. + + Returns + ------- + argparse.ArgumentParser + The initialised argument parser. The same object as the `parser` + argument. + """ + parser.description = "Add entries to a database. \ + ENV variables are used to configure the database connection.\ + ES_URL and ES_PASS are required." + + parser.add_argument( + "parsed_path", + type=Path, + help="Path to a parsed file or to a directory of parsed files.", + ) + return parser + + +def _upload_es( + article_mappings: list[dict[str, Any]], + paragraph_mappings: list[dict[str, Any]], +) -> None: + """Upload the mappings to an Elasticsearch database. + + Parameters + ---------- + article_mappings + The mappings of the articles to upload. + paragraph_mappings + The mappings of the paragraphs to upload. + + Returns + ------- + None + """ + import tqdm + import urllib3 + from bluesearch.k8s.connect import connect + from elasticsearch.helpers import bulk + + urllib3.disable_warnings() + + client = connect() + + progress = tqdm.tqdm( + desc="Uploading articles", total=len(article_mappings), unit="articles" + ) + + def bulk_articles( + article_mappings: list[dict[str, Any]], progress: Any = None + ) -> Iterable[dict[str, Any]]: + for article in article_mappings: + doc = { + "_index": "articles", + "_id": article["article_id"], + "_source": { + "article_id": article["article_id"], + "authors": article["title"], + "title": article["authors"], + "abstract": article["abstract"], + "pubmed_id": article["pubmed_id"], + "pmc_id": article["pmc_id"], + "doi": article["doi"], + }, + } + if progress: + progress.update(1) + yield doc + + resp = bulk(client, bulk_articles(article_mappings, progress)) + logger.info(f"Uploaded {resp[0]} articles.") + + progress = tqdm.tqdm( + desc="Uploading paragraphs", total=len(paragraph_mappings), unit="paragraphs" + ) + + def bulk_paragraphs( + paragraph_mappings: list[dict[str, Any]], progress: Any = None + ) -> Iterable[dict[str, Any]]: + """Yield a paragraph mapping as a document to upload to Elasticsearch. + + Parameters + ---------- + paragraph_mappings + The mappings of the paragraphs to upload. + + Returns + ------- + Iterable[dict[str, Any]] + A generator of documents to upload to Elasticsearch. + """ + for paragraph in paragraph_mappings: + doc = { + "_index": "paragraphs", + "_source": { + "article_id": paragraph["article_id"], + "section_name": paragraph["section_name"], + "text": paragraph["text"], + "paragraph_id": paragraph["paragraph_pos_in_article"], + }, + } + if progress: + progress.update(1) + yield doc + + resp = bulk(client, bulk_paragraphs(paragraph_mappings, progress)) + logger.info(f"Uploaded {resp[0]} paragraphs.") + + +def run( + *, + parsed_path: Path, +) -> int: + """Add an entry to the database. + + Parameter description and potential defaults are documented inside of the + `get_parser` function. + """ + from typing import Iterable + + from bluesearch.database.article import Article + + inputs: Iterable[Path] + if parsed_path.is_file(): + inputs = [parsed_path] + elif parsed_path.is_dir(): + inputs = sorted(parsed_path.glob("*.json")) + else: + raise ValueError( + "Argument 'parsed_path' should be a path to an existing file or directory!" + ) + + articles = [] + for inp in inputs: + serialized = inp.read_text("utf-8") + article = Article.from_json(serialized) + articles.append(article) + + if not articles: + raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") + + logger.info("Splitting text into paragraphs") + article_mappings = [] + paragraph_mappings = [] + + for article in articles: + logger.info(f"Processing {article.uid}") + + article_mapping = { + "article_id": article.uid, + "title": article.title, + "authors": ", ".join(article.authors), + "abstract": "\n".join(article.abstract), + "pubmed_id": article.pubmed_id, + "pmc_id": article.pmc_id, + "doi": article.doi, + } + article_mappings.append(article_mapping) + + for ppos, (section, text) in enumerate(article.section_paragraphs): + paragraph_mapping = { + "section_name": section, + "text": text, + "article_id": article.uid, + "paragraph_pos_in_article": ppos, + } + paragraph_mappings.append(paragraph_mapping) + + if not paragraph_mappings: + raise RuntimeWarning(f"No sentence was extracted from '{parsed_path}'!") + + # Persistence. + _upload_es(article_mappings, paragraph_mappings) + + logger.info("Adding done") + return 0 \ No newline at end of file diff --git a/src/bluesearch/entrypoint/database/parent.py b/src/bluesearch/entrypoint/database/parent.py index 30205329d..4c9c65cd3 100644 --- a/src/bluesearch/entrypoint/database/parent.py +++ b/src/bluesearch/entrypoint/database/parent.py @@ -9,6 +9,7 @@ from bluesearch.entrypoint.database import ( add, + add_es, convert_pdf, download, init, @@ -53,6 +54,11 @@ def main(argv: Sequence[str] | None = None) -> int: init_parser=add.init_parser, run=add.run, ), + "add_es": Cmd( + help="Add parsed files to ES.", + init_parser=add_es.init_parser, + run=add_es.run, + ), "convert-pdf": Cmd( help="Convert a PDF file to a TEI XML file.", init_parser=convert_pdf.init_parser, diff --git a/tests/conftest.py b/tests/conftest.py index 77798e7f3..4730c1125 100644 --- a/tests/conftest.py +++ b/tests/conftest.py @@ -496,3 +496,27 @@ def pubmed_xml_gz_path(test_data_path, tmp_path): ) as gzip_out: gzip_out.writelines(file_in) return zip_pubmed_path + + +@pytest.fixture() +def get_es_client(monkeypatch): + from bluesearch.k8s.connect import connect + from bluesearch.k8s.create_indices import remove_index + + ES_URL = "http://localhost:9200" + ES_PASS = "" + + monkeypatch.setenv("ES_URL", ES_URL) + monkeypatch.setenv("ES_PASS", ES_PASS) + + try: + client = connect() + except RuntimeError: + client = None + + yield client + + if client is not None: + for index in client.indices.get_alias().keys(): + if index in ['articles', 'paragraphs', 'test_index']: + remove_index(client, index) diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py new file mode 100644 index 000000000..23fc04f73 --- /dev/null +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -0,0 +1,38 @@ +import pytest + +from bluesearch.entrypoint.database import add_es + + +def test(get_es_client, tmp_path): + from bluesearch.database.article import Article + + client = get_es_client + breakpoint() + if client is None: + pytest.skip("Elastic search is not available") + + article_1 = Article( + title = 'some test title', + authors = 'some test authors', + abstract = 'some test abstract', + section_paragraphs = ('some test section_paragraphs 1client', + 'some test section_paragraphs 2'), + uid = 'some test uid', + ) + + article_2 = Article( + title = 'SOME test title', + authors = 'SOME test authors', + abstract = 'SOME test abstract', + section_paragraphs = ('SOME test section_paragraphs 1', + 'SOME test section_paragraphs 2'), + uid = 'SOME test uid', + ) + + article_1_path = tmp_path/'article_1.json' + article_2_path = tmp_path/'article_2.json' + + article_1_path.write_text(article_1.to_json()) + article_2_path.write_text(article_2.to_json()) + + add_es.run(parsed_path=tmp_path) \ No newline at end of file diff --git a/tests/unit/k8s/test_create_indices.py b/tests/unit/k8s/test_create_indices.py index bd668b86d..75be3178d 100644 --- a/tests/unit/k8s/test_create_indices.py +++ b/tests/unit/k8s/test_create_indices.py @@ -1,24 +1,7 @@ import pytest -from bluesearch.k8s.connect import connect from bluesearch.k8s.create_indices import add_index, remove_index -ES_URL = "http://localhost:9200" -ES_PASS = "" - - -@pytest.fixture() -def get_es_client(monkeypatch): - monkeypatch.setenv("ES_URL", ES_URL) - monkeypatch.setenv("ES_PASS", ES_PASS) - - try: - client = connect() - except RuntimeError: - client = None - - yield client - def test_create_and_remove_index(get_es_client): client = get_es_client From e8b134db78f4da265b158d87e0abbaeb82b935d4 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 23 Sep 2022 16:26:06 +0200 Subject: [PATCH 46/99] reverted article --- src/bluesearch/database/article.py | 20 ++++++++++---------- 1 file changed, 10 insertions(+), 10 deletions(-) diff --git a/src/bluesearch/database/article.py b/src/bluesearch/database/article.py index bc7fd4bfa..6c95360a1 100644 --- a/src/bluesearch/database/article.py +++ b/src/bluesearch/database/article.py @@ -28,7 +28,7 @@ from dataclasses import dataclass from io import StringIO from pathlib import Path -from typing import IO, Any, Generator, Iterable, Sequence, Tuple +from typing import IO, Generator, Iterable, Optional, Sequence, Tuple from xml.etree.ElementTree import Element # nosec from zipfile import ZipFile @@ -266,7 +266,7 @@ class JATSXMLParser(ArticleParser): The xml stream of the article. """ - def __init__(self, xml_stream: IO[Any]) -> None: + def __init__(self, xml_stream: IO) -> None: super().__init__() self.content = ElementTree.parse(xml_stream) self.ids = self.get_ids() @@ -722,7 +722,7 @@ class CORD19ArticleParser(ArticleParser): The contents of a JSON-file from the CORD-19 database. """ - def __init__(self, json_file: dict[str, Any]) -> None: + def __init__(self, json_file: dict) -> None: # data is a reference to json_file, so we shouldn't modify its contents self.data = json_file @@ -818,7 +818,7 @@ def pmc_id(self) -> str | None: """ return self.data.get("paper_id") - def __str__(self) -> str: + def __str__(self): """Get the string representation of the parser instance.""" return f'CORD-19 article ID={self.data["paper_id"]}' @@ -956,7 +956,7 @@ def doi(self) -> str | None: return self.tei_ids.get("DOI") @property - def tei_ids(self) -> dict[str, Any]: + def tei_ids(self) -> dict: """Extract all IDs of the TEI XML. Returns @@ -1066,11 +1066,11 @@ class Article(DataClassJSONMixin): authors: Sequence[str] abstract: Sequence[str] section_paragraphs: Sequence[Tuple[str, str]] - pubmed_id: str | None = None - pmc_id: str | None = None - arxiv_id: str | None = None - doi: str | None = None - uid: str | None = None + pubmed_id: Optional[str] = None + pmc_id: Optional[str] = None + arxiv_id: Optional[str] = None + doi: Optional[str] = None + uid: Optional[str] = None @classmethod def parse(cls, parser: ArticleParser) -> Article: From ea513168a1e065d5eb7ef98ce45964057f44043c Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Fri, 23 Sep 2022 16:46:02 +0200 Subject: [PATCH 47/99] Write tests --- src/bluesearch/entrypoint/database/add_es.py | 2 +- tests/conftest.py | 2 +- tests/unit/entrypoint/database/test_add_es.py | 50 ++++++++++++------- 3 files changed, 35 insertions(+), 19 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index ffc2ad87f..b7adab2a7 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -208,4 +208,4 @@ def run( _upload_es(article_mappings, paragraph_mappings) logger.info("Adding done") - return 0 \ No newline at end of file + return 0 diff --git a/tests/conftest.py b/tests/conftest.py index 4730c1125..43d0f97ba 100644 --- a/tests/conftest.py +++ b/tests/conftest.py @@ -518,5 +518,5 @@ def get_es_client(monkeypatch): if client is not None: for index in client.indices.get_alias().keys(): - if index in ['articles', 'paragraphs', 'test_index']: + if index in ["articles", "paragraphs", "test_index"]: remove_index(client, index) diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index 23fc04f73..13e681849 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -7,32 +7,48 @@ def test(get_es_client, tmp_path): from bluesearch.database.article import Article client = get_es_client - breakpoint() if client is None: pytest.skip("Elastic search is not available") article_1 = Article( - title = 'some test title', - authors = 'some test authors', - abstract = 'some test abstract', - section_paragraphs = ('some test section_paragraphs 1client', - 'some test section_paragraphs 2'), - uid = 'some test uid', + title="some test title", + authors="some test authors", + abstract="some test abstract", + section_paragraphs=( + "some test section_paragraphs 1client", + "some test section_paragraphs 2", + ), + uid="some test uid", ) article_2 = Article( - title = 'SOME test title', - authors = 'SOME test authors', - abstract = 'SOME test abstract', - section_paragraphs = ('SOME test section_paragraphs 1', - 'SOME test section_paragraphs 2'), - uid = 'SOME test uid', + title="SOME test title", + authors="SOME test authors", + abstract="SOME test abstract", + section_paragraphs=( + "SOME test section_paragraphs 1", + "SOME test section_paragraphs 2", + ), + uid="SOME test uid", ) - article_1_path = tmp_path/'article_1.json' - article_2_path = tmp_path/'article_2.json' + article_1_path = tmp_path / "article_1.json" + article_2_path = tmp_path / "article_2.json" article_1_path.write_text(article_1.to_json()) - article_2_path.write_text(article_2.to_json()) + article_2_path.write_text(article_2.to_json()) - add_es.run(parsed_path=tmp_path) \ No newline at end of file + assert set(client.indices.get_alias().keys()) == set() + + add_es.run(parsed_path=tmp_path) + client.indices.refresh(index=["articles", "paragraphs"]) + + assert set(client.indices.get_alias().keys()) == {"articles", "paragraphs"} + + # verify articles + resp = client.search(index="articles", query={"match_all": {}}) + assert resp["hits"]["total"]["value"] == 2 + + # verify paragraphs + resp = client.search(index="paragraphs", query={"match_all": {}}) + assert resp["hits"]["total"]["value"] == 4 From c592b3ecbdf03db977e7bb1581716036dd9177bd Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Fri, 23 Sep 2022 16:49:24 +0200 Subject: [PATCH 48/99] Undo changes in the add module --- src/bluesearch/entrypoint/database/add.py | 264 ++++++---------------- 1 file changed, 73 insertions(+), 191 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add.py b/src/bluesearch/entrypoint/database/add.py index 0608bc781..dd2dd8104 100644 --- a/src/bluesearch/entrypoint/database/add.py +++ b/src/bluesearch/entrypoint/database/add.py @@ -15,12 +15,9 @@ # You should have received a copy of the GNU Lesser General Public License # along with this program. If not, see . """Adding articles to the database.""" -from __future__ import annotations - import argparse import logging from pathlib import Path -from typing import Any, Iterable logger = logging.getLogger(__name__) @@ -63,197 +60,43 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: "--db-type", default="sqlite", type=str, - choices=("mariadb", "mysql", "postgres", "sqlite", "elasticsearch"), + choices=("mariadb", "mysql", "postgres", "sqlite"), help="Type of the database.", ) return parser -def _upload_sql( +def run( + *, db_url: str, + parsed_path: Path, db_type: str, - article_mappings: list[dict[str, Any]], - paragraph_mappings: list[dict[str, Any]], -) -> None: - """Upload the mappings to a SQL database. - - Parameters - ---------- - db_url - The location of the database. - db_type - Type of the database. - article_mappings - The mappings of the articles to upload. - paragraph_mappings - The mappings of the paragraphs to upload. +) -> int: + """Add an entry to the database. - Returns - ------- - None + Parameter description and potential defaults are documented inside of the + `get_parser` function. """ + from typing import Iterable + import sqlalchemy + from bluesearch.database.article import Article + from bluesearch.utils import load_spacy_model + if db_type == "sqlite": engine = sqlalchemy.create_engine(f"sqlite:///{db_url}") + elif db_type in {"mariadb", "mysql"}: engine = sqlalchemy.create_engine(f"mysql+pymysql://{db_url}") + elif db_type == "postgres": engine = sqlalchemy.create_engine(f"postgresql+pg8000://{db_url}") + else: # This branch never reached because of `choices` in `argparse` raise ValueError(f"Unrecognized database type {db_type}.") # pragma: nocover - article_keys = [ - "article_id", - "title", - "authors", - "abstract", - "pubmed_id", - "pmc_id", - "doi", - ] - article_fields = ", ".join(article_keys) - article_binds = f":{', :'.join(article_keys)}" - article_query = sqlalchemy.text( - f"INSERT INTO articles({article_fields}) VALUES({article_binds})" - ) - - logger.info("Adding entries to the articles table") - with engine.begin() as con: - con.execute(article_query, *article_mappings) - - paragraphs_keys = [ - "section_name", - "text", - "article_id", - "paragraph_pos_in_article", - ] - paragraphs_fields = ", ".join(paragraphs_keys) - paragraphs_binds = f":{', :'.join(paragraphs_keys)}" - paragraph_query = sqlalchemy.text( - f"INSERT INTO sentences({paragraphs_fields}) VALUES({paragraphs_binds})" - ) - - logger.info("Adding entries to the sentences table") - with engine.begin() as con: - con.execute(paragraph_query, *paragraph_mappings) - - -def _upload_es( - db_url: str, - article_mappings: list[dict[str, Any]], - paragraph_mappings: list[dict[str, Any]], -) -> None: - """Upload the mappings to an Elasticsearch database. - - Parameters - ---------- - db_url - The location of the database. - article_mappings - The mappings of the articles to upload. - paragraph_mappings - The mappings of the paragraphs to upload. - - Returns - ------- - None - """ - import tqdm - import urllib3 - from decouple import config - from elasticsearch import Elasticsearch - from elasticsearch.helpers import bulk - - urllib3.disable_warnings() - - client = Elasticsearch( - db_url, - basic_auth=("elastic", config("ES_PASS")), - verify_certs=False, - ) - - progress = tqdm.tqdm( - desc="Uploading articles", total=len(article_mappings), unit="articles" - ) - - def bulk_articles( - article_mappings: list[dict[str, Any]], progress: Any = None - ) -> Iterable[dict[str, Any]]: - for article in article_mappings: - doc = { - "_index": "articles", - "_id": article["article_id"], - "_source": { - "article_id": article["article_id"], - "authors": article["title"], - "title": article["authors"], - "abstract": article["abstract"], - "pubmed_id": article["pubmed_id"], - "pmc_id": article["pmc_id"], - "doi": article["doi"], - }, - } - if progress: - progress.update(1) - yield doc - - resp = bulk(client, bulk_articles(article_mappings, progress)) - print(resp) - - progress = tqdm.tqdm( - desc="Uploading paragraphs", total=len(paragraph_mappings), unit="paragraphs" - ) - - def bulk_paragraphs( - paragraph_mappings: list[dict[str, Any]], progress: Any = None - ) -> Iterable[dict[str, Any]]: - """Yield a paragraph mapping as a document to upload to Elasticsearch. - - Parameters - ---------- - paragraph_mappings - The mappings of the paragraphs to upload. - - Returns - ------- - Iterable[dict[str, Any]] - A generator of documents to upload to Elasticsearch. - """ - for paragraph in paragraph_mappings: - doc = { - "_index": "paragraphs", - "_source": { - "article_id": paragraph["article_id"], - "section_name": paragraph["section_name"], - "text": paragraph["text"], - "paragraph_id": paragraph["paragraph_pos_in_article"], - }, - } - if progress: - progress.update(1) - yield doc - - resp = bulk(client, bulk_paragraphs(paragraph_mappings, progress)) - print(resp) - - -def run( - *, - db_url: str, - parsed_path: Path, - db_type: str, -) -> int: - """Add an entry to the database. - - Parameter description and potential defaults are documented inside of the - `get_parser` function. - """ - from typing import Iterable - - from bluesearch.database.article import Article - inputs: Iterable[Path] if parsed_path.is_file(): inputs = [parsed_path] @@ -273,9 +116,12 @@ def run( if not articles: raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") - logger.info("Splitting text into paragraphs") + logger.info("Loading spacy model") + nlp = load_spacy_model("en_core_web_sm", disable=["ner"]) + + logger.info("Splitting text into sentences") article_mappings = [] - paragraph_mappings = [] + sentence_mappings = [] for article in articles: logger.info(f"Processing {article.uid}") @@ -291,25 +137,61 @@ def run( } article_mappings.append(article_mapping) - for ppos, (section, text) in enumerate(article.section_paragraphs): - paragraph_mapping = { - "section_name": section, - "text": text, - "article_id": article.uid, - "paragraph_pos_in_article": ppos, - } - paragraph_mappings.append(paragraph_mapping) + swapped = ( + (text, (section, ppos)) + for ppos, (section, text) in enumerate(article.section_paragraphs) + ) + for doc, (section, ppos) in nlp.pipe(swapped, as_tuples=True): + for spos, sent in enumerate(doc.sents): + sentence_mapping = { + "section_name": section, + "text": sent.text, + "article_id": article.uid, + "paragraph_pos_in_article": ppos, + "sentence_pos_in_paragraph": spos, + } + sentence_mappings.append(sentence_mapping) + + # Persistence. - if not paragraph_mappings: + article_keys = [ + "article_id", + "title", + "authors", + "abstract", + "pubmed_id", + "pmc_id", + "doi", + ] + article_fields = ", ".join(article_keys) + article_binds = f":{', :'.join(article_keys)}" + article_query = sqlalchemy.text( + f"INSERT INTO articles({article_fields}) VALUES({article_binds})" + ) + + logger.info("Adding entries to the articles table") + with engine.begin() as con: + con.execute(article_query, *article_mappings) + + if not sentence_mappings: raise RuntimeWarning(f"No sentence was extracted from '{parsed_path}'!") - # Persistence. - if db_type in ["mariadb", "mysql", "postgres", "sqlite"]: - _upload_sql(db_url, db_type, article_mappings, paragraph_mappings) - elif db_type == "elasticsearch": - _upload_es(db_url, article_mappings, paragraph_mappings) - else: - raise RuntimeError("Database {db_type} not supported") + sentences_keys = [ + "section_name", + "text", + "article_id", + "paragraph_pos_in_article", + "sentence_pos_in_paragraph", + ] + sentences_fields = ", ".join(sentences_keys) + sentences_binds = f":{', :'.join(sentences_keys)}" + sentence_query = sqlalchemy.text( + f"INSERT INTO sentences({sentences_fields}) VALUES({sentences_binds})" + ) + + logger.info("Adding entries to the sentences table") + with engine.begin() as con: + con.execute(sentence_query, *sentence_mappings) logger.info("Adding done") return 0 From c37585c4aa3cdbd2cbdfc9fb5b9315209d2e8c22 Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Fri, 23 Sep 2022 16:58:53 +0200 Subject: [PATCH 49/99] Fix paragraphs --- tests/unit/entrypoint/database/test_add_es.py | 16 ++++++++-------- 1 file changed, 8 insertions(+), 8 deletions(-) diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index 13e681849..dcfd4a44c 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -14,10 +14,10 @@ def test(get_es_client, tmp_path): title="some test title", authors="some test authors", abstract="some test abstract", - section_paragraphs=( - "some test section_paragraphs 1client", - "some test section_paragraphs 2", - ), + section_paragraphs=[ + ("intro", "some test section_paragraphs 1client"), + ("summary", "some test section_paragraphs 2"), + ], uid="some test uid", ) @@ -25,10 +25,10 @@ def test(get_es_client, tmp_path): title="SOME test title", authors="SOME test authors", abstract="SOME test abstract", - section_paragraphs=( - "SOME test section_paragraphs 1", - "SOME test section_paragraphs 2", - ), + section_paragraphs=[ + ("intro", "some TESTTT section_paragraphs 1client"), + ("summary", "some other test section_paragraphs 2"), + ], uid="SOME test uid", ) From f4b7536d373ee4c3aebd56993e1ad773c6402892 Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Fri, 23 Sep 2022 17:33:53 +0200 Subject: [PATCH 50/99] Make sure articles index works correctly --- src/bluesearch/entrypoint/database/add_es.py | 8 +++--- tests/unit/entrypoint/database/test_add_es.py | 25 ++++++++++++++----- 2 files changed, 23 insertions(+), 10 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index b7adab2a7..9f77a52df 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -90,8 +90,8 @@ def bulk_articles( "_id": article["article_id"], "_source": { "article_id": article["article_id"], - "authors": article["title"], - "title": article["authors"], + "authors": article["authors"], + "title": article["title"], "abstract": article["abstract"], "pubmed_id": article["pubmed_id"], "pmc_id": article["pmc_id"], @@ -184,8 +184,8 @@ def run( article_mapping = { "article_id": article.uid, "title": article.title, - "authors": ", ".join(article.authors), - "abstract": "\n".join(article.abstract), + "authors": article.authors, + "abstract": article.abstract, "pubmed_id": article.pubmed_id, "pmc_id": article.pmc_id, "doi": article.doi, diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index dcfd4a44c..c108e3a66 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -5,6 +5,7 @@ def test(get_es_client, tmp_path): from bluesearch.database.article import Article + from bluesearch.k8s.create_indices import MAPPINGS_ARTICLES, MAPPINGS_PARAGRAPHS, SETTINGS, add_index client = get_es_client if client is None: @@ -12,24 +13,24 @@ def test(get_es_client, tmp_path): article_1 = Article( title="some test title", - authors="some test authors", - abstract="some test abstract", + authors=["A", "B"], + abstract=["some test abstract", "abcd"], section_paragraphs=[ ("intro", "some test section_paragraphs 1client"), ("summary", "some test section_paragraphs 2"), ], - uid="some test uid", + uid="1", ) article_2 = Article( title="SOME test title", - authors="SOME test authors", - abstract="SOME test abstract", + authors=["Caa adsfaf", "Ddfs fdssf"], + abstract=["dsaklf", "abcd"], section_paragraphs=[ ("intro", "some TESTTT section_paragraphs 1client"), ("summary", "some other test section_paragraphs 2"), ], - uid="SOME test uid", + uid="2", ) article_1_path = tmp_path / "article_1.json" @@ -39,6 +40,8 @@ def test(get_es_client, tmp_path): article_2_path.write_text(article_2.to_json()) assert set(client.indices.get_alias().keys()) == set() + add_index(client, "articles", SETTINGS, MAPPINGS_ARTICLES) + add_index(client, "paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) add_es.run(parsed_path=tmp_path) client.indices.refresh(index=["articles", "paragraphs"]) @@ -49,6 +52,16 @@ def test(get_es_client, tmp_path): resp = client.search(index="articles", query={"match_all": {}}) assert resp["hits"]["total"]["value"] == 2 + for doc in resp["hits"]["hits"]: + if doc["_id"] == "1": + assert doc["_source"]["abstract"] == ["some test abstract", "abcd"] + assert doc["_source"]["authors"] == ["A", "B"] + assert doc["_source"]["title"] == "some test title" + else: + assert doc["_source"]["abstract"] == ["dsaklf", "abcd"] + assert doc["_source"]["authors"] == ["Caa adsfaf", "Ddfs fdssf"] + assert doc["_source"]["title"] == "SOME test title" + # verify paragraphs resp = client.search(index="paragraphs", query={"match_all": {}}) assert resp["hits"]["total"]["value"] == 4 From d2ff32dc060232775124bd9252f3406f55a03250 Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Fri, 23 Sep 2022 17:40:15 +0200 Subject: [PATCH 51/99] Make sure paragraphs correct --- tests/unit/entrypoint/database/test_add_es.py | 20 +++++++++++++++++++ 1 file changed, 20 insertions(+) diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index c108e3a66..3e88ecbf5 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -65,3 +65,23 @@ def test(get_es_client, tmp_path): # verify paragraphs resp = client.search(index="paragraphs", query={"match_all": {}}) assert resp["hits"]["total"]["value"] == 4 + + all_docs = set() + for doc in resp["hits"]["hits"]: + all_docs.add( + ( + doc["_source"]["article_id"], + doc["_source"]["paragraph_id"], + doc["_source"]["section_name"], + doc["_source"]["text"], + ) + ) + + all_docs_expected = { + ("1", 0, "intro", "some test section_paragraphs 1client"), + ("1", 1, "summary", "some test section_paragraphs 2"), + ("2", 0, "intro", "some TESTTT section_paragraphs 1client"), + ("2", 1, "summary", "some other test section_paragraphs 2"), + } + + assert all_docs == all_docs_expected From 73ba4e3993acd6b6c0d6d7462bc9e67388faee92 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 11:21:19 +0200 Subject: [PATCH 52/99] refractor add to es --- src/bluesearch/entrypoint/database/add_es.py | 192 +++++++----------- tests/unit/entrypoint/database/test_add_es.py | 18 +- 2 files changed, 89 insertions(+), 121 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index 9f77a52df..feb74fc95 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -20,7 +20,13 @@ import argparse import logging from pathlib import Path -from typing import Any, Iterable +from typing import Any, Iterable, Optional + +import tqdm +from elasticsearch import Elasticsearch +from elasticsearch.helpers import bulk + +from bluesearch.database.article import Article logger = logging.getLogger(__name__) @@ -51,99 +57,81 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: return parser -def _upload_es( - article_mappings: list[dict[str, Any]], - paragraph_mappings: list[dict[str, Any]], -) -> None: - """Upload the mappings to an Elasticsearch database. +def bulk_articles( + inputs: Iterable[Path], progress: Optional[tqdm.std.tqdm] = None +) -> Iterable[dict[str, Any]]: + """Yield an article mapping as a document to upload to Elasticsearch. Parameters ---------- - article_mappings - The mappings of the articles to upload. - paragraph_mappings - The mappings of the paragraphs to upload. - - Returns - ------- - None + inputs + Paths to the parsed files. + progress + Progress bar to update. + + Yields + ------ + dict[str, Any] + A document to upload to Elasticsearch. """ - import tqdm - import urllib3 - from bluesearch.k8s.connect import connect - from elasticsearch.helpers import bulk - - urllib3.disable_warnings() - - client = connect() - - progress = tqdm.tqdm( - desc="Uploading articles", total=len(article_mappings), unit="articles" - ) + for inp in inputs: + serialized = inp.read_text("utf-8") + article = Article.from_json(serialized) + doc = { + "_index": "articles", + "_id": article.uid, + "_source": { + "article_id": article.uid, + "authors": article.authors, + "title": article.title, + "abstract": article.abstract, + "pubmed_id": article.pubmed_id, + "pmc_id": article.pmc_id, + "doi": article.doi, + }, + } + if progress: + progress.update(1) + yield doc - def bulk_articles( - article_mappings: list[dict[str, Any]], progress: Any = None - ) -> Iterable[dict[str, Any]]: - for article in article_mappings: - doc = { - "_index": "articles", - "_id": article["article_id"], - "_source": { - "article_id": article["article_id"], - "authors": article["authors"], - "title": article["title"], - "abstract": article["abstract"], - "pubmed_id": article["pubmed_id"], - "pmc_id": article["pmc_id"], - "doi": article["doi"], - }, - } - if progress: - progress.update(1) - yield doc - resp = bulk(client, bulk_articles(article_mappings, progress)) - logger.info(f"Uploaded {resp[0]} articles.") +def bulk_paragraphs( + inputs: Iterable[Path], progress: Optional[tqdm.std.tqdm] = None +) -> Iterable[dict[str, Any]]: + """Yield a paragraph mapping as a document to upload to Elasticsearch. - progress = tqdm.tqdm( - desc="Uploading paragraphs", total=len(paragraph_mappings), unit="paragraphs" - ) + Parameters + ---------- + paragraph_mappings + The mappings of the paragraphs to upload. + progress + Progress bar to update. - def bulk_paragraphs( - paragraph_mappings: list[dict[str, Any]], progress: Any = None - ) -> Iterable[dict[str, Any]]: - """Yield a paragraph mapping as a document to upload to Elasticsearch. - - Parameters - ---------- - paragraph_mappings - The mappings of the paragraphs to upload. - - Returns - ------- - Iterable[dict[str, Any]] - A generator of documents to upload to Elasticsearch. - """ - for paragraph in paragraph_mappings: + Yields + ------ + dict[str, Any] + A document to upload to Elasticsearch. + """ + for inp in inputs: + serialized = inp.read_text("utf-8") + article = Article.from_json(serialized) + for ppos, (section, text) in enumerate(article.section_paragraphs): doc = { "_index": "paragraphs", "_source": { - "article_id": paragraph["article_id"], - "section_name": paragraph["section_name"], - "text": paragraph["text"], - "paragraph_id": paragraph["paragraph_pos_in_article"], + "article_id": article.uid, + "section_name": section, + "text": text, + "paragraph_id": ppos, }, } if progress: progress.update(1) yield doc - resp = bulk(client, bulk_paragraphs(paragraph_mappings, progress)) - logger.info(f"Uploaded {resp[0]} paragraphs.") - def run( - *, + client: Elasticsearch, parsed_path: Path, ) -> int: """Add an entry to the database. @@ -151,10 +139,6 @@ def run( Parameter description and potential defaults are documented inside of the `get_parser` function. """ - from typing import Iterable - - from bluesearch.database.article import Article - inputs: Iterable[Path] if parsed_path.is_file(): inputs = [parsed_path] @@ -165,47 +149,23 @@ def run( "Argument 'parsed_path' should be a path to an existing file or directory!" ) - articles = [] - for inp in inputs: - serialized = inp.read_text("utf-8") - article = Article.from_json(serialized) - articles.append(article) - - if not articles: + if len(inputs) == 0: raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") - logger.info("Splitting text into paragraphs") - article_mappings = [] - paragraph_mappings = [] - - for article in articles: - logger.info(f"Processing {article.uid}") - - article_mapping = { - "article_id": article.uid, - "title": article.title, - "authors": article.authors, - "abstract": article.abstract, - "pubmed_id": article.pubmed_id, - "pmc_id": article.pmc_id, - "doi": article.doi, - } - article_mappings.append(article_mapping) - - for ppos, (section, text) in enumerate(article.section_paragraphs): - paragraph_mapping = { - "section_name": section, - "text": text, - "article_id": article.uid, - "paragraph_pos_in_article": ppos, - } - paragraph_mappings.append(paragraph_mapping) + logger.info("Uploading articles to the database...") + progress = tqdm.tqdm(desc="Uploading articles", total=len(inputs), unit="articles") + resp = bulk(client, bulk_articles(inputs, progress)) + logger.info(f"Uploaded {resp[0]} articles.") - if not paragraph_mappings: - raise RuntimeWarning(f"No sentence was extracted from '{parsed_path}'!") + if resp[0] == 0: + raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") - # Persistence. - _upload_es(article_mappings, paragraph_mappings) + logger.info("Uploading articles to the database...") + progress = tqdm.tqdm( + desc="Uploading paragraphs", total=len(inputs), unit="articles" + ) + resp = bulk(client, bulk_paragraphs(inputs, progress)) + logger.info(f"Uploaded {resp[0]} paragraphs.") logger.info("Adding done") return 0 diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index 3e88ecbf5..b7dee6274 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -1,11 +1,19 @@ +from pathlib import Path + import pytest +from elasticsearch import Elasticsearch from bluesearch.entrypoint.database import add_es -def test(get_es_client, tmp_path): +def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: from bluesearch.database.article import Article - from bluesearch.k8s.create_indices import MAPPINGS_ARTICLES, MAPPINGS_PARAGRAPHS, SETTINGS, add_index + from bluesearch.k8s.create_indices import ( + MAPPINGS_ARTICLES, + MAPPINGS_PARAGRAPHS, + SETTINGS, + add_index, + ) client = get_es_client if client is None: @@ -36,14 +44,14 @@ def test(get_es_client, tmp_path): article_1_path = tmp_path / "article_1.json" article_2_path = tmp_path / "article_2.json" - article_1_path.write_text(article_1.to_json()) - article_2_path.write_text(article_2.to_json()) + article_1_path.write_text(article_1.to_json()) # type: ignore + article_2_path.write_text(article_2.to_json()) # type: ignore assert set(client.indices.get_alias().keys()) == set() add_index(client, "articles", SETTINGS, MAPPINGS_ARTICLES) add_index(client, "paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) - add_es.run(parsed_path=tmp_path) + add_es.run(client, parsed_path=tmp_path) client.indices.refresh(index=["articles", "paragraphs"]) assert set(client.indices.get_alias().keys()) == {"articles", "paragraphs"} From 9bc3abf6f191806cc3c1c4de61b27d1349f1c2ec Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 13:57:41 +0200 Subject: [PATCH 53/99] add notebook to test list in es --- notebooks/test_lists_es.ipynb | 191 ++++++++++++++++++++++++++++++++++ 1 file changed, 191 insertions(+) create mode 100644 notebooks/test_lists_es.ipynb diff --git a/notebooks/test_lists_es.ipynb b/notebooks/test_lists_es.ipynb new file mode 100644 index 000000000..dfbd767fe --- /dev/null +++ b/notebooks/test_lists_es.ipynb @@ -0,0 +1,191 @@ +{ + "cells": [ + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "from elasticsearch import Elasticsearch" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "client = Elasticsearch('http://localhost:9200')" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "from bluesearch.k8s.create_indices import (MAPPINGS_ARTICLES, MAPPINGS_PARAGRAPHS, SETTINGS, add_index)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "add_index(client, \"test_articles\", SETTINGS, MAPPINGS_ARTICLES)\n", + "add_index(client, \"test_paragraphs\", SETTINGS, MAPPINGS_PARAGRAPHS)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "client.index(\n", + " index = 'test_articles',\n", + " document = {\n", + " \"article_id\":\"1\",\n", + " \"authors\": [\"A\", \"B\"],\n", + " \"title\": \"some test title\",\n", + " \"abstract\": [\"some test abstract\", \"abcd\"],\n", + " },\n", + "id = \"1\"\n", + ")\n", + "\n", + "client.index(\n", + " index = 'test_articles',\n", + " document = {\n", + " \"article_id\":\"2\",\n", + " \"authors\": [\"Diogo\", \"Emilie\", \"Jan\", \"Francesco\"],\n", + " \"title\": \"some test title\",\n", + " \"abstract\": [\"Francesco Casalegno is the Section Manager of the Machine Learning team within the Simulation Neuroscience Division.\",\n", + " \"Together with his team, he works on the development of Machine Learning and Deep Learning models for both internal and translation projects in order to improve accuracy and scaling of current approaches.\",\n", + " \"Before joining Blue Brain, Francesco worked at RUAG Space in Switzerland and at the European Space Agency in Spain.\",\n", + " \"Francesco holds a PhD in Physics from the University of Geneva, Switzerland, and a Master in Physics from the University of Padova, Italy.\",\n", + " \"He is also a member of the IEEE Computational Intelligence Society.\",\n", + " \"His research interests include Machine Learning, Deep Learning, and Computational Neuroscience.\",\n", + " \"He is also interested in the application of Machine Learning to the field of Space Exploration.\",\n", + " \"Francesco is a member of the Blue Brain Project's Machine Learning team.\"],\n", + " },\n", + "id = \"2\"\n", + ")\n", + "\n", + "client.index(\n", + " index = 'test_articles',\n", + " document = {\n", + " \"article_id\":\"3\",\n", + " \"authors\": [\"William\", \"George\", \"Harry\"],\n", + " \"title\": \"some test title\",\n", + " \"abstract\": [\"Willim is a good guy\",\n", + " \"George is a good guy\",\n", + " \"Harry is a good guy\"],\n", + " },\n", + "id = \"3\"\n", + ")" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "resp = client.get(index = 'test_articles', id = '1')\n", + "print(resp['_source'])" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "print(type(resp['_source']['authors']))\n", + "print(resp['_source']['authors'])" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "resp = client.search(index=\"test_articles\", query={\"match\": {\"abstract\": \"test\"}})" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "print(resp)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "resp = client.search(index=\"test_articles\", query={\"match\": {\"abstract\": \"Blue Brain\"}})" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "print(resp)" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "resp = client.search(index=\"test_articles\", query={\"match\": {\"authors\": \"William\"}})" + ] + }, + { + "cell_type": "code", + "execution_count": null, + "metadata": {}, + "outputs": [], + "source": [ + "print(resp)" + ] + } + ], + "metadata": { + "kernelspec": { + "display_name": "Python 3.10.5 ('py10')", + "language": "python", + "name": "python3" + }, + "language_info": { + "codemirror_mode": { + "name": "ipython", + "version": 3 + }, + "file_extension": ".py", + "mimetype": "text/x-python", + "name": "python", + "nbconvert_exporter": "python", + "pygments_lexer": "ipython3", + "version": "3.10.5" + }, + "orig_nbformat": 4, + "vscode": { + "interpreter": { + "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" + } + } + }, + "nbformat": 4, + "nbformat_minor": 2 +} From ee4e4dd324d1cf7aa220f04aae758e8c9289a511 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 13:58:12 +0200 Subject: [PATCH 54/99] add docs --- docs/source/api/bluesearch.entrypoint.database.add_es.rst | 7 +++++++ docs/source/api/bluesearch.entrypoint.database.rst | 1 + 2 files changed, 8 insertions(+) create mode 100644 docs/source/api/bluesearch.entrypoint.database.add_es.rst diff --git a/docs/source/api/bluesearch.entrypoint.database.add_es.rst b/docs/source/api/bluesearch.entrypoint.database.add_es.rst new file mode 100644 index 000000000..7dd0f1078 --- /dev/null +++ b/docs/source/api/bluesearch.entrypoint.database.add_es.rst @@ -0,0 +1,7 @@ +bluesearch.entrypoint.database.add\_es module +============================================= + +.. automodule:: bluesearch.entrypoint.database.add_es + :members: + :undoc-members: + :show-inheritance: diff --git a/docs/source/api/bluesearch.entrypoint.database.rst b/docs/source/api/bluesearch.entrypoint.database.rst index 9f3c0c5fe..76a4a9ec8 100644 --- a/docs/source/api/bluesearch.entrypoint.database.rst +++ b/docs/source/api/bluesearch.entrypoint.database.rst @@ -8,6 +8,7 @@ Submodules :maxdepth: 4 bluesearch.entrypoint.database.add + bluesearch.entrypoint.database.add_es bluesearch.entrypoint.database.convert_pdf bluesearch.entrypoint.database.download bluesearch.entrypoint.database.init From 897b3d55aa77bf40c44331361438f90472cda956 Mon Sep 17 00:00:00 2001 From: Diogo Reis Santos Date: Mon, 26 Sep 2022 14:00:51 +0200 Subject: [PATCH 55/99] Delete test_lists_es.ipynb move to gitlab --- notebooks/test_lists_es.ipynb | 191 ---------------------------------- 1 file changed, 191 deletions(-) delete mode 100644 notebooks/test_lists_es.ipynb diff --git a/notebooks/test_lists_es.ipynb b/notebooks/test_lists_es.ipynb deleted file mode 100644 index dfbd767fe..000000000 --- a/notebooks/test_lists_es.ipynb +++ /dev/null @@ -1,191 +0,0 @@ -{ - "cells": [ - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "from elasticsearch import Elasticsearch" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "client = Elasticsearch('http://localhost:9200')" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "from bluesearch.k8s.create_indices import (MAPPINGS_ARTICLES, MAPPINGS_PARAGRAPHS, SETTINGS, add_index)" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "add_index(client, \"test_articles\", SETTINGS, MAPPINGS_ARTICLES)\n", - "add_index(client, \"test_paragraphs\", SETTINGS, MAPPINGS_PARAGRAPHS)" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "client.index(\n", - " index = 'test_articles',\n", - " document = {\n", - " \"article_id\":\"1\",\n", - " \"authors\": [\"A\", \"B\"],\n", - " \"title\": \"some test title\",\n", - " \"abstract\": [\"some test abstract\", \"abcd\"],\n", - " },\n", - "id = \"1\"\n", - ")\n", - "\n", - "client.index(\n", - " index = 'test_articles',\n", - " document = {\n", - " \"article_id\":\"2\",\n", - " \"authors\": [\"Diogo\", \"Emilie\", \"Jan\", \"Francesco\"],\n", - " \"title\": \"some test title\",\n", - " \"abstract\": [\"Francesco Casalegno is the Section Manager of the Machine Learning team within the Simulation Neuroscience Division.\",\n", - " \"Together with his team, he works on the development of Machine Learning and Deep Learning models for both internal and translation projects in order to improve accuracy and scaling of current approaches.\",\n", - " \"Before joining Blue Brain, Francesco worked at RUAG Space in Switzerland and at the European Space Agency in Spain.\",\n", - " \"Francesco holds a PhD in Physics from the University of Geneva, Switzerland, and a Master in Physics from the University of Padova, Italy.\",\n", - " \"He is also a member of the IEEE Computational Intelligence Society.\",\n", - " \"His research interests include Machine Learning, Deep Learning, and Computational Neuroscience.\",\n", - " \"He is also interested in the application of Machine Learning to the field of Space Exploration.\",\n", - " \"Francesco is a member of the Blue Brain Project's Machine Learning team.\"],\n", - " },\n", - "id = \"2\"\n", - ")\n", - "\n", - "client.index(\n", - " index = 'test_articles',\n", - " document = {\n", - " \"article_id\":\"3\",\n", - " \"authors\": [\"William\", \"George\", \"Harry\"],\n", - " \"title\": \"some test title\",\n", - " \"abstract\": [\"Willim is a good guy\",\n", - " \"George is a good guy\",\n", - " \"Harry is a good guy\"],\n", - " },\n", - "id = \"3\"\n", - ")" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "resp = client.get(index = 'test_articles', id = '1')\n", - "print(resp['_source'])" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "print(type(resp['_source']['authors']))\n", - "print(resp['_source']['authors'])" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "resp = client.search(index=\"test_articles\", query={\"match\": {\"abstract\": \"test\"}})" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "print(resp)" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "resp = client.search(index=\"test_articles\", query={\"match\": {\"abstract\": \"Blue Brain\"}})" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "print(resp)" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "resp = client.search(index=\"test_articles\", query={\"match\": {\"authors\": \"William\"}})" - ] - }, - { - "cell_type": "code", - "execution_count": null, - "metadata": {}, - "outputs": [], - "source": [ - "print(resp)" - ] - } - ], - "metadata": { - "kernelspec": { - "display_name": "Python 3.10.5 ('py10')", - "language": "python", - "name": "python3" - }, - "language_info": { - "codemirror_mode": { - "name": "ipython", - "version": 3 - }, - "file_extension": ".py", - "mimetype": "text/x-python", - "name": "python", - "nbconvert_exporter": "python", - "pygments_lexer": "ipython3", - "version": "3.10.5" - }, - "orig_nbformat": 4, - "vscode": { - "interpreter": { - "hash": "e14b248c68ef27f7e40aef879e7b97aaa0976632ef81142793ba6d8efee923a4" - } - } - }, - "nbformat": 4, - "nbformat_minor": 2 -} From a7772eec9b0857793cedc63943567ea6350e8671 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 14:03:22 +0200 Subject: [PATCH 56/99] mypy ci --- tests/unit/entrypoint/database/test_add_es.py | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index b7dee6274..cb44b4adb 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -44,8 +44,8 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: article_1_path = tmp_path / "article_1.json" article_2_path = tmp_path / "article_2.json" - article_1_path.write_text(article_1.to_json()) # type: ignore - article_2_path.write_text(article_2.to_json()) # type: ignore + article_1_path.write_text(article_1.to_json()) + article_2_path.write_text(article_2.to_json()) assert set(client.indices.get_alias().keys()) == set() add_index(client, "articles", SETTINGS, MAPPINGS_ARTICLES) From 22d3fca36d751637906565c5a6a94a515fff1128 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 15:13:14 +0200 Subject: [PATCH 57/99] from Emilie PR --- src/bluesearch/entrypoint/database/add_es.py | 7 +++++-- 1 file changed, 5 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index feb74fc95..2841d6cdb 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -150,7 +150,7 @@ def run( ) if len(inputs) == 0: - raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") + raise RuntimeWarning(f"No articles found at '{parsed_path}'!") logger.info("Uploading articles to the database...") progress = tqdm.tqdm(desc="Uploading articles", total=len(inputs), unit="articles") @@ -158,7 +158,7 @@ def run( logger.info(f"Uploaded {resp[0]} articles.") if resp[0] == 0: - raise RuntimeWarning(f"No article was loaded from '{parsed_path}'!") + raise RuntimeWarning(f"No articles were loaded to ES from '{parsed_path}'!") logger.info("Uploading articles to the database...") progress = tqdm.tqdm( @@ -167,5 +167,8 @@ def run( resp = bulk(client, bulk_paragraphs(inputs, progress)) logger.info(f"Uploaded {resp[0]} paragraphs.") + if resp[0] == 0: + raise RuntimeWarning(f"No paragraphs were loaded to ES from '{parsed_path}'!") + logger.info("Adding done") return 0 From a7b0b6e123e7488311831413da07a3e57b6d9e64 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 16:28:52 +0200 Subject: [PATCH 58/99] linters --- src/bluesearch/embedding_models.py | 2 +- src/bluesearch/k8s/embedings.py | 18 +++++++++++------- 2 files changed, 12 insertions(+), 8 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 0814f2050..fc183d222 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -140,7 +140,7 @@ def dim(self) -> int: @property def normalized(self) -> bool: - """Return true is the model as a normalization module""" + """Return true is the model as a normalization module.""" for _, module in self.senttransf_model._modules.items(): if str(module) == "Normalize()": return True diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embedings.py index 66f098689..a703d561a 100644 --- a/src/bluesearch/k8s/embedings.py +++ b/src/bluesearch/k8s/embedings.py @@ -1,3 +1,4 @@ +"""Embed the paragraphs in the database.""" from __future__ import annotations import logging @@ -8,16 +9,23 @@ from elasticsearch.helpers import scan from bluesearch.embedding_models import SentTransformer -from bluesearch.k8s.connect import connect logger = logging.getLogger(__name__) def embed_locally( - client: elasticsearch.Elasticsearch = connect(), + client: elasticsearch.Elasticsearch, model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", ) -> None: - + """Embed the paragraphs in the database locally. + + Parameters + ---------- + client + Elasticsearch client. + model_name + Name of the model to use for the embedding. + """ model = SentTransformer(model_name) # get paragraphs without embeddings @@ -40,7 +48,3 @@ def embed_locally( index="paragraphs", doc={"embedding": emb.tolist()}, id=hit["_id"] ) progress.update(1) - - -if __name__ == "__main__": - embed_locally() From 55e7d1917f11f3a2eff275035deefaafeb87da20 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 16:29:40 +0200 Subject: [PATCH 59/99] docs --- docs/source/api/bluesearch.k8s.embedings.rst | 7 +++++++ docs/source/api/bluesearch.k8s.rst | 1 + 2 files changed, 8 insertions(+) create mode 100644 docs/source/api/bluesearch.k8s.embedings.rst diff --git a/docs/source/api/bluesearch.k8s.embedings.rst b/docs/source/api/bluesearch.k8s.embedings.rst new file mode 100644 index 000000000..447db4587 --- /dev/null +++ b/docs/source/api/bluesearch.k8s.embedings.rst @@ -0,0 +1,7 @@ +bluesearch.k8s.embedings module +=============================== + +.. automodule:: bluesearch.k8s.embedings + :members: + :undoc-members: + :show-inheritance: diff --git a/docs/source/api/bluesearch.k8s.rst b/docs/source/api/bluesearch.k8s.rst index a76de5009..d15239b27 100644 --- a/docs/source/api/bluesearch.k8s.rst +++ b/docs/source/api/bluesearch.k8s.rst @@ -9,6 +9,7 @@ Submodules bluesearch.k8s.connect bluesearch.k8s.create_indices + bluesearch.k8s.embedings Module contents --------------- From 29e4a597a9939c4abe4e35661c387d807e1c89f7 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 16:32:25 +0200 Subject: [PATCH 60/99] revert mypy --- .mypy.ini | 3 --- 1 file changed, 3 deletions(-) diff --git a/.mypy.ini b/.mypy.ini index cf6fcd4fb..bc99f1f8f 100644 --- a/.mypy.ini +++ b/.mypy.ini @@ -25,6 +25,3 @@ warn_unused_ignores = True show_error_codes = True plugins = sqlmypy exclude = benchmarks/conftest.py|data_and_models/pipelines/ner/transformers_vs_spacy/transformers/|data_and_models/pipelines/sentence_embedding/training_transformers/ -disallow_any_generics = True -disallow_incomplete_defs = True -disallow_untyped_defs = True \ No newline at end of file From 450eb7214b588cf57564254c7072bad717b20da7 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 17:05:26 +0200 Subject: [PATCH 61/99] linters ci --- src/bluesearch/embedding_models.py | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index fc183d222..a38eeb31e 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -314,7 +314,7 @@ def compute_database_embeddings( def get_embedding_model( model_name_or_class: str, - checkpoint_path: pathlib.Path | str, + checkpoint_path: pathlib.Path | str | None = None, device: str = "cpu", ) -> EmbeddingModel: """Load a sentence embedding model from its name or its class and checkpoint. @@ -529,7 +529,7 @@ def run_embedding_worker( temp_h5_path: pathlib.Path, batch_size: int, checkpoint_path: pathlib.Path, - gpu: int, + gpu: int | None, h5_dataset_name: str, ) -> None: """Run per worker function. From 1dc44b1a036b31d29b1921affaf66a125ec3d000 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Mon, 26 Sep 2022 17:13:32 +0200 Subject: [PATCH 62/99] mypy local --- src/bluesearch/embedding_models.py | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index a38eeb31e..ac5cb31ee 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -314,7 +314,7 @@ def compute_database_embeddings( def get_embedding_model( model_name_or_class: str, - checkpoint_path: pathlib.Path | str | None = None, + checkpoint_path: pathlib.Path | str, device: str = "cpu", ) -> EmbeddingModel: """Load a sentence embedding model from its name or its class and checkpoint. @@ -593,7 +593,7 @@ def run_embedding_worker( logger.info("Populating h5 files") splits = np.array_split( np.arange(n_indices), n_indices / batch_size - ) # type:ignore + ) splits = [split for split in splits if len(split) > 0] for split_ix, pos_indices in enumerate(splits): From 8c8ddf2bdb25812e08bd2d4972e67139b18225e2 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 11:01:46 +0200 Subject: [PATCH 63/99] mypy --- src/bluesearch/embedding_models.py | 15 +++++++++++---- 1 file changed, 11 insertions(+), 4 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index ac5cb31ee..53d3c2dc5 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -314,7 +314,7 @@ def compute_database_embeddings( def get_embedding_model( model_name_or_class: str, - checkpoint_path: pathlib.Path | str, + checkpoint_path: pathlib.Path | str | None = None, device: str = "cpu", ) -> EmbeddingModel: """Load a sentence embedding model from its name or its class and checkpoint. @@ -350,6 +350,15 @@ def get_embedding_model( sentence_embedding_model : EmbeddingModel The sentence embedding model instance. """ + if checkpoint_path is None and model_name_or_class in [ + "SentTransformer", + "SklearnVectorizer", + ]: + raise ValueError( + "If 'model_name_or_class' in ['SentTransformer', 'SklearnVectorizer'], \ + 'checkpoint_path' should be provided." + ) + configs = { # Transformer models. "SentTransformer": lambda: SentTransformer(checkpoint_path, device), @@ -591,9 +600,7 @@ def run_embedding_worker( batch_size = min(n_indices, batch_size) logger.info("Populating h5 files") - splits = np.array_split( - np.arange(n_indices), n_indices / batch_size - ) + splits = np.array_split(np.arange(n_indices), n_indices / batch_size) splits = [split for split in splits if len(split) > 0] for split_ix, pos_indices in enumerate(splits): From e4d2e06812135c5efced25283d815c81210d17ca Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 11:34:01 +0200 Subject: [PATCH 64/99] mypy --- src/bluesearch/embedding_models.py | 45 +++++++++++++----------------- 1 file changed, 20 insertions(+), 25 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 53d3c2dc5..d966bcd28 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -350,29 +350,24 @@ def get_embedding_model( sentence_embedding_model : EmbeddingModel The sentence embedding model instance. """ - if checkpoint_path is None and model_name_or_class in [ - "SentTransformer", - "SklearnVectorizer", - ]: - raise ValueError( - "If 'model_name_or_class' in ['SentTransformer', 'SklearnVectorizer'], \ - 'checkpoint_path' should be provided." - ) + if model_name_or_class in {"SentTransformer", "SklearnVectorizer"}: + if checkpoint_path is not None: + if model_name_or_class == "SentTransformer": + model = SentTransformer(checkpoint_path, device) + elif model_name_or_class == "SklearnVectorizer": + model = SklearnVectorizer(checkpoint_path) + else: + raise ValueError("Checkpoint path must be provided for this model.") + elif model_name_or_class == "BioBERT NLI+STS": + model = SentTransformer("clagator/biobert_v1.1_pubmed_nli_sts", device) + elif model_name_or_class == "SBioBERT": + model = SentTransformer("gsarti/biobert-nli", device) + elif model_name_or_class == "SBERT": + model = SentTransformer("bert-base-nli-mean-tokens", device) + else: + raise ValueError("Unknown model name or class.") - configs = { - # Transformer models. - "SentTransformer": lambda: SentTransformer(checkpoint_path, device), - "BioBERT NLI+STS": lambda: SentTransformer( - "clagator/biobert_v1.1_pubmed_nli_sts", device - ), - "SBioBERT": lambda: SentTransformer("gsarti/biobert-nli", device), - "SBERT": lambda: SentTransformer("bert-base-nli-mean-tokens", device), - # Scikit-learn models. - "SklearnVectorizer": lambda: SklearnVectorizer(checkpoint_path), - } - if model_name_or_class not in configs: - raise ValueError(f"Unknown model name or class: {model_name_or_class}") - return configs[model_name_or_class]() + return model class MPEmbedder: @@ -537,9 +532,9 @@ def run_embedding_worker( indices: np.ndarray[Any, Any], temp_h5_path: pathlib.Path, batch_size: int, - checkpoint_path: pathlib.Path, - gpu: int | None, - h5_dataset_name: str, + checkpoint_path: pathlib.Path | None = None, + gpu: int | None = None, + h5_dataset_name: str | None = None, ) -> None: """Run per worker function. From 7fb25bb652e0a46a65983382c58c1ab010e83de3 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 11:41:15 +0200 Subject: [PATCH 65/99] mypy --- src/bluesearch/embedding_models.py | 20 +++++++++++--------- 1 file changed, 11 insertions(+), 9 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index d966bcd28..646c10ae7 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -350,26 +350,28 @@ def get_embedding_model( sentence_embedding_model : EmbeddingModel The sentence embedding model instance. """ - if model_name_or_class in {"SentTransformer", "SklearnVectorizer"}: + if model_name_or_class in ["SentTransformer", "SklearnVectorizer"]: if checkpoint_path is not None: if model_name_or_class == "SentTransformer": - model = SentTransformer(checkpoint_path, device) + return SentTransformer(checkpoint_path, device) elif model_name_or_class == "SklearnVectorizer": - model = SklearnVectorizer(checkpoint_path) + return SklearnVectorizer(checkpoint_path) + else: + raise ValueError( + f"Something went wrong, model {model_name_or_class} not " + f"implemented." + ) else: raise ValueError("Checkpoint path must be provided for this model.") elif model_name_or_class == "BioBERT NLI+STS": - model = SentTransformer("clagator/biobert_v1.1_pubmed_nli_sts", device) + return SentTransformer("clagator/biobert_v1.1_pubmed_nli_sts", device) elif model_name_or_class == "SBioBERT": - model = SentTransformer("gsarti/biobert-nli", device) + return SentTransformer("gsarti/biobert-nli", device) elif model_name_or_class == "SBERT": - model = SentTransformer("bert-base-nli-mean-tokens", device) + return SentTransformer("bert-base-nli-mean-tokens", device) else: raise ValueError("Unknown model name or class.") - return model - - class MPEmbedder: """Embedding of sentences with multiprocessing. From c1f452df8a6c1aedc22d48c8bc1f9bf311ae3f2f Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 11:46:58 +0200 Subject: [PATCH 66/99] mypy --- src/bluesearch/embedding_models.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 646c10ae7..83df266d1 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -430,7 +430,7 @@ def __init__( model_name_or_class: str, indices: np.ndarray[Any, Any], h5_path_output: pathlib.Path, - checkpoint_path: pathlib.Path | str, + checkpoint_path: pathlib.Path | str | None = None, batch_size_inference: int = 16, batch_size_transfer: int = 1000, n_processes: int = 2, From 180bcdae77934aa39561d00bb289f841650712a4 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 11:50:28 +0200 Subject: [PATCH 67/99] linters --- src/bluesearch/embedding_models.py | 1 + 1 file changed, 1 insertion(+) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 83df266d1..0cede8957 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -372,6 +372,7 @@ def get_embedding_model( else: raise ValueError("Unknown model name or class.") + class MPEmbedder: """Embedding of sentences with multiprocessing. From dbd8e5ce96332dd0cf0725dc31c73fa9c70857cd Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 12:01:23 +0200 Subject: [PATCH 68/99] unittest fix --- src/bluesearch/embedding_models.py | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index 0cede8957..e10bdc2bc 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -26,7 +26,7 @@ import numpy as np import sqlalchemy -from sentence_transformers import SentenceTransformer +import sentence_transformers from bluesearch.sql import retrieve_sentences_from_sentence_ids from bluesearch.utils import H5 @@ -129,7 +129,7 @@ def __init__( self, model_name_or_path: pathlib.Path | str, device: str | None = None ): - self.senttransf_model = SentenceTransformer( + self.senttransf_model = sentence_transformers.SentenceTransformer( str(model_name_or_path), device=device ) From 11e69d982179389013444fa56783e034f636f1bc Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 13:06:22 +0200 Subject: [PATCH 69/99] linters --- src/bluesearch/embedding_models.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index e10bdc2bc..a90757657 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -25,8 +25,8 @@ from typing import Any import numpy as np -import sqlalchemy import sentence_transformers +import sqlalchemy from bluesearch.sql import retrieve_sentences_from_sentence_ids from bluesearch.utils import H5 From 5f34f29ee21b8c6f850f310b0ba64b9fb58ed420 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 13:44:35 +0200 Subject: [PATCH 70/99] unittest remove senttrans dim and add checkpoint --- tests/unit/test_embedding_models.py | 18 ++++++++---------- 1 file changed, 8 insertions(+), 10 deletions(-) diff --git a/tests/unit/test_embedding_models.py b/tests/unit/test_embedding_models.py index 1556dacb4..6cf72c2f0 100644 --- a/tests/unit/test_embedding_models.py +++ b/tests/unit/test_embedding_models.py @@ -84,8 +84,6 @@ def test_senttransf_embedding(self, monkeypatch, n_sentences): embed_method = getattr(sbert, "embed" if n_sentences == 1 else "embed_many") # Assertions - assert sbert.dim == 768 - preprocessed_sentence = preprocess_method(dummy_sentence) assert preprocessed_sentence == dummy_sentence @@ -282,16 +280,16 @@ def test_invalid_key(self): get_embedding_model("wrong_model_name") @pytest.mark.parametrize( - "name, underlying_class", + "name, underlying_class, model_name", [ - ("BioBERT NLI+STS", "SentTransformer"), - ("SentTransformer", "SentTransformer"), - ("SklearnVectorizer", "SklearnVectorizer"), - ("SBioBERT", "SentTransformer"), - ("SBERT", "SentTransformer"), + ("BioBERT NLI+STS", "SentTransformer", None), + ("SentTransformer", "SentTransformer", "fake_model_name"), + ("SklearnVectorizer", "SklearnVectorizer", "fake_checkpoint"), + ("SBioBERT", "SentTransformer", None), + ("SBERT", "SentTransformer", None), ], ) - def test_returns_instance(self, monkeypatch, name, underlying_class): + def test_returns_instance(self, monkeypatch, name, underlying_class, model_name): fake_instance = Mock() fake_class = Mock(return_value=fake_instance) @@ -299,7 +297,7 @@ def test_returns_instance(self, monkeypatch, name, underlying_class): f"bluesearch.embedding_models.{underlying_class}", fake_class ) - returned_instance = get_embedding_model(name) + returned_instance = get_embedding_model(name, model_name) assert returned_instance is fake_instance From 7349444c0e9faac71f51449721dc1dc032c12d23 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 15:00:35 +0200 Subject: [PATCH 71/99] add tests model dim and is normalized --- tests/unit/test_embedding_models.py | 30 +++++++++++++++++++++++++++++ 1 file changed, 30 insertions(+) diff --git a/tests/unit/test_embedding_models.py b/tests/unit/test_embedding_models.py index 6cf72c2f0..3fa530f72 100644 --- a/tests/unit/test_embedding_models.py +++ b/tests/unit/test_embedding_models.py @@ -407,3 +407,33 @@ def test_do_embedding(self, monkeypatch, tmp_path, n_processes): args, _ = fake_h5.concatenate.call_args assert len(args[2]) == n_processes + + +@pytest.mark.parametrize( + "model_name", + [ + "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", + "sentence-transformers/multi-qa-mpnet-base-dot-v1", + ], +) +def test_embedding_size(model_name): + model = SentTransformer(model_name) + if model_name == "sentence-transformers/multi-qa-mpnet-base-dot-v1": + assert model.dim == 768 + elif model_name == "sentence-transformers/multi-qa-MiniLM-L6-cos-v1": + assert model.dim == 384 + + +@pytest.mark.parametrize( + "model_name", + [ + "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", + "sentence-transformers/multi-qa-mpnet-base-dot-v1", + ], +) +def test_model_is_normalized(model_name): + model = SentTransformer(model_name) + if model_name == "sentence-transformers/multi-qa-mpnet-base-dot-v1": + assert not model.normalized + elif model_name == "sentence-transformers/multi-qa-MiniLM-L6-cos-v1": + assert model.normalized From 0d411419f0eeabfad8062afe173273ffeb7ac75d Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 17:27:09 +0200 Subject: [PATCH 72/99] add tests --- src/bluesearch/entrypoint/database/add_es.py | 23 ++++++---- .../k8s/{embedings.py => embeddings.py} | 9 ++-- tests/conftest.py | 2 +- tests/unit/entrypoint/database/test_add_es.py | 26 +++++++---- tests/unit/k8s/test_add_embeedings.py | 43 +++++++++++++++++++ 5 files changed, 81 insertions(+), 22 deletions(-) rename src/bluesearch/k8s/{embedings.py => embeddings.py} (83%) create mode 100644 tests/unit/k8s/test_add_embeedings.py diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index 2841d6cdb..df148dae6 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -54,11 +54,17 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: type=Path, help="Path to a parsed file or to a directory of parsed files.", ) + + parser.add_argument( + "indices", + type=tuple[str], + help="List with two elements for articles and paragraphs index's names.", + ) return parser def bulk_articles( - inputs: Iterable[Path], progress: Optional[tqdm.std.tqdm] = None + inputs: Iterable[Path], index: str, progress: Optional[tqdm.std.tqdm] = None ) -> Iterable[dict[str, Any]]: """Yield an article mapping as a document to upload to Elasticsearch. @@ -78,7 +84,7 @@ def bulk_articles( serialized = inp.read_text("utf-8") article = Article.from_json(serialized) doc = { - "_index": "articles", + "_index": index, "_id": article.uid, "_source": { "article_id": article.uid, @@ -96,7 +102,7 @@ def bulk_articles( def bulk_paragraphs( - inputs: Iterable[Path], progress: Optional[tqdm.std.tqdm] = None + inputs: Iterable[Path], index: str, progress: Optional[tqdm.std.tqdm] = None ) -> Iterable[dict[str, Any]]: """Yield a paragraph mapping as a document to upload to Elasticsearch. @@ -117,7 +123,7 @@ def bulk_paragraphs( article = Article.from_json(serialized) for ppos, (section, text) in enumerate(article.section_paragraphs): doc = { - "_index": "paragraphs", + "_index": index, "_source": { "article_id": article.uid, "section_name": section, @@ -133,6 +139,7 @@ def bulk_paragraphs( def run( client: Elasticsearch, parsed_path: Path, + indices: tuple[str, str] = ("articles", "paragraphs"), ) -> int: """Add an entry to the database. @@ -152,19 +159,19 @@ def run( if len(inputs) == 0: raise RuntimeWarning(f"No articles found at '{parsed_path}'!") - logger.info("Uploading articles to the database...") + logger.info("Uploading articles to the {indices[0]} index...") progress = tqdm.tqdm(desc="Uploading articles", total=len(inputs), unit="articles") - resp = bulk(client, bulk_articles(inputs, progress)) + resp = bulk(client, bulk_articles(inputs, indices[0], progress)) logger.info(f"Uploaded {resp[0]} articles.") if resp[0] == 0: raise RuntimeWarning(f"No articles were loaded to ES from '{parsed_path}'!") - logger.info("Uploading articles to the database...") + logger.info("Uploading articles to the {indices[1]} index...") progress = tqdm.tqdm( desc="Uploading paragraphs", total=len(inputs), unit="articles" ) - resp = bulk(client, bulk_paragraphs(inputs, progress)) + resp = bulk(client, bulk_paragraphs(inputs, indices[1], progress)) logger.info(f"Uploaded {resp[0]} paragraphs.") if resp[0] == 0: diff --git a/src/bluesearch/k8s/embedings.py b/src/bluesearch/k8s/embeddings.py similarity index 83% rename from src/bluesearch/k8s/embedings.py rename to src/bluesearch/k8s/embeddings.py index a703d561a..c5c653590 100644 --- a/src/bluesearch/k8s/embedings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -16,6 +16,7 @@ def embed_locally( client: elasticsearch.Elasticsearch, model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", + index: str = "paragraphs", ) -> None: """Embed the paragraphs in the database locally. @@ -30,7 +31,7 @@ def embed_locally( # get paragraphs without embeddings query = {"bool": {"must_not": {"exists": {"field": "embedding"}}}} - paragraph_count = client.count(index="paragraphs", query=query)["count"] + paragraph_count = client.count(index=index, query=query)["count"] logger.info("There are {paragraph_count} paragraphs without embeddings") # creates embeddings for all the documents withouts embeddings and updates them @@ -40,11 +41,9 @@ def embed_locally( unit=" Paragraphs", desc="Updating embeddings", ) - for hit in scan(client, query=query, index="paragraphs"): + for hit in scan(client, query={"query": query}, index=index): emb = model.embed(hit["_source"]["text"]) if not model.normalized: emb /= np.linalg.norm(emb) - client.update( - index="paragraphs", doc={"embedding": emb.tolist()}, id=hit["_id"] - ) + client.update(index=index, doc={"embedding": emb.tolist()}, id=hit["_id"]) progress.update(1) diff --git a/tests/conftest.py b/tests/conftest.py index 43d0f97ba..a3cac711a 100644 --- a/tests/conftest.py +++ b/tests/conftest.py @@ -518,5 +518,5 @@ def get_es_client(monkeypatch): if client is not None: for index in client.indices.get_alias().keys(): - if index in ["articles", "paragraphs", "test_index"]: + if index in ["test_articles", "test_paragraphs", "test_index"]: remove_index(client, index) diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index cb44b4adb..4ca8db224 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -13,6 +13,7 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: MAPPINGS_PARAGRAPHS, SETTINGS, add_index, + remove_index, ) client = get_es_client @@ -47,17 +48,23 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: article_1_path.write_text(article_1.to_json()) article_2_path.write_text(article_2.to_json()) - assert set(client.indices.get_alias().keys()) == set() - add_index(client, "articles", SETTINGS, MAPPINGS_ARTICLES) - add_index(client, "paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) + assert ( + set(client.indices.get_alias().keys()) & {"test_articles", "test_paragraphs"} + ) == set() + add_index(client, "test_articles", SETTINGS, MAPPINGS_ARTICLES) + add_index(client, "test_paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) - add_es.run(client, parsed_path=tmp_path) - client.indices.refresh(index=["articles", "paragraphs"]) + add_es.run( + client, parsed_path=tmp_path, indices=("test_articles", "test_paragraphs") + ) + client.indices.refresh(index=["test_articles", "test_paragraphs"]) - assert set(client.indices.get_alias().keys()) == {"articles", "paragraphs"} + assert set(client.indices.get_alias().keys()) >= ( + {"test_articles", "test_paragraphs"} + ) # verify articles - resp = client.search(index="articles", query={"match_all": {}}) + resp = client.search(index="test_articles", query={"match_all": {}}) assert resp["hits"]["total"]["value"] == 2 for doc in resp["hits"]["hits"]: @@ -71,7 +78,7 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: assert doc["_source"]["title"] == "SOME test title" # verify paragraphs - resp = client.search(index="paragraphs", query={"match_all": {}}) + resp = client.search(index="test_paragraphs", query={"match_all": {}}) assert resp["hits"]["total"]["value"] == 4 all_docs = set() @@ -93,3 +100,6 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: } assert all_docs == all_docs_expected + + remove_index(client, "test_articles") + remove_index(client, "test_paragraphs") diff --git a/tests/unit/k8s/test_add_embeedings.py b/tests/unit/k8s/test_add_embeedings.py new file mode 100644 index 000000000..beef23a1f --- /dev/null +++ b/tests/unit/k8s/test_add_embeedings.py @@ -0,0 +1,43 @@ +import pytest + + +@pytest.mark.filterwarnings("ignore::DeprecationWarning") +def test_add_embeddings(get_es_client): + from bluesearch.k8s.create_indices import ( + MAPPINGS_PARAGRAPHS, + SETTINGS, + add_index, + remove_index, + ) + from bluesearch.k8s.embeddings import embed_locally + + client = get_es_client + + add_index(client, "test_paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) + + docs = { + "1": {"text": "some test text"}, + "2": {"text": "some other test text"}, + "3": {"text": "some final test text"}, + } + + for doc_id, doc in docs.items(): + client.create(index="test_paragraphs", id=doc_id, document=doc) + client.indices.refresh(index="test_paragraphs") + + query = {"bool": {"must_not": {"exists": {"field": "embedding"}}}} + paragraph_count = client.count(index="test_paragraphs", query=query) + assert paragraph_count["count"] == 3 + + embed_locally( + client, + model_name="sentence-transformers/multi-qa-MiniLM-L6-cos-v1", + index="test_paragraphs", + ) + client.indices.refresh(index="test_paragraphs") + + query = {"bool": {"must_not": {"exists": {"field": "embedding"}}}} + paragraph_count = client.count(index="test_paragraphs", query=query)["count"] + assert paragraph_count == 0 + + remove_index(client, "test_paragraphs") From 1d0ba006975d92270370966b41f5bbbe57f3b3d6 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 17:29:31 +0200 Subject: [PATCH 73/99] update docs --- docs/source/api/bluesearch.k8s.embeddings.rst | 7 +++++++ docs/source/api/bluesearch.k8s.embedings.rst | 7 ------- docs/source/api/bluesearch.k8s.rst | 2 +- 3 files changed, 8 insertions(+), 8 deletions(-) create mode 100644 docs/source/api/bluesearch.k8s.embeddings.rst delete mode 100644 docs/source/api/bluesearch.k8s.embedings.rst diff --git a/docs/source/api/bluesearch.k8s.embeddings.rst b/docs/source/api/bluesearch.k8s.embeddings.rst new file mode 100644 index 000000000..4e73edd0d --- /dev/null +++ b/docs/source/api/bluesearch.k8s.embeddings.rst @@ -0,0 +1,7 @@ +bluesearch.k8s.embeddings module +================================ + +.. automodule:: bluesearch.k8s.embeddings + :members: + :undoc-members: + :show-inheritance: diff --git a/docs/source/api/bluesearch.k8s.embedings.rst b/docs/source/api/bluesearch.k8s.embedings.rst deleted file mode 100644 index 447db4587..000000000 --- a/docs/source/api/bluesearch.k8s.embedings.rst +++ /dev/null @@ -1,7 +0,0 @@ -bluesearch.k8s.embedings module -=============================== - -.. automodule:: bluesearch.k8s.embedings - :members: - :undoc-members: - :show-inheritance: diff --git a/docs/source/api/bluesearch.k8s.rst b/docs/source/api/bluesearch.k8s.rst index d15239b27..207599b60 100644 --- a/docs/source/api/bluesearch.k8s.rst +++ b/docs/source/api/bluesearch.k8s.rst @@ -9,7 +9,7 @@ Submodules bluesearch.k8s.connect bluesearch.k8s.create_indices - bluesearch.k8s.embedings + bluesearch.k8s.embeddings Module contents --------------- From d0e72643ee61fc1861b52b7775d096eb34606b42 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 17:37:49 +0200 Subject: [PATCH 74/99] fix parser str nargs + --- src/bluesearch/entrypoint/database/add_es.py | 5 +++-- 1 file changed, 3 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index df148dae6..546adf39a 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -20,7 +20,7 @@ import argparse import logging from pathlib import Path -from typing import Any, Iterable, Optional +from typing import Any, Iterable, Optional, Tuple import tqdm from elasticsearch import Elasticsearch @@ -57,7 +57,8 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: parser.add_argument( "indices", - type=tuple[str], + type=str, + nargs='+', help="List with two elements for articles and paragraphs index's names.", ) return parser From 74ff6cf313924ae16fcdd5f62a7e3fbad6a3eaa6 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 17:45:04 +0200 Subject: [PATCH 75/99] mypy --- src/bluesearch/entrypoint/database/add_es.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index 546adf39a..f84d6b145 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -20,7 +20,7 @@ import argparse import logging from pathlib import Path -from typing import Any, Iterable, Optional, Tuple +from typing import Any, Iterable, Optional import tqdm from elasticsearch import Elasticsearch From 838255e26437f573fb10b23d1f515d572107e36b Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 27 Sep 2022 17:48:24 +0200 Subject: [PATCH 76/99] black --- src/bluesearch/entrypoint/database/add_es.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index f84d6b145..745b9e327 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -58,7 +58,7 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: parser.add_argument( "indices", type=str, - nargs='+', + nargs="+", help="List with two elements for articles and paragraphs index's names.", ) return parser From b2494deb1a6b7aa6876277f7cee4996ff1e3bd2c Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 09:59:26 +0200 Subject: [PATCH 77/99] pin elasticsearch --- setup.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/setup.py b/setup.py index aecd7cbe0..8c6f90b88 100644 --- a/setup.py +++ b/setup.py @@ -54,7 +54,7 @@ # Required to encrypt mysql password; >= 3.2 to fix RSA decryption vulnerability "cryptography>=3.2", "defusedxml", - "elasticsearch>=8", + "elasticsearch==8.3.3", "google-cloud-storage", "h5py", "ipython", From 2f0948d5cb65127b8875a2e8ec4dd285421a1131 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 10:30:02 +0200 Subject: [PATCH 78/99] add skip test if not es --- tests/unit/k8s/test_add_embeedings.py | 2 ++ 1 file changed, 2 insertions(+) diff --git a/tests/unit/k8s/test_add_embeedings.py b/tests/unit/k8s/test_add_embeedings.py index beef23a1f..d7e1cf432 100644 --- a/tests/unit/k8s/test_add_embeedings.py +++ b/tests/unit/k8s/test_add_embeedings.py @@ -12,6 +12,8 @@ def test_add_embeddings(get_es_client): from bluesearch.k8s.embeddings import embed_locally client = get_es_client + if client is None: + pytest.skip("Elastic search is not available") add_index(client, "test_paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) From 5f076d6cb2e5b2b9980256f165eae888c65ecb52 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 10:34:56 +0200 Subject: [PATCH 79/99] update ci ES on unit test --- .github/workflows/ci.yaml | 27 +++++++++++++-------------- 1 file changed, 13 insertions(+), 14 deletions(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index f3aecdbff..3a3d9d8cd 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -11,20 +11,6 @@ on: jobs: tox: runs-on: ubuntu-latest - services: - elasticsearch: - image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - env: - discovery.type: single-node - xpack.security.enabled: false - options: >- - --health-cmd "curl http://localhost:9200/_cluster/health" - --health-interval 10s - --health-timeout 5s - --health-retries 10 - ports: - # : - - 9200:9200 strategy: matrix: tox-env: [lint, type, docs, check-apidoc, check-packaging] @@ -54,6 +40,19 @@ jobs: run: tox -vv -e ${{ matrix.tox-env }} unit-tests: runs-on: ${{ matrix.os }} + services: + elasticsearch: + image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 + env: + discovery.type: single-node + xpack.security.enabled: false + options: >- + --health-cmd "curl http://localhost:9200/_cluster/health" + --health-interval 10s + --health-timeout 5s + --health-retries 10 + ports: + - 9200:9200 env: PIP_CACHE_DIR: .cache/pip strategy: From ac4e5b17959d72f8de5835fb11b9ea55ebddbcda Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 10:46:21 +0200 Subject: [PATCH 80/99] fix CI macos --- .github/workflows/ci.yaml | 4 +++- 1 file changed, 3 insertions(+), 1 deletion(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 3a3d9d8cd..8e918ad90 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -99,6 +99,8 @@ jobs: if: ${{ github.event_name == 'workflow_dispatch' && github.event.inputs.debug_enabled }} - name: Install mysql if: matrix.os == 'macos-latest' - run: brew install mysql + run: | + brew install mysql + brew install docker - name: Run unit tests run: tox -vv -e ${{ matrix.tox-env }} -- --color=yes From 2021d4f79c85b3fac7c670d180c23db0913cc171 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 11:10:58 +0200 Subject: [PATCH 81/99] update ci --- .github/workflows/ci.yaml | 1 + 1 file changed, 1 insertion(+) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index 8e918ad90..db6554b10 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -40,6 +40,7 @@ jobs: run: tox -vv -e ${{ matrix.tox-env }} unit-tests: runs-on: ${{ matrix.os }} + if: matrix.os == 'ubuntu-latest' services: elasticsearch: image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 From 582fabf65ea0ea39ccbe059ef0d73426a65faf6b Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 11:38:36 +0200 Subject: [PATCH 82/99] update ci docker --- .github/workflows/ci.yaml | 20 ++++---------------- 1 file changed, 4 insertions(+), 16 deletions(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index db6554b10..b143a7a02 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -22,7 +22,7 @@ jobs: - name: Checkout latest commit uses: actions/checkout@v2 with: - fetch-depth: 0 # fetch all history with version tags + fetch-depth: 0 # fetch all history with version tags - name: Set up python uses: actions/setup-python@v2 with: @@ -40,20 +40,6 @@ jobs: run: tox -vv -e ${{ matrix.tox-env }} unit-tests: runs-on: ${{ matrix.os }} - if: matrix.os == 'ubuntu-latest' - services: - elasticsearch: - image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - env: - discovery.type: single-node - xpack.security.enabled: false - options: >- - --health-cmd "curl http://localhost:9200/_cluster/health" - --health-interval 10s - --health-timeout 5s - --health-retries 10 - ports: - - 9200:9200 env: PIP_CACHE_DIR: .cache/pip strategy: @@ -81,7 +67,7 @@ jobs: - name: Checkout latest commit uses: actions/checkout@v2 with: - fetch-depth: 0 # fetch all history with version tags + fetch-depth: 0 # fetch all history with version tags - name: Set up python ${{ matrix.python-version }} uses: actions/setup-python@v2 with: @@ -103,5 +89,7 @@ jobs: run: | brew install mysql brew install docker + docker pull docker.elastic.co/elasticsearch/elasticsearch:8.3.3 + docker create -p 9200:9200 --health-cmd "curl http://localhost:9200/_cluster/health" --health-interval 10s --health-timeout 5s --health-retries 10 -e "discovery.type=single-node" -e "xpack.security.enabled=false" -e GITHUB_ACTIONS=true -e CI=true docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - name: Run unit tests run: tox -vv -e ${{ matrix.tox-env }} -- --color=yes From f164a98316d20ad7a59efbd86bee99d79c0ee7ad Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 11:43:58 +0200 Subject: [PATCH 83/99] update ci macos docker --- .github/workflows/ci.yaml | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index b143a7a02..fb8d1ab97 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -88,7 +88,7 @@ jobs: if: matrix.os == 'macos-latest' run: | brew install mysql - brew install docker + brew cask install docker docker pull docker.elastic.co/elasticsearch/elasticsearch:8.3.3 docker create -p 9200:9200 --health-cmd "curl http://localhost:9200/_cluster/health" --health-interval 10s --health-timeout 5s --health-retries 10 -e "discovery.type=single-node" -e "xpack.security.enabled=false" -e GITHUB_ACTIONS=true -e CI=true docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - name: Run unit tests From e92d248607d6fb7d591fe964df3876320f4bc6b9 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 11:46:30 +0200 Subject: [PATCH 84/99] update ci macos docker --- .github/workflows/ci.yaml | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index fb8d1ab97..e46e8eef5 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -88,7 +88,7 @@ jobs: if: matrix.os == 'macos-latest' run: | brew install mysql - brew cask install docker + brew install docker --cask docker pull docker.elastic.co/elasticsearch/elasticsearch:8.3.3 docker create -p 9200:9200 --health-cmd "curl http://localhost:9200/_cluster/health" --health-interval 10s --health-timeout 5s --health-retries 10 -e "discovery.type=single-node" -e "xpack.security.enabled=false" -e GITHUB_ACTIONS=true -e CI=true docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - name: Run unit tests From b5e835336c264ad19a58e5dec681d4dfe927bea9 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 11:55:13 +0200 Subject: [PATCH 85/99] update ci no docker macos --- .github/workflows/ci.yaml | 70 +++++++++++++++++++++++++++++++-------- 1 file changed, 56 insertions(+), 14 deletions(-) diff --git a/.github/workflows/ci.yaml b/.github/workflows/ci.yaml index e46e8eef5..aeef8edc6 100644 --- a/.github/workflows/ci.yaml +++ b/.github/workflows/ci.yaml @@ -38,14 +38,27 @@ jobs: pip install tox - name: Run tox ${{ matrix.tox-env }} run: tox -vv -e ${{ matrix.tox-env }} - unit-tests: + unit-tests-ubuntu: runs-on: ${{ matrix.os }} + services: + elasticsearch: + image: docker.elastic.co/elasticsearch/elasticsearch:8.3.3 + env: + discovery.type: single-node + xpack.security.enabled: false + options: >- + --health-cmd "curl http://localhost:9200/_cluster/health" + --health-interval 10s + --health-timeout 5s + --health-retries 10 + ports: + - 9200:9200 env: PIP_CACHE_DIR: .cache/pip strategy: fail-fast: false matrix: - os: [ubuntu-latest, macos-latest] + os: [ubuntu-latest] python-version: ["3.8", "3.9", "3.10"] include: - python-version: 3.8 @@ -54,11 +67,6 @@ jobs: tox-env: py39 - python-version: 3.10 tox-env: py310 - exclude: - - python-version: 3.8 - os: macos-latest - - python-version: 3.9 - os: macos-latest steps: - name: Cancel previous workflows that are still running uses: styfle/cancel-workflow-action@0.8.0 @@ -84,12 +92,46 @@ jobs: - name: Set up tmate session uses: mxschmitt/action-tmate@v3 if: ${{ github.event_name == 'workflow_dispatch' && github.event.inputs.debug_enabled }} - - name: Install mysql - if: matrix.os == 'macos-latest' - run: | - brew install mysql - brew install docker --cask - docker pull docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - docker create -p 9200:9200 --health-cmd "curl http://localhost:9200/_cluster/health" --health-interval 10s --health-timeout 5s --health-retries 10 -e "discovery.type=single-node" -e "xpack.security.enabled=false" -e GITHUB_ACTIONS=true -e CI=true docker.elastic.co/elasticsearch/elasticsearch:8.3.3 - name: Run unit tests run: tox -vv -e ${{ matrix.tox-env }} -- --color=yes + unit-tests-macos: + runs-on: ${{ matrix.os }} + env: + PIP_CACHE_DIR: .cache/pip + strategy: + fail-fast: false + matrix: + os: [macos-latest] + python-version: ["3.10"] + include: + - python-version: 3.10 + tox-env: py310 + steps: + - name: Cancel previous workflows that are still running + uses: styfle/cancel-workflow-action@0.8.0 + with: + access_token: ${{ github.token }} + - name: Checkout latest commit + uses: actions/checkout@v2 + with: + fetch-depth: 0 # fetch all history with version tags + - name: Set up python ${{ matrix.python-version }} + uses: actions/setup-python@v2 + with: + python-version: ${{ matrix.python-version }} + - name: Set up pip cache + uses: actions/cache@v2 + with: + path: .cache/pip + key: ${{ matrix.tox-env }}-${{ matrix.os }}-${{ hashFiles('tox.ini') }} + - name: Set up environment + run: | + pip install --upgrade pip + pip install tox + - name: Set up tmate session + uses: mxschmitt/action-tmate@v3 + if: ${{ github.event_name == 'workflow_dispatch' && github.event.inputs.debug_enabled }} + - name: Install mysql + run: brew install mysql + - name: Run unit tests + run: tox -vv -e ${{ matrix.tox-env }} -- --color=yes \ No newline at end of file From b49c323807ac95b4dc906f5f4cacdbc481252d09 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 13:48:21 +0200 Subject: [PATCH 86/99] Emilie PR review --- src/bluesearch/embedding_models.py | 90 ++++++++++++++--------------- tests/unit/test_embedding_models.py | 32 +++++----- 2 files changed, 58 insertions(+), 64 deletions(-) diff --git a/src/bluesearch/embedding_models.py b/src/bluesearch/embedding_models.py index a90757657..7f5d0f69f 100644 --- a/src/bluesearch/embedding_models.py +++ b/src/bluesearch/embedding_models.py @@ -50,7 +50,7 @@ def preprocess(self, raw_sentence: str) -> str: Parameters ---------- - raw_sentence : str + raw_sentence Raw sentence to embed. Returns @@ -60,14 +60,14 @@ def preprocess(self, raw_sentence: str) -> str: """ return raw_sentence - def preprocess_many(self, raw_sentences: list[str]) -> list[Any]: + def preprocess_many(self, raw_sentences: list[str]) -> list[str]: """Preprocess multiple sentences. This is a default implementation and can be overridden by children classes. Parameters ---------- - raw_sentences : list of str + raw_sentences List of str representing raw sentences that we want to embed. Returns @@ -83,12 +83,12 @@ def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: Parameters ---------- - preprocessed_sentence : str + preprocessed_sentence Preprocessed sentence to embed. Returns ------- - embedding : numpy.array + embedding One dimensional vector representing the embedding of the given sentence. """ @@ -100,12 +100,12 @@ def embed_many(self, preprocessed_sentences: list[str]) -> np.ndarray[Any, Any]: Parameters ---------- - preprocessed_sentences : list of str + preprocessed_sentences List of preprocessed sentences. Returns ------- - embeddings : np.ndarray + embeddings 2D numpy array with shape `(len(preprocessed_sentences), self.dim)`. Each row is an embedding of a sentence in `preprocessed_sentences`. """ @@ -117,7 +117,7 @@ class SentTransformer(EmbeddingModel): Parameters ---------- - model_name_or_path : pathlib.Path or str + model_name_or_path The name or the path of the Transformer model to load. References @@ -151,12 +151,12 @@ def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: Parameters ---------- - preprocessed_sentence : str + preprocessed_sentence Preprocessed sentence to embed. Returns ------- - embedding : numpy.array + embedding Embedding of the given sentence of shape (768,). """ return self.embed_many([preprocessed_sentence]).squeeze() @@ -166,12 +166,12 @@ def embed_many(self, preprocessed_sentences: list[str]) -> np.ndarray[Any, Any]: Parameters ---------- - preprocessed_sentences : list of str + preprocessed_sentences Preprocessed sentences to embed. Returns ------- - embedding : numpy.array + embedding Embedding of the specified sentences of shape `(len(preprocessed_sentences), 768)`. """ @@ -184,7 +184,7 @@ class SklearnVectorizer(EmbeddingModel): Parameters ---------- - checkpoint_path : pathlib.Path or str + checkpoint_path The path of the scikit-learn model to use for the embeddings in Pickle format. """ @@ -199,7 +199,7 @@ def dim(self) -> int: Returns ------- - dim : int + dim The dimension of the embedding. """ if hasattr(self.model, "n_features"): # e.g. HashingVectorizer @@ -217,13 +217,13 @@ def embed(self, preprocessed_sentence: str) -> np.ndarray[Any, Any]: Parameters ---------- - preprocessed_sentence : str + preprocessed_sentence Preprocessed sentence to embed. Can by obtained using the `preprocess` or `preprocess_many` methods. Returns ------- - embedding : numpy.ndarray + embedding Array of shape `(dim,)` with the sentence embedding. """ embedding = self.embed_many([preprocessed_sentence]) @@ -234,13 +234,13 @@ def embed_many(self, preprocessed_sentences: list[str]) -> np.ndarray[Any, Any]: Parameters ---------- - preprocessed_sentences : iterable of str + preprocessed_sentences Preprocessed sentences to embed. Can by obtained using the `preprocess` or `preprocess_many` methods. Returns ------- - embeddings : numpy.ndarray + embeddings Array of shape `(len(preprocessed_sentences), dim)` with the sentence embeddings. """ @@ -261,14 +261,14 @@ def compute_database_embeddings( Parameters ---------- - connection : sqlalchemy.engine.Engine + connection Connection to the database. - model : EmbeddingModel + model Instance of the EmbeddingModel of choice. - indices : np.ndarray + indices 1D array storing the sentence_ids for which we want to perform the embedding. - batch_size : int + batch_size Number of sentences to preprocess and embed at the same time. Should lead to major speedups. Note that the last batch will have a length of `n_sentences % batch_size` (unless it is 0). Note that some models @@ -277,10 +277,10 @@ def compute_database_embeddings( Returns ------- - final_embeddings : np.array + final_embeddings 2D numpy array with all sentences embeddings for the given models. Its shape is `(len(retrieved_indices), dim)`. - retrieved_indices : np.ndarray + retrieved_indices 1D array of sentence_ids that we managed to embed. Note that the order corresponds exactly to the rows in `final_embeddings`. """ @@ -347,7 +347,7 @@ def get_embedding_model( Returns ------- - sentence_embedding_model : EmbeddingModel + sentence_embedding_model The sentence embedding model instance. """ if model_name_or_class in ["SentTransformer", "SklearnVectorizer"]: @@ -378,48 +378,48 @@ class MPEmbedder: Parameters ---------- - database_url : str + database_url URL of the database. - model_name_or_class : str + model_name_or_class The name or class of the model for which to compute the embeddings. - indices : np.ndarray + indices 1D array storing the sentence_ids for which we want to compute the embedding. - h5_path_output : pathlib.Path + h5_path_output Path to where the output h5 file will be lying. - batch_size_inference : int + batch_size_inference Number of sentences to preprocess and embed at the same time. Should lead to major speedups. Note that the last batch will have a length of `n_sentences % batch_size` (unless it is 0). Note that some models (SBioBERT) might perform padding to the longest sentence in the batch and bigger batch size might not lead to a speedup. - batch_size_transfer : int + batch_size_transfer Batch size to be used for transfering data from the temporary h5 files to the final h5 file. - n_processes : int + n_processes Number of processes to use. Note that each process gets `len(indices) / n_processes` sentences to embed. - checkpoint_path : pathlib.Path or None + checkpoint_path If 'model_name_or_class' is the class, the path of the model to load. Otherwise, this argument is ignored. - gpus : None or list + gpus If not specified, all processes will be using CPU. If not None, then it needs to be a list of length `n_processes` where each element represents the GPU id (integer) to be used. None elements will be interpreted as CPU. - delete_temp : bool + delete_temp If True, the temporary h5 files are deleted after the final h5 is created. Disabling this flag is useful for testing and debugging purposes. temp_folder : None or pathlib.Path If None, then all temporary h5 files stored into the same folder as the output h5 file. Otherwise they are stored in the specified folder. - h5_dataset_name : str or None + h5_dataset_name The name of the dataset in the H5 file. Otherwise, the value of 'model_name_or_class' is used. start_method : str, {"fork", "forkserver", "spawn"} Start method for multiprocessing. Note that using "fork" might lead to problems when doing GPU inference. - preinitialize : bool + preinitialize If True we instantiate the model before running multiprocessing in order to download any checkpoints. Once instantiated, the model will be deleted. @@ -543,24 +543,24 @@ def run_embedding_worker( Parameters ---------- - database_url : str + database_url URL of the database. - model_name_or_class : str + model_name_or_class The name or class of the model for which to compute the embeddings. - indices : np.ndarray + indices 1D array of sentences ids indices representing what the worker needs to embed. - temp_h5_path : pathlib.Path + temp_h5_path Path to where we store the temporary h5 file. - batch_size : int + batch_size Number of sentences in the batch. - checkpoint_path : pathlib.Path or None + checkpoint_path If 'model_name_or_class' is the class, the path of the model to load. Otherwise, this argument is ignored. - gpu : int or None + gpu If None, we are going to use a CPU. Otherwise, we use a GPU with the specified id. - h5_dataset_name : str or None + h5_dataset_name The name of the dataset in the H5 file. """ current_process = mp.current_process() diff --git a/tests/unit/test_embedding_models.py b/tests/unit/test_embedding_models.py index 3fa530f72..6367eae46 100644 --- a/tests/unit/test_embedding_models.py +++ b/tests/unit/test_embedding_models.py @@ -280,7 +280,7 @@ def test_invalid_key(self): get_embedding_model("wrong_model_name") @pytest.mark.parametrize( - "name, underlying_class, model_name", + "name, underlying_class, checkpoint", [ ("BioBERT NLI+STS", "SentTransformer", None), ("SentTransformer", "SentTransformer", "fake_model_name"), @@ -289,7 +289,7 @@ def test_invalid_key(self): ("SBERT", "SentTransformer", None), ], ) - def test_returns_instance(self, monkeypatch, name, underlying_class, model_name): + def test_returns_instance(self, monkeypatch, name, underlying_class, checkpoint): fake_instance = Mock() fake_class = Mock(return_value=fake_instance) @@ -297,7 +297,7 @@ def test_returns_instance(self, monkeypatch, name, underlying_class, model_name) f"bluesearch.embedding_models.{underlying_class}", fake_class ) - returned_instance = get_embedding_model(name, model_name) + returned_instance = get_embedding_model(name, checkpoint) assert returned_instance is fake_instance @@ -410,30 +410,24 @@ def test_do_embedding(self, monkeypatch, tmp_path, n_processes): @pytest.mark.parametrize( - "model_name", + ("model_name", "expected_dim"), [ - "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", - "sentence-transformers/multi-qa-mpnet-base-dot-v1", + ("sentence-transformers/multi-qa-MiniLM-L6-cos-v1", 384), + ("sentence-transformers/multi-qa-mpnet-base-dot-v1", 768), ], ) -def test_embedding_size(model_name): +def test_embedding_size(model_name, expected_dim): model = SentTransformer(model_name) - if model_name == "sentence-transformers/multi-qa-mpnet-base-dot-v1": - assert model.dim == 768 - elif model_name == "sentence-transformers/multi-qa-MiniLM-L6-cos-v1": - assert model.dim == 384 + assert model.dim == expected_dim @pytest.mark.parametrize( - "model_name", + ("model_name", "is_normalized"), [ - "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", - "sentence-transformers/multi-qa-mpnet-base-dot-v1", + ("sentence-transformers/multi-qa-MiniLM-L6-cos-v1", True), + ("sentence-transformers/multi-qa-mpnet-base-dot-v1", False), ], ) -def test_model_is_normalized(model_name): +def test_model_is_normalized(model_name, is_normalized): model = SentTransformer(model_name) - if model_name == "sentence-transformers/multi-qa-mpnet-base-dot-v1": - assert not model.normalized - elif model_name == "sentence-transformers/multi-qa-MiniLM-L6-cos-v1": - assert model.normalized + assert model.normalized is is_normalized From b22278657fa25ec0fca831f69314596fe30e7c08 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Wed, 28 Sep 2022 13:49:59 +0200 Subject: [PATCH 87/99] Emilie PR review --- src/bluesearch/k8s/embeddings.py | 16 ++++++++++++++++ 1 file changed, 16 insertions(+) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index c5c653590..e25a108b9 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -1,3 +1,19 @@ +# Blue Brain Search is a text mining toolbox focused on scientific use cases. +# +# Copyright (C) 2020 Blue Brain Project, EPFL. +# +# This program is free software: you can redistribute it and/or modify +# it under the terms of the GNU Lesser General Public License as published by +# the Free Software Foundation, either version 3 of the License, or +# (at your option) any later version. +# +# This program is distributed in the hope that it will be useful, +# but WITHOUT ANY WARRANTY; without even the implied warranty of +# MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the +# GNU Lesser General Public License for more details. +# +# You should have received a copy of the GNU Lesser General Public License +# along with this program. If not, see . """Embed the paragraphs in the database.""" from __future__ import annotations From 0c0b1d3fcbe064afd53069f53b02bbde0b62d455 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 30 Sep 2022 11:56:30 +0200 Subject: [PATCH 88/99] add seldon embedding --- src/bluesearch/k8s/embeddings.py | 129 +++++++++++++++++++++++++++++-- 1 file changed, 122 insertions(+), 7 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index e25a108b9..0358a4d4e 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -17,22 +17,31 @@ """Embed the paragraphs in the database.""" from __future__ import annotations +import functools import logging +import os import elasticsearch import numpy as np +import requests import tqdm +from dotenv import load_dotenv from elasticsearch.helpers import scan from bluesearch.embedding_models import SentTransformer +load_dotenv() + logger = logging.getLogger(__name__) -def embed_locally( +def embed( client: elasticsearch.Elasticsearch, - model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1", index: str = "paragraphs", + embedding_method: str = "seldon", + model_name: str = "minilm", + namespace: str = "seldon", + polling: str = "mean", ) -> None: """Embed the paragraphs in the database locally. @@ -40,10 +49,26 @@ def embed_locally( ---------- client Elasticsearch client. + index + Name of the ES index. + embedding_method + Method to use to embed the paragraphs. model_name Name of the model to use for the embedding. + namespace + Namespace of the Seldon deployment. + polling + Polling method to use for the Seldon deployment. """ - model = SentTransformer(model_name) + if embedding_method == "seldon": + embed = functools.partial( + _embed_seldon, namespace=namespace, model_name=model_name, polling=polling + ) + elif embedding_method == "local": + embed = functools.partial( + _embed_locally, + model_name=model_name, + ) # get paragraphs without embeddings query = {"bool": {"must_not": {"exists": {"field": "embedding"}}}} @@ -58,8 +83,98 @@ def embed_locally( desc="Updating embeddings", ) for hit in scan(client, query={"query": query}, index=index): - emb = model.embed(hit["_source"]["text"]) - if not model.normalized: - emb /= np.linalg.norm(emb) - client.update(index=index, doc={"embedding": emb.tolist()}, id=hit["_id"]) + emb = embed(hit["_source"]["text"]) + client.update(index=index, doc={"embedding": emb}, id=hit["_id"]) progress.update(1) + + +def _embed_locally( + text: str, model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1" +) -> list[float]: + """Embed the paragraphs in the database locally. + + Parameters + ---------- + text + Text to embed. + model_name + Name of the model to use for the embedding. + + Returns + ------- + embedding + Embedding of the text. + """ + model = SentTransformer(model_name) + emb = model.embed(text) + if not model.normalized: + emb /= np.linalg.norm(emb) + return emb.tolist() + + +def _embed_seldon( + text: str, + namespace: str = "seldon", + model_name: str = "minilm", + polling: str = "mean", +) -> list[float]: + """Embed the paragraphs in the database using Seldon. + + Parameters + ---------- + text + Text to embed. + namespace + Namespace of the Seldon deployment. + model_name + Name of the Seldon deployment. + polling + Polling method to use for the Seldon deployment. + + Returns + ------- + embedding + Embedding of the text. + """ + url = ( + "http://" + + os.environ["SELDON_URL"] + + "/seldon/" + + namespace + + "/" + + model_name + + "/v2/models/transformer/infer" + ) + + # create payload + response = requests.post( + url, + json={ + "inputs": [ + { + "name": "args", + "shape": [1], + "datatype": "BYTES", + "data": text, + "parameters": {"content_type": "str"}, + } + ] + }, + ) + + # convert the response to a numpy array + tensor = response.json()["outputs"][0]["data"][0] + tensor = tensor[3:-3].split("], [") + tensor = np.vstack([np.array(t.split(", "), dtype=np.float32) for t in tensor]) + + # apply the polling method + if polling: + if polling == "max": + tensor = np.max(tensor, axis=0) + elif polling == "mean": + tensor = np.mean(tensor, axis=0) + + # normalize the embedding + tensor /= np.linalg.norm(tensor) + + return tensor.tolist() From 6771fdb005eeb819de5547c92ad7e346726b5b9e Mon Sep 17 00:00:00 2001 From: Jan Krepl Date: Tue, 4 Oct 2022 11:52:04 +0200 Subject: [PATCH 89/99] Fix CLI --- src/bluesearch/entrypoint/database/add_es.py | 37 +++++++++++++------ tests/unit/entrypoint/database/test_add_es.py | 12 +++++- 2 files changed, 35 insertions(+), 14 deletions(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index 745b9e327..e397abad4 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -27,6 +27,8 @@ from elasticsearch.helpers import bulk from bluesearch.database.article import Article +from bluesearch.k8s.connect import connect + logger = logging.getLogger(__name__) @@ -54,18 +56,25 @@ def init_parser(parser: argparse.ArgumentParser) -> argparse.ArgumentParser: type=Path, help="Path to a parsed file or to a directory of parsed files.", ) - parser.add_argument( - "indices", + "--articles-index-name", + type=str, + default="articles", + help="Desired name of the index holding articles.", + ) + parser.add_argument( + "--paragraphs-index-name", type=str, - nargs="+", - help="List with two elements for articles and paragraphs index's names.", + default="paragraphs", + help="Desired name of the index holding paragraphs.", ) return parser def bulk_articles( - inputs: Iterable[Path], index: str, progress: Optional[tqdm.std.tqdm] = None + inputs: Iterable[Path], + index: str, + progress: Optional[tqdm.std.tqdm] = None, ) -> Iterable[dict[str, Any]]: """Yield an article mapping as a document to upload to Elasticsearch. @@ -103,7 +112,9 @@ def bulk_articles( def bulk_paragraphs( - inputs: Iterable[Path], index: str, progress: Optional[tqdm.std.tqdm] = None + inputs: Iterable[Path], + index: str, + progress: Optional[tqdm.std.tqdm] = None, ) -> Iterable[dict[str, Any]]: """Yield a paragraph mapping as a document to upload to Elasticsearch. @@ -138,9 +149,9 @@ def bulk_paragraphs( def run( - client: Elasticsearch, parsed_path: Path, - indices: tuple[str, str] = ("articles", "paragraphs"), + articles_index_name: str, + paragraphs_index_name: str, ) -> int: """Add an entry to the database. @@ -160,19 +171,21 @@ def run( if len(inputs) == 0: raise RuntimeWarning(f"No articles found at '{parsed_path}'!") - logger.info("Uploading articles to the {indices[0]} index...") + # Creating a client + client = connect() + logger.info("Uploading articles to the {articles_index_name} index...") progress = tqdm.tqdm(desc="Uploading articles", total=len(inputs), unit="articles") - resp = bulk(client, bulk_articles(inputs, indices[0], progress)) + resp = bulk(client, bulk_articles(inputs, articles_index_name, progress)) logger.info(f"Uploaded {resp[0]} articles.") if resp[0] == 0: raise RuntimeWarning(f"No articles were loaded to ES from '{parsed_path}'!") - logger.info("Uploading articles to the {indices[1]} index...") + logger.info("Uploading articles to the {paragraphs_index_name} index...") progress = tqdm.tqdm( desc="Uploading paragraphs", total=len(inputs), unit="articles" ) - resp = bulk(client, bulk_paragraphs(inputs, indices[1], progress)) + resp = bulk(client, bulk_paragraphs(inputs, paragraphs_index_name, progress)) logger.info(f"Uploaded {resp[0]} paragraphs.") if resp[0] == 0: diff --git a/tests/unit/entrypoint/database/test_add_es.py b/tests/unit/entrypoint/database/test_add_es.py index 4ca8db224..179e73b59 100644 --- a/tests/unit/entrypoint/database/test_add_es.py +++ b/tests/unit/entrypoint/database/test_add_es.py @@ -1,4 +1,5 @@ from pathlib import Path +from unittest.mock import Mock import pytest from elasticsearch import Elasticsearch @@ -6,7 +7,7 @@ from bluesearch.entrypoint.database import add_es -def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: +def test(get_es_client: Elasticsearch, tmp_path: Path, monkeypatch) -> None: from bluesearch.database.article import Article from bluesearch.k8s.create_indices import ( MAPPINGS_ARTICLES, @@ -20,6 +21,9 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: if client is None: pytest.skip("Elastic search is not available") + fake_connect = Mock(return_value=client) + monkeypatch.setattr("bluesearch.entrypoint.database.add_es.connect", fake_connect) + article_1 = Article( title="some test title", authors=["A", "B"], @@ -55,8 +59,12 @@ def test(get_es_client: Elasticsearch, tmp_path: Path) -> None: add_index(client, "test_paragraphs", SETTINGS, MAPPINGS_PARAGRAPHS) add_es.run( - client, parsed_path=tmp_path, indices=("test_articles", "test_paragraphs") + parsed_path=tmp_path, + articles_index_name="test_articles", + paragraphs_index_name="test_paragraphs", ) + + assert fake_connect.call_count == 1 client.indices.refresh(index=["test_articles", "test_paragraphs"]) assert set(client.indices.get_alias().keys()) >= ( From 1fc5f73760a203a7ce596f5894abca4deeb99cd4 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 11:56:46 +0200 Subject: [PATCH 90/99] lint add es --- src/bluesearch/entrypoint/database/add_es.py | 1 - 1 file changed, 1 deletion(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index e397abad4..212609f1b 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -23,7 +23,6 @@ from typing import Any, Iterable, Optional import tqdm -from elasticsearch import Elasticsearch from elasticsearch.helpers import bulk from bluesearch.database.article import Article From 2f5db4bdb714d0f659f8d3d93b614f17cdb87d50 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 13:15:29 +0200 Subject: [PATCH 91/99] fix embedding function --- src/bluesearch/k8s/embeddings.py | 8 ++++---- 1 file changed, 4 insertions(+), 4 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index 0358a4d4e..37552d03f 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -62,11 +62,11 @@ def embed( """ if embedding_method == "seldon": embed = functools.partial( - _embed_seldon, namespace=namespace, model_name=model_name, polling=polling + embed_seldon, namespace=namespace, model_name=model_name, polling=polling ) elif embedding_method == "local": embed = functools.partial( - _embed_locally, + embed_locally, model_name=model_name, ) @@ -88,7 +88,7 @@ def embed( progress.update(1) -def _embed_locally( +def embed_locally( text: str, model_name: str = "sentence-transformers/multi-qa-MiniLM-L6-cos-v1" ) -> list[float]: """Embed the paragraphs in the database locally. @@ -112,7 +112,7 @@ def _embed_locally( return emb.tolist() -def _embed_seldon( +def embed_seldon( text: str, namespace: str = "seldon", model_name: str = "minilm", From b9d7b50b00eec42cc50f6e7f075afd0535b00789 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 14:06:43 +0200 Subject: [PATCH 92/99] isort --- src/bluesearch/entrypoint/database/add_es.py | 1 - 1 file changed, 1 deletion(-) diff --git a/src/bluesearch/entrypoint/database/add_es.py b/src/bluesearch/entrypoint/database/add_es.py index 63119c4f8..709b3f962 100644 --- a/src/bluesearch/entrypoint/database/add_es.py +++ b/src/bluesearch/entrypoint/database/add_es.py @@ -28,7 +28,6 @@ from bluesearch.database.article import Article from bluesearch.k8s.connect import connect - logger = logging.getLogger(__name__) From 0f098a56c672c14b57f7813696b51b4d9513b8c2 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 14:37:38 +0200 Subject: [PATCH 93/99] add bentoml --- src/bluesearch/k8s/embeddings.py | 50 +++++++++++++++++++++++++++ tests/unit/k8s/test_add_embeedings.py | 9 ++--- 2 files changed, 55 insertions(+), 4 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index 37552d03f..bd068e043 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -64,6 +64,8 @@ def embed( embed = functools.partial( embed_seldon, namespace=namespace, model_name=model_name, polling=polling ) + elif embedding_method == "bentoml": + embed = functools.partial(embed_bentoml, model_name=model_name) elif embedding_method == "local": embed = functools.partial( embed_locally, @@ -178,3 +180,51 @@ def embed_seldon( tensor /= np.linalg.norm(tensor) return tensor.tolist() + + +def embed_bentoml( + text: str, model_name: str = "minilm", polling: str = "mean" +) -> list[float]: + """Embed the paragraphs in the database using BentoML. + + Parameters + ---------- + text + Text to embed. + model_name + Name of the BentoML deployment. + + Returns + ------- + embedding + Embedding of the text. + """ + url = ( + "http://" + + os.environ["BENTOML_URL"] + + "/" + + model_name + ) + + # create payload + response = requests.post( + url, + headers={"accept": "application/json", "Content-Type": "text/plain"}, + data="string", + ) + + # convert the response to a numpy array + tensor = response.json() + tensor = np.vstack(tensor[0]) + + # apply the polling method + if polling: + if polling == "max": + tensor = np.max(tensor, axis=0) + elif polling == "mean": + tensor = np.mean(tensor, axis=0) + + # normalize the embedding + tensor /= np.linalg.norm(tensor) + + return tensor diff --git a/tests/unit/k8s/test_add_embeedings.py b/tests/unit/k8s/test_add_embeedings.py index d7e1cf432..db5336364 100644 --- a/tests/unit/k8s/test_add_embeedings.py +++ b/tests/unit/k8s/test_add_embeedings.py @@ -2,14 +2,14 @@ @pytest.mark.filterwarnings("ignore::DeprecationWarning") -def test_add_embeddings(get_es_client): +def test_add_embeddings_locally(get_es_client): from bluesearch.k8s.create_indices import ( MAPPINGS_PARAGRAPHS, SETTINGS, add_index, remove_index, ) - from bluesearch.k8s.embeddings import embed_locally + from bluesearch.k8s.embeddings import embed client = get_es_client if client is None: @@ -31,10 +31,11 @@ def test_add_embeddings(get_es_client): paragraph_count = client.count(index="test_paragraphs", query=query) assert paragraph_count["count"] == 3 - embed_locally( + embed( client, - model_name="sentence-transformers/multi-qa-MiniLM-L6-cos-v1", index="test_paragraphs", + embedding_method="local", + model_name="sentence-transformers/multi-qa-MiniLM-L6-cos-v1", ) client.indices.refresh(index="test_paragraphs") From 405b6bf02cc30cc2cf83feb3c6724fc6d84e2b50 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 14:55:20 +0200 Subject: [PATCH 94/99] update tests --- src/bluesearch/k8s/embeddings.py | 8 +++++++- tests/unit/k8s/test_add_embeedings.py | 10 +++++++++- 2 files changed, 16 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index bd068e043..daf4badce 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -164,6 +164,9 @@ def embed_seldon( }, ) + if not response.status_code == 200: + raise ValueError("Error in the request") + # convert the response to a numpy array tensor = response.json()["outputs"][0]["data"][0] tensor = tensor[3:-3].split("], [") @@ -210,9 +213,12 @@ def embed_bentoml( response = requests.post( url, headers={"accept": "application/json", "Content-Type": "text/plain"}, - data="string", + data=text, ) + if not response.status_code == 200: + raise ValueError("Error in the request") + # convert the response to a numpy array tensor = response.json() tensor = np.vstack(tensor[0]) diff --git a/tests/unit/k8s/test_add_embeedings.py b/tests/unit/k8s/test_add_embeedings.py index db5336364..0163e771c 100644 --- a/tests/unit/k8s/test_add_embeedings.py +++ b/tests/unit/k8s/test_add_embeedings.py @@ -1,5 +1,5 @@ import pytest - +import numpy as np @pytest.mark.filterwarnings("ignore::DeprecationWarning") def test_add_embeddings_locally(get_es_client): @@ -44,3 +44,11 @@ def test_add_embeddings_locally(get_es_client): assert paragraph_count == 0 remove_index(client, "test_paragraphs") + + +def test_embedding_bentoml(): + from bluesearch.k8s.embeddings import embed_locally, embed_bentoml + + emb_local = embed_locally("some test text") + emb_bentoml = embed_bentoml("some test text") + assert np.allclose(emb_local, emb_bentoml, rtol=1e-04, atol=1e-07).all() \ No newline at end of file From 28a0146d13cd593e7fcbc3ac6774a9db9241af1e Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 15:00:49 +0200 Subject: [PATCH 95/99] linters --- src/bluesearch/k8s/embeddings.py | 7 +------ tests/unit/k8s/test_add_embeedings.py | 7 ++++--- 2 files changed, 5 insertions(+), 9 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index daf4badce..a830ca67f 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -202,12 +202,7 @@ def embed_bentoml( embedding Embedding of the text. """ - url = ( - "http://" - + os.environ["BENTOML_URL"] - + "/" - + model_name - ) + url = "http://" + os.environ["BENTOML_URL"] + "/" + model_name # create payload response = requests.post( diff --git a/tests/unit/k8s/test_add_embeedings.py b/tests/unit/k8s/test_add_embeedings.py index 0163e771c..6f110bffb 100644 --- a/tests/unit/k8s/test_add_embeedings.py +++ b/tests/unit/k8s/test_add_embeedings.py @@ -1,5 +1,6 @@ -import pytest import numpy as np +import pytest + @pytest.mark.filterwarnings("ignore::DeprecationWarning") def test_add_embeddings_locally(get_es_client): @@ -47,8 +48,8 @@ def test_add_embeddings_locally(get_es_client): def test_embedding_bentoml(): - from bluesearch.k8s.embeddings import embed_locally, embed_bentoml + from bluesearch.k8s.embeddings import embed_bentoml, embed_locally emb_local = embed_locally("some test text") emb_bentoml = embed_bentoml("some test text") - assert np.allclose(emb_local, emb_bentoml, rtol=1e-04, atol=1e-07).all() \ No newline at end of file + assert np.allclose(emb_local, emb_bentoml, rtol=1e-04, atol=1e-07) From 97846c18569e8fac6fe9f0ced6e63b360a400dff Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Tue, 4 Oct 2022 15:34:44 +0200 Subject: [PATCH 96/99] fix test bentml not available --- tests/unit/k8s/test_add_embeedings.py | 5 +++++ 1 file changed, 5 insertions(+) diff --git a/tests/unit/k8s/test_add_embeedings.py b/tests/unit/k8s/test_add_embeedings.py index 6f110bffb..879305f18 100644 --- a/tests/unit/k8s/test_add_embeedings.py +++ b/tests/unit/k8s/test_add_embeedings.py @@ -1,3 +1,5 @@ +import os + import numpy as np import pytest @@ -48,6 +50,9 @@ def test_add_embeddings_locally(get_es_client): def test_embedding_bentoml(): + if os.environ.get("BENTOML_URL") is None: + pytest.skip("BENTOML_URL is not available") + from bluesearch.k8s.embeddings import embed_bentoml, embed_locally emb_local = embed_locally("some test text") From 17f9cb261ac80f0082d2fc94a2ca38c8b2bfb76f Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 21 Oct 2022 16:29:03 +0200 Subject: [PATCH 97/99] add force embeddings --- src/bluesearch/k8s/embeddings.py | 10 ++++++++-- 1 file changed, 8 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index a830ca67f..06f85995a 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -42,6 +42,7 @@ def embed( model_name: str = "minilm", namespace: str = "seldon", polling: str = "mean", + force: bool = False, ) -> None: """Embed the paragraphs in the database locally. @@ -71,9 +72,14 @@ def embed( embed_locally, model_name=model_name, ) + else: + raise ValueError(f"Unknown embedding method: {embedding_method}") # get paragraphs without embeddings - query = {"bool": {"must_not": {"exists": {"field": "embedding"}}}} + if force: + query = {"query": {"match_all": {}}} + else: + query = {"query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}}} paragraph_count = client.count(index=index, query=query)["count"] logger.info("There are {paragraph_count} paragraphs without embeddings") @@ -202,7 +208,7 @@ def embed_bentoml( embedding Embedding of the text. """ - url = "http://" + os.environ["BENTOML_URL"] + "/" + model_name + url = "http://" + os.environ["BENTOML_EMBEDDING_URL"] + "/" + model_name # create payload response = requests.post( From 24609239f2c867152d029a01ea33c357ffa3afa5 Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 21 Oct 2022 16:31:48 +0200 Subject: [PATCH 98/99] lint --- src/bluesearch/k8s/embeddings.py | 7 +++++-- 1 file changed, 5 insertions(+), 2 deletions(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index 06f85995a..fbe72273b 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -20,6 +20,7 @@ import functools import logging import os +from typing import Any import elasticsearch import numpy as np @@ -77,9 +78,11 @@ def embed( # get paragraphs without embeddings if force: - query = {"query": {"match_all": {}}} + query: dict[str, Any] = {"query": {"match_all": {}}} else: - query = {"query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}}} + query: dict[str, Any] = { + "query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}} + } paragraph_count = client.count(index=index, query=query)["count"] logger.info("There are {paragraph_count} paragraphs without embeddings") From a5ede0317518ced4ad0963d3948dacc2fe3783cf Mon Sep 17 00:00:00 2001 From: Diogo Santos Date: Fri, 21 Oct 2022 16:32:45 +0200 Subject: [PATCH 99/99] small fix --- src/bluesearch/k8s/embeddings.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/src/bluesearch/k8s/embeddings.py b/src/bluesearch/k8s/embeddings.py index fbe72273b..96abadc70 100644 --- a/src/bluesearch/k8s/embeddings.py +++ b/src/bluesearch/k8s/embeddings.py @@ -80,7 +80,7 @@ def embed( if force: query: dict[str, Any] = {"query": {"match_all": {}}} else: - query: dict[str, Any] = { + query = { "query": {"bool": {"must_not": {"exists": {"field": "embedding"}}}} } paragraph_count = client.count(index=index, query=query)["count"]