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</a>
|
||
</div>
|
||
|
||
<span class="search-input-link user-guide-link" role="navigation" aria-label="User guide">
|
||
<a href="/help/"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="user_guide">
|
||
User Guide
|
||
</a>
|
||
</span>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
|
||
</form>
|
||
|
||
|
||
<div id="article-page-header">
|
||
<div id="article-top-actions-bar" class="article-top-actions-bar">
|
||
<div class="inner-wrap">
|
||
<div class="actions-container">
|
||
<div class="return-to-search">
|
||
|
||
|
||
</div>
|
||
|
||
<div class="multiple-results-actions " role="region" aria-label="save, email, send to">
|
||
<button id="save-results-panel-trigger"
|
||
type="button"
|
||
class="save-results save-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="save-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="open">
|
||
Save
|
||
</button><button id="email-results-panel-trigger"
|
||
type="button"
|
||
class="email-results email-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="email-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="open">
|
||
Email
|
||
</button><div class="more-actions dropdown-block"><button id="more-actions-trigger"
|
||
type="button"
|
||
class="trigger more-actions-trigger"
|
||
ref="linksrc=show_moreactions_btn"
|
||
aria-label="Send to"
|
||
aria-controls="more-actions-dropdown">Send to</button><div id="more-actions-dropdown" class="dropdown dropdown-container" hidden><div class="content"><ul class="more-actions-links"><li><a class="clipboard-panel-trigger dropdown-block-link "
|
||
href="#"
|
||
role="button"
|
||
data-ga-category="save_share"
|
||
data-ga-action="clipboard"
|
||
data-ga-label="send">
|
||
Clipboard
|
||
</a></li><li><a role="button" class="dropdown-block-link bibliography-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F24315997%2F%23open-bibliography-panel">My Bibliography</a></li><li><a role="button" class="dropdown-block-link collections-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F24315997%2F%23open-collections-panel">Collections</a></li><li><a role="button" class="citation-manager-panel-trigger dropdown-block-link citation-manager-trigger-target" href="#">Citation manager</a></li></ul></div></div></div>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region">
|
||
<button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog">
|
||
<span class="button-label">Display options</span>
|
||
</button>
|
||
|
||
<div class="dropdown" hidden>
|
||
<div class="title">
|
||
Display options
|
||
</div>
|
||
|
||
<div class="content">
|
||
|
||
<div class="format-container">
|
||
<span class="option-label">
|
||
Format
|
||
</span>
|
||
<select name="format" data-initial-value="abstract" aria-label="Display format" id="article-display-format">
|
||
<option value="abstract">Abstract</option>
|
||
|
||
<option value="pubmed">PubMed</option>
|
||
|
||
<option value="pmid">PMID</option>
|
||
|
||
</select>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="article-panels-container" class="article-panels-container">
|
||
<div id="save-action-panel" class="save-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Save citation to file
|
||
</h2>
|
||
<form id="save-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="save-action-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="save-action-format" name="results-format" class="action-panel-selector">
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="pubmed-text">PubMed</option>
|
||
<option value="pmid">PMID</option>
|
||
<option value="abstract">Abstract (text)</option>
|
||
<option value="csv">CSV</option>
|
||
</select>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Save citations to file' panel"
|
||
ref="linksrc=close_save_panel"
|
||
aria-controls="save-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="email-action-panel"
|
||
class="email-action-panel action-panel"
|
||
aria-hidden="true"
|
||
data-recaptcha-script-url="https://www.recaptcha.net/recaptcha/enterprise.js?render=explicit&onload=onloadCaptchaCallback"
|
||
data-recaptcha-enabled="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Email citation
|
||
</h2>
|
||
<form id="email-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/send-email/"
|
||
data-by-search-action="/results-export-email-by-search-data/"
|
||
data-by-ids-action="/send-email/"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post"
|
||
method="post"
|
||
>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<span class="action-panel-label">
|
||
Subject:
|
||
</span>
|
||
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 24315997 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 24315997"/>
|
||
<input type="hidden" name="email-subject-hash" value="a01b68f0b66c11b18ae026418fcf5f18c776bde49fb7258b3996260291cbb013"/>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-to" class="action-panel-label required-field-asterisk">
|
||
To:
|
||
</label>
|
||
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-from" class="action-panel-label">
|
||
From:
|
||
</label>
|
||
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
|
||
</div>
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-citation-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
|
||
<option selected="selected" value="summary">Summary</option>
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="abstract">Abstract</option>
|
||
<option value="abstract-text">Abstract (text)</option>
|
||
|
||
</select>
|
||
</div>
|
||
<div class="include-supplemental-container">
|
||
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
|
||
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="form-field recaptcha ">
|
||
|
||
|
||
|
||
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
|
||
|
||
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="send">
|
||
Send email
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Email citations' panel"
|
||
ref="linksrc=close_email_panel"
|
||
aria-controls="email-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
<input type="hidden" name="email-search-details" value="" />
|
||
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="collections-action-panel"
|
||
class="collections-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-collections-open-panel-enabled="false"
|
||
data-collections-open-panel-url-hash="#open-collections-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to Collections
|
||
</h3>
|
||
|
||
|
||
<form id="collections-action-panel-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-add-to-collection-max-amount="1000"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
|
||
|
||
<div class="choice-group" role="radiogroup">
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_new">
|
||
<label for="collections-action-panel-new">Create a new collection</label>
|
||
</li>
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_existing">
|
||
<label for="collections-action-panel-existing">Add to an existing collection</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
|
||
<div class="controls-wrapper">
|
||
<div class="action-panel-control-wrap new-collections-controls">
|
||
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label>
|
||
<input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-panel-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="save_share"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection">
|
||
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div>
|
||
</div>
|
||
<div class="action-panel-control-wrap existing-collections-controls">
|
||
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label>
|
||
<select id="collections-action-panel-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="save_share"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
|
||
</select>
|
||
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="add">
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="bibliography-action-panel"
|
||
class="bibliography-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-bibliography-open-panel-enabled="false"
|
||
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to My Bibliography
|
||
</h3>
|
||
<form id="bibliography-action-panel-form"
|
||
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-add-to-bibliography-max-amount="100"
|
||
data-add-to-bibliography-batch-size="10"
|
||
data-bibliography-delegates-url="/list-bibliography-delegates/"
|
||
data-add-to-bibliography-url="/add-to-bibliography/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap bibliographies-controls">
|
||
<div class="choice-group">
|
||
<ul class="bibliographies-action-add radio-group-items">
|
||
<li>
|
||
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
|
||
<label for="my-bibliography">My Bibliography</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your delegates due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore>
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to bibliography' panel"
|
||
ref="linksrc=close_bibliography_panel"
|
||
aria-controls="bibliography-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="mybib"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
|
||
data-saved-search-open-panel-enabled="false"
|
||
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your saved search
|
||
</h2>
|
||
|
||
<form id="saved-search-action-panel-form"
|
||
class="saved-search-action-panel-form action-panel-content action-form"
|
||
data-create-saved-search-url="/create-saved-search/"
|
||
data-try-search-terms-url="/try-search-term/"
|
||
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
|
||
Name of saved search:
|
||
</label>
|
||
<input maxlength="200"
|
||
type="text"
|
||
name="saved-search-name"
|
||
id="saved-search-name"
|
||
class="saved-search-name"
|
||
value=""
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
|
||
Search terms:
|
||
</label>
|
||
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
|
||
</div>
|
||
<div class="test-search-term-wrap">
|
||
<a href="#" class="try-search-term">Test search terms</a>
|
||
</div>
|
||
<div class="choice-group action-panel-extra-margin-top">
|
||
<span class="action-panel-label" id="fieldset-label">
|
||
Would you like email updates of new search results?
|
||
</span>
|
||
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
|
||
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
|
||
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
|
||
</li>
|
||
<li>
|
||
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
|
||
<label for="saved-search-alert-no" class="action-panel-label">No</label>
|
||
</li>
|
||
</ul>
|
||
</fieldset>
|
||
</div>
|
||
|
||
<div class="alert-schedule-wrap">
|
||
<div class="action-panel-control-wrap">
|
||
<label class="action-panel-label">
|
||
Email:
|
||
</label>
|
||
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
|
||
</div>
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="saved-search-frequency" class="action-panel-label">
|
||
Frequency:
|
||
</label>
|
||
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
|
||
<option value="monthly">Monthly</option>
|
||
<option value="weekly">Weekly</option>
|
||
<option value="daily">Daily</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-monthly-additional">
|
||
<label for="saved-search-monthly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
|
||
<option value="Sunday">The first Sunday</option>
|
||
<option value="Monday">The first Monday</option>
|
||
<option value="Tuesday">The first Tuesday</option>
|
||
<option value="Wednesday">The first Wednesday</option>
|
||
<option value="Thursday">The first Thursday</option>
|
||
<option value="Friday">The first Friday</option>
|
||
<option value="Saturday">The first Saturday</option>
|
||
<option value="day">The first day</option>
|
||
<option value="weekday">The first weekday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-weekly-additional">
|
||
<label for="saved-search-weekly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
|
||
<option value="Sunday">Sunday</option>
|
||
<option value="Monday">Monday</option>
|
||
<option value="Tuesday">Tuesday</option>
|
||
<option value="Wednesday">Wednesday</option>
|
||
<option value="Thursday">Thursday</option>
|
||
<option value="Friday">Friday</option>
|
||
<option value="Saturday">Saturday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-report" class="action-panel-label">
|
||
Report format:
|
||
</label>
|
||
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
|
||
<option value="DocSum">Summary</option>
|
||
<option value="DocSumText">Summary (text)</option>
|
||
<option value="Abstract">Abstract</option>
|
||
<option value="AbstractText">Abstract (text)</option>
|
||
<option value="MEDLINE">PubMed</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-amount" class="action-panel-label">
|
||
Send at most:
|
||
</label>
|
||
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
|
||
<option value="1">1 item</option>
|
||
<option value="5" selected>5 items</option>
|
||
<option value="10">10 items</option>
|
||
<option value="20">20 items</option>
|
||
<option value="50">50 items</option>
|
||
<option value="100">100 items</option>
|
||
<option value="200">200 items</option>
|
||
</select>
|
||
</div>
|
||
<div>
|
||
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
|
||
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
|
||
Send even when there aren't any new results
|
||
</label>
|
||
</div>
|
||
<div class="action-panel-control-wrap option-text-in-email-wrap">
|
||
<label for="saved-search-email-text" class="action-panel-label">
|
||
Optional text in email:
|
||
</label>
|
||
<textarea name="saved-search-email-text"
|
||
id="saved-search-email-text"
|
||
class="saved-search-email-text"></textarea>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Save
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your saved search' panel"
|
||
ref="linksrc=close_saved_search_panel"
|
||
aria-controls="saved-search-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Create a file for external citation management software
|
||
</h2>
|
||
<form id="citation-manager-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
|
||
|
||
<input name="results-format" type="hidden" value="pubmed"/>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Send citations to citation manager' panel"
|
||
ref="linksrc=close_citation_manager_panel"
|
||
aria-controls="citation-manager-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your RSS Feed
|
||
</h2>
|
||
|
||
<form id="rss-action-panel-form"
|
||
class="rss-action-panel-form action-panel-content action-form"
|
||
data-create-rss-feed-url="/create-rss-feed-url/"
|
||
data-search-form-term-value="">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="rss-name" class="action-panel-label required-field-asterisk">
|
||
Name of RSS Feed:
|
||
</label>
|
||
<input maxlength="200"
|
||
placeholder="Name"
|
||
type="text"
|
||
name="rss-name"
|
||
id="rss-name"
|
||
class="rss-name"
|
||
value=''
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="rss-limit-wrap">
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="rss-limit" class="action-panel-label">
|
||
Number of items displayed:
|
||
</label>
|
||
<select id="rss-limit" class="no-border-panel-selector rss-limit">
|
||
<option value="5">5</option>
|
||
<option value="10">10</option>
|
||
<option value="15" selected="selected">15</option>
|
||
<option value="20">20</option>
|
||
<option value="50">50</option>
|
||
<option value="100">100</option>
|
||
</select>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Creating..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Create RSS
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your RSS' panel"
|
||
ref="linksrc=close_rss_panel"
|
||
aria-controls="rss-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap rss-link-copy-wrap">
|
||
<label for="rss-link" class="usa-sr-only">RSS Link</label>
|
||
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
|
||
<button
|
||
type="button"
|
||
disabled
|
||
class="rss-link-copy-button disabled"
|
||
data-ga-category="save_share"
|
||
data-ga-action="rss"
|
||
data-ga-label="copy">
|
||
Copy
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="article-page" id="article-page" data-article-pmid="24315997">
|
||
<aside class="page-sidebar">
|
||
<div class="inner-wrap">
|
||
|
||
<div class="full-text-links">
|
||
<div class="full-view">
|
||
<h3 class="title">
|
||
Full text links
|
||
</h3>
|
||
<div class="full-text-links-list">
|
||
<a class="link-item
|
||
|
||
dialog-focus"
|
||
href="https://linkinghub.elsevier.com/retrieve/pii/S1074-7613(13)00509-8"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=3048&itool=Abstract-def&log$=linkouticon&uid=24315997&db=pubmed&nlmid=9432918"
|
||
title="See full text options at Elsevier Science"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="Elsevier Science"
|
||
data-ga-label="24315997"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-celloa.png" alt="Elsevier Science full text link"><span class="text">
|
||
|
||
Elsevier Science
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/24315997/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=24315997&db=pubmed&nlmid=9432918"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="24315997"
|
||
><span class="text">
|
||
|
||
Free PMC article
|
||
|
||
</span></a>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="short-view">
|
||
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
|
||
Full text links
|
||
</a>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
|
||
aria-label="Open dialog with citation text in different styles"
|
||
data-ga-category="save_share"
|
||
data-ga-action="cite"
|
||
data-ga-label="open"
|
||
data-all-citations-url="/24315997/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/24315997/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="24315997" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
|
||
aria-label="Save article in MyNCBI collections."
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_button"
|
||
data-collections-open-dialog-enabled="false"
|
||
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F24315997%2F%23open-collections-dialog"
|
||
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
|
||
class="dialog collections-dialog"
|
||
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="TEsBkuMfUq0F7GDqJCUUj4FXS8CtHwKBarcGXkfBu1N917JgmVxWNcbBqckFA7iV"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
|
||
id="collections-action-dialog-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
|
||
id="collections-action-dialog-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label><input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-dialog-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label><select id="collections-action-dialog-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="add">
|
||
Add
|
||
</button><button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger"
|
||
title="Open dialog with more actions to take"
|
||
ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region"><button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title">
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Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation
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Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation
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data-ga-label="Gaelle Le Friec">Gaelle Le Friec</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK." href="#short-view-affiliation-2" ref="linksrc=author_aff">
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4
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data-ga-label="Christian Drouet">Christian Drouet</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Université Joseph Fourier, GREPI/AGIM CNRS FRE3405, Grenoble, F-38041, France." href="#short-view-affiliation-5" ref="linksrc=author_aff">
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5
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6
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6
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8
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data-ga-label="Santiago Rodriguez de Cordoba">Santiago Rodriguez de Cordoba</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Departamento de Immunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 28006, Spain." href="#short-view-affiliation-3" ref="linksrc=author_aff">
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<li data-affiliation-id="short-view-affiliation-9"
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><sup class="key">9</sup> MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK; Biomedical Research Centre, King's Health Partners, Guy's Hospital, London SE1 9RT, UK.</li>
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<li data-affiliation-id="short-view-affiliation-10"
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id="short-view-affiliation-10"
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><sup class="key">10</sup> MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, King's College London, Guy's Hospital, London SE1 9RT, UK. Electronic address: claudia.kemper@kcl.ac.uk.</li>
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Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.
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Copyright © 2013 Elsevier Inc. All rights reserved.
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Graphical abstract
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Resting Human CD4 <sup> + </sup> T… </p></div>
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<p> Figure 1 </p>
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<div class="figure-caption-contents"><p> Resting Human CD4 <sup> + </sup> T Cells Contain Stores of C3 and C3-Activating Cathepsin… </p></div>
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Figure 1
|
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<div class="figure-caption-contents">Resting Human CD4<sup>+</sup> T Cells Contain Stores of C3 and C3-Activating Cathepsin L (A) CTSL-mediated C3 cleavage in the presence of CTSL inhibitors, including a chemical inhibitor, a function-blocking (Ab1) and a non-function-blocking antibody to CTSL (Ab2) and analysis by immunoblotting for C3 cleavage components. (B) CTSL-mediated cleavage of C3 generates C3a. C3 incubation with CTSL (50, 100, and 200 ng) generates C3a detected by silver staining (left panel) and immunoblotting with two anti-C3a antibodies to cleaved C3a and C3a contained in the C3 α chain (right panel). (C) T cells contain mRNAs coding for C3, CTSL, and the C3a receptor (C3aR). Data shown in (A)–(C) are representative of three experiments (n = 3). (D) Resting CD4<sup>+</sup> T cells contain intracellular C3 and CTSL as assessed by flow cytometry analysis. (E) Subcellular localization of C3 and CTSL stores assessed by confocal microscopy. Scale bars represent 10 μM. (D and E) are representative of n = 5 experiments. Clnx, calnexin, endoplasmic reticulum marker; EEAI, early endosomal vesicle marker; Lamp1, lysosomal marker; MFI, mean fluorescence intensity; Rab5, late endosomal vesicle marker. (I, magnification ×60; II to VII, magnification ×100). See also Figure S1.</div>
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<strong class="figure-label">
|
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<p> Figure 2 </p>
|
||
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|
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|
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<div class="figure-caption-contents"><p> CTSL Generates Intracellular and Extracellular… </p></div>
|
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|
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<p> Figure 2 </p>
|
||
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|
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<div class="figure-caption-contents"><p> CTSL Generates Intracellular and Extracellular C3a (A) C3a generation in resting and activated… </p></div>
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Figure 2
|
||
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|
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|
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<div class="figure-caption-contents">CTSL Generates Intracellular and Extracellular C3a (A) C3a generation in resting and activated T cells (1 hr) in the presence of different CTSL-blocking reagents: a chemical CTSL inhibitor (CTSLi), a function-blocking (block), and a non-function-blocking antibody to CTSL (non-block) (left panel). Expression of CTSL, C3b, and C3aR was also measured but without addition of CTSL-blocking reagents (right panels). Shown are representative data of three independently performed experiments (n = 3). (B and C) C3b and C3a and their respective receptors translocate and colocalize upon T cell activation. Nonactivated or anti-CD3 and anti-CD46-activated T cells, permeabilized and stained for C3, CTSL, C3a, C3aR, and CD46 in the combinations depicted and analyzed by confocal microscopy (B). Shown are two representative staining examples side-by-side for each condition from eight similarly performed experiments with a different donor each time (n = 8). Scale bar represents 5 μM. (C) Statistical analysis ± SD for colocalization events of the proteins assessed under (B) with Pearson’s Correlation Coefficient method. (Magnification ×100). <sup>∗</sup>p < 0.05. See also Figure S2.</div>
|
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|
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|
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|
||
<p> Figure 3 </p>
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> CD4 <sup> + </sup> T Cell Survival… </p></div>
|
||
|
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||
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|
||
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|
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|
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|
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<p> Figure 3 </p>
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> CD4 <sup> + </sup> T Cell Survival Is Dependent on CTSL-Mediated C3 Processing and Intracellular… </p></div>
|
||
|
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<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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|
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Figure 3
|
||
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|
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|
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|
||
<div class="figure-caption-contents">CD4<sup>+</sup> T Cell Survival Is Dependent on CTSL-Mediated C3 Processing and Intracellular C3aR Signaling (A and B) Viability (A) and mTOR activation (B) in resting T cells with increasing amounts of CTSL inhibitor with or without concurrent addition of C3a (100 ng/ml) at 12 hr postaddition of reagents. (C) Effect of C3aR-specific siRNA (left panel) on viability (middle panel) and mTOR activity (right panel) in nonactivated T cells 24 hr after transfection. (D) Effect of GPCR inhibition with pertussis toxin on viability (left panel) and mTOR activation (right panel) with and without C3a addition. Data ± SD shown are derived from three independently performed experiments (n = 3). (E) Confocal microscopy analysis for C3aR, mTOR, and RagC expression and colocalization in resting CD4<sup>+</sup> T cells (n = 2). Scale bar represents 5 μM. (F) <i>C3</i> mRNA and intracellular C3a protein in cells from serum C3-deficient patients. (Fi) <i>C3</i> mRNA in peripheral blood mononuclear cells (PBMCs) from three serum C3-deficient patients (P1, P2 and P3) and a healthy donor (HD). (Fii) Comparison of <i>C3</i> mRNA between PBMCs and CD4<sup>+</sup> T cells from P1. Other C3 primer pairs gave similar results (data not shown). (Fiii) Activated C3 (intracellular C3a) in purified CD4<sup>+</sup> T cells from C3-deficient Patients 1, 2, and 3. CD4<sup>+</sup> T cells from Patient 1 were also assessed for C3a presence by confocal microscopy (two panels below). Scale bar represents 25 μM. Data (±SD) are from three experiments (n = 3) in (A)–(D). (E) ×100 magnification and (Fiii, lower panels) ×60 magnification. Conc., concentration; Ctrl. siRNA, control siRNA; Mock-transf., mock-transfected. <sup>∗</sup>p < 0.05; <sup>∗∗</sup>p < 0.005. See also Figure S3.</div>
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|
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<p> Figure 4 </p>
|
||
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|
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|
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|
||
|
||
<div class="figure-caption-contents"><p> Th1 and Th17 Cell Induction… </p></div>
|
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|
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|
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|
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<p> Figure 4 </p>
|
||
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|
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|
||
|
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<div class="figure-caption-contents"><p> Th1 and Th17 Cell Induction Requires Cell Surface Activation of CD46 and C3aR… </p></div>
|
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Figure 4
|
||
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|
||
<div class="figure-caption-contents">Th1 and Th17 Cell Induction Requires Cell Surface Activation of CD46 and C3aR by CTSL-Generated C3 Activation Fragments (A and B) C3a supplementation rescues CTSL inhibitor (CTSLi)-mediated diminution of Th1 cell induction. CD4<sup>+</sup> T cells were stimulated as shown in media with 5 nM CTSLi with or without addition of C3a (100 ng/ml). (A) 5 nM CTSL inhibitor leaves cell viability (see Figure S4B) and mTOR activity (right panel) unaffected. (B) IFN-γ production by cells activated under these conditions was measured 36 hr after activation with IFN-γ production by CD3- (left panel) or CD3<sup>+</sup>CD46-activated cells (right panel) set at 100%. (C) Effect of anti-CTSL function-blocking or function-non-blocking antibodies on Th1 cell induction. (D) Effects of CTSL inhibition on Th2 and Th17 cell-mediated responses. Experiments were performed as described under (A) and (B) and production of indicated cytokines measured 36 hr after activation. Data ± SD are from five independent experiments (n = 5) in (A)–(C) and from three independent experiments in (D) with results shown as mean values of conditions performed in duplicate (n = 3). See also Figure S4.</div>
|
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|
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<p> Figure 5 </p>
|
||
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|
||
|
||
|
||
|
||
<div class="figure-caption-contents"><p> Enhanced Cytokine Production by T… </p></div>
|
||
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<p> Figure 5 </p>
|
||
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|
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|
||
<div class="figure-caption-contents"><p> Enhanced Cytokine Production by T Cells in the Synovial Fluid from a Patient… </p></div>
|
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Figure 5
|
||
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<div class="figure-caption-contents">Enhanced Cytokine Production by T Cells in the Synovial Fluid from a Patient with Juvenile Arthritis Is Normalized by CTSL Inhibition (A) CD4<sup>+</sup> T cells from blood of a healthy donor (HD) or blood and synovial fluid (Syn. fluid) of a patient with juvenile arthritis (JA) were assessed for intracellular C3a and mTOR immediately after purification. (B) Cytokine production of the stimulated HD and JA P1 peripheral blood T cells were assessed at 18 hr postactivation. (C) Intracellular C3a and activated mTOR amounts and (D) cytokine production of stimulated T cells from synovial fluid of JA P1 in presence of shown CTSL inhibitor (CTSLi) concentrations assessed at 18 hr. The addition of 5 nM CTSLi had no effect on cell viability. Supplementation of media with 20 nM CTSLi had no effect on nonactivated and CD3-activated cells and reduced cell viability by 5% (±2.7%) in CD3 + CD28 and CD3 + CD46-activated cells (not shown). Data represent mean values of conditions performed in duplicate. See also Figure S5.</div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Effector and Regulatory T Cells… </p></div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Effector and Regulatory T Cells Engage Distinct Complement Receptor Pathways (A) CTSL and… </p></div>
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Figure 6
|
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<div class="figure-caption-contents">Effector and Regulatory T Cells Engage Distinct Complement Receptor Pathways (A) CTSL and complement protein expression in regulatory (Treg) and effector (Teff) T cells in resting and activated (1 hr) states. (B) CD46 mRNA (i) and protein expression (ii) in resting and activated (12 hr) Treg and Teff cells. (C) Effect of CD46 activation on Treg cell suppressive activity at a 1:1 Treg:Teff cell ratio. Results shown in (A)–(C) are derived from three independent experiments (n = 3) with the mean ± SD (C). BC1, C1, BC2, and C2 refer to the proteins forms and differently spliced mRNAs coding for the four protein isoforms of CD46. The mRNAs for C1 and C2 in (Bi) and the γ-secretase-processed CYT-1 of CD46 in (Bii) give weak signals at this exposure time but are clearly visible upon overexposure (data not shown). (D) Phenotype of Treg cells from a CD46-deficient (CD46-def.) patient and age- and sex-matched healthy controls (HD). Shown are (i) percentage of bulk CD4<sup>+</sup>CD25<sup>hi</sup>CD127<sup>lo</sup> Treg cells, FOXP3 expression and percentages of Treg cell subpopulations I (CD4<sup>+</sup>CD25<sup>hi</sup>CD127<sup>lo</sup>CD45RA<sup>+</sup>), III (CD4<sup>+</sup>CD25<sup>hi</sup>CD127<sup>lo</sup>CD45RA<sup>−</sup>), and II (CD4<sup>+</sup>CD25<sup>bright</sup>CD127<sup>lo</sup>CD45RA<sup>+</sup>), (ii) suppressive function of Treg cells via <sup>3</sup>H-thymidine incorporation measurement in 1:1 coculture, and (iii) calculated percentage suppression with mean values ± SD. <sup>∗</sup>p < 0.05; <sup>∗∗</sup>p < 0.01; <sup>∗∗∗</sup>p < 0.005. See also Figure S6.</div>
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<strong class="figure-label">
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<p> Figure 7 </p>
|
||
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|
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<div class="figure-caption-contents"><p> Intracellular C3 Stores and “Tonic”… </p></div>
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<strong class="figure-label">
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<p> Figure 7 </p>
|
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</strong>
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<div class="figure-caption-contents"><p> Intracellular C3 Stores and “Tonic” Intracellular C3a Generation Occurs in Myeloid, Lymphoid, and… </p></div>
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Figure 7
|
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<div class="figure-caption-contents">Intracellular C3 Stores and “Tonic” Intracellular C3a Generation Occurs in Myeloid, Lymphoid, and Nonmyeloid, Nonlymphoid Cell Populations Freshly isolated monocytes, neutrophils, CD8<sup>+</sup> T cells, B cells, and cultured epithelial cells, endothelial cells, and fibroblasts were assessed for presence of intracellular C3b by flow cytometry and confocal microscopy image analyses (first and second column of panels, respectively), as well as for C3a (third and fourth column of panels, respectively) in the resting state. Results shown are representative of three independently performed experiments (n = 3). Scale bar represents 10 μM. MFI, mean fluorescence intensity.</div>
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Innate immunity: The inside story on complement activation.
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aria-controls="keyword-actions-publication-types-0"
|
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aria-expanded="false"
|
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Research Support, N.I.H., Extramural
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|
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Research Support, Non-U.S. Gov't
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</div>
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|
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<div id="mesh-terms" class="mesh-terms keywords-section">
|
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<h2 class="title">
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MeSH terms
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Adult
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Add to Search
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
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aria-expanded="false"
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Cathepsin L / metabolism*
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
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Cell Differentiation*
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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data-pinger-ignore>
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Cell Line
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</button><div id="keyword-actions-mesh-terms-7"
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hidden
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Search in PubMed
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
||
aria-label="Toggle dropdown menu for keyword Cell Survival / immunology"
|
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tabindex="0"
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aria-controls="keyword-actions-mesh-terms-8"
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Cell Survival / immunology
|
||
</button><div id="keyword-actions-mesh-terms-8"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Cell Survival / immunology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Cell+Survival%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Cell+Survival%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Cell Survival/immunology"[MeSH]"
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Cell+Survival"
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Search in MeSH
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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data-ga-label=""Cell Survival/immunology"[MeSH]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Child"
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tabindex="0"
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Child
|
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</button><div id="keyword-actions-mesh-terms-9"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
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hidden
|
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aria-label="Dropdown menu for keyword Child"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
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href="/?term=%22Child%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Child%22%5BMeSH%5D&sort=date&sort_order=desc"
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Child"[MeSH]"
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Child"
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data-ga-category="search_mesh"
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Search in MeSH
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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data-search-term=""Child"[MeSH]"
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data-ga-label=""Child"[MeSH]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
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aria-label="Toggle dropdown menu for keyword Complement Activation / physiology*"
|
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tabindex="0"
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aria-controls="keyword-actions-mesh-terms-major-10"
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aria-expanded="false"
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data-pinger-ignore>
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Complement Activation / physiology*
|
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</button><div id="keyword-actions-mesh-terms-major-10"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Complement Activation / physiology*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Complement+Activation%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc"
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data-href="/?term=%22Complement+Activation%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc"
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Complement Activation/physiology"[MAJR]"
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Complement+Activation"
|
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Search in MeSH
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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data-search-term=""Complement Activation/physiology"[MAJR]"
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Complement Activation/physiology"[MAJR]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Complement C3 / immunology"
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tabindex="0"
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aria-controls="keyword-actions-mesh-terms-11"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Complement C3 / immunology
|
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</button><div id="keyword-actions-mesh-terms-11"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Complement C3 / immunology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
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href="/?term=%22Complement+C3%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
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data-href="/?term=%22Complement+C3%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Complement C3/immunology"[MeSH]"
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data-ga-action="mesh_term"
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data-ga-label="Complement C3 / immunology">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Complement+C3"
|
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data-ga-category="search_mesh"
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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role="button"
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data-search-term=""Complement C3/immunology"[MeSH]"
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data-ga-category="search"
|
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data-ga-action="add_to_search"
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data-ga-label=""Complement C3/immunology"[MeSH]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
|
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aria-label="Toggle dropdown menu for keyword Complement C3 / metabolism*"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-major-12"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Complement C3 / metabolism*
|
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</button><div id="keyword-actions-mesh-terms-major-12"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Complement C3 / metabolism*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Complement+C3%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc"
|
||
data-href="/?term=%22Complement+C3%2Fmetabolism%22%5BMAJR%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Complement C3/metabolism"[MAJR]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Complement C3 / metabolism*">
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Complement+C3"
|
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data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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|
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role="button"
|
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data-search-term=""Complement C3/metabolism"[MAJR]"
|
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data-ga-category="search"
|
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data-ga-action="add_to_search"
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data-ga-label=""Complement C3/metabolism"[MAJR]"
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href="#">
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
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aria-label="Toggle dropdown menu for keyword Complement C3a / metabolism"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-13"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Complement C3a / metabolism
|
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</button><div id="keyword-actions-mesh-terms-13"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Complement C3a / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Complement+C3a%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Complement+C3a%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Complement C3a/metabolism"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Complement C3a / metabolism">
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Complement+C3a"
|
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data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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data-ga-label="Complement C3a / metabolism">
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Complement C3a/metabolism"[MeSH]"
|
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data-ga-category="search"
|
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data-ga-action="add_to_search"
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data-ga-label=""Complement C3a/metabolism"[MeSH]"
|
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href="#">
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
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aria-label="Toggle dropdown menu for keyword Complement C3b / metabolism"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-14"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Complement C3b / metabolism
|
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</button><div id="keyword-actions-mesh-terms-14"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Complement C3b / metabolism"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
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href="/?term=%22Complement+C3b%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Complement+C3b%2Fmetabolism%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Complement C3b/metabolism"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Complement C3b / metabolism">
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Search in PubMed
|
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Complement+C3b"
|
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data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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data-ga-label="Complement C3b / metabolism">
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Complement C3b/metabolism"[MeSH]"
|
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Complement C3b/metabolism"[MeSH]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
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aria-label="Toggle dropdown menu for keyword Gene Expression Regulation / immunology"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-15"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Gene Expression Regulation / immunology
|
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</button><div id="keyword-actions-mesh-terms-15"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Gene Expression Regulation / immunology"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
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href="/?term=%22Gene+Expression+Regulation%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Gene+Expression+Regulation%2Fimmunology%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Gene Expression Regulation/immunology"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Gene Expression Regulation / immunology">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
|
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ref="linksrc=search_in_mesh_link"
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Gene+Expression+Regulation"
|
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data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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data-ga-label="Gene Expression Regulation / immunology">
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Gene Expression Regulation/immunology"[MeSH]"
|
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data-ga-category="search"
|
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data-ga-action="add_to_search"
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data-ga-label=""Gene Expression Regulation/immunology"[MeSH]"
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link major"
|
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aria-label="Toggle dropdown menu for keyword Homeostasis / physiology*"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-major-16"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Homeostasis / physiology*
|
||
</button><div id="keyword-actions-mesh-terms-major-16"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Homeostasis / physiology*"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
||
href="/?term=%22Homeostasis%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Homeostasis%2Fphysiology%22%5BMAJR%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Homeostasis/physiology"[MAJR]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Homeostasis / physiology*">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Homeostasis"
|
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data-ga-category="search_mesh"
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data-ga-action="mesh_term_link"
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
|
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ref="linksrc=add_to_search_link"
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role="button"
|
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data-search-term=""Homeostasis/physiology"[MAJR]"
|
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data-ga-category="search"
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data-ga-action="add_to_search"
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data-ga-label=""Homeostasis/physiology"[MAJR]"
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href="#">
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Add to Search
|
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
|
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aria-label="Toggle dropdown menu for keyword Humans"
|
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tabindex="0"
|
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aria-controls="keyword-actions-mesh-terms-17"
|
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Humans
|
||
</button><div id="keyword-actions-mesh-terms-17"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
|
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aria-label="Dropdown menu for keyword Humans"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
|
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href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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data-href="/?term=%22Humans%22%5BMeSH%5D&sort=date&sort_order=desc"
|
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ref="linksrc=search_in_pubmed_keyword_link&mesh="Humans"[MeSH]"
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data-ga-category="search"
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data-ga-action="mesh_term"
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data-ga-label="Humans">
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Search in PubMed
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</a></li><li><a class="search-in-mesh-link dropdown-block-link"
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ref="linksrc=search_in_mesh_link"
|
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href="https://www.ncbi.nlm.nih.gov/mesh?term=Humans"
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data-ga-category="search_mesh"
|
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Search in MeSH
|
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</a></li><li><a class="add-to-search-link dropdown-block-link"
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data-search-term=""Humans"[MeSH]"
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data-ga-category="search"
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Add to Search
|
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</a></li></ul></div></div></div></li></ul>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
|
||
<div id="substances" class="substances keywords-section">
|
||
<h2 class="title">
|
||
Substances
|
||
</h2>
|
||
|
||
<ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Complement C3"
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tabindex="0"
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aria-controls="keyword-actions-substances-0"
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aria-expanded="false"
|
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data-pinger-ignore>
|
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Complement C3
|
||
</button><div id="keyword-actions-substances-0"
|
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class="keyword-actions-dropdown dropdown dropdown-container"
|
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hidden
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href="https://www.nih.gov/">NIH</a>
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var meta_nwds_ver = document.createElement('meta');
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