772 lines
No EOL
96 KiB
HTML
772 lines
No EOL
96 KiB
HTML
<?xml version="1.0" encoding="utf-8"?>
|
||
<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd">
|
||
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en">
|
||
|
||
<head><meta http-equiv="Content-Type" content="text/html; charset=utf-8" />
|
||
<!-- AppResources meta begin -->
|
||
<meta name="paf-app-resources" content="" />
|
||
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
||
|
||
<!-- AppResources meta end -->
|
||
|
||
<!-- TemplateResources meta begin -->
|
||
<meta name="paf_template" content="" />
|
||
|
||
<!-- TemplateResources meta end -->
|
||
|
||
<!-- Logger begin -->
|
||
<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK47336" /><meta name="ncbi_domain" content="mlprobe" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK47336/" /><meta name="ncbi_pagename" content="Identification of lipid storage modulators - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
|
||
<!-- Logger end -->
|
||
|
||
<title>Identification of lipid storage modulators - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
|
||
|
||
<!-- AppResources external_resources begin -->
|
||
<link rel="stylesheet" href="/core/jig/1.15.2/css/jig.min.css" /><script type="text/javascript" src="/core/jig/1.15.2/js/jig.min.js"></script>
|
||
|
||
<!-- AppResources external_resources end -->
|
||
|
||
<!-- Page meta begin -->
|
||
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Identification of lipid storage modulators" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2010/09/02" /><meta name="citation_author" content="Mathias Beller" /><meta name="citation_author" content="Craig Thomas" /><meta name="citation_author" content="Min Shen" /><meta name="citation_author" content="Douglas Auld" /><meta name="citation_pmid" content="21433352" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK47336/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Identification of lipid storage modulators" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Mathias Beller" /><meta name="DC.Contributor" content="Craig Thomas" /><meta name="DC.Contributor" content="Min Shen" /><meta name="DC.Contributor" content="Douglas Auld" /><meta name="DC.Date" content="2010/09/02" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK47336/" /><meta name="description" content="Storing lipids as a reservoir for energy or the anabolism of elementary metabolites is a common feature of life in organisms from bacteria to humans. The chemical probes yielded by this project should serve as useful tools for providing a better understanding of cellular and organismic lipid storage on a functional and evolutionary level. Furthermore, active substances might result in the identification of lead compounds for the treatment of emerging lipid storage-associated diseases, including atherosclerosis, diabetes, or obesity. Also, the present assay will establish a profile of compounds that modulate this ubiquitous area of biology. The probe described here came from initial screening of known bioactive compound collections within the MLSMR. By combining the small molecule screening results with lipid metabolism modulating gene functions identified in the genome-wide RNAi screen, we were able to identify and link the Golgi Type I coat proteins known as cotamer, COPI to lipid storage. The developed probe, ML084 (CID-310557; Exo1), was shown to induce a lipid storage phenotype in cells through modulation of the protein trafficking pathways." /><meta name="og:title" content="Identification of lipid storage modulators" /><meta name="og:type" content="book" /><meta name="og:description" content="Storing lipids as a reservoir for energy or the anabolism of elementary metabolites is a common feature of life in organisms from bacteria to humans. The chemical probes yielded by this project should serve as useful tools for providing a better understanding of cellular and organismic lipid storage on a functional and evolutionary level. Furthermore, active substances might result in the identification of lead compounds for the treatment of emerging lipid storage-associated diseases, including atherosclerosis, diabetes, or obesity. Also, the present assay will establish a profile of compounds that modulate this ubiquitous area of biology. The probe described here came from initial screening of known bioactive compound collections within the MLSMR. By combining the small molecule screening results with lipid metabolism modulating gene functions identified in the genome-wide RNAi screen, we were able to identify and link the Golgi Type I coat proteins known as cotamer, COPI to lipid storage. The developed probe, ML084 (CID-310557; Exo1), was shown to induce a lipid storage phenotype in cells through modulation of the protein trafficking pathways." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK47336/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml084/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK47336/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
|
||
|
||
<!-- Page meta end -->
|
||
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico" /><meta name="ncbi_phid" content="CE8D22A97D65392100000000011600F5.m_13" />
|
||
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3985586/3808861/4121862/3974050/3917732/251717/4216701/14534/45193/4113719/3849091/3984811/3751656/4033350/3840896/3577051/3852958/4008682/4207974/4206132/4062871/12930/3964959/3854974/36029/4128070/9685/3549676/3609192/3609193/3609213/3395586.css" /><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3411343/3882866.css" media="print" /></head>
|
||
<body class="book-part">
|
||
<div class="grid">
|
||
<div class="col twelve_col nomargin shadow">
|
||
<!-- System messages like service outage or JS required; this is handled by the TemplateResources portlet -->
|
||
<div class="sysmessages">
|
||
<noscript>
|
||
<p class="nojs">
|
||
<strong>Warning:</strong>
|
||
The NCBI web site requires JavaScript to function.
|
||
<a href="/guide/browsers/#enablejs" title="Learn how to enable JavaScript" target="_blank">more...</a>
|
||
</p>
|
||
</noscript>
|
||
</div>
|
||
<!--/.sysmessage-->
|
||
<div class="wrap">
|
||
<div class="page">
|
||
<div class="top">
|
||
<div id="universal_header">
|
||
<section class="usa-banner">
|
||
<div class="usa-accordion">
|
||
<header class="usa-banner-header">
|
||
<div class="usa-grid usa-banner-inner">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/favicons/favicon-57.png" alt="U.S. flag" />
|
||
<p>An official website of the United States government</p>
|
||
<button class="non-usa-accordion-button usa-banner-button" aria-expanded="false" aria-controls="gov-banner-top" type="button">
|
||
<span class="usa-banner-button-text">Here's how you know</span>
|
||
</button>
|
||
</div>
|
||
</header>
|
||
<div class="usa-banner-content usa-grid usa-accordion-content" id="gov-banner-top" aria-hidden="true">
|
||
<div class="usa-banner-guidance-gov usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-dot-gov.svg" alt="Dot gov" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The .gov means it's official.</strong>
|
||
<br />
|
||
Federal government websites often end in .gov or .mil. Before
|
||
sharing sensitive information, make sure you're on a federal
|
||
government site.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
<div class="usa-banner-guidance-ssl usa-width-one-half">
|
||
<img class="usa-banner-icon usa-media_block-img" src="https://www.ncbi.nlm.nih.gov/coreutils/uswds/img/icon-https.svg" alt="Https" />
|
||
<div class="usa-media_block-body">
|
||
<p>
|
||
<strong>The site is secure.</strong>
|
||
<br />
|
||
The <strong>https://</strong> ensures that you are connecting to the
|
||
official website and that any information you provide is encrypted
|
||
and transmitted securely.
|
||
</p>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<div class="usa-overlay"></div>
|
||
<header class="ncbi-header" role="banner" data-section="Header">
|
||
|
||
<div class="usa-grid">
|
||
<div class="usa-width-one-whole">
|
||
|
||
<div class="ncbi-header__logo">
|
||
<a href="/" class="logo" aria-label="NCBI Logo" data-ga-action="click_image" data-ga-label="NIH NLM Logo">
|
||
<img src="https://www.ncbi.nlm.nih.gov/coreutils/nwds/img/logos/AgencyLogo.svg" alt="NIH NLM Logo" />
|
||
</a>
|
||
</div>
|
||
|
||
<div class="ncbi-header__account">
|
||
<a id="account_login" href="https://account.ncbi.nlm.nih.gov" class="usa-button header-button" style="display:none" data-ga-action="open_menu" data-ga-label="account_menu">Log in</a>
|
||
<button id="account_info" class="header-button" style="display:none" aria-controls="account_popup" type="button">
|
||
<span class="fa fa-user" aria-hidden="true">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 24 24" width="20px" height="20px">
|
||
<g style="fill: #fff">
|
||
<ellipse cx="12" cy="8" rx="5" ry="6"></ellipse>
|
||
<path d="M21.8,19.1c-0.9-1.8-2.6-3.3-4.8-4.2c-0.6-0.2-1.3-0.2-1.8,0.1c-1,0.6-2,0.9-3.2,0.9s-2.2-0.3-3.2-0.9 C8.3,14.8,7.6,14.7,7,15c-2.2,0.9-3.9,2.4-4.8,4.2C1.5,20.5,2.6,22,4.1,22h15.8C21.4,22,22.5,20.5,21.8,19.1z"></path>
|
||
</g>
|
||
</svg>
|
||
</span>
|
||
<span class="username desktop-only" aria-hidden="true" id="uname_short"></span>
|
||
<span class="sr-only">Show account info</span>
|
||
</button>
|
||
</div>
|
||
|
||
<div class="ncbi-popup-anchor">
|
||
<div class="ncbi-popup account-popup" id="account_popup" aria-hidden="true">
|
||
<div class="ncbi-popup-head">
|
||
<button class="ncbi-close-button" data-ga-action="close_menu" data-ga-label="account_menu" type="button">
|
||
<span class="fa fa-times">
|
||
<svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 48 48" width="24px" height="24px">
|
||
<path d="M38 12.83l-2.83-2.83-11.17 11.17-11.17-11.17-2.83 2.83 11.17 11.17-11.17 11.17 2.83 2.83 11.17-11.17 11.17 11.17 2.83-2.83-11.17-11.17z"></path>
|
||
</svg>
|
||
</span>
|
||
<span class="usa-sr-only">Close</span></button>
|
||
<h4>Account</h4>
|
||
</div>
|
||
<div class="account-user-info">
|
||
Logged in as:<br />
|
||
<b><span class="username" id="uname_long">username</span></b>
|
||
</div>
|
||
<div class="account-links">
|
||
<ul class="usa-unstyled-list">
|
||
<li><a id="account_myncbi" href="/myncbi/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_myncbi">Dashboard</a></li>
|
||
<li><a id="account_pubs" href="/myncbi/collections/bibliography/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_pubs">Publications</a></li>
|
||
<li><a id="account_settings" href="/account/settings/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_settings">Account settings</a></li>
|
||
<li><a id="account_logout" href="/account/signout/" class="set-base-url" data-ga-action="click_menu_item" data-ga-label="account_logout">Log out</a></li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</header>
|
||
<div role="navigation" aria-label="access keys">
|
||
<a id="nws_header_accesskey_0" href="https://www.ncbi.nlm.nih.gov/guide/browsers/#ncbi_accesskeys" class="usa-sr-only" accesskey="0" tabindex="-1">Access keys</a>
|
||
<a id="nws_header_accesskey_1" href="https://www.ncbi.nlm.nih.gov" class="usa-sr-only" accesskey="1" tabindex="-1">NCBI Homepage</a>
|
||
<a id="nws_header_accesskey_2" href="/myncbi/" class="set-base-url usa-sr-only" accesskey="2" tabindex="-1">MyNCBI Homepage</a>
|
||
<a id="nws_header_accesskey_3" href="#maincontent" class="usa-sr-only" accesskey="3" tabindex="-1">Main Content</a>
|
||
<a id="nws_header_accesskey_4" href="#" class="usa-sr-only" accesskey="4" tabindex="-1">Main Navigation</a>
|
||
</div>
|
||
<section data-section="Alerts">
|
||
<div class="ncbi-alerts-placeholder"></div>
|
||
</section>
|
||
</div>
|
||
<div class="header">
|
||
<div class="res_logo"><h1 class="res_name"><a href="/books/" title="Bookshelf home">Bookshelf</a></h1><h2 class="res_tagline"></h2></div>
|
||
<div class="search"><form method="get" action="/books/"><div class="search_form"><label for="database" class="offscreen_noflow">Search database</label><select id="database"><optgroup label="Recent"><option value="books" selected="selected" data-ac_dict="bookshelf-search">Books</option><option value="pubmed">PubMed</option><option value="clinvar">ClinVar</option><option value="refseq" class="last">RefSeq</option></optgroup><optgroup label="All"><option value="gquery">All Databases</option><option value="assembly">Assembly</option><option value="biocollections">Biocollections</option><option value="bioproject">BioProject</option><option value="biosample">BioSample</option><option value="books" data-ac_dict="bookshelf-search">Books</option><option value="clinvar">ClinVar</option><option value="cdd">Conserved Domains</option><option value="gap">dbGaP</option><option value="dbvar">dbVar</option><option value="gene">Gene</option><option value="genome">Genome</option><option value="gds">GEO DataSets</option><option value="geoprofiles">GEO Profiles</option><option value="gtr">GTR</option><option value="ipg">Identical Protein Groups</option><option value="medgen">MedGen</option><option value="mesh">MeSH</option><option value="nlmcatalog">NLM Catalog</option><option value="nuccore">Nucleotide</option><option value="omim">OMIM</option><option value="pmc">PMC</option><option value="protein">Protein</option><option value="proteinclusters">Protein Clusters</option><option value="protfam">Protein Family Models</option><option value="pcassay">PubChem BioAssay</option><option value="pccompound">PubChem Compound</option><option value="pcsubstance">PubChem Substance</option><option value="pubmed">PubMed</option><option value="snp">SNP</option><option value="sra">SRA</option><option value="structure">Structure</option><option value="taxonomy">Taxonomy</option><option value="toolkit">ToolKit</option><option value="toolkitall">ToolKitAll</option><option value="toolkitbookgh">ToolKitBookgh</option></optgroup></select><div class="nowrap"><label for="term" class="offscreen_noflow" accesskey="/">Search term</label><div class="nowrap"><input type="text" name="term" id="term" title="Search Books. Use up and down arrows to choose an item from the autocomplete." value="" class="jig-ncbiclearbutton jig-ncbiautocomplete" data-jigconfig="dictionary:'bookshelf-search',disableUrl:'NcbiSearchBarAutoComplCtrl'" autocomplete="off" data-sbconfig="ds:'no',pjs:'no',afs:'no'" /></div><button id="search" type="submit" class="button_search nowrap" cmd="go">Search</button></div></div></form><ul class="searchlinks inline_list"><li>
|
||
<a href="/books/browse/">Browse Titles</a>
|
||
</li><li>
|
||
<a href="/books/advanced/">Advanced</a>
|
||
</li><li class="help">
|
||
<a href="/books/NBK3833/">Help</a>
|
||
</li><li class="disclaimer">
|
||
<a target="_blank" data-ga-category="literature_resources" data-ga-action="link_click" data-ga-label="disclaimer_link" href="https://www.ncbi.nlm.nih.gov/books/about/disclaimer/">Disclaimer</a>
|
||
</li></ul></div>
|
||
</div>
|
||
|
||
|
||
|
||
<!--<component id="Page" label="headcontent"/>-->
|
||
|
||
</div>
|
||
<div class="content">
|
||
<!-- site messages -->
|
||
<!-- Custom content 1 -->
|
||
<div class="col1">
|
||
|
||
</div>
|
||
|
||
<div class="container">
|
||
<div id="maincontent" class="content eight_col col">
|
||
<!-- Custom content in the left column above book nav -->
|
||
<div class="col2">
|
||
|
||
</div>
|
||
|
||
<!-- Book content -->
|
||
|
||
|
||
<!-- Custom content between navigation and content -->
|
||
<div class="col3">
|
||
|
||
</div>
|
||
|
||
<div class="document">
|
||
<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK47336_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK47336_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml085/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml083/" title="Next page in this title">Next ></a></div></div></div></div></div>
|
||
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK47336_"><span class="title" itemprop="name">Identification of lipid storage modulators</span></h1><p class="contrib-group"><span itemprop="author">Mathias Beller</span>, <span itemprop="author">Craig Thomas</span>, <span itemprop="author">Min Shen</span>, and <span itemprop="author">Douglas Auld</span>.</p><p class="small">Received: <span itemprop="datePublished">April 16, 2009</span>; Last Update: <span itemprop="dateModified">September 2, 2010</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Storing lipids as a reservoir for energy or the anabolism of elementary metabolites is a common feature of life in organisms from bacteria to humans. The chemical probes yielded by this project should serve as useful tools for providing a better understanding of cellular and organismic lipid storage on a functional and evolutionary level. Furthermore, active substances might result in the identification of lead compounds for the treatment of emerging lipid storage-associated diseases, including atherosclerosis, diabetes, or obesity. Also, the present assay will establish a profile of compounds that modulate this ubiquitous area of biology. The probe described here came from initial screening of known bioactive compound collections within the MLSMR. By combining the small molecule screening results with lipid metabolism modulating gene functions identified in the genome-wide RNAi screen, we were able to identify and link the Golgi Type I coat proteins known as cotamer, COPI to lipid storage. The developed probe, ML084 (CID-310557; Exo1), was shown to induce a lipid storage phenotype in cells through modulation of the protein trafficking pathways.</p></div><div class="h2"></div><p>
|
||
<b>Assigned Assay Grant #:</b> 1 R03 MH085686-01 </p><p>
|
||
<b>Screening Center Name & PI:</b> NIH Chemical Genomics Center,
|
||
Christopher Austin </p><p>
|
||
<b>Chemistry Center Name & PI:</b> NIH Chemical Genomics Center,
|
||
Christopher Austin </p><p>
|
||
<b>Assay Submitter & Institution:</b> Dr. Mathias Beller, Max Planck
|
||
Institute for Biophysical Chemistry </p><p><b>PubChem Primary Bioassay Identifier (AID):</b>
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1519" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1519</a></p><div id="ml084.s1"><h2 id="_ml084_s1_">Probe Structure & Characteristics</h2><div id="ml084.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47336/table/ml084.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml084.tu1_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PubChem CID</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID-310557</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">273.76</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C<sub>15</sub>H<sub>12</sub>FNO<sub>3</sub></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">XLogP</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">273.08</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">55.4</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td></tr></tbody></table></div></div><div id="ml084.fu1" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu1.jpg" alt="Image ml084fu1" /></div></div><div id="ml084.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47336/table/ml084.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml084.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml084.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML</th><th id="hd_h_ml084.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml084.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub>
|
||
(μM) [SID, AID]</th><th id="hd_h_ml084.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml084.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub>
|
||
(μM) [SID, AID]</th><th id="hd_h_ml084.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml084.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity Assay(s) Name:
|
||
IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID,
|
||
AID]<sup>§</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml084.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID-310557/<a href="/pcsubstance/?term=ML084[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML084</a></td><td headers="hd_h_ml084.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COPI</td><td headers="hd_h_ml084.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5 ± 2.5<br />
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/11114231" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-11114231</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1519" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1519</a>]</td><td headers="hd_h_ml084.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cytotoxicity</td><td headers="hd_h_ml084.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Inactive @40 μM,
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/11114231" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-11114231</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1561" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1561</a>]</td><td headers="hd_h_ml084.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>10-fold</td><td headers="hd_h_ml084.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cell-Titer Glo [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/11114231" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-11114231</a>,
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1561" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1561</a>]</td></tr></tbody></table></div></div></div><div id="ml084.s3"><h2 id="_ml084_s3_">Recommendations for the scientific use of this probe</h2><p>The probe Exo-1 is a modulator of protein trafficking. Our work has linked the Golgi
|
||
Type I coat proteins known as cotamer, COPI to lipid storage. Exo-1 can be used to
|
||
induce a lipid storage phenotype in cells through modulation of the protein
|
||
trafficking pathways.</p><div id="ml084.s4"><h3>Specific Aim</h3><p>We have developed a cell-based assay in <i>Drosophila melanogaster</i>
|
||
embryonic Kc167 and S3 cells capable of analyzing the effects of alterations in
|
||
lipid metabolism. We have recently used a similar assay successfully in a
|
||
genome-wide RNAi screen to identify gene functions regulating cellular lipid
|
||
storage. This assay was adapted to laser-scanning microplate cytometry suitable
|
||
for a 1,536-well microtiter plate format, which will allow the assay to be
|
||
screened against the 300K MLSMR collection. The goal is to identify chemical
|
||
probes affecting lipid storage regulation.</p></div><div id="ml084.s5"><h3>Significance</h3><p>The chemical probes yielded by this project should be useful tools for providing
|
||
a better understanding of cellular and organismic lipid storage on a functional
|
||
and evolutionary level. Furthermore, active substances might result in the
|
||
identification of lead compounds for the treatment of emerging lipid
|
||
storage-associated diseases, including atherosclerosis, diabetes or obesity.
|
||
Also, the present assay will establish a profile of compounds within the MLSMR
|
||
that modulate this ubiquitous area of biology. The probe described here came
|
||
from initial screening of known bioactive compound collections. By combining the
|
||
small molecule screening results with lipid metabolism modulating gene functions
|
||
identified in the genome-wide RNAi screen, we were able to identify COPI
|
||
proteins as negative regulators of lipid storage and the probe Exo1 as chemical
|
||
probe to modulate lipid storage.</p></div><div id="ml084.s6"><h3>Rationale</h3><p>Storing lipids as a reservoir for energy or the anabolism of elementary
|
||
metabolites is a common feature of life in organisms from bacteria to humans.
|
||
The universal cellular lipid storage organelle is the so-called lipid storage
|
||
droplet (LD). Despite their ubiquitous nature, LDs share a simple, stereotyped
|
||
structure of a hydrophobic core harboring the storage lipids, which is shielded
|
||
by a droplet-specific phospholipid monolayer to which proteins are attached. The
|
||
current model of LD biogenesis involves an incorporation of the lipid core into
|
||
the membrane leaflets of the endoplasmic reticulum (ER), followed by a
|
||
subsequent budding-like maturation of a LD, which ultimately pinches off. Once
|
||
released, LD volume can increase by localized lipogenesis or fusion of existing
|
||
droplets. Storage lipids are re-mobilized enzymatically by lipase activity.
|
||
Lipase regulation in the adipocyte is heavily studied and involves multiple
|
||
components including catecholamine signaling (<a class="bk_pop" href="#ml084.r1">1</a>), the LD-associated proteins Perilipin and
|
||
comparative gene identification 58 (CGI-58) (<a class="bk_pop" href="#ml084.r2">2</a>), and at least two lipases named hormone sensitive
|
||
lipase (HSL) (<a class="bk_pop" href="#ml084.r3">3</a>) and adipocyte
|
||
triglyceride lipase (ATGL) (<a class="bk_pop" href="#ml084.r4" data-bk-pop-others="ml084.r5 ml084.r6">4–6</a>). LD biogenesis, turnover and
|
||
mobilization are poorly understood and only few components are known. However,
|
||
there is an urgent need to learn more about ectopic fat depots as mislocalized
|
||
storage of lipids, for example in the liver or muscle, is an eminent health
|
||
problem associated with insulin resistance or the metabolic syndrome (<a class="bk_pop" href="#ml084.r7">7</a>).</p></div></div><div id="ml084.s7"><h2 id="_ml084_s7_">Assay Implementation and Screening</h2><div id="ml084.s8"><h3>PubChem Bioassay Name</h3><p><i>Dmel</i> lipid storage</p></div><div id="ml084.s9"><h3>List of PubChem bioassay identifiers generated for this screening project
|
||
(AIDs)</h3><div id="ml084.tu3" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47336/table/ml084.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml084.tu3_lrgtbl__"><table><thead><tr><th id="hd_h_ml084.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml084.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml084.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Concentration</th><th id="hd_h_ml084.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Bioassay type</th></tr></thead><tbody><tr><td headers="hd_h_ml084.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1519" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1519</a></td><td headers="hd_h_ml084.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S3 cells</td><td headers="hd_h_ml084.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40 μM to 0.26 nM</td><td headers="hd_h_ml084.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Primary qHTS</td></tr><tr><td headers="hd_h_ml084.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1569" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1569</a></td><td headers="hd_h_ml084.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S3 cells</td><td headers="hd_h_ml084.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40 μM to 0.26 nM</td><td headers="hd_h_ml084.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Confirmatory</td></tr><tr><td headers="hd_h_ml084.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1561" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1561</a></td><td headers="hd_h_ml084.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cytotoxicity</td><td headers="hd_h_ml084.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40 μM to 0.26 nM</td><td headers="hd_h_ml084.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Selectivity</td></tr><tr><td headers="hd_h_ml084.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1547" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1547</a></td><td headers="hd_h_ml084.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NEFA incorporation/release</td><td headers="hd_h_ml084.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5 μM</td><td headers="hd_h_ml084.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary</td></tr><tr><td headers="hd_h_ml084.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1623" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1623</a></td><td headers="hd_h_ml084.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Lipid over-storage</td><td headers="hd_h_ml084.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td><td headers="hd_h_ml084.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary</td></tr></tbody></table></div></div></div><div id="ml084.s10"><h3>Primary Assay Description as defined in PubChem</h3><div id="ml084.s11"><h4>Overview</h4><p>The primary goal of this project is to identify chemical probes that either
|
||
increase or decrease the lipid content of cells. Most cells are capable of
|
||
storing energy rich lipids (mainly triacylglycerols), which are generated on
|
||
basis of <i>de novo</i> synthesized fatty acids or non-esterified
|
||
free fatty acids (NEFA) taken up from the environment. There are only few
|
||
drugs for treating metabolic diseases and a very limited number of chemical
|
||
probes to study lipid storage <i>in vitro</i>. We have found that
|
||
embryonic <i>Drosophila</i> S3 and Kc167 cells are capable of
|
||
depositing LDs, and we developed an assay to measure lipid storage amounts
|
||
by fluorescent staining of LDs in S3 cells, using laser-scanning microplate
|
||
cytometry for detection. Importantly, most results obtained in the
|
||
<i>Drosophila</i> cell systems could be successfully
|
||
translated into different mammalian cell culture models, opening up the
|
||
possibility to test for evolutionary conservation of mechanism.</p></div><div id="ml084.s12"><h4>Protocol</h4><p>Detection of lipid droplets was performed using <i>Drosophila</i>
|
||
S3 (obtained from NIDDK) cells, following 400 μM oleic acid
|
||
feeding in growth media. In the assay 4 μL of S3 cells at 1.25 x
|
||
10<sup>6</sup> cells/mL in growth media was dispensed into LoBase Aurora
|
||
1,536-well plates (black walled, clear bottom COP plastic; Aurora) (<a class="bk_pop" href="#ml084.r8">8</a>) using a bottle-valve
|
||
solenoid-based dispenser (<a class="bk_pop" href="#ml084.r9">9</a>) to
|
||
give 5,000 cells/well. Twenty-three nL of compound solution was transferred
|
||
to the assay plates using a Kalypsys pin tool (San Diego, CA) equipped with
|
||
a 1,536-pin array containing 10 nL slotted pins (FP1S10, 0.457 mm diameter,
|
||
50.8 mm long; V&P Scientific5). Next, 1 μl of oleic acid
|
||
(400 μM) was added and the plates were lidded with stainless
|
||
steel rubber gasket-lined lids containing pin-holes for gas exchange and
|
||
incubated for 18–24 hr at 24 °C, 95%
|
||
humidity. Detection was performed by the addition of the lipid-droplet
|
||
specific dye BODIPY 493/503 (Molecular Probes), and CellTracker™
|
||
Red CMTPX (Invitrogen) was used to enumerate cell number. Lipid droplet
|
||
accumulation was measured using the Acumen Explorer (TTP LapTech) (<a class="bk_pop" href="#ml084.r10">10</a>) using a 488 nm laser. The
|
||
total intensity in channel 1 (500–530 nm) was used to measure
|
||
lipid droplet accumulation with cell objects defined using channel 3
|
||
(575–640 nm) and a 5 μm width and 100 μm
|
||
depth filters. The ratio of the total intensity in PMT channel 1 over total
|
||
intensity channel 3 was also calculated.</p></div></div><div id="ml084.s13"><h3>Summary of the Primary Screen</h3><div id="ml084.s14"><h4>Assay principle and protocol</h4><div id="ml084.f1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47336/bin/ml084f1.jpg" alt="Figure 1. Top, distribution of the fluorescent signal in PMT 1 (lipid specific channel) without (left) and with (right) oleic acid (OA) feeding." /></div><h3><span class="label">Figure 1</span></h3><div class="caption"><p>Top, distribution of the fluorescent signal in PMT 1 (lipid specific
|
||
channel) without (left) and with (right) oleic acid (OA) feeding.
|
||
The populations are defined using width and depth filters using the
|
||
fluorescent signal from PMT 3 (cell- specific channel) to define
|
||
cell-objects. Cell objects with low PMT 1 fluorescence are defined
|
||
in the absence of OA feeding (“unfed
|
||
population”, orange data), and a shift to brighter
|
||
fluorescence is observed following OA feeding that is used to define
|
||
lipid-containing cells (“fed population”,
|
||
green data at top right). Unclassified objects not used in the
|
||
calculation are shown as red. Middle pictures show false color (same
|
||
color code as in histograms) plate well images from the Acumen for
|
||
unfed (left) and fed (right) cells. The bottom two panels represent
|
||
images from the InCell1000 using the same cell stains. Cells are
|
||
treated with 400 μM OA in the presence (top) or absence
|
||
(bottom) of the inhibitor Triacsin C. In the fused image, the InCell
|
||
software swaps the colors so that the red color represent the lipid
|
||
stain and the green represent the cell stain.</p></div></div><p>The optimized 1536-well protocol is given in <a class="figpopup" href="/books/NBK47336/table/ml084.t1/?report=objectonly" target="object" rid-figpopup="figml084t1" rid-ob="figobml084t1">Table 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml084t1"><a href="/books/NBK47336/table/ml084.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml084t1" rid-ob="figobml084t1"><img class="small-thumb" src="/books/NBK47336/table/ml084.t1/?report=thumb" src-large="/books/NBK47336/table/ml084.t1/?report=previmg" alt="Table 1. Final 1536-well assay protocol." /></a><div class="icnblk_cntnt"><h4 id="ml084.t1"><a href="/books/NBK47336/table/ml084.t1/?report=objectonly" target="object" rid-ob="figobml084t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Final 1536-well assay protocol. </p></div></div><p>Following adaptation of the lipid droplet assay to 1536-well plates, we used
|
||
the assay to screen several libraries. The libraries were screened at
|
||
between seven and fifteen concentrations using quantitative HTS (qHTS)
|
||
(<a class="bk_pop" href="#ml084.r11">11</a>). A total of 98
|
||
1536-well plates were screened (<a class="figpopup" href="/books/NBK47336/figure/ml084.f2/?report=objectonly" target="object" rid-figpopup="figml084f2" rid-ob="figobml084f2">Figure
|
||
2</a>). This included 27 DMSO blanks, a 15 point titration of the
|
||
LOPAC library (Sigma), a 13 point titration of the Prestwick library, seven
|
||
point titrations of two combinatorial libraries targeted to GPCRs and
|
||
kinases (PTL1 and PTL2), seven point titrations of two libraries from
|
||
Spectrum/Micorsource and a fifteen point titration of the Tocris library.
|
||
Overall the assay showed excellent performance with a Z′
|
||
= 0.77 ± 0.23, S/B = 25 ±
|
||
68, CV = 3 ± 3%. Three plates failed QC
|
||
(arrows and low Z-factor plates in <a class="figpopup" href="/books/NBK47336/figure/ml084.f2/?report=objectonly" target="object" rid-figpopup="figml084f2" rid-ob="figobml084f2">Figure 2c,d</a>) due to a clogged tip.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml084f2" co-legend-rid="figlgndml084f2"><a href="/books/NBK47336/figure/ml084.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml084f2" rid-ob="figobml084f2"><img class="small-thumb" src="/books/NBK47336/bin/ml084f2.gif" src-large="/books/NBK47336/bin/ml084f2.jpg" alt="Figure 2. Validation of the 1536-well Acumen-based lipid droplet assay in Drosophila cells." /></a><div class="icnblk_cntnt" id="figlgndml084f2"><h4 id="ml084.f2"><a href="/books/NBK47336/figure/ml084.f2/?report=objectonly" target="object" rid-ob="figobml084f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Validation of the 1536-well Acumen-based lipid droplet assay in
|
||
<i>Drosophila</i> cells. a) heatmap representation of fed cell objects. Four control columns
|
||
are present at left containing untreated cells (column 1, no OA), a
|
||
titration of Triacsin C (column 2), <a href="/books/NBK47336/figure/ml084.f2/?report=objectonly" target="object" rid-ob="figobml084f2">(more...)</a></p></div></div><div id="ml084.s15"><h5>Identification of Exo1</h5><p>Following the qHTS, the CRC data was subjected to a classification scheme
|
||
to rank the quality of the CRCs as described by Inglese and co-workers
|
||
(<a class="bk_pop" href="#ml084.r11">11</a>) (see <a class="figpopup" href="/books/NBK47336/figure/ml084.f3/?report=objectonly" target="object" rid-figpopup="figml084f3" rid-ob="figobml084f3">scheme 1</a>). Briefly, CRCs are
|
||
placed into four classes. Class 1 contains complete CRCs showing both
|
||
upper and lower asymptotes and r<sup>2</sup> values > 0.9. Class
|
||
2 contains incomplete CRCs lacking the lower asymptote and shows
|
||
r<sup>2</sup> values greater than 0.9. Class 3 curves are of the
|
||
lowest confidence because they are defined by a single concentration
|
||
point where the minimal acceptable activity is set at 3 SD of the mean
|
||
activity calculated from the lowest tested concentration. Finally, class
|
||
4 contains compounds that do not show any CRCs and are therefore
|
||
classified as inactive.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml084f3" co-legend-rid="figlgndml084f3"><a href="/books/NBK47336/figure/ml084.f3/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml084f3" rid-ob="figobml084f3"><img class="small-thumb" src="/books/NBK47336/bin/ml084f3.gif" src-large="/books/NBK47336/bin/ml084f3.jpg" alt="Scheme 1. Example qHTS data and classification scheme for assignment of resulting curve-fit data into classes." /></a><div class="icnblk_cntnt" id="figlgndml084f3"><h4 id="ml084.f3"><a href="/books/NBK47336/figure/ml084.f3/?report=objectonly" target="object" rid-ob="figobml084f3">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Example qHTS data and classification scheme for assignment of
|
||
resulting curve-fit data into classes. <i>Top</i>, qHTS curve-fit data from AID-361 binned into
|
||
curve classifications 1–4 based classification
|
||
criteria. <i>Below</i>, Examples of curves fitting the
|
||
following <a href="/books/NBK47336/figure/ml084.f3/?report=objectonly" target="object" rid-ob="figobml084f3">(more...)</a></p></div></div></div><div id="ml084.s16"><h5>qHTS summary of assay results</h5><p>Compounds showing decreasing lipid storage were generally associated with
|
||
cytotoxicity, except for the positive control Triacsin C as identified
|
||
in the red cell stain channel. However, we found many compounds that
|
||
induced lipid overstorage (<a class="figpopup" href="/books/NBK47336/figure/ml084.f4/?report=objectonly" target="object" rid-figpopup="figml084f4" rid-ob="figobml084f4">Figure
|
||
3</a>). In the Tocris library, we noted a small molecule Arf1
|
||
modulator (Exo1) (<a class="bk_pop" href="#ml084.r12">12</a>) that
|
||
increased lipid droplet accumulation (EC<sub>50</sub> = 5
|
||
μM) in S3 cells (<a class="figpopup" href="/books/NBK47336/figure/ml084.f5/?report=objectonly" target="object" rid-figpopup="figml084f5" rid-ob="figobml084f5">Figure
|
||
4</a>). This compound is known to inhibit the vesicle-mediated
|
||
Coat Protein complex I (COPI) transport complex. Further, we have
|
||
identified key <i>Drosophila</i> candidate genes for lipid
|
||
droplet regulation by RNA interference (RNAi) screening that included
|
||
the COPI transport complex, which was found to be required for limiting
|
||
lipid storage.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml084f4" co-legend-rid="figlgndml084f4"><a href="/books/NBK47336/figure/ml084.f4/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml084f4" rid-ob="figobml084f4"><img class="small-thumb" src="/books/NBK47336/bin/ml084f4.gif" src-large="/books/NBK47336/bin/ml084f4.jpg" alt="Figure 3. Example CRCs (fed objects) for lipids storage activators from the qHTS of S3 cells." /></a><div class="icnblk_cntnt" id="figlgndml084f4"><h4 id="ml084.f4"><a href="/books/NBK47336/figure/ml084.f4/?report=objectonly" target="object" rid-ob="figobml084f4">Figure 3</a></h4><p class="float-caption no_bottom_margin">Example CRCs (fed objects) for lipids storage activators from
|
||
the qHTS of S3 cells. </p></div></div></div></div></div></div><div id="ml084.s17"><h2 id="_ml084_s17_">Probe Characterization</h2><p>We found that interference with COPI function by RNAi in <i>Drosophila</i>
|
||
Kc167 cells, as well as in mouse 3T3-L1 or AML12 cells, results in increased lipid
|
||
storage (see <a class="figpopup" href="/books/NBK47336/figure/ml084.f5/?report=objectonly" target="object" rid-figpopup="figml084f5" rid-ob="figobml084f5">Figure 4</a> and Beller et al.,
|
||
(<a class="bk_pop" href="#ml084.r13">13</a>)). In order to characterize the
|
||
COPI knockdown effects on lipid storage in greater detail, and to confirm the
|
||
independently identified effect of the Exo1 compound, we utilized different
|
||
secondary assays. In addition to Exo1, we used BFA, another compound that has been
|
||
implicated in the modulation of COPI-mediated trafficking in mammalian cells (<a class="bk_pop" href="#ml084.r14">14</a>). In order to support our finding of
|
||
evolutionary conservation of COPI effects on lipid storage, we also utilized Exo1
|
||
and BFA in the mammalian cell system. Both compounds reduced NEFA release to the
|
||
same extent as the siRNAs targeting COPI subunit encoding mRNAs (<a class="figpopup" href="/books/NBK47336/figure/ml084.f6/?report=objectonly" target="object" rid-figpopup="figml084f6" rid-ob="figobml084f6">Figure 5</a> and see Ref [<a class="bk_pop" href="#ml084.r13">13</a>]). Mimicking genetic
|
||
epistasis experiments by combining RNAi and compound treatment, we furthermore
|
||
obtained results supporting the hypothesis that COPI-functions in the same pathway
|
||
as ATGL and might be involved in its activation (see <a class="figpopup" href="/books/NBK47336/figure/ml084.f6/?report=objectonly" target="object" rid-figpopup="figml084f6" rid-ob="figobml084f6">Figure 5</a> and Ref[<a class="bk_pop" href="#ml084.r13">13</a>]), opening up new possibilities to study
|
||
this currently heavily studied question. Positive regulation of lipolysis by the
|
||
COPI retrograde vesicle trafficking pathway was the most striking and unexpected
|
||
result of both the RNAi and small molecule compound screen. We propose that COPI is
|
||
likely to function directly at the lipid droplet surface and rather than indirectly
|
||
through the Golgi. See Beller et al. (<a class="bk_pop" href="#ml084.r13">13</a>) for a full description of these findings.</p><div id="ml084.s18"><h3>Mode of action for Exo1</h3><div id="ml084.f5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47336/bin/ml084f5.jpg" alt="Figure 4. The COPI-Mediated Retrograde Trafficking Pathway is a negative regulator of lipid storage." /></div><h3><span class="label">Figure 4</span><span class="title">The COPI-Mediated Retrograde Trafficking Pathway is a
|
||
negative regulator of lipid storage</span></h3><div class="caption"><p>(A–F) Drosophila cells with or without oleic acid
|
||
stained with BODIPY493/503 to detect lipid. Control cells not
|
||
treated with dsRNA (A and D) or cells incubated with dsRNAs
|
||
targeting Arf79F (an Arf1 homolog) (B and E) or alphaCop (C and
|
||
F) are shown. (G) All COPI, and several COPII members as well as
|
||
additional Arfs, were retested using independent dsRNAs and gave
|
||
similar results. Results and number of dsRNAs present in the
|
||
primary screen (including oleic acid) and retests are given. (H)
|
||
Dose response of Drosophila S3 cells to Exo1 (structure inset)
|
||
showing the %-activity derived either from the lipid
|
||
specific signal (filled circles) or the lipid/cell ratio (open
|
||
circles). Percent activity refers hereby to the changes of lipid
|
||
storage relative to Triacsin C treatment, which decreases lipid
|
||
storage by blocking TG synthesis. Increased activity indicates
|
||
increased lipid storage, which increased with concentration.
|
||
Scale bar in (A) represents 10. Adopted from Beller et al. 2008.
|
||
(<a class="bk_pop" href="#ml084.r13">13</a>)</p></div></div><div id="ml084.f6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47336/bin/ml084f6.jpg" alt="Figure 5. NEFA Incorporation and NEFA Release Measured in AML12 Cells after compound treatment." /></div><h3><span class="label">Figure 5</span><span class="title">NEFA Incorporation and NEFA Release Measured in AML12 Cells after
|
||
compound treatment</span></h3><div class="caption"><p>Relative activity [(experimental/ALLStars negative control
|
||
(control) and DMSO) Radiolabel assays for NEFA release (nM) relative to
|
||
total protein concentration in cells treated with siRNAs targeting the
|
||
indicated transcripts in the presence of DMSO only (open bar), BFA (5
|
||
μM) in DMSO (light-grey bar), or Exo1 (5 μM) in DMSO
|
||
(dark-grey bar). Significance at p<0.01, unpaired t-test, is shown
|
||
(indicated by an asterisk [*]). Standard
|
||
error is indicated by the bars.</p></div></div></div><div id="ml084.s19"><h3>Synthesis of Exo1 analogs</h3><div id="ml084.s20"><h4>General procedure for the synthesis of Exo-1 (CID-310557) and its
|
||
analogues</h4><p>To a solution of the appropriate aryl acid (220 mg, 1.45 mmol) in DCM (20 ml)
|
||
was added SOCl<sub>2</sub> (2.12 ml, 29.0 mmol) and several drops of DMF,
|
||
and the mixture was stirred at room temperature for 0.5 h. The solvent and
|
||
excess SOCl<sub>2</sub> were removed under reduced pressure and the
|
||
resulting film was reconstituted in DCM (10 ml) followed by the addition of
|
||
Et<sub>3</sub>N (2.42 ml, 1.74 mmol, 1.2 eq.) and the appropriate
|
||
analine (253 mg, 1.60 mmol, 1.1 eq). The resulting mixture was stirred for 3
|
||
h and water (10 ml) was added, and the organic layer was separated. The
|
||
aqueous layer was further extracted with DCM (20 ml). The combined organic
|
||
layers were washed with brine and dried over Na<sub>2</sub>SO<sub>4</sub>.
|
||
After the removal of solvent, the residue was purified by column
|
||
chromatography (EtOAc/DCM= 1/40) to afford desired product (297
|
||
mg, 75%).</p><div id="ml084.fu2" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu2.jpg" alt="Image ml084fu2" /></div></div><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 12.03 (brs, 1H),
|
||
8.92 (dd, <i>J</i><sub>HH</sub>= 8.6, 1.0 Hz, 1H),
|
||
8.04–8.15 (m, 3H), 7.61 (td,
|
||
<i>J</i><sub>HH</sub>= 8.0, 1.6 Hz, 1H),
|
||
7.20–7.43 (m, 3H), 3.97 (s, 3H); (TOFMS) <i>m/z</i>
|
||
274.0878 (M+H<sup>+</sup>) (calculated for
|
||
C<sub>15</sub>H<sub>13F</sub>NO<sub>3</sub>+) 274.0879.</p><div id="ml084.fu3" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu3.jpg" alt="Image ml084fu3" /></div></div><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.71 (brs, 1H),
|
||
8.60 (dd, <i>J</i><sub>HH</sub>= 8.0, 1.6 Hz, 1H),
|
||
8.42 (d, <i>J</i><sub>HH</sub>= 0.4 Hz, 1H),
|
||
7.96–8.02 (m, 3H), 7.87–7.92 (m, 1H),
|
||
7.55–7.62 (m, 2H), 7.03–7.14 (m, 2H), 6.95 (dd,
|
||
<i>J</i><sub>HH</sub>= 8.0 Hz, 1.6 Hz, 1H), 3.95
|
||
(s, 3H); (TOFMS) <i>m/z</i>
|
||
(M+H<sup>+</sup>) 278.1196 (calculated for
|
||
C<sub>18</sub>H<sub>16</sub>NO<sub>2</sub>+) 278.1181</p><div id="ml084.fu4" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu4.jpg" alt="Image ml084fu4" /></div></div><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 12.21 (brs, 1H),
|
||
8.89 (d, <i>J</i><sub>HH</sub>= 8.2 Hz, 2H), 8.15 (d,
|
||
<i>J</i><sub>HH</sub>= 8.4 Hz, 1H), 8.11 (dd,
|
||
<i>J</i><sub>HH</sub>= 8.0, 1.6 Hz, 1H), 7.82 (d,
|
||
<i>J</i><sub>HH</sub>= 8.2 Hz, 2H), 7.63 (td,
|
||
<i>J</i><sub>HH</sub>= 7.8, 1.6 Hz, 1H), 7.17 (m,
|
||
1H), 3.98 (s, 3H); (TOFMS) <i>m/z</i> 281.0925
|
||
(M+H<sup>+</sup>) (calculated for
|
||
C<sub>16</sub>H<sub>13</sub>N<sub>2</sub>O<sub>3</sub>+)
|
||
281.0926.</p><div id="ml084.fu5" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu5.jpg" alt="Image ml084fu5" /></div></div><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 11.82 (d,
|
||
<i>J</i><sub>HF</sub>= 7.2 Hz, 1H), 8.92 (dd,
|
||
<i>J</i><sub>HH</sub>= 8.4, 0.8 Hz, 1H),
|
||
8.04–8.15 (m, 2H), 7.60 (td,
|
||
<i>J</i><sub>HH</sub>= 7.0, 1.6 Hz, 1H), 7.14 (td,
|
||
<i>J</i><sub>HH</sub>= 7.6, 0.8 Hz, 1H),
|
||
6.90–7.06 (m, 2H), 3.94 (s, 3H); (TOFMS) <i>m/z</i>
|
||
292.0781 (M+H<sup>+</sup>) (calculated for
|
||
C<sub>15</sub>H<sub>12</sub>F<sub>2</sub>NO<sub>3</sub>+)
|
||
292.0785.</p></div></div><div id="ml084.s21"><h3>SAR of Exo1 analogs</h3><div id="ml084.fu6" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu6.jpg" alt="Image ml084fu6" /></div></div><p>NCGC-000168461 shows the weakest activity in agreement with the SAR derived from
|
||
characterization of Exo1 analogs in mammalian cells by Feng et al. (<a class="bk_pop" href="#ml084.r12">12</a>)</p><p>This compound has been provided to the MLSMR: MLS-000722799</p><p><i>Canonical SMILES:</i>
|
||
COC(=O)C1=CC=CC=C1NC(=O)C2=CC=C(C=C2)F</p><p><i>InChI:</i>
|
||
InChI=1/C15H12FNO3/c1-20-15(19)12-4-2-3-5-13(12)17-14(18)10-6-8-11(16)9-7-10/h2-9H,1H3,(H,17,18)/f/h17H</p></div><div id="ml084.s23"><h3>Description of secondary assays used in probe characterization</h3><div id="ml084.s24"><h4>Lipolysis and lipogenesis measurements in AML12 cells</h4><p>Measurements of NEFA released from lipid droplets or incorporated into the TG
|
||
fraction were performed as previously described (<a class="bk_pop" href="#ml084.r13">13</a>). Briefly, AML12 cells treated with or without
|
||
specific siRNAs (10 nM) for 4 d were incubated overnight with growth medium,
|
||
supplemented with 400 μM oleic acid complexed to
|
||
0.4% bovine serum albumin, to promote triacylglycerol deposition
|
||
and [3H] oleic acid, at 1 x 10<sup>6</sup> dpm/well,
|
||
was included as a tracer. In lipolysis experiments, re-esterification of
|
||
fatty acids in AML12 cells was prevented by including 10 μM
|
||
Triacsin C (Biomol), an inhibitor of acyl coenzyme A synthetase, in the
|
||
medium. Quadruplicate wells were tested for each condition. Lipolysis was
|
||
determined by measuring radioactivity released into the media in 1 h. For
|
||
the lipid extraction and thin layer chromatography, the cell monolayer was
|
||
washed with ice-cold PBS and scraped into 1 ml of PBS. Lipids were extracted
|
||
by the Bligh-Dyer method [84], and 10%
|
||
of the total lipid was analyzed by thin layer chromatography. AML12 cells
|
||
treated with or without specific siRNAs were additionally incubated with
|
||
either vehicle (DMSO), 5 μM of Exo1 (12.5 mg/ml DMSO), or BFA
|
||
(10 mg/ml DMSO) during the time of radioactivity release into the media (2
|
||
h). NEFA incorporation into the TG fraction and NEFA release are calculated
|
||
as nanomoles/milligram protein. Protein measurements were performed using a
|
||
commercial BCA assay kit (Pierce Biotechnology) according to the
|
||
manufacturer’s instructions. Statistical significance was tested
|
||
by impaired Student t test (GraphPad software).</p></div></div></div><div id="ml084.s25"><h2 id="_ml084_s25_">Probe</h2><div id="ml084.s26"><h3>a. Chemical name</h3><p>Methyl 2-(4-fluorobenzamido)benzoate (<a href="/pcsubstance/?term=ML084[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML084</a>)</p></div><div id="ml084.s27"><h3>b. Probe chemical structure</h3><div id="ml084.fu7" class="figure"><div class="graphic"><img src="/books/NBK47336/bin/ml084fu7.jpg" alt="Image ml084fu7" /></div></div></div><div id="ml084.s28"><h3>c. Structural Verification Information of probe SID
|
||
(11114231)</h3><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 12.03
|
||
(brs, 1H), 8.92 (dd, <i>J</i><sub>HH</sub>=
|
||
8.6, 1.0 Hz, 1H), 8.04–8.15 (m, 3H), 7.61 (td,
|
||
<i>J</i><sub>HH</sub>= 8.0, 1.6 Hz, 1H),
|
||
7.20–7.43 (m, 3H), 3.97 (s, 3H); (TOFMS)
|
||
<i>m/z</i> 274.0878
|
||
(M+H<sup>+</sup>) (calculated for
|
||
C<sub>15</sub>H<sub>13F</sub>NO<sub>3</sub>+)
|
||
274.0879.</p></div><div id="ml084.s29"><h3>d. PubChem CID (corresponding to the SID)</h3><p>310557</p></div><div id="ml084.s30"><h3>e. Availability from a vendor</h3><p>Exo1 is sold by Tocris Biosciences (Tocris-1850).</p></div><div id="ml084.s31"><h3>f. Mode of action for biological activity of probe</h3><p>Increases lipid droplet storage by inhibition of COPI function.</p></div><div id="ml084.s32"><h3>g. Detailed synthetic pathway for making probe</h3><p>See <a href="#ml084.s20">page 11</a></p></div><div id="ml084.s33"><h3>h. Summary of probe properties</h3><p>Exo1 is not fluorescent using 488 nm excitation. Possess adequate
|
||
solubility for in vitro use. Probe is not toxic to cells at 60 µM
|
||
testing concentration (24 hr incubation). Probe properties such as
|
||
solubility are available at Tocris Biosciences.</p></div></div><div id="ml084.s34"><h2 id="_ml084_s34_">Compound preparation</h2><p>Compound is prepared in DMSO at 10 mM stock concentration. Assays described above
|
||
have 0.6% DMSO final concentration in buffer.</p></div><div id="ml084.bib"><h2 id="_ml084_bib_">Bibliography</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml084.r1">Langin D. Adipose tissue lipolysis as a metabolic pathway to define
|
||
pharmacological strategies against obesity and the metabolic
|
||
syndrome. <span><span class="ref-journal">Pharmacol Res. </span>2006;<span class="ref-vol">53</span>:482–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16644234" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16644234</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml084.r2">Subramanian V, Rothenberg A, Gomez C, Cohen AW, Garcia A, Bhattacharyya S, Shapiro L, Dolios G, Wang R, Lisanti MP, Brasaemle DL. Perilipin A mediates the reversible binding of CGI-58 to
|
||
lipid droplets in 3T3-L1 adipocytes. <span><span class="ref-journal">J Biol Chem. </span>2004;<span class="ref-vol">279</span>:42062–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15292255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15292255</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml084.r3">Vaughan M, Berger JE, Steinberg D. Hormone-Sensitive Lipase and Monoglyceride Lipase Activities
|
||
in Adipose Tissue. <span><span class="ref-journal">J Biol Chem. </span>1964;<span class="ref-vol">239</span>:401–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14169138" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14169138</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml084.r4">Gronke S, Mildner A, Fellert S, Tennagels N, Petry S, Muller G, Jackle H, Kuhnlein RP. Brummer lipase is an evolutionary conserved fat storage
|
||
regulator in Drosophila. <span><span class="ref-journal">Cell Metab. </span>2005;<span class="ref-vol">1</span>:323–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16054079" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16054079</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml084.r5">Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M, Hoefler G, Zechner R. Defective lipolysis and altered energy metabolism in mice
|
||
lacking adipose triglyceride lipase. <span><span class="ref-journal">Science. </span>2006;<span class="ref-vol">312</span>:734–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16675698" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16675698</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml084.r6">Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose
|
||
triglyceride lipase. <span><span class="ref-journal">Science. </span>2004;<span class="ref-vol">306</span>:1383–6.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15550674" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15550674</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml084.r7">Frayn KN, Arner P, Yki-Jarvinen H. Fatty acid metabolism in adipose tissue, muscle and liver in
|
||
health and disease. <span><span class="ref-journal">Essays Biochem. </span>2006;<span class="ref-vol">42</span>:89–103.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17144882" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17144882</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml084.r8">Niles WD, Coassin PJ. Cyclic olefin polymers: innovative materials for high-density
|
||
multiwell plates. <span><span class="ref-journal">Assay Drug Dev Technol. </span>2008;<span class="ref-vol">6</span>:577–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18537466" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18537466</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml084.r9">Niles WD, Coassin PJ. Piezo- and Solenoid Valve-Based Liquid Dispensing for
|
||
Miniaturized Assays. <span><span class="ref-journal">Assay Drug. Devel. Technol. </span>2005;<span class="ref-vol">3</span>:189–202.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15871693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15871693</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml084.r10">Bowen WP, Wylie PG. Application of Laser-Scanning Fluorescence Microplate
|
||
Cytometry in High Content Screening. <span><span class="ref-journal">Assay Drug Dev Technol. </span>2006;<span class="ref-vol">4</span>:209–221.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16712425" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16712425</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml084.r11">Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP. Quantitative high-throughput screening: A titration-based
|
||
approach that efficiently identifies biological activities in large
|
||
chemical libraries. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2006;<span class="ref-vol">103</span>:11473–8.</span> [<a href="/pmc/articles/PMC1518803/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1518803</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16864780" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16864780</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml084.r12">Feng Y, Yu S, Lasell TK, Jadhav AP, Macia E, Chardin P, Melancon P, Roth M, Mitchison T, Kirchhausen T. Exo1: a new chemical inhibitor of the exocytic
|
||
pathway. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2003;<span class="ref-vol">100</span>:6469–74.</span> [<a href="/pmc/articles/PMC164470/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC164470</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12738886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12738886</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml084.r13">Beller M, Sztalryd C, Southall N, Bell M, Jackle H, Auld DS, Oliver B. COPI complex is a regulator of lipid
|
||
homeostasis. <span><span class="ref-journal">PLoS Biol. </span>2008;<span class="ref-vol">6</span>:2530–2549.</span> [<a href="/pmc/articles/PMC2586367/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2586367</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19067489" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19067489</span></a>]</div></dd><dt>14.</dt><dd><div class="bk_ref" id="ml084.r14">Lippincott-Schwartz J, Yuan L, Tipper C, Amherdt M, Orci L, Klausner RD. Brefeldin A’s effects on endosomes, lysosomes,
|
||
and the TGN suggest a general mechanism for regulating organelle
|
||
structure and membrane traffic. <span><span class="ref-journal">Cell. </span>1991;<span class="ref-vol">67</span>:601–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1682055" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1682055</span></a>]</div></dd></dl></div><div style="display:none"><div style="display:none" id="figml084f5"><img alt="Image ml084f5" src-large="/books/NBK47336/bin/ml084f5.jpg" /></div><div style="display:none" id="figml084f6"><img alt="Image ml084f6" src-large="/books/NBK47336/bin/ml084f6.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div>
|
||
<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK47336</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/21433352" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">21433352</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml085/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml083/" title="Next page in this title">Next ></a></div></div></div></div>
|
||
|
||
</div>
|
||
|
||
<!-- Custom content below content -->
|
||
<div class="col4">
|
||
|
||
</div>
|
||
|
||
|
||
<!-- Book content -->
|
||
|
||
<!-- Custom contetnt below bottom nav -->
|
||
<div class="col5">
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div id="rightcolumn" class="four_col col last">
|
||
<!-- Custom content above discovery portlets -->
|
||
<div class="col6">
|
||
<div id="ncbi_share_book"><a href="#" class="ncbi_share" data-ncbi_share_config="popup:false,shorten:true" ref="id=NBK47336&db=books">Share</a></div>
|
||
|
||
</div>
|
||
<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK47336/?report=reader">PubReader</a></li><li><a href="/books/NBK47336/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK47336" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK47336" style="display:none" title="Cite this Page"><div class="bk_tt">Beller M, Thomas C, Shen M, et al. Identification of lipid storage modulators. 2009 Apr 16 [Updated 2010 Sep 2]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK47336/pdf/Bookshelf_NBK47336.pdf">PDF version of this page</a> (959K)</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml084.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml084.s3" ref="log$=inpage&link_id=inpage">Recommendations for the scientific use of this probe</a></li><li><a href="#ml084.s7" ref="log$=inpage&link_id=inpage">Assay Implementation and Screening</a></li><li><a href="#ml084.s17" ref="log$=inpage&link_id=inpage">Probe Characterization</a></li><li><a href="#ml084.s25" ref="log$=inpage&link_id=inpage">Probe</a></li><li><a href="#ml084.s34" ref="log$=inpage&link_id=inpage">Compound preparation</a></li><li><a href="#ml084.bib" ref="log$=inpage&link_id=inpage">Bibliography</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=2358038" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=2358038" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2358038" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26269925" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Translational Metabolomics of Head Injury: Exploring Dysfunctional Cerebral Metabolism with Ex Vivo NMR Spectroscopy-Based Metabolite Quantification.</a><span class="source">[Brain Neurotrauma: Molecular, ...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Translational Metabolomics of Head Injury: Exploring Dysfunctional Cerebral Metabolism with Ex Vivo NMR Spectroscopy-Based Metabolite Quantification.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Wolahan SM, Hirt D, Glenn TC. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. 2015</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/23905198" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Modulators of Lipid Storage.</a><span class="source">[Probe Reports from the NIH Mol...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Modulators of Lipid Storage.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Boxer MB, Shen M, Zhang Y, Liu L, Auld DS, Beller M. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Probe Reports from the NIH Molecular Libraries Program. 2010</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/22325608" ref="ordinalpos=1&linkpos=3&log$=relatedarticles&logdbfrom=pubmed">Genome-wide screens for gene products regulating lipid droplet dynamics.</a><span class="source">[Methods Cell Biol. 2012]</span><div class="brieflinkpop offscreen_noflow">Genome-wide screens for gene products regulating lipid droplet dynamics.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Fei W, Yang H. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Methods Cell Biol. 2012; 108:303-16. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/23521767" ref="ordinalpos=1&linkpos=4&log$=relatedarticles&logdbfrom=pubmed">Phenotypic screening with oleaginous microalgae reveals modulators of lipid productivity.</a><span class="source">[ACS Chem Biol. 2013]</span><div class="brieflinkpop offscreen_noflow">Phenotypic screening with oleaginous microalgae reveals modulators of lipid productivity.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Franz AK, Danielewicz MA, Wong DM, Anderson LA, Boothe JR. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">ACS Chem Biol. 2013 May 17; 8(5):1053-62. Epub 2013 Mar 22.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/22289369" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> A novel strategy to identify drugs that interfere with endosomal lipids.</a><span class="source">[Chimia (Aarau). 2011]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> A novel strategy to identify drugs that interfere with endosomal lipids.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Moreau D, Scott C, Gruenberg J. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Chimia (Aarau). 2011; 65(11):846-8. </em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=21433352" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=21433352" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d66c3467c23b31e0b41c22">Identification of lipid storage modulators - Probe Reports from the NIH Molecula...</a><div class="ralinkpop offscreen_noflow">Identification of lipid storage modulators - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=2" href="/portal/utils/pageresolver.fcgi?recordid=67d66c3384f3725e592e3593">Placental Alkaline Phosphatase (PLAP) Luminescent HTS assay - Probe 1 - Probe Re...</a><div class="ralinkpop offscreen_noflow">Placental Alkaline Phosphatase (PLAP) Luminescent HTS assay - Probe 1 - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=3" href="/portal/utils/pageresolver.fcgi?recordid=67d66c3167c23b31e0b413d0">The Role of PHOSPHO1 in the Initiation of Skeletal Calcification - Probe Reports...</a><div class="ralinkpop offscreen_noflow">The Role of PHOSPHO1 in the Initiation of Skeletal Calcification - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=4" href="/portal/utils/pageresolver.fcgi?recordid=67d66c302f30673f7bf947fc">HTS identification of compounds activating TNAP at an intermediate concentration...</a><div class="ralinkpop offscreen_noflow">HTS identification of compounds activating TNAP at an intermediate concentration of phosphate acceptor detected in luminescent assay - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=5" href="/portal/utils/pageresolver.fcgi?recordid=67d66c2f84f3725e592e25ae">Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1 - Probe Reports fro...</a><div class="ralinkpop offscreen_noflow">Therapeutic Inhibitors of Phosphomannose Isomerase - Probe 1 - Probe Reports from the NIH Molecular Libraries Program<div class="brieflinkpopdesc"></div></div><div class="tertiary"></div></li></ul><p class="HTOn">Your browsing activity is empty.</p><p class="HTOff">Activity recording is turned off.</p><p id="turnOn" class="HTOff"><a href="javascript:historyDisplayState('HTOn')">Turn recording back on</a></p><a class="seemore" href="/sites/myncbi/recentactivity">See more...</a></div></div></div>
|
||
|
||
<!-- Custom content below discovery portlets -->
|
||
<div class="col7">
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<!-- Custom content after all -->
|
||
<div class="col8">
|
||
|
||
</div>
|
||
<div class="col9">
|
||
|
||
</div>
|
||
|
||
<script type="text/javascript" src="/corehtml/pmc/js/jquery.scrollTo-1.4.2.js"></script>
|
||
<script type="text/javascript">
|
||
(function($){
|
||
$('.skiplink').each(function(i, item){
|
||
var href = $($(item).attr('href'));
|
||
href.attr('tabindex', '-1').addClass('skiptarget'); // ensure the target can receive focus
|
||
$(item).on('click', function(event){
|
||
event.preventDefault();
|
||
$.scrollTo(href, 0, {
|
||
onAfter: function(){
|
||
href.focus();
|
||
}
|
||
});
|
||
});
|
||
});
|
||
})(jQuery);
|
||
</script>
|
||
</div>
|
||
<div class="bottom">
|
||
|
||
<div id="NCBIFooter_dynamic">
|
||
<!--<component id="Breadcrumbs" label="breadcrumbs"/>
|
||
<component id="Breadcrumbs" label="helpdesk"/>-->
|
||
|
||
</div>
|
||
|
||
<div class="footer" id="footer">
|
||
<section class="icon-section">
|
||
<div id="icon-section-header" class="icon-section_header">Follow NCBI</div>
|
||
<div class="grid-container container">
|
||
<div class="icon-section_container">
|
||
<a class="footer-icon" id="footer_twitter" href="https://twitter.com/ncbi" aria-label="Twitter"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11 {
|
||
fill: #737373;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>Twitter</title>
|
||
<path class="cls-11" d="M250.11,105.48c-7,3.14-13,3.25-19.27.14,8.12-4.86,8.49-8.27,11.43-17.46a78.8,78.8,0,0,1-25,9.55,39.35,39.35,0,0,0-67,35.85,111.6,111.6,0,0,1-81-41.08A39.37,39.37,0,0,0,81.47,145a39.08,39.08,0,0,1-17.8-4.92c0,.17,0,.33,0,.5a39.32,39.32,0,0,0,31.53,38.54,39.26,39.26,0,0,1-17.75.68,39.37,39.37,0,0,0,36.72,27.3A79.07,79.07,0,0,1,56,223.34,111.31,111.31,0,0,0,116.22,241c72.3,0,111.83-59.9,111.83-111.84,0-1.71,0-3.4-.1-5.09C235.62,118.54,244.84,113.37,250.11,105.48Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_facebook" href="https://www.facebook.com/ncbi.nlm" aria-label="Facebook"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>Facebook</title>
|
||
<path class="cls-11" d="M210.5,115.12H171.74V97.82c0-8.14,5.39-10,9.19-10h27.14V52l-39.32-.12c-35.66,0-42.42,26.68-42.42,43.77v19.48H99.09v36.32h27.24v109h45.41v-109h35Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_linkedin" href="https://www.linkedin.com/company/ncbinlm" aria-label="LinkedIn"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<title>LinkedIn</title>
|
||
<path class="cls-11" d="M101.64,243.37H57.79v-114h43.85Zm-22-131.54h-.26c-13.25,0-21.82-10.36-21.82-21.76,0-11.65,8.84-21.15,22.33-21.15S101.7,78.72,102,90.38C102,101.77,93.4,111.83,79.63,111.83Zm100.93,52.61A17.54,17.54,0,0,0,163,182v61.39H119.18s.51-105.23,0-114H163v13a54.33,54.33,0,0,1,34.54-12.66c26,0,44.39,18.8,44.39,55.29v58.35H198.1V182A17.54,17.54,0,0,0,180.56,164.44Z">
|
||
</path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_github" href="https://github.com/ncbi" aria-label="GitHub"><svg xmlns="http://www.w3.org/2000/svg" data-name="Layer 1" viewBox="0 0 300 300">
|
||
<defs>
|
||
<style>
|
||
.cls-11,
|
||
.cls-12 {
|
||
fill: #737373;
|
||
}
|
||
|
||
.cls-11 {
|
||
fill-rule: evenodd;
|
||
}
|
||
</style>
|
||
</defs>
|
||
<title>GitHub</title>
|
||
<path class="cls-11" d="M151.36,47.28a105.76,105.76,0,0,0-33.43,206.1c5.28,1,7.22-2.3,7.22-5.09,0-2.52-.09-10.85-.14-19.69-29.42,6.4-35.63-12.48-35.63-12.48-4.81-12.22-11.74-15.47-11.74-15.47-9.59-6.56.73-6.43.73-6.43,10.61.75,16.21,10.9,16.21,10.9,9.43,16.17,24.73,11.49,30.77,8.79,1-6.83,3.69-11.5,6.71-14.14C108.57,197.1,83.88,188,83.88,147.51a40.92,40.92,0,0,1,10.9-28.39c-1.1-2.66-4.72-13.42,1-28,0,0,8.88-2.84,29.09,10.84a100.26,100.26,0,0,1,53,0C198,88.3,206.9,91.14,206.9,91.14c5.76,14.56,2.14,25.32,1,28a40.87,40.87,0,0,1,10.89,28.39c0,40.62-24.74,49.56-48.29,52.18,3.79,3.28,7.17,9.71,7.17,19.58,0,14.15-.12,25.54-.12,29,0,2.82,1.9,6.11,7.26,5.07A105.76,105.76,0,0,0,151.36,47.28Z">
|
||
</path>
|
||
<path class="cls-12" d="M85.66,199.12c-.23.52-1.06.68-1.81.32s-1.2-1.06-.95-1.59,1.06-.69,1.82-.33,1.21,1.07.94,1.6Zm-1.3-1">
|
||
</path>
|
||
<path class="cls-12" d="M90,203.89c-.51.47-1.49.25-2.16-.49a1.61,1.61,0,0,1-.31-2.19c.52-.47,1.47-.25,2.17.49s.82,1.72.3,2.19Zm-1-1.08">
|
||
</path>
|
||
<path class="cls-12" d="M94.12,210c-.65.46-1.71,0-2.37-.91s-.64-2.07,0-2.52,1.7,0,2.36.89.65,2.08,0,2.54Zm0,0"></path>
|
||
<path class="cls-12" d="M99.83,215.87c-.58.64-1.82.47-2.72-.41s-1.18-2.06-.6-2.7,1.83-.46,2.74.41,1.2,2.07.58,2.7Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M107.71,219.29c-.26.82-1.45,1.2-2.64.85s-2-1.34-1.74-2.17,1.44-1.23,2.65-.85,2,1.32,1.73,2.17Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M116.36,219.92c0,.87-1,1.59-2.24,1.61s-2.29-.68-2.3-1.54,1-1.59,2.26-1.61,2.28.67,2.28,1.54Zm0,0">
|
||
</path>
|
||
<path class="cls-12" d="M124.42,218.55c.15.85-.73,1.72-2,1.95s-2.37-.3-2.52-1.14.73-1.75,2-2,2.37.29,2.53,1.16Zm0,0"></path>
|
||
</svg></a>
|
||
<a class="footer-icon" id="footer_blog" href="https://ncbiinsights.ncbi.nlm.nih.gov/" aria-label="Blog">
|
||
<svg xmlns="http://www.w3.org/2000/svg" id="Layer_1" data-name="Layer 1" viewBox="0 0 40 40">
|
||
<defs><style>.cls-1{fill:#737373;}</style></defs>
|
||
<title>NCBI Insights Blog</title>
|
||
<path class="cls-1" d="M14,30a4,4,0,1,1-4-4,4,4,0,0,1,4,4Zm11,3A19,19,0,0,0,7.05,15a1,1,0,0,0-1,1v3a1,1,0,0,0,.93,1A14,14,0,0,1,20,33.07,1,1,0,0,0,21,34h3a1,1,0,0,0,1-1Zm9,0A28,28,0,0,0,7,6,1,1,0,0,0,6,7v3a1,1,0,0,0,1,1A23,23,0,0,1,29,33a1,1,0,0,0,1,1h3A1,1,0,0,0,34,33Z"></path>
|
||
</svg>
|
||
</a>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
|
||
<section class="container-fluid bg-primary">
|
||
<div class="container pt-5">
|
||
<div class="row mt-3">
|
||
<div class="col-lg-3 col-12">
|
||
<p><a class="text-white" href="https://www.nlm.nih.gov/socialmedia/index.html">Connect with NLM</a></p>
|
||
<ul class="list-inline social_media">
|
||
<li class="list-inline-item"><a href="https://twitter.com/NLM_NIH" aria-label="Twitter" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st20 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st30 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Twitter</title>
|
||
<g>
|
||
<g>
|
||
<g>
|
||
<path class="st20" d="M192.9,88.1c-5,2.2-9.2,2.3-13.6,0.1c5.7-3.4,6-5.8,8.1-12.3c-5.4,3.2-11.4,5.5-17.6,6.7 c-10.5-11.2-28.1-11.7-39.2-1.2c-7.2,6.8-10.2,16.9-8,26.5c-22.3-1.1-43.1-11.7-57.2-29C58,91.6,61.8,107.9,74,116 c-4.4-0.1-8.7-1.3-12.6-3.4c0,0.1,0,0.2,0,0.4c0,13.2,9.3,24.6,22.3,27.2c-4.1,1.1-8.4,1.3-12.5,0.5c3.6,11.3,14,19,25.9,19.3 c-11.6,9.1-26.4,13.2-41.1,11.5c12.7,8.1,27.4,12.5,42.5,12.5c51,0,78.9-42.2,78.9-78.9c0-1.2,0-2.4-0.1-3.6 C182.7,97.4,189.2,93.7,192.9,88.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st30" cx="124.4" cy="128.8" r="108.2"></circle>
|
||
</g>
|
||
</svg></a></li>
|
||
<li class="list-inline-item"><a href="https://www.facebook.com/nationallibraryofmedicine" aria-label="Facebook" rel="noopener noreferrer" target="_blank">
|
||
<svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<style type="text/css">
|
||
.st10 {
|
||
fill: #FFFFFF;
|
||
}
|
||
|
||
.st110 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
</style>
|
||
<title>Facebook</title>
|
||
<g>
|
||
<g>
|
||
<path class="st10" d="M159,99.1h-24V88.4c0-5,3.3-6.2,5.7-6.2h16.8V60l-24.4-0.1c-22.1,0-26.2,16.5-26.2,27.1v12.1H90v22.5h16.9 v67.5H135v-67.5h21.7L159,99.1z"></path>
|
||
</g>
|
||
</g>
|
||
<circle class="st110" cx="123.6" cy="123.2" r="108.2"></circle>
|
||
</svg>
|
||
</a></li>
|
||
<li class="list-inline-item"><a href="https://www.youtube.com/user/NLMNIH" aria-label="Youtube" target="_blank" rel="noopener noreferrer"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink" version="1.1" x="0px" y="0px" viewBox="0 0 249 249" style="enable-background:new 0 0 249 249;" xml:space="preserve">
|
||
<title>Youtube</title>
|
||
<style type="text/css">
|
||
.st4 {
|
||
fill: none;
|
||
stroke: #FFFFFF;
|
||
stroke-width: 8;
|
||
stroke-miterlimit: 10;
|
||
}
|
||
|
||
.st5 {
|
||
fill: #FFFFFF;
|
||
}
|
||
</style>
|
||
<circle class="st4" cx="124.2" cy="123.4" r="108.2"></circle>
|
||
<g transform="translate(0,-952.36218)">
|
||
<path class="st5" d="M88.4,1037.4c-10.4,0-18.7,8.3-18.7,18.7v40.1c0,10.4,8.3,18.7,18.7,18.7h72.1c10.4,0,18.7-8.3,18.7-18.7 v-40.1c0-10.4-8.3-18.7-18.7-18.7H88.4z M115.2,1058.8l29.4,17.4l-29.4,17.4V1058.8z"></path>
|
||
</g>
|
||
</svg></a></li>
|
||
</ul>
|
||
</div>
|
||
<div class="col-lg-3 col-12">
|
||
<p class="address_footer text-white">National Library of Medicine<br />
|
||
<a href="https://www.google.com/maps/place/8600+Rockville+Pike,+Bethesda,+MD+20894/@38.9959508,-77.101021,17z/data=!3m1!4b1!4m5!3m4!1s0x89b7c95e25765ddb:0x19156f88b27635b8!8m2!3d38.9959508!4d-77.0988323" class="text-white" target="_blank" rel="noopener noreferrer">8600 Rockville Pike<br />
|
||
Bethesda, MD 20894</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a href="https://www.nlm.nih.gov/web_policies.html" class="text-white">Web Policies</a><br />
|
||
<a href="https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/freedom-information-act-office" class="text-white">FOIA</a><br />
|
||
<a href="https://www.hhs.gov/vulnerability-disclosure-policy/index.html" class="text-white" id="vdp">HHS Vulnerability Disclosure</a></p>
|
||
</div>
|
||
<div class="col-lg-3 col-12 centered-lg">
|
||
<p><a class="supportLink text-white" href="https://support.nlm.nih.gov/">Help</a><br />
|
||
<a href="https://www.nlm.nih.gov/accessibility.html" class="text-white">Accessibility</a><br />
|
||
<a href="https://www.nlm.nih.gov/careers/careers.html" class="text-white">Careers</a></p>
|
||
</div>
|
||
</div>
|
||
<div class="row">
|
||
<div class="col-lg-12 centered-lg">
|
||
<nav class="bottom-links">
|
||
<ul class="mt-3">
|
||
<li>
|
||
<a class="text-white" href="//www.nlm.nih.gov/">NLM</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.nih.gov/">NIH</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.hhs.gov/">HHS</a>
|
||
</li>
|
||
<li>
|
||
<a class="text-white" href="https://www.usa.gov/">USA.gov</a>
|
||
</li>
|
||
</ul>
|
||
</nav>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
</section>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentOmnitureBaseJS/InstrumentNCBIConfigJS/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js?v=1"> </script>
|
||
<script type="text/javascript" src="/portal/portal3rc.fcgi/static/js/hfjs2.js"> </script>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<!--/.page-->
|
||
</div>
|
||
<!--/.wrap-->
|
||
</div><!-- /.twelve_col -->
|
||
</div>
|
||
<!-- /.grid -->
|
||
|
||
<span class="PAFAppResources"></span>
|
||
|
||
<!-- BESelector tab -->
|
||
|
||
|
||
|
||
<noscript><img alt="statistics" src="/stat?jsdisabled=true&ncbi_db=books&ncbi_pdid=book-part&ncbi_acc=NBK47336&ncbi_domain=mlprobe&ncbi_report=record&ncbi_type=fulltext&ncbi_objectid=&ncbi_pcid=/NBK47336/&ncbi_pagename=Identification of lipid storage modulators - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf&ncbi_bookparttype=chapter&ncbi_app=bookshelf" /></noscript>
|
||
|
||
|
||
<!-- usually for JS scripts at page bottom -->
|
||
<!--<component id="PageFixtures" label="styles"></component>-->
|
||
|
||
|
||
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal106 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
||
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
||
|
||
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3879255/4121861/3501987/4008961/3893018/3821238/4062932/4209313/4212053/4076480/3921943/3400083/3426610.js" snapshot="books"></script></body>
|
||
</html> |