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<meta name="description" content="<span><i>MYBPC3</i>, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accord</span> …"><meta name="keywords" content="pmid:39594661, PMC11592734, doi:10.3390/cells13221913, Darshini Desai, Taejeong Song, Sakthivel Sadayappan, Calcium / metabolism, Cardiomyopathy, Hypertrophic / genetics, Cardiomyopathy, Hypertrophic / metabolism, Cardiomyopathy, Hypertrophic / pathology, Carrier Proteins* / genetics, Carrier Proteins* / metabolism, Humans, Induced Pluripotent Stem Cells* / cytology, Induced Pluripotent Stem Cells* / metabolism, Myocardial Contraction, Myocardium / metabolism, Myocytes, Cardiac* / metabolism, Organoids* / metabolism, Sarcomeres / metabolism, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/39594661/"><meta property="og:description" content="<span><i>MYBPC3</i>, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accord</span> …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/39594661/"><meta name="twitter:description" content="<span><i>MYBPC3</i>, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accord</span> …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">
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|
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<span class="search-input-link user-guide-link" role="navigation" aria-label="User guide">
|
||
<a href="/help/"
|
||
data-ga-category="featured_link"
|
||
data-ga-action="user_guide">
|
||
User Guide
|
||
</a>
|
||
</span>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
|
||
</form>
|
||
|
||
|
||
<div id="article-page-header">
|
||
<div id="article-top-actions-bar" class="article-top-actions-bar">
|
||
<div class="inner-wrap">
|
||
<div class="actions-container">
|
||
<div class="return-to-search">
|
||
|
||
|
||
</div>
|
||
|
||
<div class="multiple-results-actions " role="region" aria-label="save, email, send to">
|
||
<button id="save-results-panel-trigger"
|
||
type="button"
|
||
class="save-results save-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="save-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="open">
|
||
Save
|
||
</button><button id="email-results-panel-trigger"
|
||
type="button"
|
||
class="email-results email-results-panel-trigger"
|
||
aria-expanded="false"
|
||
aria-controls="email-action-panel"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="open">
|
||
Email
|
||
</button><div class="more-actions dropdown-block"><button id="more-actions-trigger"
|
||
type="button"
|
||
class="trigger more-actions-trigger"
|
||
ref="linksrc=show_moreactions_btn"
|
||
aria-label="Send to"
|
||
aria-controls="more-actions-dropdown">Send to</button><div id="more-actions-dropdown" class="dropdown dropdown-container" hidden><div class="content"><ul class="more-actions-links"><li><a class="clipboard-panel-trigger dropdown-block-link "
|
||
href="#"
|
||
role="button"
|
||
data-ga-category="save_share"
|
||
data-ga-action="clipboard"
|
||
data-ga-label="send">
|
||
Clipboard
|
||
</a></li><li><a role="button" class="dropdown-block-link bibliography-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F39594661%2F%23open-bibliography-panel">My Bibliography</a></li><li><a role="button" class="dropdown-block-link collections-trigger-target" href="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F39594661%2F%23open-collections-panel">Collections</a></li><li><a role="button" class="citation-manager-panel-trigger dropdown-block-link citation-manager-trigger-target" href="#">Citation manager</a></li></ul></div></div></div>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region">
|
||
<button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog">
|
||
<span class="button-label">Display options</span>
|
||
</button>
|
||
|
||
<div class="dropdown" hidden>
|
||
<div class="title">
|
||
Display options
|
||
</div>
|
||
|
||
<div class="content">
|
||
|
||
<div class="format-container">
|
||
<span class="option-label">
|
||
Format
|
||
</span>
|
||
<select name="format" data-initial-value="abstract" aria-label="Display format" id="article-display-format">
|
||
<option value="abstract">Abstract</option>
|
||
|
||
<option value="pubmed">PubMed</option>
|
||
|
||
<option value="pmid">PMID</option>
|
||
|
||
</select>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
</div>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="article-panels-container" class="article-panels-container">
|
||
<div id="save-action-panel" class="save-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Save citation to file
|
||
</h2>
|
||
<form id="save-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="save-action-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="save-action-format" name="results-format" class="action-panel-selector">
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="pubmed-text">PubMed</option>
|
||
<option value="pmid">PMID</option>
|
||
<option value="abstract">Abstract (text)</option>
|
||
<option value="csv">CSV</option>
|
||
</select>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Save citations to file' panel"
|
||
ref="linksrc=close_save_panel"
|
||
aria-controls="save-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="save"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="email-action-panel"
|
||
class="email-action-panel action-panel"
|
||
aria-hidden="true"
|
||
data-recaptcha-script-url="https://www.recaptcha.net/recaptcha/enterprise.js?render=explicit&onload=onloadCaptchaCallback"
|
||
data-recaptcha-enabled="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Email citation
|
||
</h2>
|
||
<form id="email-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/send-email/"
|
||
data-by-search-action="/results-export-email-by-search-data/"
|
||
data-by-ids-action="/send-email/"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post"
|
||
method="post"
|
||
>
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<span class="action-panel-label">
|
||
Subject:
|
||
</span>
|
||
<span class="email-subject" id="email-subject" aria-label="Email subject">1 selected item: 39594661 - PubMed</span>
|
||
<input type="hidden" name="email-subject" value="1 selected item: 39594661"/>
|
||
<input type="hidden" name="email-subject-hash" value="8f2abb7672d41c85b5c477eaa48057896ff85c24121bc358d3827b2ef1243e70"/>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-to" class="action-panel-label required-field-asterisk">
|
||
To:
|
||
</label>
|
||
<input type="email" aria-label="Recipient Email Address" placeholder="email@example.com" id="email-to" class="email-to" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="100" required>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-from" class="action-panel-label">
|
||
From:
|
||
</label>
|
||
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
|
||
</div>
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="email-citation-format" class="action-panel-label">
|
||
Format:
|
||
</label>
|
||
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
|
||
<option selected="selected" value="summary">Summary</option>
|
||
<option value="summary-text">Summary (text)</option>
|
||
<option value="abstract">Abstract</option>
|
||
<option value="abstract-text">Abstract (text)</option>
|
||
|
||
</select>
|
||
</div>
|
||
<div class="include-supplemental-container">
|
||
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
|
||
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
|
||
</div>
|
||
|
||
|
||
|
||
<div class="form-field recaptcha ">
|
||
|
||
|
||
|
||
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
|
||
|
||
|
||
|
||
|
||
|
||
</div>
|
||
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
|
||
|
||
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="send">
|
||
Send email
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Email citations' panel"
|
||
ref="linksrc=close_email_panel"
|
||
aria-controls="email-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="email"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
<input type="hidden" name="email-search-details" value="" />
|
||
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="collections-action-panel"
|
||
class="collections-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-collections-open-panel-enabled="false"
|
||
data-collections-open-panel-url-hash="#open-collections-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to Collections
|
||
</h3>
|
||
|
||
|
||
<form id="collections-action-panel-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-add-to-collection-max-amount="1000"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
|
||
|
||
<div class="choice-group" role="radiogroup">
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_new">
|
||
<label for="collections-action-panel-new">Create a new collection</label>
|
||
</li>
|
||
<li>
|
||
<input type="radio"
|
||
id="collections-action-panel-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="collections_radio_existing">
|
||
<label for="collections-action-panel-existing">Add to an existing collection</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
|
||
<div class="controls-wrapper">
|
||
<div class="action-panel-control-wrap new-collections-controls">
|
||
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label>
|
||
<input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-panel-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="save_share"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection">
|
||
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div>
|
||
</div>
|
||
<div class="action-panel-control-wrap existing-collections-controls">
|
||
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label>
|
||
<select id="collections-action-panel-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="save_share"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
|
||
</select>
|
||
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="add">
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="collections"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="bibliography-action-panel"
|
||
class="bibliography-action-panel action-panel in-progress-dots-panel"
|
||
aria-hidden="true"
|
||
data-bibliography-open-panel-enabled="false"
|
||
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
|
||
<div class="inner-wrap">
|
||
<h3 class="action-panel-heading">
|
||
Add to My Bibliography
|
||
</h3>
|
||
<form id="bibliography-action-panel-form"
|
||
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-add-to-bibliography-max-amount="100"
|
||
data-add-to-bibliography-batch-size="10"
|
||
data-bibliography-delegates-url="/list-bibliography-delegates/"
|
||
data-add-to-bibliography-url="/add-to-bibliography/"
|
||
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
|
||
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
|
||
|
||
<div class="action-panel-control-wrap bibliographies-controls">
|
||
<div class="choice-group">
|
||
<ul class="bibliographies-action-add radio-group-items">
|
||
<li>
|
||
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
|
||
<label for="my-bibliography">My Bibliography</label>
|
||
</li>
|
||
</ul>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your delegates due to an error<br>
|
||
<a href="#">Please try again</a>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore>
|
||
Add
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Add to bibliography' panel"
|
||
ref="linksrc=close_bibliography_panel"
|
||
aria-controls="bibliography-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="mybib"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
|
||
data-saved-search-open-panel-enabled="false"
|
||
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your saved search
|
||
</h2>
|
||
|
||
<form id="saved-search-action-panel-form"
|
||
class="saved-search-action-panel-form action-panel-content action-form"
|
||
data-create-saved-search-url="/create-saved-search/"
|
||
data-try-search-terms-url="/try-search-term/"
|
||
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
|
||
Name of saved search:
|
||
</label>
|
||
<input maxlength="200"
|
||
type="text"
|
||
name="saved-search-name"
|
||
id="saved-search-name"
|
||
class="saved-search-name"
|
||
value=""
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
|
||
Search terms:
|
||
</label>
|
||
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
|
||
</div>
|
||
<div class="test-search-term-wrap">
|
||
<a href="#" class="try-search-term">Test search terms</a>
|
||
</div>
|
||
<div class="choice-group action-panel-extra-margin-top">
|
||
<span class="action-panel-label" id="fieldset-label">
|
||
Would you like email updates of new search results?
|
||
</span>
|
||
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
|
||
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
|
||
<ul class="radio-group-items">
|
||
<li>
|
||
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
|
||
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
|
||
</li>
|
||
<li>
|
||
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
|
||
<label for="saved-search-alert-no" class="action-panel-label">No</label>
|
||
</li>
|
||
</ul>
|
||
</fieldset>
|
||
</div>
|
||
|
||
<div class="alert-schedule-wrap">
|
||
<div class="action-panel-control-wrap">
|
||
<label class="action-panel-label">
|
||
Email:
|
||
</label>
|
||
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
|
||
</div>
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="saved-search-frequency" class="action-panel-label">
|
||
Frequency:
|
||
</label>
|
||
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
|
||
<option value="monthly">Monthly</option>
|
||
<option value="weekly">Weekly</option>
|
||
<option value="daily">Daily</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-monthly-additional">
|
||
<label for="saved-search-monthly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
|
||
<option value="Sunday">The first Sunday</option>
|
||
<option value="Monday">The first Monday</option>
|
||
<option value="Tuesday">The first Tuesday</option>
|
||
<option value="Wednesday">The first Wednesday</option>
|
||
<option value="Thursday">The first Thursday</option>
|
||
<option value="Friday">The first Friday</option>
|
||
<option value="Saturday">The first Saturday</option>
|
||
<option value="day">The first day</option>
|
||
<option value="weekday">The first weekday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap saved-search-weekly-additional">
|
||
<label for="saved-search-weekly-on-day" class="action-panel-label">
|
||
Which day?
|
||
</label>
|
||
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
|
||
<option value="Sunday">Sunday</option>
|
||
<option value="Monday">Monday</option>
|
||
<option value="Tuesday">Tuesday</option>
|
||
<option value="Wednesday">Wednesday</option>
|
||
<option value="Thursday">Thursday</option>
|
||
<option value="Friday">Friday</option>
|
||
<option value="Saturday">Saturday</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-report" class="action-panel-label">
|
||
Report format:
|
||
</label>
|
||
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
|
||
<option value="DocSum">Summary</option>
|
||
<option value="DocSumText">Summary (text)</option>
|
||
<option value="Abstract">Abstract</option>
|
||
<option value="AbstractText">Abstract (text)</option>
|
||
<option value="MEDLINE">PubMed</option>
|
||
</select>
|
||
</div>
|
||
<div class="action-panel-control-wrap">
|
||
<label for="saved-search-amount" class="action-panel-label">
|
||
Send at most:
|
||
</label>
|
||
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
|
||
<option value="1">1 item</option>
|
||
<option value="5" selected>5 items</option>
|
||
<option value="10">10 items</option>
|
||
<option value="20">20 items</option>
|
||
<option value="50">50 items</option>
|
||
<option value="100">100 items</option>
|
||
<option value="200">200 items</option>
|
||
</select>
|
||
</div>
|
||
<div>
|
||
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
|
||
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
|
||
Send even when there aren't any new results
|
||
</label>
|
||
</div>
|
||
<div class="action-panel-control-wrap option-text-in-email-wrap">
|
||
<label for="saved-search-email-text" class="action-panel-label">
|
||
Optional text in email:
|
||
</label>
|
||
<textarea name="saved-search-email-text"
|
||
id="saved-search-email-text"
|
||
class="saved-search-email-text"></textarea>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Saving..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Save
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your saved search' panel"
|
||
ref="linksrc=close_saved_search_panel"
|
||
aria-controls="saved-search-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Create a file for external citation management software
|
||
</h2>
|
||
<form id="citation-manager-action-panel-form"
|
||
class="action-panel-content action-form"
|
||
action="/results-export-ids/"
|
||
data-by-search-action="/results-export-search-data/"
|
||
data-by-ids-action="/results-export-ids/"
|
||
method="post"
|
||
data-by-search-method="post"
|
||
data-by-ids-method="post">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
|
||
|
||
<input name="results-format" type="hidden" value="pubmed"/>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Sending..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="save">
|
||
Create file
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Send citations to citation manager' panel"
|
||
ref="linksrc=close_citation_manager_panel"
|
||
aria-controls="citation-manager-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="citation_manager"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
|
||
<div class="inner-wrap">
|
||
<h2 class="action-panel-heading">
|
||
Your RSS Feed
|
||
</h2>
|
||
|
||
<form id="rss-action-panel-form"
|
||
class="rss-action-panel-form action-panel-content action-form"
|
||
data-create-rss-feed-url="/create-rss-feed-url/"
|
||
data-search-form-term-value="">
|
||
|
||
<input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy">
|
||
|
||
<div class="action-panel-control-wrap">
|
||
<label for="rss-name" class="action-panel-label required-field-asterisk">
|
||
Name of RSS Feed:
|
||
</label>
|
||
<input maxlength="200"
|
||
placeholder="Name"
|
||
type="text"
|
||
name="rss-name"
|
||
id="rss-name"
|
||
class="rss-name"
|
||
value=''
|
||
required
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/">
|
||
</div>
|
||
|
||
<div class="rss-limit-wrap">
|
||
<div class="action-panel-control-wrap action-panel-extra-margin-top">
|
||
<label for="rss-limit" class="action-panel-label">
|
||
Number of items displayed:
|
||
</label>
|
||
<select id="rss-limit" class="no-border-panel-selector rss-limit">
|
||
<option value="5">5</option>
|
||
<option value="10">10</option>
|
||
<option value="15" selected="selected">15</option>
|
||
<option value="20">20</option>
|
||
<option value="50">50</option>
|
||
<option value="100">100</option>
|
||
</select>
|
||
</div>
|
||
</div>
|
||
|
||
<div class="action-panel-actions">
|
||
<button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Creating..."
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="save">
|
||
Create RSS
|
||
</button>
|
||
<button class="action-panel-cancel"
|
||
aria-label="Close 'Your RSS' panel"
|
||
ref="linksrc=close_rss_panel"
|
||
aria-controls="rss-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="save_share"
|
||
data-ga-action="alert"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button>
|
||
</div>
|
||
|
||
<div class="action-panel-control-wrap rss-link-copy-wrap">
|
||
<label for="rss-link" class="usa-sr-only">RSS Link</label>
|
||
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
|
||
<button
|
||
type="button"
|
||
disabled
|
||
class="rss-link-copy-button disabled"
|
||
data-ga-category="save_share"
|
||
data-ga-action="rss"
|
||
data-ga-label="copy">
|
||
Copy
|
||
</button>
|
||
</div>
|
||
</form>
|
||
</div>
|
||
</div>
|
||
|
||
</div>
|
||
</div>
|
||
|
||
<div class="article-page" id="article-page" data-article-pmid="39594661">
|
||
<aside class="page-sidebar">
|
||
<div class="inner-wrap">
|
||
|
||
<div class="full-text-links">
|
||
<div class="full-view">
|
||
<h3 class="title">
|
||
Full text links
|
||
</h3>
|
||
<div class="full-text-links-list">
|
||
<a class="link-item
|
||
|
||
dialog-focus"
|
||
href="https://www.mdpi.com/resolver?pii=cells13221913"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=False&PrId=6383&itool=Abstract-def&log$=linkouticon&uid=39594661&db=pubmed&nlmid=101600052"
|
||
title="See full text options at MDPI"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="MDPI"
|
||
data-ga-label="39594661"
|
||
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--res.mdpi.com-data-pubmed-linkout.png" alt="MDPI full text link"><span class="text">
|
||
|
||
MDPI
|
||
|
||
</span></a><a class="link-item
|
||
pmc
|
||
"
|
||
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/39594661/"
|
||
target="_blank"
|
||
rel="noopener"
|
||
|
||
ref="linksrc=fulltextorjournal_fulltext&is_pmc=True&PrId=3494&itool=Abstract-def&log$=linkouticon&uid=39594661&db=pubmed&nlmid=101600052"
|
||
title="Free full text at PubMed Central"
|
||
|
||
data-ga-category="full_text"
|
||
data-ga-action="PMC"
|
||
data-ga-label="39594661"
|
||
><span class="text">
|
||
|
||
Free PMC article
|
||
|
||
</span></a>
|
||
</div>
|
||
|
||
</div>
|
||
|
||
<div class="short-view">
|
||
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
|
||
Full text links
|
||
</a>
|
||
</div>
|
||
</div>
|
||
|
||
|
||
|
||
|
||
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
|
||
aria-label="Open dialog with citation text in different styles"
|
||
data-ga-category="save_share"
|
||
data-ga-action="cite"
|
||
data-ga-label="open"
|
||
data-all-citations-url="/39594661/citations/"
|
||
data-citation-style="nlm"
|
||
data-pubmed-format-link="/39594661/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="39594661" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
|
||
aria-label="Save article in MyNCBI collections."
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_button"
|
||
data-collections-open-dialog-enabled="false"
|
||
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F39594661%2F%23open-collections-dialog"
|
||
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
|
||
class="dialog collections-dialog"
|
||
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
|
||
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
|
||
data-existing-collections-url="/list-existing-collections/"
|
||
data-add-to-existing-collection-url="/add-to-existing-collection/"
|
||
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
|
||
data-myncbi-max-collection-name-length="100"
|
||
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="1GJ2wBIGN5NJkiU3BAUllI5XSurkRJ0eitt79rb2nGAdeJ0TeTxnPQBBqy9wKkyy"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
|
||
id="collections-action-dialog-new"
|
||
class="collections-new"
|
||
name="collections"
|
||
value="new"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
|
||
id="collections-action-dialog-existing"
|
||
class="collections-existing"
|
||
name="collections"
|
||
value="existing"
|
||
checked="true"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
|
||
Name your collection:
|
||
</label><input
|
||
type="text"
|
||
name="add-to-new-collection"
|
||
id="collections-action-dialog-add-to-new"
|
||
class="collections-action-add-to-new"
|
||
pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"
|
||
maxlength="100"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="create_collection"
|
||
data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
|
||
Name must be less than 100 characters
|
||
</div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label">
|
||
Choose a collection:
|
||
</label><select id="collections-action-dialog-add-to-existing"
|
||
class="action-panel-selector collections-action-add-to-existing"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="select_collection"
|
||
data-ga-label="($('.collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
|
||
Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit"
|
||
type="submit"
|
||
data-loading-label="Adding..."
|
||
data-pinger-ignore
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="add">
|
||
Add
|
||
</button><button class="action-panel-cancel"
|
||
aria-label="Close 'Add to Collections' panel"
|
||
ref="linksrc=close_collections_panel"
|
||
aria-controls="collections-action-panel"
|
||
aria-expanded="false"
|
||
data-ga-category="collections_button"
|
||
data-ga-action="click"
|
||
data-ga-label="cancel">
|
||
Cancel
|
||
</button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger"
|
||
title="Open dialog with more actions to take"
|
||
ref="linksrc=more_actions_btn"></button><div class="display-options" data-format-key="format"
|
||
data-default-format-value="abstract"
|
||
data-current-format-value="abstract" role="region"><button
|
||
class="trigger usa-button"
|
||
title="Change format"
|
||
data-ga-category="display_options"
|
||
data-ga-action="display_options_dialog"><span class="button-label">Display options</span></button><div class="dropdown" hidden><div class="title">
|
||
Display options
|
||
</div><div class="content"><div class="format-container"><span class="option-label">
|
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<i>MYBPC3</i> D389V Variant Induces Hypercontractility in Cardiac Organoids
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data-ga-label="Sakthivel Sadayappan">Sakthivel Sadayappan</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA." href="#full-view-affiliation-1" ref="linksrc=author_aff">
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<i>MYBPC3</i> D389V Variant Induces Hypercontractility in Cardiac Organoids
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</a></li></ul></div></div></div><span class="period">. </span><span class="cit">2024 Nov 19;13(22):1913.</span>
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<i>MYBPC3</i>, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in <i>MYBPC3</i> by using isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). The hiPSC-derived cardiomyocytes (hiPSC-CMs) and hCOs were generated from human subjects to define the molecular, cellular, functional, and energetic changes caused by the <i>MYBPC3</i><sup>D389V</sup> variant, which is associated with increased fractional shortening and highly prevalent in South Asian descendants. Recombinant C0-C2, N' region of cMyBP-C (wild-type and D389V), and myosin S2 proteins were also utilized to perform binding and motility assays in vitro. Confocal and electron microscopic analyses of hCOs generated from noncarriers (NC) and carriers of the <i>MYBPC3</i><sup>D389V</sup> variant revealed the presence of highly organized sarcomeres. Furthermore, functional experiments showed hypercontractility, faster calcium cycling, and faster contractile kinetics in hCOs expressing <i>MYBPC3</i><sup>D389V</sup> than NC hCOs. Interestingly, significantly increased cMyBP-C phosphorylation in <i>MYBPC3</i><sup>D389V</sup> hCOs was observed, but without changes in total protein levels, in addition to higher oxidative stress and lower mitochondrial membrane potential (ΔΨm). Next, spatial mapping revealed the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes in the hCOs. The hypercontractile function was significantly improved after the treatment of the myosin inhibitor mavacamten (CAMZYOS<sup>®</sup>) in <i>MYBPC3</i><sup>D389V</sup> hCOs. Lastly, various vitro binding assays revealed a significant loss of affinity in the presence of <i>MYBPC3</i><sup>D389V</sup> with myosin S2 region as a likely mechanism for hypercontraction. Conceptually, we showed the feasibility of assessing the functional and molecular mechanisms of HCM using highly translatable hCOs through pragmatic experiments that led to determining the <i>MYBPC3</i><sup>D389V</sup> hypercontractile phenotype, which was rescued by the administration of a myosin inhibitor.
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MYBPC3; cardiac organoids; hypercontraction; hypertrophic cardiomyopathy; mavacamten.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">Sadayappan provides consulting and collaborative research studies to the Leducq Foundation (CURE-PLAN), Red Saree Inc., Alexion, Regel Therapeutics, Affinia Therapeutics Inc., Cardiocare Genetics—Cosmogene Skincare Pvt Ltd., but such work is unrelated to the content of this article.</p>
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<div class="figure-caption-contents"><p> Generation and characterization of 3D cardiac organoids using hiPSC lines using Wnt signaling.… </p></div>
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<div class="figure-caption-contents">Generation and characterization of 3D cardiac organoids using hiPSC lines using Wnt signaling. (<b>A</b>,<b>B</b>) Cultured hiPSCs in a 6-well plate were seeded into the agarose mold for 48 h. The maintenance medium, mTESR1, was changed to RPMI 1640 containing B27 without insulin with the subsequent addition of CHIR99021 and then IWP4 to drive cardiomyocyte maturation. Organoids were transferred after 96 h to an ultra-low attachment plate with RPMI1640 medium supplemented with B27 plus insulin and changed every 48 h until beating. (<b>C</b>) Transmission electron microscopy analyses of hCOs on day 30 demonstrate representative sarcomeres with Z-bands in D389V and NC organoids. (<b>D</b>–<b>G</b>) Representative wholemount cardiac organoid stained with (<b>D</b>) vimentin in red, cMyBP-C in green, and DAPI in blue, (<b>E</b>) cTnI in green and DAPI in blue, (<b>F</b>) cMyBP-C in green and DAPI in blue, and (<b>G</b>) α-actinin staining of the sarcomere in red and DAPI in blue. The last row represents the organoid area with higher magnification at 63X.</div>
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<div class="figure-caption-contents"><p> Hypercontractility was observed in D389V hCOs and was mitigated by mavacamten. Fresh beating… </p></div>
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<div class="figure-caption-contents">Hypercontractility was observed in D389V hCOs and was mitigated by mavacamten. Fresh beating hCOs on day 30 were used to measure contractile parameters using the IonOptix instrument. (<b>A</b>,<b>B</b>) Contraction and relaxation velocity in the absence and presence of 300 nM MyK-461 at 0.5 Hz frequency. (<b>C</b>,<b>D</b>) The time point taken to peak at 50% and 70% in the absence and presence of 300 nM MyK-461 at 0.5 Hz frequency. (<b>E</b>,<b>F</b>) Time to relax 90% and 50% was measured in the absence and presence of MyK-461 at 0.5 Hz frequency. The experiments were performed using n = 22 to 40 hCOs in 3 independent experiments on different days and averaged the data. Data are expressed as mean ± S.E.M. (error bars) of the number of hCOs. Statistical analyses in all groups were performed by ordinary two-way ANOVA, followed by a multiple-comparison test. For all groups: * <i>p</i> ≤ 0.05, ** <i>p</i> ≤ 0.01, *** <i>p</i> ≤ 0.001 and **** <i>p</i> ≤ 0.0001 and ns is non-significant.</div>
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<div class="figure-caption-contents">Faster Ca<sup>2+</sup> kinetics were determined in D389V hCOs, which were not altered by MyK-461. Fresh beating hCOs on day 30 were used to determine the amplitude and kinetics of intracellular Ca<sup>2+</sup> transients using fluorescent Fura-2 am dye. (<b>A</b>) Representative intracellular diastolic calcium levels tracings. (<b>B</b>) Intracellular diastolic calcium levels in D389V and NC hCOs with and without 300 nM Myk-461. (<b>C</b>) Ca<sup>2+</sup> transient amplitude as indicated by Fura-2 ratio (340/380 nm) in the absence and presence of 300 nM MyK-461 at 0.5 Hz with 1.8 mm Ca<sup>2+</sup>. (<b>D</b>) Time to 50% decay of the calcium transient in the absence and presence of MyK-461. We used n = 22 to 40 hCOs in 3 independent experiments on different days and averaged the data. Data are expressed as mean ± S.E.M. (error bars), and statistical analyses were performed for all groups by ordinary two-way ANOVA, followed by multiple-comparison test. * <i>p</i> ≤ 0.05, and **** <i>p</i> ≤ 0.0001 for all groups, ns is non-significant.</div>
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Figure 4
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<div class="figure-caption-contents">Expression of the D389V variant results in cellular hypertrophy and HCM phenotype, as evidenced by RNAseq analyses in hCOs. (<b>A</b>) Pathway enrichment analysis showing the KEGG, GOBP, and GOMF pathways for the upregulated genes in D389V hCOs compared to NC hCOs at day 30. (<b>B</b>–<b>E</b>) Enrichment plot using the GSEA analysis of the genes regulating the cardiac muscle contraction, HCM pathway, oxidative phosphorylation, glycolysis–gluconeogenesis, and fatty acid metabolism in D389V hCOs. (<b>F</b>–<b>I</b>) Heatmap representing DEGs associated with cardiac muscle contraction, HCM pathway, oxidative phosphorylation, glycolysis–gluconeogenesis, and fatty acid metabolism in D389V hCOs (n = 4 sample set with 25–30 organoids in each set; D389V vs. NC); (fold change cutoff 2, adjusted <i>p</i>-value < 0.05).</div>
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<p> Figure 5 </p>
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<div class="figure-caption-contents"><p> Expression of the D389V variant… </p></div>
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<p> Figure 5 </p>
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<div class="figure-caption-contents"><p> Expression of the D389V variant in hCOs increases the levels of cMyBP-C phosphorylation… </p></div>
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Figure 5
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<div class="figure-caption-contents">Expression of the D389V variant in hCOs increases the levels of cMyBP-C phosphorylation and oxidative stress. Total proteins were collected from hCOs on day 30 for Western blot analyses. (<b>A</b>) Representative of Western blot images and normalized protein expression levels comparing D389V and NC and hCOs. (<b>B</b>–<b>D</b>) Quantification of protein expression of cMyBP-C normalized with GAPDH for all three blots. (<b>E−G</b>) Quantification of the phosphorylation of human cMyBP-C at serine 275, 284, and 304 normalized with the level of total cMyBP-C protein. Data are expressed as mean ± S.E.M (error bars) on the number of organoids, and statistical analyses were performed in all groups <i>t</i>-test unpaired test. * <i>p</i> ≤ 0.05; ** <i>p</i> ≤ 0.01 for all groups. (<b>H</b>) DCFDA stain fluorescence at 485/535 nm of NC and D389V at baseline and after NAC treatment. Organoids imaged in brightfield microscopy (middle panel). All images are of scale 1000 µm and images at magnitude of 4X. (<b>I</b>) Quantitation of the ROS generation measurement of the fluorescent intensity emitted by the DCFDA dye measured in the hCOs. Data are expressed as mean ± S.E.M (error bars) (n = 3 sample sets, each sample set containing 40–50 organoids), and statistical analyses were performed in all groups <i>t</i>-test unpaired test. *** <i>p</i> ≤ 0.001 for all groups. (<b>J</b>) Quantification of the membrane potential, measured as the fluorescent intensity in the organoids. Data are expressed as mean ± S.E.M. (error bars) on the number of wells consisting of cells isolated from organoids, and statistical analyses were performed in all groups <i>t</i>-test unpaired test. ** <i>p</i> ≤ 0.01 for all groups. ns is non-significant.</div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Spatial RNA detection determined all… </p></div>
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<p> Figure 6 </p>
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<div class="figure-caption-contents"><p> Spatial RNA detection determined all the cell types and cell–cell interactions in formalin-fixed… </p></div>
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Figure 6
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<div class="figure-caption-contents">Spatial RNA detection determined all the cell types and cell–cell interactions in formalin-fixed paraffin-embedded hCOs. Fresh hCOs on day 30 were fixed in formalin, embedded in paraffin, and sectioned in 4–6 µm thickness for RNA profiling using a Human RNA TAP Panel (1000-plex) and SMI-0119 custom panel. (<b>A</b>) Uniform manifold approximation and projections of hCOs based on gene expression matrix in dimension 1 vs. dimension 2. Color denotes cell types from a to f types (a, a cluster of cells identified as a mixture of immune, endothelial, and fibroblast; b, macrophages; c, a cluster of cardiomyocytes, endothelial cells, and fibroblasts; d, cardiomyocytes; e, a cluster of cardiomyocytes; and f, immune cells). (<b>B</b>) Comparison of the gene expression levels in the same cluster of cells between D389V and NC hCOs in each cell type. (<b>C</b>) Heat map of gene expression profiles in each cluster in D389V and NC hCOs.</div>
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<p> Figure 7 </p>
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<div class="figure-caption-contents"><p> D389V mutation in the C2… </p></div>
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<p> Figure 7 </p>
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||
<div class="figure-caption-contents"><p> D389V mutation in the C2 domain of cMyBP-C reduces its binding to the… </p></div>
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||
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Figure 7
|
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|
||
<div class="figure-caption-contents">D389V mutation in the C2 domain of cMyBP-C reduces its binding to the myosin S2 region. (<b>A</b>) Co-sedimentation analysis of various recombinant hC0-C2 of cMyBP-C protein concentrations binding to full-length β-myosin heavy chains that were purified from mouse hearts. Quantification of bound hC0-C2 with myosin (y-axis) against utilized hC0-C2 (x-axis) in the assay was blotted for relative binding max (Bmax) and dissociation constant (<i>K</i>d). Data were fit to the Michaelis–Menten binding fit, and statistical analyses were performed using an unpaired <i>t</i>-test. Error bars indicate ± S.E.M. (* <i>p</i> < 0.05). (<b>B</b>) Solid-phase binding analysis between human myosin S2 (hS2) recombinant proteins and hC0-C2<sup>WT</sup> as well as hS2 and hC0-C2<sup>D389V</sup>. Data were fit to the Michaelis–Menten binding fit, and statistical analyses were performed using an unpaired <i>t</i>-test to calculate the significance between the <i>K</i>d values. n = 3 with replicates of three for each n value. Data are expressed as the mean ± S.E.M. (<b>C</b>) Isothermal calorimetry analysis showing the sigmoidal curve for the titration of hS2 to hC0-C2 yields the dissociation constant (1/slope) and stoichiometry of the reaction. Both hC0-C2<sup>WT</sup> and hC0-C2<sup>D389V</sup> were titrated against 350 µM hS2 recombinant proteins. Statistical analyses were performed using one-way ANOVA with Tukey’s multiple-comparison test and single pooled variance (n = 3). Data are expressed as the mean ± S.E.M. (<b>D</b>) Scatterplot of in vitro motility assay to measure the average velocity of actin thin filaments over human myosin HMM thick filaments in the absence (green) and the presence of hC0-C2<sup>WT</sup> (red) and hC0-C2<sup>D389V</sup> (blue) proteins. Statistical analyses were performed using one-way ANOVA with Tukey’s multiple-comparison test and single pooled variance (n = 3). Data are expressed as the mean ± S.E.M. (* <i>p</i> < 0.05).</div>
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<em>MYBPC3</em> D389V Variant Induces Hypercontractility in Cardiac Organoids.
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<div class="docsum-citation full-citation">
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<span class="docsum-authors full-authors">Desai D, Song T, Singh RR, Baby A, McNamara J, Green L, Nabavizadeh P, Ericksen M, Bazrafshan S, Natesan S, Sadayappan S.</span>
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<span class="docsum-authors short-authors">Desai D, et al.</span>
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<span class="docsum-journal-citation full-journal-citation">bioRxiv [Preprint]. 2024 May 30:2024.05.29.596463. doi: 10.1101/2024.05.29.596463.</span>
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<span class="docsum-journal-citation short-journal-citation">bioRxiv. 2024.</span>
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data-ga-label="linked-update">Cells. 2024 Nov 19;13(22):1913. doi: 10.3390/cells13221913.</a>
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<span class="citation-part">PMID: <span class="docsum-pmid">38853909</span></span>
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<span class="correction-label spaced-citation-item citation-part">Updated.</span>
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<span class="publication-type spaced-citation-item citation-part">Preprint.</span>
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Carrier Proteins* / genetics
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Carrier Proteins* / metabolism
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Myocardium / metabolism
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Search in PubMed
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Search in MeSH
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Add to Search
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Myocytes, Cardiac* / metabolism
|
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</button><div id="keyword-actions-mesh-terms-major-11"
|
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Organoids* / metabolism
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Sarcomeres / metabolism
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</div>
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<div id="substances" class="substances keywords-section">
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<h2 class="title">
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Substances
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<ul class="keywords-list"><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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myosin-binding protein C
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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tabindex="0"
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data-pinger-ignore>
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Carrier Proteins
|
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</button><div id="keyword-actions-substances-1"
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class="keyword-actions-dropdown dropdown dropdown-container"
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hidden
|
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aria-label="Dropdown menu for keyword Carrier Proteins"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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Search in PubMed
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Search in MeSH
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Add to Search
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</a></li></ul></div></div></div></li><li><div class="keyword-actions dropdown-block"><button class="keyword-actions-trigger trigger keyword-link"
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aria-label="Toggle dropdown menu for keyword Calcium"
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Calcium
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</button><div id="keyword-actions-substances-2"
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class="keyword-actions-dropdown dropdown dropdown-container"
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aria-label="Dropdown menu for keyword Calcium"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link"
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data-href="/?term=%22Calcium%22%5Bnm%5D&sort=date&sort_order=desc"
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Search in PubMed
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Add to Search
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</a></li></ul></div></div></div></li></ul>
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</div>
|
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|
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|
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|
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|
||
|
||
|
||
|
||
|
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|
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|
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|
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<div id="related-links" class="related-links">
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<h2 class="title">
|
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Related information
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</h2>
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<ul class="related-links-list"><li><a title="Related GEO DataSets" href="https://www.ncbi.nlm.nih.gov/gds?linkname=pubmed_gds&from_uid=39594661"
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GEO DataSets
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MedGen
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</a></li><li><a title="Related PubChem Compound via MeSH" href="https://www.ncbi.nlm.nih.gov/pccompound?linkname=pubmed_pccompound_mesh&from_uid=39594661"
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ref="log$=recordlinks&logdbfrom=pubmed&ncbi_uid=39594661&ordinalpos=1&linkpos=3">
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PubChem Compound (MeSH Keyword)
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</a></li><li><a title="Related Projects" href="https://www.ncbi.nlm.nih.gov/bioproject?linkname=pubmed_bioproject&from_uid=39594661"
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SRA
|
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</a></li></ul>
|
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</div>
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|
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<div id="grants" class="grants">
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<h2 class="title">
|
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Grants and funding
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</h2>
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<div class="grants-list"><ul id="grants-head-list"><li class="grant-item"><a
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Show all 8 grants
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<h2 class="title">
|
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LinkOut - more resources
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</h2>
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|
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<ul class="linkout-list"><li><h3 class="linkout-category">Full Text Sources</h3><ul class="linkout-category-links"><li><a
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