CINXE.COM

<!DOCTYPE html> <html lang="en" xmlns:fb="http://www.facebook.com/2008/fbml" class="wf-loading"> <head prefix="og: https://ogp.me/ns# fb: https://ogp.me/ns/fb# academia: https://ogp.me/ns/fb/academia#"> <meta charset="utf-8"> <meta name=viewport content="width=device-width"> <meta rel="search" type="application/opensearchdescription+xml" href="/open_search.xml" title="Academia.edu"> <title>Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology - Academia.edu</title>  <link href="//a.academia-assets.com/images/favicons/favicon-production.ico" rel="shortcut icon" type="image/vnd.microsoft.icon"> <link rel="apple-touch-icon" sizes="57x57" href="//a.academia-assets.com/images/favicons/apple-touch-icon-57x57.png"> <link rel="apple-touch-icon" sizes="60x60" href="//a.academia-assets.com/images/favicons/apple-touch-icon-60x60.png"> <link rel="apple-touch-icon" sizes="72x72" href="//a.academia-assets.com/images/favicons/apple-touch-icon-72x72.png"> <link rel="apple-touch-icon" sizes="76x76" href="//a.academia-assets.com/images/favicons/apple-touch-icon-76x76.png"> <link rel="apple-touch-icon" sizes="114x114" href="//a.academia-assets.com/images/favicons/apple-touch-icon-114x114.png"> <link rel="apple-touch-icon" sizes="120x120" href="//a.academia-assets.com/images/favicons/apple-touch-icon-120x120.png"> <link rel="apple-touch-icon" sizes="144x144" href="//a.academia-assets.com/images/favicons/apple-touch-icon-144x144.png"> <link rel="apple-touch-icon" sizes="152x152" href="//a.academia-assets.com/images/favicons/apple-touch-icon-152x152.png"> <link rel="apple-touch-icon" sizes="180x180" href="//a.academia-assets.com/images/favicons/apple-touch-icon-180x180.png"> <link rel="icon" type="image/png" href="//a.academia-assets.com/images/favicons/favicon-32x32.png" sizes="32x32"> <link rel="icon" type="image/png" href="//a.academia-assets.com/images/favicons/favicon-194x194.png" sizes="194x194"> <link rel="icon" type="image/png" href="//a.academia-assets.com/images/favicons/favicon-96x96.png" sizes="96x96"> <link rel="icon" type="image/png" href="//a.academia-assets.com/images/favicons/android-chrome-192x192.png" sizes="192x192"> <link rel="icon" type="image/png" href="//a.academia-assets.com/images/favicons/favicon-16x16.png" sizes="16x16"> <link rel="manifest" href="//a.academia-assets.com/images/favicons/manifest.json"> <meta name="msapplication-TileColor" content="#2b5797"> <meta name="msapplication-TileImage" content="//a.academia-assets.com/images/favicons/mstile-144x144.png"> <meta name="theme-color" content="#ffffff"> <script> window.performance && window.performance.measure && window.performance.measure("Time To First Byte", "requestStart", "responseStart"); </script> <script> (function() { if (!window.URLSearchParams || !window.history || !window.history.replaceState) { return; } var searchParams = new URLSearchParams(window.location.search); var paramsToDelete = [ 'fs', 'sm', 'swp', 'iid', 'nbs', 'rcc', // related content category 'rcpos', // related content carousel position 'rcpg', // related carousel page 'rchid', // related content hit id 'f_ri', // research interest id, for SEO tracking 'f_fri', // featured research interest, for SEO tracking (param key without value) 'f_rid', // from research interest directory for SEO tracking 'f_loswp', // from research interest pills on LOSWP sidebar for SEO tracking 'rhid', // referrring hit id ]; if (paramsToDelete.every((key) => searchParams.get(key) === null)) { return; } paramsToDelete.forEach((key) => { searchParams.delete(key); }); var cleanUrl = new URL(window.location.href); cleanUrl.search = searchParams.toString(); history.replaceState({}, document.title, cleanUrl); })(); </script> <script async src="https://www.googletagmanager.com/gtag/js?id=G-5VKX33P2DS"></script> <script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'G-5VKX33P2DS', { cookie_domain: 'academia.edu', send_page_view: false, }); gtag('event', 'page_view', { 'controller': "journals/articles", 'action': "show", 'controller_action': 'journals/articles#show', 'logged_in': 'false', 'edge': 'unknown', // Send nil if there is no A/B test bucket, in case some records get logged // with missing data - that way we can distinguish between the two cases. // ab_test_bucket should be of the form <ab_test_name>:<bucket> 'ab_test_bucket': null, }) </script> <script type="text/javascript"> window.sendUserTiming = function(timingName) { if (!(window.performance && window.performance.measure)) return; var entries = window.performance.getEntriesByName(timingName, "measure"); if (entries.length !== 1) return; var timingValue = Math.round(entries[0].duration); gtag('event', 'timing_complete', { name: timingName, value: timingValue, event_category: 'User-centric', }); }; window.sendUserTiming("Time To First Byte"); </script> <meta name="csrf-param" content="authenticity_token" /> <meta name="csrf-token" content="wLrTegYX3nXUYe3LLriIbjBxcaBdtBg0+KczjpAXwjfFVEoM27yd/dSw68oUzj5ferE8P0AvWoT5kzic6dp4gQ==" /> <style type="text/css">@media(max-width: 567px){:root{--token-mode: Rebrand;--dropshadow: 0 2px 4px 0 #22223340;--primary-brand: #0645b1;--error-dark: #b60000;--success-dark: #05b01c;--inactive-fill: #ebebee;--hover: #0c3b8d;--pressed: #082f75;--button-primary-fill-inactive: #ebebee;--button-text-inactive: #91919e;--button-secondary-stroke-inactive: #b1b1ba;--background-beige: #f9f7f4;--error-light: #fff2f2;--text-placeholder: #91919e;--stroke-dark: #141413;--stroke-light: #dddde2;--stroke-medium: #535366;--accent-green: #ccffd4;--accent-turquoise: #ccf7ff;--accent-yellow: #f7ffcc;--accent-peach: #ffd4cc;--accent-violet: #f7ccff;--accent-purple: #f4f7fc;--text-primary: #141413;--button-primary-fill: #0645b1;--button-secondary-fill: #eef2f9;--secondary-brand: #0645b1;--button-secondary-text: #082f75;--button-primary-text: #ffffff;--text-hover: #0c3b8d;--button-primary-fill-hover: #0c3b8d;--button-primary-fill-press: #082f75;--button-focus: #0645b1;--button-secondary-fill-press: #cddaef;--button-secondary-fill-inactive: #ebebee;--text-white: #ffffff;--text-link: #0645b1;--text-press: #082f75;--success-light: #f0f8f1;--background-light-blue: #f4f7fc;--background-white: #ffffff;--premium-dark: #877440;--premium-light: #f9f6ed;--stroke-white: #ffffff;--inactive-content: #b1b1ba;--annotate-light: #a35dff;--annotate-dark: #824acc;--grid: #eef2f9;--button-secondary-stroke: #cddaef;--button-secondary-stroke-hover: #c8c8cf;--button-secondary-stroke-press: #0645b1;--button-secondary-text-inactive: #b1b1ba;--button-primary-icon: #ffffff;--button-secondary-icon: #082f75;--button-secondary-fill-hover: #e6ecf7;--inactive-stroke: #ebebee;--shadow: rgba(34, 34, 51, 0.25);--button-primary-fill-inverse: #ffffff;--button-primary-text-inverse: #0645b1;--button-secondary-stroke-inverse: #ffffff;--button-primary-icon-inverse: #0645b1;--button-icon-inactive: #91919e;--button-secondary-fill-inverse: #eef2f9;--button-secondary-icon-inverse: #ffffff;--button-secondary-icon-hover: #082f75;--button-secondary-icon-press: #082f75;--button-secondary-text-inverse: #ffffff;--button-secondary-text-hover: #0c3b8d;--button-secondary-text-press: #082f75;--text-inactive: #6d6d7d;--text-error: #b60000;--stroke-error: #b60000;--background-error: #fff2f2;--background-black: #141413;--icon-default: #141413;--icon-blue: #0645b1;--background-grey: #dddde2;--icon-grey: #91919e;--button-xs-stroke: #141413;--button-xs-stroke-hover: #0c3b8d;--button-xs-stroke-press: #082f75;--button-xs-stroke-inactive: #0645b1;--button-xs-text: #141413;--button-xs-text-hover: #0c3b8d;--button-xs-text-press: #082f75;--button-xs-text-inactive: #b1b1ba;--button-xs-icon: #141413;--button-xs-icon-hover: #0c3b8d;--button-xs-icon-press: #082f75;--button-xs-icon-inactive: #b1b1ba;--button-xs-fill: #ffffff;--text-focus: #082f75;--brand-colors-neutral-black: #141413;--brand-colors-neutral-900: #535366;--brand-colors-neutral-800: #6d6d7d;--brand-colors-neutral-700: #91919e;--brand-colors-neutral-600: #b1b1ba;--brand-colors-neutral-500: #c8c8cf;--brand-colors-neutral-400: #dddde2;--brand-colors-neutral-300: #ebebee;--brand-colors-neutral-200: #f8f8fb;--brand-colors-neutral-100: #fafafa;--brand-colors-neutral-white: #ffffff;--brand-colors-blue-900: #043059;--brand-colors-blue-800: #082f75;--brand-colors-blue-700: #0c3b8d;--brand-colors-blue-600: #0645b1;--brand-colors-blue-500: #386ac1;--brand-colors-blue-400: #cddaef;--brand-colors-blue-300: #e6ecf7;--brand-colors-blue-200: #eef2f9;--brand-colors-blue-100: #f4f7fc;--brand-colors-gold-500: #877440;--brand-colors-gold-400: #e9e3d4;--brand-colors-gold-300: #f2efe8;--brand-colors-gold-200: #f9f6ed;--brand-colors-gold-100: #f9f7f4;--brand-colors-error-900: #920000;--brand-colors-error-500: #b60000;--brand-colors-success-900: #035c0f;--brand-colors-green: #ccffd4;--brand-colors-turquoise: #ccf7ff;--brand-colors-yellow: #f7ffcc;--brand-colors-peach: #ffd4cc;--brand-colors-violet: #f7ccff;--brand-colors-error-100: #fff2f2;--brand-colors-success-500: #05b01c;--brand-colors-success-100: #f0f8f1;--text-secondary: #535366;--icon-white: #ffffff;--background-beige-darker: #f2efe8;--type-font-family-sans-serif: DM Sans;--type-font-family-serif: Gupter;--type-font-family-mono: IBM Plex Mono;--type-weights-300: 300;--type-weights-400: 400;--type-weights-500: SemiBold;--type-weights-700: 700;--type-sizes-12: 12px;--type-sizes-14: 14px;--type-sizes-16: 16px;--type-sizes-18: 18px;--type-sizes-20: 20px;--type-sizes-22: 22px;--type-sizes-24: 24px;--type-sizes-28: 28px;--type-sizes-30: 30px;--type-sizes-32: 32px;--type-sizes-40: 40px;--type-sizes-42: 42px;--type-sizes-48-2: 48px;--type-line-heights-16: 16px;--type-line-heights-23: 23px;--type-line-heights-24: 24px;--type-line-heights-25: 25px;--type-line-heights-26: 26px;--type-line-heights-29: 29px;--type-line-heights-30: 30px;--type-line-heights-32: 32px;--type-line-heights-34: 34px;--type-line-heights-35: 35px;--type-line-heights-36: 36px;--type-line-heights-38: 38px;--type-line-heights-40: 40px;--type-line-heights-46: 46px;--type-line-heights-48: 48px;--type-line-heights-52: 52px;--type-line-heights-58: 58px;--type-line-heights-68: 68px;--type-line-heights-74: 74px;--type-line-heights-82: 82px;--type-paragraph-spacings-0: 0px;--type-paragraph-spacings-4: 4px;--type-paragraph-spacings-16: 16px;--type-sans-serif-xl-font-weight: 400;--type-sans-serif-xl-size: 32px;--type-sans-serif-xl-line-height: 46px;--type-sans-serif-xl-paragraph-spacing: 16px;--type-sans-serif-lg-font-weight: 400;--type-sans-serif-lg-size: 30px;--type-sans-serif-lg-line-height: 36px;--type-sans-serif-lg-paragraph-spacing: 16px;--type-sans-serif-md-font-weight: 400;--type-sans-serif-md-line-height: 30px;--type-sans-serif-md-paragraph-spacing: 16px;--type-sans-serif-md-size: 24px;--type-sans-serif-xs-font-weight: 700;--type-sans-serif-xs-line-height: 24px;--type-sans-serif-xs-paragraph-spacing: 0px;--type-sans-serif-xs-size: 18px;--type-sans-serif-sm-font-weight: 400;--type-sans-serif-sm-line-height: 32px;--type-sans-serif-sm-paragraph-spacing: 16px;--type-sans-serif-sm-size: 20px;--type-body-xl-font-weight: 400;--type-body-xl-size: 24px;--type-body-xl-line-height: 36px;--type-body-xl-paragraph-spacing: 0px;--type-body-sm-font-weight: 400;--type-body-sm-size: 14px;--type-body-sm-line-height: 23px;--type-body-sm-paragraph-spacing: 16px;--type-body-xs-font-weight: 400;--type-body-xs-size: 12px;--type-body-xs-line-height: 16px;--type-body-xs-paragraph-spacing: 0px;--type-body-md-font-weight: 400;--type-body-md-size: 16px;--type-body-md-line-height: 24px;--type-body-md-paragraph-spacing: 4px;--type-body-lg-font-weight: 400;--type-body-lg-size: 20px;--type-body-lg-line-height: 26px;--type-body-lg-paragraph-spacing: 16px;--type-body-lg-medium-font-weight: SemiBold;--type-body-lg-medium-size: 20px;--type-body-lg-medium-line-height: 32px;--type-body-lg-medium-paragraph-spacing: 16px;--type-body-md-medium-font-weight: SemiBold;--type-body-md-medium-size: 16px;--type-body-md-medium-line-height: 24px;--type-body-md-medium-paragraph-spacing: 4px;--type-body-sm-bold-font-weight: 700;--type-body-sm-bold-size: 14px;--type-body-sm-bold-line-height: 23px;--type-body-sm-bold-paragraph-spacing: 16px;--type-serif-md-font-weight: 400;--type-serif-md-size: 32px;--type-serif-md-paragraph-spacing: 0px;--type-serif-md-line-height: 40px;--type-serif-sm-font-weight: 400;--type-serif-sm-size: 24px;--type-serif-sm-paragraph-spacing: 0px;--type-serif-sm-line-height: 32px;--type-serif-lg-font-weight: 400;--type-serif-lg-size: 48px;--type-serif-lg-paragraph-spacing: 0px;--type-serif-lg-line-height: 52px;--type-serif-xs-font-weight: 400;--type-serif-xs-size: 18px;--type-serif-xs-line-height: 24px;--type-serif-xs-paragraph-spacing: 0px;--type-serif-xl-font-weight: 400;--type-serif-xl-size: 48px;--type-serif-xl-paragraph-spacing: 0px;--type-serif-xl-line-height: 58px;--type-mono-md-font-weight: 400;--type-mono-md-size: 22px;--type-mono-md-line-height: 24px;--type-mono-md-paragraph-spacing: 0px;--type-mono-lg-font-weight: 400;--type-mono-lg-size: 40px;--type-mono-lg-line-height: 40px;--type-mono-lg-paragraph-spacing: 0px;--type-mono-sm-font-weight: 400;--type-mono-sm-size: 14px;--type-mono-sm-line-height: 24px;--type-mono-sm-paragraph-spacing: 0px;--spacing-xs-4: 4px;--spacing-xs-8: 8px;--spacing-xs-16: 16px;--spacing-sm-24: 24px;--spacing-sm-32: 32px;--spacing-md-40: 40px;--spacing-md-48: 48px;--spacing-lg-64: 64px;--spacing-lg-80: 80px;--spacing-xlg-104: 104px;--spacing-xlg-152: 152px;--spacing-page-section: 80px;--spacing-card-list-spacing: 48px;--spacing-text-section-spacing: 64px;--spacing-md-xs-headings: 40px;--corner-radius-radius-lg: 16px;--corner-radius-radius-sm: 4px;--corner-radius-radius-md: 8px;--corner-radius-radius-round: 104px;--page-setup-page-width: 360px;--page-setup-page-margin-page-margin-lg: 156px;--page-setup-page-margin-page-margin-md: 40px;--page-setup-page-margin-page-margin-sm: 24px;--page-setup-margin-l-r: 24px;--buttons-small-buttons-corner-radius: 16px;--buttons-small-buttons-l-r-padding: 20px;--buttons-small-buttons-height: 48px;--buttons-small-buttons-gap: 8px;--buttons-small-buttons-icon-only-width: 48px;--buttons-small-buttons-icon-size: 20px;--buttons-large-buttons-l-r-padding: 32px;--buttons-large-buttons-height: 64px;--buttons-large-buttons-icon-only-width: 64px;--buttons-large-buttons-icon-size: 20px;--buttons-large-buttons-gap: 8px;--buttons-large-buttons-corner-radius: 16px;--buttons-extra-small-buttons-l-r-padding: 8px;--buttons-extra-small-buttons-height: 32px;--buttons-extra-small-buttons-icon-size: 16px;--buttons-extra-small-buttons-gap: 4px;--buttons-extra-small-buttons-corner-radius: 8px}}@media(min-width: 568px)and (max-width: 1279px){:root{--token-mode: Rebrand;--dropshadow: 0 2px 4px 0 #22223340;--primary-brand: #0645b1;--error-dark: #b60000;--success-dark: #05b01c;--inactive-fill: #ebebee;--hover: #0c3b8d;--pressed: #082f75;--button-primary-fill-inactive: #ebebee;--button-text-inactive: #91919e;--button-secondary-stroke-inactive: #b1b1ba;--background-beige: #f9f7f4;--error-light: #fff2f2;--text-placeholder: #91919e;--stroke-dark: #141413;--stroke-light: #dddde2;--stroke-medium: #535366;--accent-green: #ccffd4;--accent-turquoise: #ccf7ff;--accent-yellow: #f7ffcc;--accent-peach: #ffd4cc;--accent-violet: #f7ccff;--accent-purple: #f4f7fc;--text-primary: #141413;--button-primary-fill: #0645b1;--button-secondary-fill: #eef2f9;--secondary-brand: #0645b1;--button-secondary-text: #082f75;--button-primary-text: #ffffff;--text-hover: #0c3b8d;--button-primary-fill-hover: #0c3b8d;--button-primary-fill-press: #082f75;--button-focus: #0645b1;--button-secondary-fill-press: #cddaef;--button-secondary-fill-inactive: #ebebee;--text-white: #ffffff;--text-link: #0645b1;--text-press: #082f75;--success-light: #f0f8f1;--background-light-blue: #f4f7fc;--background-white: #ffffff;--premium-dark: #877440;--premium-light: #f9f6ed;--stroke-white: #ffffff;--inactive-content: #b1b1ba;--annotate-light: #a35dff;--annotate-dark: #824acc;--grid: #eef2f9;--button-secondary-stroke: #cddaef;--button-secondary-stroke-hover: #c8c8cf;--button-secondary-stroke-press: #0645b1;--button-secondary-text-inactive: #b1b1ba;--button-primary-icon: #ffffff;--button-secondary-icon: #082f75;--button-secondary-fill-hover: #e6ecf7;--inactive-stroke: #ebebee;--shadow: rgba(34, 34, 51, 0.25);--button-primary-fill-inverse: #ffffff;--button-primary-text-inverse: #0645b1;--button-secondary-stroke-inverse: #ffffff;--button-primary-icon-inverse: #0645b1;--button-icon-inactive: #91919e;--button-secondary-fill-inverse: #eef2f9;--button-secondary-icon-inverse: #ffffff;--button-secondary-icon-hover: #082f75;--button-secondary-icon-press: #082f75;--button-secondary-text-inverse: #ffffff;--button-secondary-text-hover: #0c3b8d;--button-secondary-text-press: #082f75;--text-inactive: #6d6d7d;--text-error: #b60000;--stroke-error: #b60000;--background-error: #fff2f2;--background-black: #141413;--icon-default: #141413;--icon-blue: #0645b1;--background-grey: #dddde2;--icon-grey: #91919e;--button-xs-stroke: #141413;--button-xs-stroke-hover: #0c3b8d;--button-xs-stroke-press: #082f75;--button-xs-stroke-inactive: #0645b1;--button-xs-text: #141413;--button-xs-text-hover: #0c3b8d;--button-xs-text-press: #082f75;--button-xs-text-inactive: #b1b1ba;--button-xs-icon: #141413;--button-xs-icon-hover: #0c3b8d;--button-xs-icon-press: #082f75;--button-xs-icon-inactive: #b1b1ba;--button-xs-fill: #ffffff;--text-focus: #082f75;--brand-colors-neutral-black: #141413;--brand-colors-neutral-900: #535366;--brand-colors-neutral-800: #6d6d7d;--brand-colors-neutral-700: #91919e;--brand-colors-neutral-600: #b1b1ba;--brand-colors-neutral-500: #c8c8cf;--brand-colors-neutral-400: #dddde2;--brand-colors-neutral-300: #ebebee;--brand-colors-neutral-200: #f8f8fb;--brand-colors-neutral-100: #fafafa;--brand-colors-neutral-white: #ffffff;--brand-colors-blue-900: #043059;--brand-colors-blue-800: #082f75;--brand-colors-blue-700: #0c3b8d;--brand-colors-blue-600: #0645b1;--brand-colors-blue-500: #386ac1;--brand-colors-blue-400: #cddaef;--brand-colors-blue-300: #e6ecf7;--brand-colors-blue-200: #eef2f9;--brand-colors-blue-100: #f4f7fc;--brand-colors-gold-500: #877440;--brand-colors-gold-400: #e9e3d4;--brand-colors-gold-300: #f2efe8;--brand-colors-gold-200: #f9f6ed;--brand-colors-gold-100: #f9f7f4;--brand-colors-error-900: #920000;--brand-colors-error-500: #b60000;--brand-colors-success-900: #035c0f;--brand-colors-green: #ccffd4;--brand-colors-turquoise: #ccf7ff;--brand-colors-yellow: #f7ffcc;--brand-colors-peach: #ffd4cc;--brand-colors-violet: #f7ccff;--brand-colors-error-100: #fff2f2;--brand-colors-success-500: #05b01c;--brand-colors-success-100: #f0f8f1;--text-secondary: #535366;--icon-white: #ffffff;--background-beige-darker: #f2efe8;--type-font-family-sans-serif: DM Sans;--type-font-family-serif: Gupter;--type-font-family-mono: IBM Plex Mono;--type-weights-300: 300;--type-weights-400: 400;--type-weights-500: SemiBold;--type-weights-700: 700;--type-sizes-12: 12px;--type-sizes-14: 14px;--type-sizes-16: 16px;--type-sizes-18: 18px;--type-sizes-20: 20px;--type-sizes-22: 22px;--type-sizes-24: 24px;--type-sizes-28: 28px;--type-sizes-30: 30px;--type-sizes-32: 32px;--type-sizes-40: 40px;--type-sizes-42: 42px;--type-sizes-48-2: 48px;--type-line-heights-16: 16px;--type-line-heights-23: 23px;--type-line-heights-24: 24px;--type-line-heights-25: 25px;--type-line-heights-26: 26px;--type-line-heights-29: 29px;--type-line-heights-30: 30px;--type-line-heights-32: 32px;--type-line-heights-34: 34px;--type-line-heights-35: 35px;--type-line-heights-36: 36px;--type-line-heights-38: 38px;--type-line-heights-40: 40px;--type-line-heights-46: 46px;--type-line-heights-48: 48px;--type-line-heights-52: 52px;--type-line-heights-58: 58px;--type-line-heights-68: 68px;--type-line-heights-74: 74px;--type-line-heights-82: 82px;--type-paragraph-spacings-0: 0px;--type-paragraph-spacings-4: 4px;--type-paragraph-spacings-16: 16px;--type-sans-serif-xl-font-weight: 400;--type-sans-serif-xl-size: 42px;--type-sans-serif-xl-line-height: 46px;--type-sans-serif-xl-paragraph-spacing: 16px;--type-sans-serif-lg-font-weight: 400;--type-sans-serif-lg-size: 32px;--type-sans-serif-lg-line-height: 36px;--type-sans-serif-lg-paragraph-spacing: 16px;--type-sans-serif-md-font-weight: 400;--type-sans-serif-md-line-height: 34px;--type-sans-serif-md-paragraph-spacing: 16px;--type-sans-serif-md-size: 28px;--type-sans-serif-xs-font-weight: 700;--type-sans-serif-xs-line-height: 25px;--type-sans-serif-xs-paragraph-spacing: 0px;--type-sans-serif-xs-size: 20px;--type-sans-serif-sm-font-weight: 400;--type-sans-serif-sm-line-height: 30px;--type-sans-serif-sm-paragraph-spacing: 16px;--type-sans-serif-sm-size: 24px;--type-body-xl-font-weight: 400;--type-body-xl-size: 24px;--type-body-xl-line-height: 36px;--type-body-xl-paragraph-spacing: 0px;--type-body-sm-font-weight: 400;--type-body-sm-size: 14px;--type-body-sm-line-height: 23px;--type-body-sm-paragraph-spacing: 16px;--type-body-xs-font-weight: 400;--type-body-xs-size: 12px;--type-body-xs-line-height: 16px;--type-body-xs-paragraph-spacing: 0px;--type-body-md-font-weight: 400;--type-body-md-size: 16px;--type-body-md-line-height: 24px;--type-body-md-paragraph-spacing: 4px;--type-body-lg-font-weight: 400;--type-body-lg-size: 20px;--type-body-lg-line-height: 29px;--type-body-lg-paragraph-spacing: 16px;--type-body-lg-medium-font-weight: SemiBold;--type-body-lg-medium-size: 20px;--type-body-lg-medium-line-height: 32px;--type-body-lg-medium-paragraph-spacing: 16px;--type-body-md-medium-font-weight: SemiBold;--type-body-md-medium-size: 16px;--type-body-md-medium-line-height: 24px;--type-body-md-medium-paragraph-spacing: 4px;--type-body-sm-bold-font-weight: 700;--type-body-sm-bold-size: 14px;--type-body-sm-bold-line-height: 23px;--type-body-sm-bold-paragraph-spacing: 16px;--type-serif-md-font-weight: 400;--type-serif-md-size: 40px;--type-serif-md-paragraph-spacing: 0px;--type-serif-md-line-height: 48px;--type-serif-sm-font-weight: 400;--type-serif-sm-size: 28px;--type-serif-sm-paragraph-spacing: 0px;--type-serif-sm-line-height: 36px;--type-serif-lg-font-weight: 400;--type-serif-lg-size: 58px;--type-serif-lg-paragraph-spacing: 0px;--type-serif-lg-line-height: 68px;--type-serif-xs-font-weight: 400;--type-serif-xs-size: 18px;--type-serif-xs-line-height: 24px;--type-serif-xs-paragraph-spacing: 0px;--type-serif-xl-font-weight: 400;--type-serif-xl-size: 74px;--type-serif-xl-paragraph-spacing: 0px;--type-serif-xl-line-height: 82px;--type-mono-md-font-weight: 400;--type-mono-md-size: 22px;--type-mono-md-line-height: 24px;--type-mono-md-paragraph-spacing: 0px;--type-mono-lg-font-weight: 400;--type-mono-lg-size: 40px;--type-mono-lg-line-height: 40px;--type-mono-lg-paragraph-spacing: 0px;--type-mono-sm-font-weight: 400;--type-mono-sm-size: 14px;--type-mono-sm-line-height: 24px;--type-mono-sm-paragraph-spacing: 0px;--spacing-xs-4: 4px;--spacing-xs-8: 8px;--spacing-xs-16: 16px;--spacing-sm-24: 24px;--spacing-sm-32: 32px;--spacing-md-40: 40px;--spacing-md-48: 48px;--spacing-lg-64: 64px;--spacing-lg-80: 80px;--spacing-xlg-104: 104px;--spacing-xlg-152: 152px;--spacing-page-section: 104px;--spacing-card-list-spacing: 48px;--spacing-text-section-spacing: 80px;--spacing-md-xs-headings: 40px;--corner-radius-radius-lg: 16px;--corner-radius-radius-sm: 4px;--corner-radius-radius-md: 8px;--corner-radius-radius-round: 104px;--page-setup-page-width: 768px;--page-setup-page-margin-page-margin-lg: 156px;--page-setup-page-margin-page-margin-md: 40px;--page-setup-page-margin-page-margin-sm: 24px;--page-setup-margin-l-r: 40px;--buttons-small-buttons-corner-radius: 16px;--buttons-small-buttons-l-r-padding: 20px;--buttons-small-buttons-height: 48px;--buttons-small-buttons-gap: 8px;--buttons-small-buttons-icon-only-width: 48px;--buttons-small-buttons-icon-size: 20px;--buttons-large-buttons-l-r-padding: 32px;--buttons-large-buttons-height: 64px;--buttons-large-buttons-icon-only-width: 64px;--buttons-large-buttons-icon-size: 20px;--buttons-large-buttons-gap: 8px;--buttons-large-buttons-corner-radius: 16px;--buttons-extra-small-buttons-l-r-padding: 8px;--buttons-extra-small-buttons-height: 32px;--buttons-extra-small-buttons-icon-size: 16px;--buttons-extra-small-buttons-gap: 4px;--buttons-extra-small-buttons-corner-radius: 8px}}@media(min-width: 1280px){:root{--token-mode: Rebrand;--dropshadow: 0 2px 4px 0 #22223340;--primary-brand: #0645b1;--error-dark: #b60000;--success-dark: #05b01c;--inactive-fill: #ebebee;--hover: #0c3b8d;--pressed: #082f75;--button-primary-fill-inactive: #ebebee;--button-text-inactive: #91919e;--button-secondary-stroke-inactive: #b1b1ba;--background-beige: #f9f7f4;--error-light: #fff2f2;--text-placeholder: #91919e;--stroke-dark: #141413;--stroke-light: #dddde2;--stroke-medium: #535366;--accent-green: #ccffd4;--accent-turquoise: #ccf7ff;--accent-yellow: #f7ffcc;--accent-peach: #ffd4cc;--accent-violet: #f7ccff;--accent-purple: #f4f7fc;--text-primary: #141413;--button-primary-fill: #0645b1;--button-secondary-fill: #eef2f9;--secondary-brand: #0645b1;--button-secondary-text: #082f75;--button-primary-text: #ffffff;--text-hover: #0c3b8d;--button-primary-fill-hover: #0c3b8d;--button-primary-fill-press: #082f75;--button-focus: #0645b1;--button-secondary-fill-press: #cddaef;--button-secondary-fill-inactive: #ebebee;--text-white: #ffffff;--text-link: #0645b1;--text-press: #082f75;--success-light: #f0f8f1;--background-light-blue: #f4f7fc;--background-white: #ffffff;--premium-dark: #877440;--premium-light: #f9f6ed;--stroke-white: #ffffff;--inactive-content: #b1b1ba;--annotate-light: #a35dff;--annotate-dark: #824acc;--grid: #eef2f9;--button-secondary-stroke: #cddaef;--button-secondary-stroke-hover: #c8c8cf;--button-secondary-stroke-press: #0645b1;--button-secondary-text-inactive: #b1b1ba;--button-primary-icon: #ffffff;--button-secondary-icon: #082f75;--button-secondary-fill-hover: #e6ecf7;--inactive-stroke: #ebebee;--shadow: rgba(34, 34, 51, 0.25);--button-primary-fill-inverse: #ffffff;--button-primary-text-inverse: #0645b1;--button-secondary-stroke-inverse: #ffffff;--button-primary-icon-inverse: #0645b1;--button-icon-inactive: #91919e;--button-secondary-fill-inverse: #eef2f9;--button-secondary-icon-inverse: #ffffff;--button-secondary-icon-hover: #082f75;--button-secondary-icon-press: #082f75;--button-secondary-text-inverse: #ffffff;--button-secondary-text-hover: #0c3b8d;--button-secondary-text-press: #082f75;--text-inactive: #6d6d7d;--text-error: #b60000;--stroke-error: #b60000;--background-error: #fff2f2;--background-black: #141413;--icon-default: #141413;--icon-blue: #0645b1;--background-grey: #dddde2;--icon-grey: #91919e;--button-xs-stroke: #141413;--button-xs-stroke-hover: #0c3b8d;--button-xs-stroke-press: #082f75;--button-xs-stroke-inactive: #0645b1;--button-xs-text: #141413;--button-xs-text-hover: #0c3b8d;--button-xs-text-press: #082f75;--button-xs-text-inactive: #b1b1ba;--button-xs-icon: #141413;--button-xs-icon-hover: #0c3b8d;--button-xs-icon-press: #082f75;--button-xs-icon-inactive: #b1b1ba;--button-xs-fill: #ffffff;--text-focus: #082f75;--brand-colors-neutral-black: #141413;--brand-colors-neutral-900: #535366;--brand-colors-neutral-800: #6d6d7d;--brand-colors-neutral-700: #91919e;--brand-colors-neutral-600: #b1b1ba;--brand-colors-neutral-500: #c8c8cf;--brand-colors-neutral-400: #dddde2;--brand-colors-neutral-300: #ebebee;--brand-colors-neutral-200: #f8f8fb;--brand-colors-neutral-100: #fafafa;--brand-colors-neutral-white: #ffffff;--brand-colors-blue-900: #043059;--brand-colors-blue-800: #082f75;--brand-colors-blue-700: #0c3b8d;--brand-colors-blue-600: #0645b1;--brand-colors-blue-500: #386ac1;--brand-colors-blue-400: #cddaef;--brand-colors-blue-300: #e6ecf7;--brand-colors-blue-200: #eef2f9;--brand-colors-blue-100: #f4f7fc;--brand-colors-gold-500: #877440;--brand-colors-gold-400: #e9e3d4;--brand-colors-gold-300: #f2efe8;--brand-colors-gold-200: #f9f6ed;--brand-colors-gold-100: #f9f7f4;--brand-colors-error-900: #920000;--brand-colors-error-500: #b60000;--brand-colors-success-900: #035c0f;--brand-colors-green: #ccffd4;--brand-colors-turquoise: #ccf7ff;--brand-colors-yellow: #f7ffcc;--brand-colors-peach: #ffd4cc;--brand-colors-violet: #f7ccff;--brand-colors-error-100: #fff2f2;--brand-colors-success-500: #05b01c;--brand-colors-success-100: #f0f8f1;--text-secondary: #535366;--icon-white: #ffffff;--background-beige-darker: #f2efe8;--type-font-family-sans-serif: DM Sans;--type-font-family-serif: Gupter;--type-font-family-mono: IBM Plex Mono;--type-weights-300: 300;--type-weights-400: 400;--type-weights-500: SemiBold;--type-weights-700: 700;--type-sizes-12: 12px;--type-sizes-14: 14px;--type-sizes-16: 16px;--type-sizes-18: 18px;--type-sizes-20: 20px;--type-sizes-22: 22px;--type-sizes-24: 24px;--type-sizes-28: 28px;--type-sizes-30: 30px;--type-sizes-32: 32px;--type-sizes-40: 40px;--type-sizes-42: 42px;--type-sizes-48-2: 48px;--type-line-heights-16: 16px;--type-line-heights-23: 23px;--type-line-heights-24: 24px;--type-line-heights-25: 25px;--type-line-heights-26: 26px;--type-line-heights-29: 29px;--type-line-heights-30: 30px;--type-line-heights-32: 32px;--type-line-heights-34: 34px;--type-line-heights-35: 35px;--type-line-heights-36: 36px;--type-line-heights-38: 38px;--type-line-heights-40: 40px;--type-line-heights-46: 46px;--type-line-heights-48: 48px;--type-line-heights-52: 52px;--type-line-heights-58: 58px;--type-line-heights-68: 68px;--type-line-heights-74: 74px;--type-line-heights-82: 82px;--type-paragraph-spacings-0: 0px;--type-paragraph-spacings-4: 4px;--type-paragraph-spacings-16: 16px;--type-sans-serif-xl-font-weight: 400;--type-sans-serif-xl-size: 42px;--type-sans-serif-xl-line-height: 46px;--type-sans-serif-xl-paragraph-spacing: 16px;--type-sans-serif-lg-font-weight: 400;--type-sans-serif-lg-size: 32px;--type-sans-serif-lg-line-height: 38px;--type-sans-serif-lg-paragraph-spacing: 16px;--type-sans-serif-md-font-weight: 400;--type-sans-serif-md-line-height: 34px;--type-sans-serif-md-paragraph-spacing: 16px;--type-sans-serif-md-size: 28px;--type-sans-serif-xs-font-weight: 700;--type-sans-serif-xs-line-height: 25px;--type-sans-serif-xs-paragraph-spacing: 0px;--type-sans-serif-xs-size: 20px;--type-sans-serif-sm-font-weight: 400;--type-sans-serif-sm-line-height: 30px;--type-sans-serif-sm-paragraph-spacing: 16px;--type-sans-serif-sm-size: 24px;--type-body-xl-font-weight: 400;--type-body-xl-size: 24px;--type-body-xl-line-height: 36px;--type-body-xl-paragraph-spacing: 0px;--type-body-sm-font-weight: 400;--type-body-sm-size: 14px;--type-body-sm-line-height: 23px;--type-body-sm-paragraph-spacing: 16px;--type-body-xs-font-weight: 400;--type-body-xs-size: 12px;--type-body-xs-line-height: 16px;--type-body-xs-paragraph-spacing: 0px;--type-body-md-font-weight: 400;--type-body-md-size: 16px;--type-body-md-line-height: 24px;--type-body-md-paragraph-spacing: 4px;--type-body-lg-font-weight: 400;--type-body-lg-size: 20px;--type-body-lg-line-height: 29px;--type-body-lg-paragraph-spacing: 16px;--type-body-lg-medium-font-weight: SemiBold;--type-body-lg-medium-size: 20px;--type-body-lg-medium-line-height: 32px;--type-body-lg-medium-paragraph-spacing: 16px;--type-body-md-medium-font-weight: SemiBold;--type-body-md-medium-size: 16px;--type-body-md-medium-line-height: 24px;--type-body-md-medium-paragraph-spacing: 4px;--type-body-sm-bold-font-weight: 700;--type-body-sm-bold-size: 14px;--type-body-sm-bold-line-height: 23px;--type-body-sm-bold-paragraph-spacing: 16px;--type-serif-md-font-weight: 400;--type-serif-md-size: 40px;--type-serif-md-paragraph-spacing: 0px;--type-serif-md-line-height: 48px;--type-serif-sm-font-weight: 400;--type-serif-sm-size: 28px;--type-serif-sm-paragraph-spacing: 0px;--type-serif-sm-line-height: 36px;--type-serif-lg-font-weight: 400;--type-serif-lg-size: 58px;--type-serif-lg-paragraph-spacing: 0px;--type-serif-lg-line-height: 68px;--type-serif-xs-font-weight: 400;--type-serif-xs-size: 18px;--type-serif-xs-line-height: 24px;--type-serif-xs-paragraph-spacing: 0px;--type-serif-xl-font-weight: 400;--type-serif-xl-size: 74px;--type-serif-xl-paragraph-spacing: 0px;--type-serif-xl-line-height: 82px;--type-mono-md-font-weight: 400;--type-mono-md-size: 22px;--type-mono-md-line-height: 24px;--type-mono-md-paragraph-spacing: 0px;--type-mono-lg-font-weight: 400;--type-mono-lg-size: 40px;--type-mono-lg-line-height: 40px;--type-mono-lg-paragraph-spacing: 0px;--type-mono-sm-font-weight: 400;--type-mono-sm-size: 14px;--type-mono-sm-line-height: 24px;--type-mono-sm-paragraph-spacing: 0px;--spacing-xs-4: 4px;--spacing-xs-8: 8px;--spacing-xs-16: 16px;--spacing-sm-24: 24px;--spacing-sm-32: 32px;--spacing-md-40: 40px;--spacing-md-48: 48px;--spacing-lg-64: 64px;--spacing-lg-80: 80px;--spacing-xlg-104: 104px;--spacing-xlg-152: 152px;--spacing-page-section: 152px;--spacing-card-list-spacing: 48px;--spacing-text-section-spacing: 80px;--spacing-md-xs-headings: 40px;--corner-radius-radius-lg: 16px;--corner-radius-radius-sm: 4px;--corner-radius-radius-md: 8px;--corner-radius-radius-round: 104px;--page-setup-page-width: 1440px;--page-setup-page-margin-page-margin-lg: 156px;--page-setup-page-margin-page-margin-md: 40px;--page-setup-page-margin-page-margin-sm: 24px;--page-setup-margin-l-r: 156px;--buttons-small-buttons-corner-radius: 16px;--buttons-small-buttons-l-r-padding: 20px;--buttons-small-buttons-height: 48px;--buttons-small-buttons-gap: 8px;--buttons-small-buttons-icon-only-width: 48px;--buttons-small-buttons-icon-size: 20px;--buttons-large-buttons-l-r-padding: 32px;--buttons-large-buttons-height: 64px;--buttons-large-buttons-icon-only-width: 64px;--buttons-large-buttons-icon-size: 20px;--buttons-large-buttons-gap: 8px;--buttons-large-buttons-corner-radius: 16px;--buttons-extra-small-buttons-l-r-padding: 8px;--buttons-extra-small-buttons-height: 32px;--buttons-extra-small-buttons-icon-size: 16px;--buttons-extra-small-buttons-gap: 4px;--buttons-extra-small-buttons-corner-radius: 8px}}</style><link rel="stylesheet" media="screen" href="//a.academia-assets.com/assets/journals/article-page_dsv3-0c488f01fa88c96cc706787c6e1f987cf9b30470c3f0593264335a1e77f7869e.css" /><link rel="stylesheet" media="all" href="//a.academia-assets.com/assets/design_system/stat-5a1ab982b37d6c89510629d9f023874a3baa0f1020d9eaa02b0c0502b3442538.css" /><link crossorigin="" href="https://fonts.gstatic.com/" rel="preconnect" /><link href="https://fonts.googleapis.com/css2?family=DM+Sans:ital,opsz,wght@0,9..40,100..1000;1,9..40,100..1000&family=Gupter:wght@400;500;700&family=IBM+Plex+Mono:wght@300;400&family=Material+Symbols+Outlined:opsz,wght,FILL,GRAD@20,400,0,0&display=swap" rel="stylesheet" /> <meta name="citation_author" content="Günter Müller" /> <meta name="citation_publisher" content="Academia.edu Journals" /> <meta name="citation_title" content="Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology" /> <meta name="citation_publication_date" content="2024/11/21" /> <meta name="citation_journal_title" content="Academia Molecular Biology and Genomics" /> <meta name="citation_volume" content="1" /> <meta name="citation_issue" content="1" /> <meta name="citation_issn" content="3064-9765" /> <meta name="description" content="Academia.edu is the platform to share, find, and explore 50 Million research papers. Join us to accelerate your research needs & academic interests." /> <meta name="google-site-verification" content="bKJMBZA7E43xhDOopFZkssMMkBRjvYERV-NaN4R6mrs" /> <script> var $controller_name = 'articles'; var $action_name = "show"; var $rails_env = 'production'; var $app_rev = '49879c2402910372f4abc62630a427bbe033d190'; var $domain = 'academia.edu'; var $app_host = "academia.edu"; var $asset_host = "academia-assets.com"; var $start_time = new Date().getTime(); var $recaptcha_key = "6LdxlRMTAAAAADnu_zyLhLg0YF9uACwz78shpjJB"; var $recaptcha_invisible_key = "6Lf3KHUUAAAAACggoMpmGJdQDtiyrjVlvGJ6BbAj"; var $disableClientRecordHit = false; </script> <script> window.Aedu = { hit_data: null }; window.Aedu.SiteStats = {"premium_universities_count":15275,"monthly_visitors":"113 million","monthly_visitor_count":113468711,"monthly_visitor_count_in_millions":113,"user_count":277119335,"paper_count":55203019,"paper_count_in_millions":55,"page_count":432000000,"page_count_in_millions":432,"pdf_count":16500000,"pdf_count_in_millions":16}; window.Aedu.serverRenderTime = new Date(1732380419000); window.Aedu.timeDifference = new Date().getTime() - 1732380419000; window.Aedu.isUsingCssV1 = false; window.Aedu.enableLocalization = true; window.Aedu.activateFullstory = false; window.Aedu.serviceAvailability = { status: {"attention_db":"on","bibliography_db":"on","contacts_db":"on","email_db":"on","indexability_db":"on","mentions_db":"on","news_db":"on","notifications_db":"on","offsite_mentions_db":"on","redshift":"on","redshift_exports_db":"on","related_works_db":"on","ring_db":"on","user_tests_db":"on"}, serviceEnabled: function(service) { return this.status[service] === "on"; }, readEnabled: function(service) { return this.serviceEnabled(service) || this.status[service] === "read_only"; }, }; window.Aedu.viewApmTrace = function() { // Check if x-apm-trace-id meta tag is set, and open the trace in APM // in a new window if it is. var apmTraceId = document.head.querySelector('meta[name="x-apm-trace-id"]'); if (apmTraceId) { var traceId = apmTraceId.content; // Use trace ID to construct URL, an example URL looks like: // https://app.datadoghq.com/apm/traces?query=trace_id%31298410148923562634 var apmUrl = 'https://app.datadoghq.com/apm/traces?query=trace_id%3A' + traceId; window.open(apmUrl, '_blank'); } }; </script>  <link href="https://fonts.googleapis.com/css?family=Roboto:100,100i,300,300i,400,400i,500,500i,700,700i,900,900i" rel="stylesheet"> <link href="//maxcdn.bootstrapcdn.com/font-awesome/4.3.0/css/font-awesome.min.css" rel="stylesheet"> <link rel="stylesheet" media="all" href="//a.academia-assets.com/assets/libraries-a9675dcb01ec4ef6aa807ba772c7a5a00c1820d3ff661c1038a20f80d06bb4e4.css" /> <link rel="stylesheet" media="all" href="//a.academia-assets.com/assets/academia-296162c7af6fd81dcdd76f1a94f1fad04fb5f647401337d136fe8b68742170b1.css" /> <link rel="stylesheet" media="all" href="//a.academia-assets.com/assets/design_system_legacy-056a9113b9a0f5343d013b29ee1929d5a18be35fdcdceb616600b4db8bd20054.css" /> <script src="//a.academia-assets.com/assets/webpack_bundles/runtime-bundle-005434038af4252ca37c527588411a3d6a0eabb5f727fac83f8bbe7fd88d93bb.js"></script> <script src="//a.academia-assets.com/assets/webpack_bundles/webpack_libraries_and_infrequently_changed.wjs-bundle-8d53a22151f33ab413d88fa1c02f979c3f8706d470fc1bced09852c72a9f3454.js"></script> <script src="//a.academia-assets.com/assets/webpack_bundles/core_webpack.wjs-bundle-f8fe82512740391f81c9e8cc48220144024b425b359b08194e316f4de070b9e8.js"></script> <script src="//a.academia-assets.com/assets/webpack_bundles/sentry.wjs-bundle-5fe03fddca915c8ba0f7edbe64c194308e8ce5abaed7bffe1255ff37549c4808.js"></script> <script> jade = window.jade || {}; jade.helpers = window.$h; jade._ = window._; </script>  <script id="tag-manager-head-root">(function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer_old','GTM-5G9JF7Z');</script>  <script> window.gptadslots = []; window.googletag = window.googletag || {}; window.googletag.cmd = window.googletag.cmd || []; </script> <script type="text/javascript"> // TODO(jacob): This should be defined, may be rare load order problem. // Checking if null is just a quick fix, will default to en if unset. // Better fix is to run this immedietely after I18n is set. if (window.I18n != null) { I18n.defaultLocale = "en"; I18n.locale = "en"; I18n.fallbacks = true; } </script> </head>   <body class='c-journals/articles a-show logged_out'>  <div id="fb-root"></div><script>window.fbAsyncInit = function() { FB.init({ appId: "2369844204", version: "v8.0", status: true, cookie: true, xfbml: true }); // Additional initialization code. if (window.InitFacebook) { // facebook.ts already loaded, set it up. window.InitFacebook(); } else { // Set a flag for facebook.ts to find when it loads. window.academiaAuthReadyFacebook = true; } };</script><script>window.fbAsyncLoad = function() { // Protection against double calling of this function if (window.FB) { return; } (function(d, s, id){ var js, fjs = d.getElementsByTagName(s)[0]; if (d.getElementById(id)) {return;} js = d.createElement(s); js.id = id; js.src = "//connect.facebook.net/en_US/sdk.js"; fjs.parentNode.insertBefore(js, fjs); }(document, 'script', 'facebook-jssdk')); } if (!window.defer_facebook) { // Autoload if not deferred window.fbAsyncLoad(); } else { // Defer loading by 5 seconds setTimeout(function() { window.fbAsyncLoad(); }, 5000); }</script> <div id="google-root"></div><script>window.loadGoogle = function() { if (window.InitGoogle) { // google.ts already loaded, set it up. window.InitGoogle("331998490334-rsn3chp12mbkiqhl6e7lu2q0mlbu0f1b"); } else { // Set a flag for google.ts to use when it loads. window.GoogleClientID = "331998490334-rsn3chp12mbkiqhl6e7lu2q0mlbu0f1b"; } };</script><script>window.googleAsyncLoad = function() { // Protection against double calling of this function (function(d) { var js; var id = 'google-jssdk'; var ref = d.getElementsByTagName('script')[0]; if (d.getElementById(id)) { return; } js = d.createElement('script'); js.id = id; js.async = true; js.onload = loadGoogle; js.src = "https://accounts.google.com/gsi/client" ref.parentNode.insertBefore(js, ref); }(document)); } if (!window.defer_google) { // Autoload if not deferred window.googleAsyncLoad(); } else { // Defer loading by 5 seconds setTimeout(function() { window.googleAsyncLoad(); }, 5000); }</script> <div id="tag-manager-body-root">  <noscript><iframe src="https://www.googletagmanager.com/ns.html?id=GTM-5G9JF7Z" height="0" width="0" style="display:none;visibility:hidden"></iframe></noscript>   <script> window.addEventListener('load', function() { if (document.querySelector('input[name="commit"]')) { document.querySelector('input[name="commit"]').addEventListener('click', function() { gtag('event', 'click', { event_category: 'button', event_label: 'Log In' }) }) } }); </script> </div> <script>var _comscore = _comscore || []; _comscore.push({ c1: "2", c2: "26766707" }); (function() { var s = document.createElement("script"), el = document.getElementsByTagName("script")[0]; s.async = true; s.src = (document.location.protocol == "https:" ? "https://sb" : "http://b") + ".scorecardresearch.com/beacon.js"; el.parentNode.insertBefore(s, el); })();</script><img src="https://sb.scorecardresearch.com/p?c1=2&c2=26766707&cv=2.0&cj=1" style="position: absolute; visibility: hidden" /> <div id='react-modal'></div> <div class='DesignSystem'> <a class='u-showOnFocus' href='#site'> Skip to main content </a> </div> <div id="upgrade_ie_banner" style="display: none;"><p>Academia.edu no longer supports Internet Explorer.</p><p>To browse Academia.edu and the wider internet faster and more securely, please take a few seconds to <a href="https://www.academia.edu/upgrade-browser">upgrade your browser</a>.</p></div><script>// Show this banner for all versions of IE if (!!window.MSInputMethodContext || /(MSIE)/.test(navigator.userAgent)) { document.getElementById('upgrade_ie_banner').style.display = 'block'; }</script> <div class="ds2-5-sticky"><div id="js-react-on-rails-context" style="display:none" data-rails-context="{"inMailer":false,"i18nLocale":"en","i18nDefaultLocale":"en","href":"https://www.academia.edu/3064-9765/1/1/10.20935/AcadMolBioGen7401","location":"/3064-9765/1/1/10.20935/AcadMolBioGen7401","scheme":"https","host":"www.academia.edu","port":null,"pathname":"/3064-9765/1/1/10.20935/AcadMolBioGen7401","search":null,"httpAcceptLanguage":null,"serverSide":false}"></div> <div class="js-react-on-rails-component" style="display:none" data-component-name="JournalNavbar" data-props="{"unread_mentions_count":0,"messages_count":0,"journal":{"id":10,"name":"Academia Molecular Biology and Genomics","slug":"academia-molecular-biology-and-genomics","topic":"molecular biology and genomics","issn":"3064-9765","banner_logo_url":"https://journals.academia-photos.com/microsite/10/mobile_text_and_logo_white.svg","banner_background_color":"#2B3654","logo_url":"journals/microsite/blue_seal.svg","subfields":["Cellular and Molecular Biology","Computational Genomics and Bioinformatics","Functional Genomics and Systems Biology","Genetic Regulation and Variation","Human Health and Diseases","Neurobiology","Plant Genetics and Genomics"],"subfield_headings":null,"production_email_address":"publishing@academia.edu","special_issues":["Molecular Mechanisms of Fungal Virulence"],"editorial_office_email":"acadmolbiogen@journals.academia-mail.com","formatted_apc_waive_until":"December 31st, 2024","show_articles":true,"show_journal_awards":false,"show_special_issues":true,"show_sections":true,"show_editorial_board":true},"canSeeAboutMenu":true}" data-trace="false" data-dom-id="JournalNavbar-react-component-ce5057de-6144-4ad3-8028-7a627f93209b"></div> <div id="JournalNavbar-react-component-ce5057de-6144-4ad3-8028-7a627f93209b"></div> </div> <div id='site' class='fixed'> <div id="content" class="clearfix"> <script>document.addEventListener('DOMContentLoaded', function(){ var $dismissible = $(".dismissible_banner"); $dismissible.click(function(ev) { $dismissible.hide(); }); });</script> <script async="" src="//cdn.jsdelivr.net/npm/mathjax@3/es5/tex-mml-chtml.js"></script><script src="//a.academia-assets.com/assets/webpack_bundles/journals_article.wjs-bundle-c7a286300daec1255a91182ebb9f549df5fa6d31e8adfcbdc60c14e8ea25efb4.js"></script><div id="article-metadata"><style type="text/css">html{font-size:16px !important}.ds2-5-article-card__metadata{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-sm-size, 14px);line-height:var(--type-body-sm-line-height, 20px);font-weight:var(--type-body-sm-font-weight, 400);display:flex;flex-direction:row}.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata__publication_date{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata__publication_date{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata__publication_date{width:33%}}.ds2-5-article-card__metadata__article-type{display:flex;align-items:center}.ds2-5-article-card__metadata__article-type .color-indicator{display:inline-block;margin-right:8px;height:16px;width:16px;border:2px solid var(--stroke-gray, #676e7b);border-radius:50%;background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__metadata__article-type .color-indicator.research_article{background:var(--accent-green, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.review_article{background:var(--accent-turquoise, #ccf7ff)}.ds2-5-article-card__metadata__article-type .color-indicator.communications{background:var(--accent-peach, #ffd4cc)}.ds2-5-article-card__metadata__article-type .color-indicator.clinical_trial{background:var(--accent-violet, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.case_study{background:var(--accent-yellow, #f7ffcc)}</style><div class="ds2-5-article-card__metadata"><div class="ds2-5-article-card__metadata__article-type"><span class="color-indicator review_article"></span><span>Review article</span></div><div class="ds2-5-article-card__metadata__publication_date">November 21, 2024</div></div></div><div id="article-header"><div class="sap__header-grid-container"><div id="article-metadata-mobile"><div class="sap__metadata-section"><div class="sap__sidebar-sub-section"><div class="sap__title">Academia Molecular Biology and Genomics</div><div class="sap__sidebar-content">Volume 1; Issue 1</div></div><div class="sap__metadata-section"><div class="sap__title" id="article-metadata-show-more"><div class="show-more"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">add</span>Show more</div><div class="show-less"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">remove</span>Show less</div></div><div id="article-metadata-extra"><div class="sap__sidebar-section"><div class="sap__sidebar-sub-section-row"><div class="sap__sidebar-dates-graphic"><svg fill="none" height="131" viewBox="0 0 5 131" width="5" xmlns="http://www.w3.org/2000/svg"><line stroke="black" x1="2.5" x2="2.50001" y1="131" y2="4"></line><circle cx="2.5" cy="2.5" fill="black" r="2.5"></circle><circle cx="2.5" cy="65.5" fill="black" r="2.5"></circle><circle cx="2.5" cy="128.5" fill="black" r="2.5"></circle></svg></div><div class="sap__sidebar-sub-section-dates"><div class="sap__sidebar-sub-section"><div class="sap__title">Received</div><div class="sap__sidebar-content">May 13, 2024</div></div><div class="sap__sidebar-sub-section"><div class="sap__title">Accepted</div><div class="sap__sidebar-content">October 17, 2024</div></div><div class="sap__sidebar-sub-section"><div class="sap__title">Published</div><div class="sap__sidebar-content">November 21, 2024</div></div></div></div></div><div class="sap__sidebar-section"><div class="sap__sidebar-sub-section"><div class="sap__title_bold">Academic editors</div></div><style type="text/css">html{font-size:16px !important}.ds2-5-person-metadata{display:flex;flex-direction:column}.ds2-5-person-metadata__title{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400);color:var(--text-primary, #070A15)}.ds2-5-person-metadata__content{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400);color:var(--text-secondary, #676E7B);overflow-wrap:break-word;word-break:break-word}.ds2-5-person-metadata__links-container{display:flex;gap:var(--spacing-xs-16, 16px);padding-top:var(--spacing-xs-4, 4px)}.ds2-5-person-metadata__link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400);text-decoration-line:underline;color:var(--text-primary, #070A15)}</style><div class="ds2-5-person-metadata"><div class="ds2-5-person-metadata__title">Dr. Ian J. Martins</div><div class="ds2-5-person-metadata__content">Editorial Board Member</div><div class="ds2-5-person-metadata__links-container"><a class="ds2-5-person-metadata__link" href="https://uwa.academia.edu/IanMartins" target="_blank">Profile</a><a class="ds2-5-person-metadata__link" href="https://www.ecu.edu.au/schools/medical-and-health-sciences/our-staff/profiles/research-fellows/dr-ian-martins" target="_blank">Institution</a></div></div></div></div></div></div></div><div class="sap__header-grid-contents"><div class="sap__header-mobile-top-row"><div class="js-react-on-rails-component" style="display:none" data-component-name="DownloadButton" data-props="{"author":{"id":10425173,"first_name":"Günter","middle_initials":null,"last_name":"Müller","page_name":"GünterMüller","domain_name":"independent","created_at":"2014-03-23T20:07:37.142-07:00","display_name":"Günter Müller","url":"https://independent.academia.edu/G%C3%BCnterM%C3%BCller","photo":"/images/s200_no_pic.png"},"downloadUrl":"https://www.academia.edu/attachments/119727764/download_file?s=sap","reactionPrompt":null,"work":{"id":125739613,"title":"Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology","translatedTitle":"","metadata":{"doi":"10.20935/AcadMolBioGen7401","issn":"3064-9765","abstract":"The detection of DNA as the transforming principle in bacteria 95 years ago, almost immediately led to (i) refutation of the old and heavily disputed concept of inheritance of acquired featured, since this would necessitate rewriting of “the book of life“ by environmental factors, such as nutrition, stress, and (ii) exclusion of the existence of any matter of inheritance different from DNA and genes. In this hypothesis paper we intend to overcome this narrowing by (i) re-consideration of other cellular constituents, in particular plasma membranes (PMs) and organelles, and (ii) inclusion of the recently identified extracellular vesicles and micelle-like complexes as putative non-genetic matter of inheritance. Micelle-like complexes consist of glycosylphosphatidylinositol-anchored proteins (GPI-APs), cholesterol and (lyso)phospholipids, which induce the formation of so-called “membrane environment landscapes” (MELs), among them blebs and protuberances, at the PMs at sites of local accumulation of GPI-APs, G-proteins and cytoskeletal elements. Upon release from donor cells and subsequent transfer to and replication by self-organization (rather than self-assembly) in acceptor cells those MELs induce novel metabolic phenotypes, such as stimulation of lipid and glycogen synthesis. Most critical, in rats and humans transfer and structure of MELs are susceptible to environmental factors, such as mechanical and oxidative stress, plasma glucose and insulin levels, nutrition, which may contribute to phenotypic plasticity and the inheritance of acquired traits. Those epigenetic mechanisms, which are apparently not based on modifications of DNA and DNA-associated proteins, have not been adequately addressed so far in studies on the pathogenesis of metabolic diseases. The reasons for this ongoing neglection have to be addressed by future studies of philosophy of biology, in general, and science and technology studies with emphasis on agential realism, in particular.","publisher":"Academia.edu","publicationDate":{"day":21,"month":11,"year":2024,"errors":{}},"publicationName":"Academia Molecular Biology and Genomics"},"translatedAbstract":"The detection of DNA as the transforming principle in bacteria 95 years ago, almost immediately led to (i) refutation of the old and heavily disputed concept of inheritance of acquired featured, since this would necessitate rewriting of “the book of life“ by environmental factors, such as nutrition, stress, and (ii) exclusion of the existence of any matter of inheritance different from DNA and genes. In this hypothesis paper we intend to overcome this narrowing by (i) re-consideration of other cellular constituents, in particular plasma membranes (PMs) and organelles, and (ii) inclusion of the recently identified extracellular vesicles and micelle-like complexes as putative non-genetic matter of inheritance. Micelle-like complexes consist of glycosylphosphatidylinositol-anchored proteins (GPI-APs), cholesterol and (lyso)phospholipids, which induce the formation of so-called “membrane environment landscapes” (MELs), among them blebs and protuberances, at the PMs at sites of local accumulation of GPI-APs, G-proteins and cytoskeletal elements. Upon release from donor cells and subsequent transfer to and replication by self-organization (rather than self-assembly) in acceptor cells those MELs induce novel metabolic phenotypes, such as stimulation of lipid and glycogen synthesis. Most critical, in rats and humans transfer and structure of MELs are susceptible to environmental factors, such as mechanical and oxidative stress, plasma glucose and insulin levels, nutrition, which may contribute to phenotypic plasticity and the inheritance of acquired traits. Those epigenetic mechanisms, which are apparently not based on modifications of DNA and DNA-associated proteins, have not been adequately addressed so far in studies on the pathogenesis of metabolic diseases. The reasons for this ongoing neglection have to be addressed by future studies of philosophy of biology, in general, and science and technology studies with emphasis on agential realism, in particular.","internalUrl":"https://www.academia.edu/125739613/Glycosylphosphatidylinositol_anchored_proteins_as_non_DNA_matter_of_inheritance_from_molecular_to_cell_to_philosophical_biology","translatedInternalUrl":"","createdAt":"2024-11-21T06:02:27.752-08:00","previewUrl":null,"currentUserCanEdit":null,"currentUserIsOwner":null,"ownerId":10425173,"coauthorsCanEdit":true,"documentType":"paper","coAuthorTags":[],"downloadableAttachments":[{"id":119727764,"title":"","fileType":"pdf","scribdThumbnailUrl":"https://attachments.academia-assets.com/119727764/thumbnails/1.jpg","fileName":"271665_WEBPDF20241121-8739-4mvy56.pdf","downloadUrl":"https://www.academia.edu/attachments/119727764/download_file","bulkDownloadFileName":"Glycosylphosphatidylinositol_anchored_pr.pdf","bulkDownloadUrl":"https://d1wqtxts1xzle7.cloudfront.net/119727764/271665_WEBPDF20241121-8739-4mvy56-libre.pdf?1732199584=\u0026response-content-disposition=attachment%3B+filename%3DGlycosylphosphatidylinositol_anchored_pr.pdf\u0026Expires=1732384018\u0026Signature=LINYTJ6BaWAPlseKg3547LXsxen9G4yGLMXPltHAHHL3dDBM1PcJng~Fuh7NKA4deiwAoqdJNDCHlH3c78AzfIQpaBf5wLxFL~T2BwcUhnN5O0kKd5vOesCuZSGxUqGbdj9s4uuHeZW0S2lIaupIa750ntMWheqZcOkddKAYj17xwMBqawaAMUBF5NI3RoUo~4AN173Iidti46GUFo3w68EjiVlIq0wMBpsAnrRLeNqZjOh1msq5T633oUhVtDVErcw~seLMJhg0UyFFISPq8tSoyXF~-WkE4rgCN0-n19nOQ8rgFstUCBo6AfOcOYq0xE9i2UullBpKeMsZ6Q-W2A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Glycosylphosphatidylinositol_anchored_proteins_as_non_DNA_matter_of_inheritance_from_molecular_to_cell_to_philosophical_biology","translatedSlug":"","pageCount":36,"language":"en","contentType":"Work","owner":{"id":10425173,"firstName":"Günter","middleInitials":null,"lastName":"Müller","pageName":"GünterMüller","domainName":"independent","createdAt":"2014-03-23T20:07:37.142-07:00","displayName":"Günter Müller","url":"https://independent.academia.edu/G%C3%BCnterM%C3%BCller"},"attachments":[{"id":119727764,"title":"","fileType":"pdf","scribdThumbnailUrl":"https://attachments.academia-assets.com/119727764/thumbnails/1.jpg","fileName":"271665_WEBPDF20241121-8739-4mvy56.pdf","downloadUrl":"https://www.academia.edu/attachments/119727764/download_file","bulkDownloadFileName":"Glycosylphosphatidylinositol_anchored_pr.pdf","bulkDownloadUrl":"https://d1wqtxts1xzle7.cloudfront.net/119727764/271665_WEBPDF20241121-8739-4mvy56-libre.pdf?1732199584=\u0026response-content-disposition=attachment%3B+filename%3DGlycosylphosphatidylinositol_anchored_pr.pdf\u0026Expires=1732384018\u0026Signature=LINYTJ6BaWAPlseKg3547LXsxen9G4yGLMXPltHAHHL3dDBM1PcJng~Fuh7NKA4deiwAoqdJNDCHlH3c78AzfIQpaBf5wLxFL~T2BwcUhnN5O0kKd5vOesCuZSGxUqGbdj9s4uuHeZW0S2lIaupIa750ntMWheqZcOkddKAYj17xwMBqawaAMUBF5NI3RoUo~4AN173Iidti46GUFo3w68EjiVlIq0wMBpsAnrRLeNqZjOh1msq5T633oUhVtDVErcw~seLMJhg0UyFFISPq8tSoyXF~-WkE4rgCN0-n19nOQ8rgFstUCBo6AfOcOYq0xE9i2UullBpKeMsZ6Q-W2A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"researchInterests":[],"urls":[]},"displayClass":null}" data-trace="false" data-dom-id="DownloadButton-react-component-d20beb6d-23aa-48bc-b443-5be28ecc9c30"></div> <div id="DownloadButton-react-component-d20beb6d-23aa-48bc-b443-5be28ecc9c30"></div> <div class="js-react-on-rails-component" style="display:none" data-component-name="CitationButton" data-props="{"citations":[{"name":"MLA","citation":"Müller, Günter. Glycosylphosphatidylinositol-Anchored Proteins as Non- DNA Matter of Inheritance: from Molecular to Cell to Philosophical Biology. Vol. 1, no. 1, Academia Molecular Biology and Genomics, 2024. https://doi.org/10.20935/AcadMolBioGen7401"},{"name":"APA","citation":"Müller, G. (2024). Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology, 1(1). https://doi.org/10.20935/AcadMolBioGen7401"},{"name":"Chicago","citation":"Müller, Günter. “Glycosylphosphatidylinositol-Anchored Proteins as Non- DNA Matter of Inheritance: from Molecular to Cell to Philosophical Biology” 1, no. 1 (2024). doi:10.20935/AcadMolBioGen7401."},{"name":"Vancouver","citation":"Müller G. Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology. 2024;1(1). https://doi.org/10.20935/AcadMolBioGen7401"},{"name":"Harvard","citation":"Müller, G. (2024) “Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology.” Academia Molecular Biology and Genomics, 1(1). doi: 10.20935/AcadMolBioGen7401."}],"published_letter_id":7401}" data-trace="false" data-dom-id="CitationButton-react-component-e53bb55d-157a-4922-978b-27363bbc1455"></div> <div id="CitationButton-react-component-e53bb55d-157a-4922-978b-27363bbc1455"></div> </div></div></div></div><div id="article-stats"><div class="sap__stats-container"><div class="ds2-5-stat-with-graphic"><div class="ds2-5-stat--basic-large"><div class="ds2-5-stat--basic-large__label">Downloads</div><div class="ds2-5-stat--basic-large__value">116</div></div><div class="ds2-5-stat--graphic"><svg fill="none" height="45" viewBox="0 0 71 45" width="71" xmlns="http://www.w3.org/2000/svg"><path d="M29.8689 18.6812C15.101 27.6249 7.7171 40.0466 0.333158 43.955L0.332999 44.7939H70.3328L70.333 0.793945C47.8919 19.2502 44.3229 9.92772 29.8689 18.6812Z" fill="url(#paint0_linear_7284_156)"></path><defs><lineargradient gradientUnits="userSpaceOnUse" id="paint0_linear_7284_156" x1="35.333" x2="35.333" y1="0.793945" y2="44.7939"><stop stop-color="#5069E6" stop-opacity="0.7"></stop><stop offset="1" stop-color="#5069E6" stop-opacity="0.1"></stop></lineargradient></defs></svg></div></div><div class="ds2-5-stat-with-graphic"><div class="ds2-5-stat--basic-large"><div class="ds2-5-stat--basic-large__label">Views</div><div class="ds2-5-stat--basic-large__value">289</div></div><div class="ds2-5-stat--graphic"><svg fill="none" height="45" viewBox="0 0 71 45" width="71" xmlns="http://www.w3.org/2000/svg"><path d="M29.8689 18.6812C15.101 27.6249 7.7171 40.0466 0.333158 43.955L0.332999 44.7939H70.3328L70.333 0.793945C47.8919 19.2502 44.3229 9.92772 29.8689 18.6812Z" fill="url(#paint0_linear_7284_156)"></path><defs><lineargradient gradientUnits="userSpaceOnUse" id="paint0_linear_7284_156" x1="35.333" x2="35.333" y1="0.793945" y2="44.7939"><stop stop-color="#5069E6" stop-opacity="0.7"></stop><stop offset="1" stop-color="#5069E6" stop-opacity="0.1"></stop></lineargradient></defs></svg></div></div></div></div><div id="article-table-of-contents"></div><div id="article-metadata-sidebar"><div class="sap__sidebar-section"><div class="sap__sidebar-sub-section"><div class="sap__title">Academia Molecular Biology and Genomics</div><div class="sap__sidebar-content">Volume 1; Issue 1 <a class="sap__sidebar-content" href="https://www.doi.org/10.20935/AcadMolBioGen7401">doi.org/10.20935/AcadMolBioGen7401</a></div></div><div class="sap__sidebar-sub-section-row"><div class="sap__sidebar-dates-graphic"><svg fill="none" height="131" viewBox="0 0 5 131" width="5" xmlns="http://www.w3.org/2000/svg"><line stroke="black" x1="2.5" x2="2.50001" y1="131" y2="4"></line><circle cx="2.5" cy="2.5" fill="black" r="2.5"></circle><circle cx="2.5" cy="65.5" fill="black" r="2.5"></circle><circle cx="2.5" cy="128.5" fill="black" r="2.5"></circle></svg></div><div class="sap__sidebar-sub-section-dates"><div class="sap__sidebar-sub-section"><div class="sap__title">Received</div><div class="sap__sidebar-content">May 13, 2024</div></div><div class="sap__sidebar-sub-section"><div class="sap__title">Accepted</div><div class="sap__sidebar-content">October 17, 2024</div></div><div class="sap__sidebar-sub-section"><div class="sap__title">Published</div><div class="sap__sidebar-content">November 21, 2024</div></div></div></div></div><div class="sap__sidebar-section"><div class="sap__sidebar-sub-section"><div class="sap__title_bold">Academic editors</div></div><style type="text/css">html{font-size:16px !important}.ds2-5-person-metadata{display:flex;flex-direction:column}.ds2-5-person-metadata__title{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400);color:var(--text-primary, #070A15)}.ds2-5-person-metadata__content{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400);color:var(--text-secondary, #676E7B);overflow-wrap:break-word;word-break:break-word}.ds2-5-person-metadata__links-container{display:flex;gap:var(--spacing-xs-16, 16px);padding-top:var(--spacing-xs-4, 4px)}.ds2-5-person-metadata__link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400);text-decoration-line:underline;color:var(--text-primary, #070A15)}</style><div class="ds2-5-person-metadata"><div class="ds2-5-person-metadata__title">Dr. Ian J. Martins</div><div class="ds2-5-person-metadata__content">Editorial Board Member</div><div class="ds2-5-person-metadata__links-container"><a class="ds2-5-person-metadata__link" href="https://uwa.academia.edu/IanMartins" target="_blank">Profile</a><a class="ds2-5-person-metadata__link" href="https://www.ecu.edu.au/schools/medical-and-health-sciences/our-staff/profiles/research-fellows/dr-ian-martins" target="_blank">Institution</a></div></div></div></div><div class="sap__section" id="article-about"><a id="about"></a><h2 class="sap__main-title">About this article</h2><div class="sap__sub-section"><h3 class="sap__section-title">Citation</h3><div class="sap__citation-grid"><div class="sap__citation-container"><div class="sap__title">MLA</div><div class="sap__content">Müller, Günter. Glycosylphosphatidylinositol-Anchored Proteins as Non- DNA Matter of Inheritance: from Molecular to Cell to Philosophical Biology. Vol. 1, no. 1, Academia Molecular Biology and Genomics, 2024. https://doi.org/10.20935/AcadMolBioGen7401</div></div><div class="sap__citation-container"><div class="sap__title">APA</div><div class="sap__content">Müller, G. (2024). Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology, 1(1). https://doi.org/10.20935/AcadMolBioGen7401</div></div><div class="sap__citation-container"><div class="sap__title">Chicago</div><div class="sap__content">Müller, Günter. “Glycosylphosphatidylinositol-Anchored Proteins as Non- DNA Matter of Inheritance: from Molecular to Cell to Philosophical Biology” 1, no. 1 (2024). doi:10.20935/AcadMolBioGen7401.</div></div><div class="sap__citation-container"><div class="sap__title">Vancouver</div><div class="sap__content">Müller G. Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology. 2024;1(1). https://doi.org/10.20935/AcadMolBioGen7401</div></div><div class="sap__citation-container"><div class="sap__title">Harvard</div><div class="sap__content">Müller, G. (2024) “Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology.” Academia Molecular Biology and Genomics, 1(1). doi: 10.20935/AcadMolBioGen7401.</div></div></div></div><div class="sap__sub-section"><h3 class="sap__section-title">Publication dates & DOI</h3><div class="sap__publication-section-row"><div class="sap__content-container"><div class="sap__title">Received</div><div class="sap__content">May 13, 2024</div></div><div class="sap__content-container"><div class="sap__title">Accepted</div><div class="sap__content">October 17, 2024</div></div><div class="sap__content-container"><div class="sap__title">Published</div><div class="sap__content">November 21, 2024</div></div></div></div><div class="sap__sub-section"><div class="sap__title">DOI</div><a class="sap__content" href="https://www.doi.org/10.20935/AcadMolBioGen7401">doi.org/10.20935/AcadMolBioGen7401</a></div></div><div id="article-download-container"><div class="js-react-on-rails-component" style="display:none" data-component-name="DownloadButton" data-props="{"author":{"id":10425173,"first_name":"Günter","middle_initials":null,"last_name":"Müller","page_name":"GünterMüller","domain_name":"independent","created_at":"2014-03-23T20:07:37.142-07:00","display_name":"Günter Müller","url":"https://independent.academia.edu/G%C3%BCnterM%C3%BCller","photo":"/images/s200_no_pic.png"},"downloadUrl":"https://www.academia.edu/attachments/119727764/download_file?s=sap","reactionPrompt":null,"work":{"id":125739613,"title":"Glycosylphosphatidylinositol-anchored proteins as non- DNA matter of inheritance: from molecular to cell to philosophical biology","translatedTitle":"","metadata":{"doi":"10.20935/AcadMolBioGen7401","issn":"3064-9765","abstract":"The detection of DNA as the transforming principle in bacteria 95 years ago, almost immediately led to (i) refutation of the old and heavily disputed concept of inheritance of acquired featured, since this would necessitate rewriting of “the book of life“ by environmental factors, such as nutrition, stress, and (ii) exclusion of the existence of any matter of inheritance different from DNA and genes. In this hypothesis paper we intend to overcome this narrowing by (i) re-consideration of other cellular constituents, in particular plasma membranes (PMs) and organelles, and (ii) inclusion of the recently identified extracellular vesicles and micelle-like complexes as putative non-genetic matter of inheritance. Micelle-like complexes consist of glycosylphosphatidylinositol-anchored proteins (GPI-APs), cholesterol and (lyso)phospholipids, which induce the formation of so-called “membrane environment landscapes” (MELs), among them blebs and protuberances, at the PMs at sites of local accumulation of GPI-APs, G-proteins and cytoskeletal elements. Upon release from donor cells and subsequent transfer to and replication by self-organization (rather than self-assembly) in acceptor cells those MELs induce novel metabolic phenotypes, such as stimulation of lipid and glycogen synthesis. Most critical, in rats and humans transfer and structure of MELs are susceptible to environmental factors, such as mechanical and oxidative stress, plasma glucose and insulin levels, nutrition, which may contribute to phenotypic plasticity and the inheritance of acquired traits. Those epigenetic mechanisms, which are apparently not based on modifications of DNA and DNA-associated proteins, have not been adequately addressed so far in studies on the pathogenesis of metabolic diseases. The reasons for this ongoing neglection have to be addressed by future studies of philosophy of biology, in general, and science and technology studies with emphasis on agential realism, in particular.","publisher":"Academia.edu","publicationDate":{"day":21,"month":11,"year":2024,"errors":{}},"publicationName":"Academia Molecular Biology and Genomics"},"translatedAbstract":"The detection of DNA as the transforming principle in bacteria 95 years ago, almost immediately led to (i) refutation of the old and heavily disputed concept of inheritance of acquired featured, since this would necessitate rewriting of “the book of life“ by environmental factors, such as nutrition, stress, and (ii) exclusion of the existence of any matter of inheritance different from DNA and genes. In this hypothesis paper we intend to overcome this narrowing by (i) re-consideration of other cellular constituents, in particular plasma membranes (PMs) and organelles, and (ii) inclusion of the recently identified extracellular vesicles and micelle-like complexes as putative non-genetic matter of inheritance. Micelle-like complexes consist of glycosylphosphatidylinositol-anchored proteins (GPI-APs), cholesterol and (lyso)phospholipids, which induce the formation of so-called “membrane environment landscapes” (MELs), among them blebs and protuberances, at the PMs at sites of local accumulation of GPI-APs, G-proteins and cytoskeletal elements. Upon release from donor cells and subsequent transfer to and replication by self-organization (rather than self-assembly) in acceptor cells those MELs induce novel metabolic phenotypes, such as stimulation of lipid and glycogen synthesis. Most critical, in rats and humans transfer and structure of MELs are susceptible to environmental factors, such as mechanical and oxidative stress, plasma glucose and insulin levels, nutrition, which may contribute to phenotypic plasticity and the inheritance of acquired traits. Those epigenetic mechanisms, which are apparently not based on modifications of DNA and DNA-associated proteins, have not been adequately addressed so far in studies on the pathogenesis of metabolic diseases. The reasons for this ongoing neglection have to be addressed by future studies of philosophy of biology, in general, and science and technology studies with emphasis on agential realism, in particular.","internalUrl":"https://www.academia.edu/125739613/Glycosylphosphatidylinositol_anchored_proteins_as_non_DNA_matter_of_inheritance_from_molecular_to_cell_to_philosophical_biology","translatedInternalUrl":"","createdAt":"2024-11-21T06:02:27.752-08:00","previewUrl":null,"currentUserCanEdit":null,"currentUserIsOwner":null,"ownerId":10425173,"coauthorsCanEdit":true,"documentType":"paper","coAuthorTags":[],"downloadableAttachments":[{"id":119727764,"title":"","fileType":"pdf","scribdThumbnailUrl":"https://attachments.academia-assets.com/119727764/thumbnails/1.jpg","fileName":"271665_WEBPDF20241121-8739-4mvy56.pdf","downloadUrl":"https://www.academia.edu/attachments/119727764/download_file","bulkDownloadFileName":"Glycosylphosphatidylinositol_anchored_pr.pdf","bulkDownloadUrl":"https://d1wqtxts1xzle7.cloudfront.net/119727764/271665_WEBPDF20241121-8739-4mvy56-libre.pdf?1732199584=\u0026response-content-disposition=attachment%3B+filename%3DGlycosylphosphatidylinositol_anchored_pr.pdf\u0026Expires=1732384018\u0026Signature=LINYTJ6BaWAPlseKg3547LXsxen9G4yGLMXPltHAHHL3dDBM1PcJng~Fuh7NKA4deiwAoqdJNDCHlH3c78AzfIQpaBf5wLxFL~T2BwcUhnN5O0kKd5vOesCuZSGxUqGbdj9s4uuHeZW0S2lIaupIa750ntMWheqZcOkddKAYj17xwMBqawaAMUBF5NI3RoUo~4AN173Iidti46GUFo3w68EjiVlIq0wMBpsAnrRLeNqZjOh1msq5T633oUhVtDVErcw~seLMJhg0UyFFISPq8tSoyXF~-WkE4rgCN0-n19nOQ8rgFstUCBo6AfOcOYq0xE9i2UullBpKeMsZ6Q-W2A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Glycosylphosphatidylinositol_anchored_proteins_as_non_DNA_matter_of_inheritance_from_molecular_to_cell_to_philosophical_biology","translatedSlug":"","pageCount":36,"language":"en","contentType":"Work","owner":{"id":10425173,"firstName":"Günter","middleInitials":null,"lastName":"Müller","pageName":"GünterMüller","domainName":"independent","createdAt":"2014-03-23T20:07:37.142-07:00","displayName":"Günter Müller","url":"https://independent.academia.edu/G%C3%BCnterM%C3%BCller"},"attachments":[{"id":119727764,"title":"","fileType":"pdf","scribdThumbnailUrl":"https://attachments.academia-assets.com/119727764/thumbnails/1.jpg","fileName":"271665_WEBPDF20241121-8739-4mvy56.pdf","downloadUrl":"https://www.academia.edu/attachments/119727764/download_file","bulkDownloadFileName":"Glycosylphosphatidylinositol_anchored_pr.pdf","bulkDownloadUrl":"https://d1wqtxts1xzle7.cloudfront.net/119727764/271665_WEBPDF20241121-8739-4mvy56-libre.pdf?1732199584=\u0026response-content-disposition=attachment%3B+filename%3DGlycosylphosphatidylinositol_anchored_pr.pdf\u0026Expires=1732384018\u0026Signature=LINYTJ6BaWAPlseKg3547LXsxen9G4yGLMXPltHAHHL3dDBM1PcJng~Fuh7NKA4deiwAoqdJNDCHlH3c78AzfIQpaBf5wLxFL~T2BwcUhnN5O0kKd5vOesCuZSGxUqGbdj9s4uuHeZW0S2lIaupIa750ntMWheqZcOkddKAYj17xwMBqawaAMUBF5NI3RoUo~4AN173Iidti46GUFo3w68EjiVlIq0wMBpsAnrRLeNqZjOh1msq5T633oUhVtDVErcw~seLMJhg0UyFFISPq8tSoyXF~-WkE4rgCN0-n19nOQ8rgFstUCBo6AfOcOYq0xE9i2UullBpKeMsZ6Q-W2A__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"researchInterests":[],"urls":[]},"displayClass":"article-attachment-download-button"}" data-trace="false" data-dom-id="DownloadButton-react-component-aae21eb1-2e75-4a7e-8249-0244dc355e2b"></div> <div id="DownloadButton-react-component-aae21eb1-2e75-4a7e-8249-0244dc355e2b"></div> </div><div class="sap__section" id="related-articles"><a id="related"></a><h2 class="sap__main-title">Related articles</h2><div class="article-card-list"><style type="text/css">html{font-size:16px !important}.ds2-5-article-card{font-size:16px;color:var(--text-primary, #070a15);display:flex;flex-direction:column;border-top:1px solid var(--stroke-dark, #070A15);color:var(--text-primary, #070A15);width:100%;padding-top:var(--content-card-padding-t, 24px);gap:var(--spacing-xs-16, 16px)}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card{padding-top:var(--content-card-padding-t, 40px)}}@media(min-width: 1280px){.ds2-5-article-card{padding-top:var(--content-card-padding-t, 40px)}}.ds2-5-article-card__metadata{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-sm-size, 14px);line-height:var(--type-body-sm-line-height, 20px);font-weight:var(--type-body-sm-font-weight, 400);display:flex;flex-direction:row}.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:33%}}@media(max-width: 567px){.ds2-5-article-card__metadata{justify-content:space-between}}.ds2-5-article-card__metadata__article-type{display:flex;align-items:center}.ds2-5-article-card__metadata__article-type .color-indicator{display:inline-block;margin-right:8px;height:16px;width:16px;border:2px solid var(--stroke-medium, #676e7b);border-radius:50%;background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__metadata__article-type .color-indicator.research_article{background:var(--accent-green, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.review_article{background:var(--accent-turquoise, #ccf7ff)}.ds2-5-article-card__metadata__article-type .color-indicator.communications{background:var(--accent-peach, #ffd4cc)}.ds2-5-article-card__metadata__article-type .color-indicator.clinical_trial{background:var(--accent-violet, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.case_study{background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__article-title-link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-sans-serif-md-size, 24px);line-height:var(--type-sans-serif-md-line-height, 32px);font-weight:var(--type-sans-serif-md-font-weight, 400);color:var(--primary, #070a15);text-decoration:none;justify-content:flex-start}.ds2-5-article-card__article-title-link:hover{color:var(--hover, #4960d1);border-color:var(--hover, #4960d1);text-decoration:underline}.ds2-5-article-card__article-title-link:hover:focus{color:var(--hover, #4960d1)}.ds2-5-article-card__article-title-link:focus{color:var(--primary, #070a15);text-decoration:none;outline:none}.ds2-5-article-card__figure-highlight{display:flex}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight{gap:48px}}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight{gap:48px}}.ds2-5-article-card__figure-highlight__title-link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-sans-serif-md-size, 24px);line-height:var(--type-sans-serif-md-line-height, 32px);font-weight:var(--type-sans-serif-md-font-weight, 400);color:var(--primary, #070a15);text-decoration:none;justify-content:flex-start}.ds2-5-article-card__figure-highlight__title-link:hover{color:var(--hover, #4960d1);border-color:var(--hover, #4960d1);text-decoration:underline}.ds2-5-article-card__figure-highlight__title-link:hover:focus{color:var(--hover, #4960d1)}.ds2-5-article-card__figure-highlight__title-link:focus{color:var(--primary, #070a15);text-decoration:none;outline:none}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__title-link{width:66%;display:inline-block;vertical-align:top}}.ds2-5-article-card__figure-highlight__small-image-link img{max-width:196px;max-height:196px;border:1px solid var(--stroke-dark, #070A15)}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__small-image-link img{width:33%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__small-image-link{display:none}}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__small-image-link{display:none}}.ds2-5-article-card__figure-highlight__article-info{display:flex;flex-direction:column;gap:var(--spacing-xs-16, 16px)}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__article-info{width:75%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__article-info{width:66%}}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__article-info{width:100%}}.ds2-5-article-card__figure-highlight__article-info__title-with-image{display:flex;flex-direciton:row;gap:16px}.ds2-5-article-card__figure-highlight__big-image-link img{width:100%;max-width:196px;max-height:196px;float:right;border:1px solid var(--stroke-dark, #070A15)}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__big-image-link{width:25%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__big-image-link{width:33%}}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__big-image-link{display:none}}.ds2-5-article-card__authors{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400)}.ds2-5-article-card__stat-group{display:flex;flex-direction:row;width:100%}.ds2-5-article-card__stat-group__stat{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__stat-group__stat{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__stat-group__stat{width:33%}}</style><div class="ds2-5-article-card"><div class="ds2-5-article-card__metadata"><div class="ds2-5-article-card__metadata__article-type"><span class="color-indicator review_article"></span><span>Review article</span></div><div class="ds2-5-article-card__metadata__publication_date">November 12, 2024</div></div><a class="ds2-5-article-card__article-title-link" href="/articles/10.20935/AcadMolBioGen7400?source=academia-molecular-biology-and-genomics-sap-page">Fungi that are medically relevant to humans and their prospect in a global warming scenario</a><div class="ds2-5-article-card__authors">José Ascención Martínez-Álvarez, Bernardo Franco, Naurú Idalia Vargas-Maya, Felipe Padilla-Vaca, Fátima Berenice Ramírez-Montiel</div><div class="ds2-5-article-card__stat-group"><div class="ds2-5-article-card__stat-group__stat"><div class="ds2-5-stat--basic-small"><div class="ds2-5-stat--basic-small__label">downloads</div><div class="ds2-5-stat--basic-small__value">390</div></div></div><div class="ds2-5-article-card__stat-group__stat"><div class="ds2-5-stat--basic-small"><div class="ds2-5-stat--basic-small__label">views</div><div class="ds2-5-stat--basic-small__value">780</div></div></div></div></div><style type="text/css">html{font-size:16px !important}.ds2-5-article-card{font-size:16px;color:var(--text-primary, #070a15);display:flex;flex-direction:column;border-top:1px solid var(--stroke-dark, #070A15);color:var(--text-primary, #070A15);width:100%;padding-top:var(--content-card-padding-t, 24px);gap:var(--spacing-xs-16, 16px)}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card{padding-top:var(--content-card-padding-t, 40px)}}@media(min-width: 1280px){.ds2-5-article-card{padding-top:var(--content-card-padding-t, 40px)}}.ds2-5-article-card__metadata{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-sm-size, 14px);line-height:var(--type-body-sm-line-height, 20px);font-weight:var(--type-body-sm-font-weight, 400);display:flex;flex-direction:row}.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:33%}}@media(max-width: 567px){.ds2-5-article-card__metadata{justify-content:space-between}}.ds2-5-article-card__metadata__article-type{display:flex;align-items:center}.ds2-5-article-card__metadata__article-type .color-indicator{display:inline-block;margin-right:8px;height:16px;width:16px;border:2px solid var(--stroke-medium, #676e7b);border-radius:50%;background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__metadata__article-type .color-indicator.research_article{background:var(--accent-green, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.review_article{background:var(--accent-turquoise, #ccf7ff)}.ds2-5-article-card__metadata__article-type .color-indicator.communications{background:var(--accent-peach, #ffd4cc)}.ds2-5-article-card__metadata__article-type .color-indicator.clinical_trial{background:var(--accent-violet, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.case_study{background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__article-title-link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-sans-serif-md-size, 24px);line-height:var(--type-sans-serif-md-line-height, 32px);font-weight:var(--type-sans-serif-md-font-weight, 400);color:var(--primary, #070a15);text-decoration:none;justify-content:flex-start}.ds2-5-article-card__article-title-link:hover{color:var(--hover, #4960d1);border-color:var(--hover, #4960d1);text-decoration:underline}.ds2-5-article-card__article-title-link:hover:focus{color:var(--hover, #4960d1)}.ds2-5-article-card__article-title-link:focus{color:var(--primary, #070a15);text-decoration:none;outline:none}.ds2-5-article-card__figure-highlight{display:flex}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight{gap:48px}}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight{gap:48px}}.ds2-5-article-card__figure-highlight__title-link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-sans-serif-md-size, 24px);line-height:var(--type-sans-serif-md-line-height, 32px);font-weight:var(--type-sans-serif-md-font-weight, 400);color:var(--primary, #070a15);text-decoration:none;justify-content:flex-start}.ds2-5-article-card__figure-highlight__title-link:hover{color:var(--hover, #4960d1);border-color:var(--hover, #4960d1);text-decoration:underline}.ds2-5-article-card__figure-highlight__title-link:hover:focus{color:var(--hover, #4960d1)}.ds2-5-article-card__figure-highlight__title-link:focus{color:var(--primary, #070a15);text-decoration:none;outline:none}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__title-link{width:66%;display:inline-block;vertical-align:top}}.ds2-5-article-card__figure-highlight__small-image-link img{max-width:196px;max-height:196px;border:1px solid var(--stroke-dark, #070A15)}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__small-image-link img{width:33%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__small-image-link{display:none}}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__small-image-link{display:none}}.ds2-5-article-card__figure-highlight__article-info{display:flex;flex-direction:column;gap:var(--spacing-xs-16, 16px)}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__article-info{width:75%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__article-info{width:66%}}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__article-info{width:100%}}.ds2-5-article-card__figure-highlight__article-info__title-with-image{display:flex;flex-direciton:row;gap:16px}.ds2-5-article-card__figure-highlight__big-image-link img{width:100%;max-width:196px;max-height:196px;float:right;border:1px solid var(--stroke-dark, #070A15)}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__big-image-link{width:25%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__big-image-link{width:33%}}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__big-image-link{display:none}}.ds2-5-article-card__authors{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400)}.ds2-5-article-card__stat-group{display:flex;flex-direction:row;width:100%}.ds2-5-article-card__stat-group__stat{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__stat-group__stat{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__stat-group__stat{width:33%}}</style><div class="ds2-5-article-card"><div class="ds2-5-article-card__metadata"><div class="ds2-5-article-card__metadata__article-type"><span class="color-indicator research_article"></span><span>Research article</span></div><div class="ds2-5-article-card__metadata__publication_date">October 10, 2024</div></div><a class="ds2-5-article-card__article-title-link" href="/articles/10.20935/AcadMolBioGen7370?source=academia-molecular-biology-and-genomics-sap-page">MiR-27 and MiR-145 mediate neural differentiation signaling pathways in dental pulp stem cells</a><div class="ds2-5-article-card__authors">Hunter Triplett, Charlton Bassett, Karl Kingsley, Katherine M. Howard</div><div class="ds2-5-article-card__stat-group"><div class="ds2-5-article-card__stat-group__stat"><div class="ds2-5-stat--basic-small"><div class="ds2-5-stat--basic-small__label">downloads</div><div class="ds2-5-stat--basic-small__value">93</div></div></div><div class="ds2-5-article-card__stat-group__stat"><div class="ds2-5-stat--basic-small"><div class="ds2-5-stat--basic-small__label">views</div><div class="ds2-5-stat--basic-small__value">308</div></div></div></div></div><style type="text/css">html{font-size:16px !important}.ds2-5-article-card{font-size:16px;color:var(--text-primary, #070a15);display:flex;flex-direction:column;border-top:1px solid var(--stroke-dark, #070A15);color:var(--text-primary, #070A15);width:100%;padding-top:var(--content-card-padding-t, 24px);gap:var(--spacing-xs-16, 16px)}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card{padding-top:var(--content-card-padding-t, 40px)}}@media(min-width: 1280px){.ds2-5-article-card{padding-top:var(--content-card-padding-t, 40px)}}.ds2-5-article-card__metadata{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-sm-size, 14px);line-height:var(--type-body-sm-line-height, 20px);font-weight:var(--type-body-sm-font-weight, 400);display:flex;flex-direction:row}.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__metadata__article-type,.ds2-5-article-card__metadata __publication_date{width:33%}}@media(max-width: 567px){.ds2-5-article-card__metadata{justify-content:space-between}}.ds2-5-article-card__metadata__article-type{display:flex;align-items:center}.ds2-5-article-card__metadata__article-type .color-indicator{display:inline-block;margin-right:8px;height:16px;width:16px;border:2px solid var(--stroke-medium, #676e7b);border-radius:50%;background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__metadata__article-type .color-indicator.research_article{background:var(--accent-green, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.review_article{background:var(--accent-turquoise, #ccf7ff)}.ds2-5-article-card__metadata__article-type .color-indicator.communications{background:var(--accent-peach, #ffd4cc)}.ds2-5-article-card__metadata__article-type .color-indicator.clinical_trial{background:var(--accent-violet, #ccffd4)}.ds2-5-article-card__metadata__article-type .color-indicator.case_study{background:var(--accent-yellow, #f7ffcc)}.ds2-5-article-card__article-title-link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-sans-serif-md-size, 24px);line-height:var(--type-sans-serif-md-line-height, 32px);font-weight:var(--type-sans-serif-md-font-weight, 400);color:var(--primary, #070a15);text-decoration:none;justify-content:flex-start}.ds2-5-article-card__article-title-link:hover{color:var(--hover, #4960d1);border-color:var(--hover, #4960d1);text-decoration:underline}.ds2-5-article-card__article-title-link:hover:focus{color:var(--hover, #4960d1)}.ds2-5-article-card__article-title-link:focus{color:var(--primary, #070a15);text-decoration:none;outline:none}.ds2-5-article-card__figure-highlight{display:flex}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight{gap:48px}}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight{gap:48px}}.ds2-5-article-card__figure-highlight__title-link{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-sans-serif-md-size, 24px);line-height:var(--type-sans-serif-md-line-height, 32px);font-weight:var(--type-sans-serif-md-font-weight, 400);color:var(--primary, #070a15);text-decoration:none;justify-content:flex-start}.ds2-5-article-card__figure-highlight__title-link:hover{color:var(--hover, #4960d1);border-color:var(--hover, #4960d1);text-decoration:underline}.ds2-5-article-card__figure-highlight__title-link:hover:focus{color:var(--hover, #4960d1)}.ds2-5-article-card__figure-highlight__title-link:focus{color:var(--primary, #070a15);text-decoration:none;outline:none}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__title-link{width:66%;display:inline-block;vertical-align:top}}.ds2-5-article-card__figure-highlight__small-image-link img{max-width:196px;max-height:196px;border:1px solid var(--stroke-dark, #070A15)}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__small-image-link img{width:33%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__small-image-link{display:none}}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__small-image-link{display:none}}.ds2-5-article-card__figure-highlight__article-info{display:flex;flex-direction:column;gap:var(--spacing-xs-16, 16px)}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__article-info{width:75%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__article-info{width:66%}}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__article-info{width:100%}}.ds2-5-article-card__figure-highlight__article-info__title-with-image{display:flex;flex-direciton:row;gap:16px}.ds2-5-article-card__figure-highlight__big-image-link img{width:100%;max-width:196px;max-height:196px;float:right;border:1px solid var(--stroke-dark, #070A15)}@media(min-width: 1280px){.ds2-5-article-card__figure-highlight__big-image-link{width:25%}}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__figure-highlight__big-image-link{width:33%}}@media(max-width: 567px){.ds2-5-article-card__figure-highlight__big-image-link{display:none}}.ds2-5-article-card__authors{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400)}.ds2-5-article-card__stat-group{display:flex;flex-direction:row;width:100%}.ds2-5-article-card__stat-group__stat{width:50%}@media(min-width: 568px)and (max-width: 1279px){.ds2-5-article-card__stat-group__stat{width:33%}}@media(min-width: 1280px){.ds2-5-article-card__stat-group__stat{width:33%}}</style><div class="ds2-5-article-card"><div class="ds2-5-article-card__metadata"><div class="ds2-5-article-card__metadata__article-type"><span class="color-indicator review_article"></span><span>Review article</span></div><div class="ds2-5-article-card__metadata__publication_date">September 05, 2024</div></div><a class="ds2-5-article-card__article-title-link" href="/articles/10.20935/AcadMolBioGen7329?source=academia-molecular-biology-and-genomics-sap-page">Promising RNA-based Therapies for Viral infections, Genetic Disorders and Cancer</a><div class="ds2-5-article-card__authors">Dickson Achimugu Musa, Mohammed Olumide Raji, Akeem Babatunde Sikiru, Kolawole Harun Aremu, Egbenoma Andrew Aigboeghian</div><div class="ds2-5-article-card__stat-group"><div class="ds2-5-article-card__stat-group__stat"><div class="ds2-5-stat--basic-small"><div class="ds2-5-stat--basic-small__label">downloads</div><div class="ds2-5-stat--basic-small__value">295</div></div></div><div class="ds2-5-article-card__stat-group__stat"><div class="ds2-5-stat--basic-small"><div class="ds2-5-stat--basic-small__label">views</div><div class="ds2-5-stat--basic-small__value">962</div></div></div></div></div></div></div><div><!DOCTYPE html PUBLIC "-//W3C//DTD HTML 4.01 Transitional//EN" "http://www.w3.org/TR/html4/loose.dtd"> <html> <head> <meta http-equiv="Content-Type" content="text/html; charset=UTF-8"> <title>Müller and Martins: Glycosylphosphatidylinositol-anchored proteins as non-DNA matter of inheritance: from molecular to cell to philosophical biology</title> </head> <body><div id="article-root"> <div id="article-front-container" class="sap__front-container"> <div id="article-front-column" class="sap__front"> <div id="article-front" class="sap__front"> <div class="sap__metadata sap__centered"><h1 class="sap__document-title">Glycosylphosphatidylinositol-anchored proteins as non-DNA matter of inheritance: from molecular to cell to philosophical biology</h1></div> <div class="sap__metadata sap__author-list"><div class="sap__metadata sap__author"> <div class="sap__author-names"><div class="sap__metadata-group"><p class="sap__metadata-entry"><a id="id1"></a>Günter A. Müller<a href="#anote-1">*</a><span class="sap__generated"> [</span><a href="#aff1">1</a>,<a href="#aff2">2</a><span class="sap__generated">]</span></p></div></div> <div class="sap__author-info"><div class="sap__metadata-group"></div></div> </div></div> <div class="affiliation-list-link-area"><a id="affiliation-list-link" data-target="#affiliation-list" data-toggle="collapse" href="javascript:void(0)"><span>Author Affiliations</span><svg xmlns="http://www.w3.org/2000/svg" id="chevron" class="" width="16px" height="16px" viewbox="0 0 24 24" style="vertical-align: middle;"><path d="m12 15.375-6-6 1.4-1.4 4.6 4.6 4.6-4.6 1.4 1.4Z" class="expand-more" fill="#222233"></path></svg></a></div> <div id="affiliation-list" class="sap__metadata sap__two-column sap__table collapse"><div class="affiliation-list-items"><div class="sap__row"> <div class="sap__cell sap__empty"></div> <div class="sap__cell"><div class="sap__metadata-group"> <p class="sap__metadata-entry"><a id="aff1"></a><sup>1</sup>Biology and Technology Studies Institute Munich (BITSIM), Munich 80939, Germany.</p> <p class="sap__metadata-entry"><a id="aff2"></a><sup>2</sup>Institute of Diabetes and Obesity (IDO), Helmholtz Diabetes Center (HDC) at Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Oberschleissheim 85764, Germany.</p> <a id="anote-1"></a><p class="sap__metadata-entry">*Correspondence to guenter.al.mueller@t-online.de</p> </div></div> </div></div></div> <div class="sap__dates-and-open-access"><div class="sap__metadata-area"> <p class="sap__metadata-entry"><span class="sap__generated"><a id="open-access-link" data-target="#sap__Open-Access" data-toggle="collapse" href="javascript:void(0)"><span>Open Access</span><svg xmlns="http://www.w3.org/2000/svg" id="chevron-open-access" class="" width="16px" height="16px" viewbox="0 0 24 24" style="vertical-align: middle;"><path d="m12 15.375-6-6 1.4-1.4 4.6 4.6 4.6-4.6 1.4 1.4Z" class="expand-more" fill="#222233"></path></svg></a></span></p> <div class="sap__metadata-chunk"><div id="sap__Open-Access" class="collapse"><div class="sap__metadata-chunk-content"><p>© 2024 copyright by the authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). <a target="xrefwindow" href="https://creativecommons.org/licenses/by/4.0/">https://creativecommons.org/licenses/by/4.0/</a></p></div></div></div> </div></div> </div> <div class="sap__section"> <a id="id2"></a><h2 class="sap__main-title"><span class="sap__generated">Abstract</span></h2> <p class="first" id="id3">Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are cell surface proteins attached to the outer leaflet of eukaryotic plasma membranes (PMs) by a covalently attached GPI. Some GPI-APs may be released extracellularly in response to certain stimuli, such as a high-fat diet, leading to their presence in interstitial spaces or the bloodstream, with their GPI anchor remaining intact. This is accomplished by incorporation of GPI fatty acids into the outer phospholipid monolayer of extracellular vesicles (EVs) or alternatively, together with (lyso)phospholipids and cholesterol into micelle-like complexes. The transfer of released full-length GPI-APs via micelle-like complexes or EVs from donor to acceptor cells, either within the same or distant tissue, is known to have functional consequences, such as the stimulation of glycogen and lipid synthesis. This article explores the possibility that the intercellular transfer of GPI-APs via EVs or micelle-like complexes mediates a form of biological inheritance of non-DNA matter. This novel paradigm may be summarized as follows: (i) donor cells not only transfer DNA to acceptor cells but also GPI-APs, transmembrane proteins, and cytoskeletal elements, which constitute the so-called membrane environment landscapes (MELs), via EVs or micelle-like complexes. (ii) The transferred MLs, such as protuberances and invaginations, are replicated by self-organization and amenable to topological changes in response to environmental factors. (iii) Transfer of MELs induces novel phenotypes in acceptor cells. (iv) This transfer of non-DNA matter is understood as epigenetic mechanism for phenotypic plasticity and the inheritance of acquired traits. (v) The reasons for the missing consideration of non-DNA matter in heredity research should become the subject of future studies in the philosophy of biology, in general, and science and technology studies, in particular.</p> </div> </div> <div class="sap__spacer"></div> </div> <div id="article-container"> <div id="article-text"> <div id="article-body" class="sap__body"> <div class="sap__section"> <a id="sec1"></a><h2 class="sap__main-title">1. Introduction</h2> <p id="id4">Current thinking concerning the relationship between dead and living matter, i.e., the biological origin of life and its maintenance throughout evolution, is limited by circular argumentation, with the priority of operating as the “initiator” of life being attributed either to DNA or to cells. This so-called “DNA–cell dilemma”, which resembles the “chicken and egg dilemma”, refers to the question of why a cell only arises from a preexisting cell, despite the fact that all the information required to form a cell is seemingly contained exclusively in its DNA. Apparently, the continuous uninterrupted existence of cells critically depends on hereditary processes that are not adequately explained by DNA alone. The following question may arise: what matter, information, or both must be transferred from donor or mother cells to acceptor or daughter cells to guarantee the transgenerational continuity and recapitulation of the same morphological and functional state? Moreover, this happens despite considerable alterations in both morphology and function during cell division. Questions like these have most likely been asked by any biologist interested in the phenomena of cell inheritance and division but so far have presumably not been linked to biological membranes in general (<b><a href="#fig001">Figure 1</a></b>) and more specifically, to a particular class of membrane proteins.</p> <p id="id5">In fact, eukaryotic cells, from yeast to mammals, express glycosylphosphatidylinositol-anchored proteins (GPI-APs), which are attached to the cell surface by a covalently attached glycolipid (glycosylphosphatidylinositol, GPI) structure, anchored to the outer leaflet of cellular plasma membranes (PMs) (<b><a href="#fig002">Figure 2</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig001"></a><h5 class="sap__label">Figure 1</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Structure of biological membranes according to the fluid mosaic model proposed by Singer and Nicolson [<a href="#ref1">1</a>]. (A) Integral membrane proteins (a, b, monotopic; c, polytopic) interact extensively with the hydrocarbon region of the phospholipid bilayer (for a review, see [<a href="#ref2">2</a>]). Peripheral membrane proteins (d) bind to the surface of integral membrane proteins. (B) Schematic visualization of the cleavage plane passing through the middle of the bilayer membrane using the technique of freeze-fracture electron microscopy. (C) Three-dimensional view of membrane proteins “floating” within a sea of membrane phospholipids arranged in a bilayer structure (adapted from [<a href="#ref3">3</a>, <a href="#ref4">4</a>]). At the time point of publication of these text sources, glycosylphosphatidylinositol-anchored proteins had not yet been discovered.</h4></div> <img alt="media/image4.png" src="https://journals.academia-photos.com/10/7401/image4.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig002"></a><h5 class="sap__label">Figure 2</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Structure and different types of enzymatic (GPI-PLC/D, GPI-specific PLC/PLD) and chemical (HF, hydrogen fluoride dephosphorylation; NA, nitrous acid deamination) release of glycosylphosphatidylinositol-anchored proteins from plasma membranes into the extracellular space (for details, see [<a href="#ref5">5</a>] with copyright permission of Nova Science Publishers).</h4></div> <img alt="media/image5.png" src="https://journals.academia-photos.com/10/7401/image5.png"> </div> <p id="id6">The terminal phosphoethanolamine residue of the glycosylphosphatidylinositol (GPI) anchor is covalently linked via an amide bond to the carboxy terminus of the protein moiety. The detailed structure of the GPI anchor was first described in 1985 [<a href="#ref6">6</a>], which subsequently attracted considerable interest in biochemical and cell biological research (for a review, see [<a href="#ref7">7</a>–<a href="#ref11">11</a>]) (<b><a href="#fig002">Figure 2</a></b>).</p> <p id="id7">According to current annotation, about 1.2–1.5% of all human proteins are candidate GPI-APs [<a href="#ref12">12</a>–<a href="#ref14">14</a>]. Over the past decades, experimental evidence has accumulated for the liberation of GPI-APs from the cell surface into extracellular compartments of mammalian organisms, which may involve either the (proteolytic or lipolytic) loss of the GPI anchor or its retention as a full-length structure. There is pronounced structural diversity in the configurations of released full-length GPI-APs. This diversity encompasses (i) monomers of GPI-APs bound to amphiphilic carrier proteins; (ii) multimeric aggregates of GPI-APs devoid of any phospholipids; (iii) GPI-APs arranged in (lyso)phospholipid- and cholesterol-containing micelles, referred to as micelle-like complexes (for a review, see [<a href="#ref15">15</a>, <a href="#ref16">16</a>]); (iv) GPI-APs inserted into the outer-membrane leaflet of extracellular vesicles (EVs), thereby constituting either exosomes or microparticles (for a review, see [<a href="#ref17">17</a>–<a href="#ref28">28</a>]); and (v) GPI-APs incorporated into surfactant-like particles, including unilamellar lipoprotein-like particles and multilamellar milk fat globules (for a review, see [<a href="#ref5">5</a>, <a href="#ref29">29</a>–<a href="#ref31">31</a>]). This structural diversity is manifested in the multitude of different molecular mechanisms underlying the release from mother or donor cells into interstitial spaces or the blood compartment. Release may happen spontaneously or in response to specific intrinsic or extrinsic stimuli or environmental factors (E), resulting in the transfer of GPI-APs to daughter or acceptor cells in the same or different tissue depots. The following functional and (patho)physiological consequences or biotechnological applications of the various strategies of the liberation and intercellular transfer of GPI-APs may be considered: (i) use as novel biomarkers for the prediction, diagnosis, and stratification of common complex diseases [<a href="#ref5">5</a>, <a href="#ref20">20</a>], and (ii) phenotypic switching, i.e., the acquisition of novel properties by the cells on the basis of enzymatic, signaling, or structural characteristics of the transferred GPI-APs [<a href="#ref32">32</a>]. In this regard, the stable stimulation of lipid and glycogen synthesis in response to the intercellular or transgenerational transfer of micelle-like complexes or EVs harboring GPI-APs between somatic cells or multiple generations of mammalian organisms has been demonstrated previously [<a href="#ref15">15</a>, <a href="#ref33">33</a>]. Over the past decade, research on soluble GPI-APs was predominantly aimed at the characterization of their stimulus-induced release from donor cells into micelle-like complexes and the fate of the associated full-length GPI-AP versions. In particular, it was studied whether the potential transfer of GPI-APs from donor to acceptor cells, which may be considered as a type of inheritance of non-DNA matter, is associated with any physiological consequences.</p> </div> <div class="sap__section"> <a id="sec2"></a><h2 class="sap__main-title">2. Method for the detection of the transfer of non-DNA matter</h2> <p id="id8">The method that has previously been proved to be of exquisite sensitivity and high reliability and used predominantly, albeit not exclusively, for the molecular identification and phenomenological characterization of micelle-like GPI-AP complexes relies on chip-based biosensing with surface acoustic waves (SAW) [<a href="#ref34">34</a>, <a href="#ref35">35</a>]. For this purpose, the complexes are specifically captured by the gold or titanium surface of microfluidic chips (<b><a href="#fig003">Figure 3</a></b>).</p> <p id="id9">Then, antibodies or binding proteins against components of the complexes, such as anti-GPI-APs antibodies, α-toxin interacting with GPI, or annexin-V interacting with phosphatidylserine, are injected into the chip channels. The mass increases occurring at the chip surface, resulting from the capture of the complexes (by α-toxin) and the binding of the antibodies or annexin-V, cause rightward shifts in the phase, i.e., a decrease in frequency, and reductions in the amplitude of the SAW propagating along the chip surface.</p> <p id="id10">For the analysis of the transfer of full-length GPI-APs from micelle-like complexes to PMs by SAW biosensing, PM vesicles from isolated rat adipocytes or human erythrocytes, serving as acceptors, were captured by the titanium surface of the chip in a two-step procedure, i.e., first through ionic and then through covalent bonds (<b><a href="#fig004">Figure 4</a></b>).</p> <p id="id11">Thereafter, micelle-like GPI-AP complexes, serving as donors, were injected into the chip channels. The transfer of GPI-APs from the micelle-like complexes to the adipocyte or erythrocyte PMs may happen during incubation, i.e., at stopped flow, and may be affected by the presence or absence of additions, such as serum proteins. The increase in mass loaded onto the chip surface, in concert with elevated elasticity due to a higher protein-to-phospholipid ratio, is reflected in the measured increase in SAW phase shift and indicates the transfer of GPI-APs in real time.</p> <div class="sap__fig sap__figure_panel"> <a id="fig003"></a><h5 class="sap__label">Figure 3</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Principle of chip-based biosensing of micelle-like glycosylphosphatidylinositol-anchored protein complexes using surface acoustic waves (for details, see [<a href="#ref36">36</a>, <a href="#ref37">37</a>] with permission of the publisher). Following non-covalent capture of plasma membrane vesicles from acceptor cells via ionic bonds by the TiO<sub>2</sub> chip surface and subsequent injection of glycosylphosphatidylinositol-anchored protein complexes into the microfluidic chip channels, successful transfer of glycosylphosphatidylinositol-anchored proteins from the complexes to the captured vesicles is monitored as phase shift of the surface acoustic waves, which becomes amplified during the injection of specific binding proteins, such as annexin-V for phospholipids, and antibodies for glycosylphosphatidylinositol-anchored proteins.</h4></div> <img alt="media/image6.png" src="https://journals.academia-photos.com/10/7401/image6.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig004"></a><h5 class="sap__label">Figure 4</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Principle of surface acoustic wave biosensing of the transfer of glycosylphosphatidylinositol-anchored proteins from micelle-like complexes to plasma membranes (for details, see [<a href="#ref38">38</a>] with copyright permission from the authors). Micelle-like glycosylphosphatidylinositol-anchored protein complexes are captured by non-covalent interaction with α-toxin, which is covalently bound to the chip surface (configurated as a two-dimensional self-assembled monolayer) by typical linker biochemistry and specifically recognizes the highly conserved glycan core of glycosylphosphatidylinositol-anchored proteins. The increase in mass loaded onto the chip, often accompanied by a reduction in elasticity (i.e., an increase in viscosity), exerted by the bound vesicles, causes a rightward shift of the phase (i.e., a decrease in frequency) and often concomitantly a reduction in the amplitude of the surface acoustic waves, propagating across the gold surface between the interdigitated electrodes. Both the capturing of the vesicles and the specific detection of their resident components, such as phosphatidylserine by injection of annexin-V, can be monitored as discrete phase shifts and amplitude reductions.</h4></div> <img alt="media/image7.png" src="https://journals.academia-photos.com/10/7401/image7.png"> </div> </div> <div class="sap__section"> <a id="sec3"></a><h2 class="sap__main-title">3. Transfer of isolated non-DNA matter to somatic cells</h2> <p id="id12">The ionic and subsequent covalent coupling of PMs from human erythroleukemia cells (ELCs) or primary rat adipocytes, prepared after incubation with micelle-like GPI-AP complexes, is reflected in stable increases in phase shift following the consecutive washing steps with EGTA/NaCl and buffer [<a href="#ref39">39</a>]. Mutant ELCs completely lacking endogenous GPI-APs (due to defective synthesis of the GPI anchor; see [<a href="#ref40">40</a>, <a href="#ref41">41</a>]) and adipocytes with reduced synthesis of endogenous GPI-APs (due to cell culture in the presence of an inhibitor of GPI anchor biosynthesis, methyl-ß-cyclodextrin (mßCD); see [<a href="#ref42">42</a>]) were used to facilitate the detection of GPI-AP transfer and putative functional consequences. Incubation of micelle-like GPI-AP complexes liberated from rat adipocytes with human ELCs or rat adipose cells caused an upregulation of phase shift in a time- and concentration-dependent fashion upon injection of antibodies directed against the GPI-APs CD55, tissue nonspecific alkaline phosphatase (TNAP), CD73 (5′-nucleotidase), and acetylcholinesterase (AChE), indicative of their successful transfer from micelle-like complexes to the acceptor cells.</p> <p id="id13">By contrast, the phase shift provoked upon injection of antibodies directed toward the transmembrane proteins band-3, glucose transporter-4 (Glut4), and insulin receptor (IR) was not elevated, thereby reflecting neosynthesis by the acceptor cells and concomitantly ruling out transfer from micelle-like complexes. Thus, importantly, the critical parameter for transfer is the amount- and time-dependent increase in phase shift rather than the phase shift per se. Strikingly, the transfer of full-length GPI-APs from released rat adipocyte complexes, displaying the full panel of PM GPI-APs, to ELCs or primary rat adipocytes was associated with considerable upregulations of glycogen and lipid synthesis, respectively, depending on the amount of GPI-APs transferred. By contrast, complexes that had been reconstituted in vitro solely with the purified GPI-APs, CD73, and/or AChE did not elicit stimulation of glycogen or lipid synthesis. Furthermore, the use of acceptor cells with blocked or diminished expression of GPI-APs, i.e., GPI-deficient ELCs and mßCD-treated adipocytes, respectively, was required to detect the metabolic effects of the transfer of GPI-APs from the micelle-like complexes in the acceptor cells.</p> </div> <div class="sap__section"> <a id="sec4"></a><h2 class="sap__main-title">4. Transfer of non-DNA matter between somatic cells</h2> <p id="id14">After having demonstrated the transfer of full-length GPI-APs from liberated micelle-like complexes to acceptor cells, chip-based SAW biosensing was used to study the transfer of GPI-APs from intact donor to acceptor cells (<b><a href="#fig005">Figure 5</a></b>).</p> <p id="id15">For this, the donor cells, such as human differentiated adipocytes, were grown in the top compartment (insert well) of a transwell coculture at the surface of a filter plate, which is compatible with the passage of large macromolecules and complexes but blocks the passage of EVs and cells. The acceptor cells, such as GPI-deficient ELCs, were cultured in the bottom well. In the course of growth, differentiation, and aging of the adipocytes, GPI-APs may be released and transferred across the filter plate to the GPI-deficient ELCs, with considerable increase in their number at the cell surface (<b><a href="#fig005">Figure 5</a></b>, green arrow).</p> <p id="id16">As indicated schematically, GPI-AP binding serum proteins (BSPs) interfere with transfer by binding to the glycan core of the GPI anchor, bacterial phosphatidylinositol-specific phospholipase C (PI-PLC) by degrading the GPI anchor, antibodies by recognizing the GPI-AP protein moieties, and α-toxin by interacting with the glycan core of the GPI anchor (<b><a href="#fig005">Figure 5</a></b>, red arrow; see [<a href="#ref43">43</a>–<a href="#ref45">45</a>]).</p> <p id="id17">The original data, as published previously [<a href="#ref39">39</a>], showed that incubation of wild-type ELCs or untreated differentiated adipose cells with GPI-deficient acceptor ELCs in transwell coculture led to time-dependent upregulations in phase shift elicited by antibodies against the GPI-APs CD55, CD59, AChE, TNAP, and CD73. By contrast, the phase shifts triggered by antibodies against band-3, Glut1, glycophorin, and Glut4 remained constant with increasing incubation time, indicating that these transmembrane proteins were expressed solely by the acceptor cells rather than being transferred from the donor cells. As shown above for the transfer of GPI-APs from micelle-like complexes, glycogen synthesis was significantly upregulated in the GPI-deficient acceptor ELCs with increasing incubation time, correlating with the amount of transferred GPI-APs. As a control, no upregulation of glycogen synthesis was observed when donor cells were used that (i) completely lacked GPI-AP expression (mutant GPI-deficient ELCs), (ii) exhibited only considerably reduced GPI-AP expression (mannosamine-treated human adipocytes, see [<a href="#ref46">46</a>, <a href="#ref47">47</a>]), or (iii) when donor cells were omitted from the transwell coculture. Moreover, the addition of Phenyl Sepharose beads, capable of efficiently extracting GPI-APs from the surface of intact cells and micelle-like complexes, to either the upper or lower compartment of the transwell coculture completely blocked the transfer of GPI-APs from wild-type ELCs or differentiated, untreated adipose donor cells to GPI-deficient acceptor ELCs, as well as incubation time-dependent stimulation of glycogen synthesis. Subsequent proteomic analysis of the materials bound to the Phenyl Sepharose beads confirmed their specificity for GPI-APs, which had been extracted from the cell surface and/or micelle-like complexes before and/or during their transfer. Other molecules, such as (anabolic) hormones, cytokines, and metabolites, which could be released during the incubation and responsible for glycogen synthesis upregulation, were not recovered with the Phenyl Sepharose beads (as assayed with the Proteome Profiler Human Adipokine Array Kit for 58 adipocytokines from R&D Systems, Inc., Minneapolis, MN). This also hold true for transmembrane and peripheral proteins (as assayed by immuneblotting for Glut1, IR, and annexin-V). Together, these controls for the transwell experiments strongly argue that the phenotypic changes elicited in the acceptor cells are due to the transfer of GPI-APs rather than other molecules.</p> <p id="id18">These data and a multitude of additional experimental findings, performed over the past decade, such as those obtained with a combination of large mature and small young primary rat adipocytes in the transwell coculture system [<a href="#ref48">48</a>], demonstrated the paracrine transfer of full-length GPI-APs from differentiated unilocular adipocytes filled with a single large lipid droplet (LD) to preadipocytes harboring only a few small LDs. Transfer was found to be associated with the stimulation of lipid synthesis and concomitantly, LD biogenesis (<b><a href="#fig006">Figure 6</a></b>), aligning with current hypothetical models [<a href="#ref49">49</a>–<a href="#ref53">53</a>].</p> <div class="sap__fig sap__figure_panel"> <a id="fig005"></a><h5 class="sap__label">Figure 5</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Principle of surface acoustic wave biosensing of the transfer of glycosylphosphatidylinositol-anchored proteins from intact donor to acceptor cells (for details, see [<a href="#ref33">33</a>] with copyright permission of the authors). The upper and lower compartments of a transwell coculture are separated by a filter plate that enables only the passage of small molecules, including nutrients and serum proteins, as well as larger molecular aggregates, such as glycosylphosphatidylinositol-anchored proteins and micelle-like complexes but not EVs and cells exceeding 50 nM in diameter. In the insert wells, human differentiated adipocytes are cultured on top of the filter plate, while glycosylphosphatidylinositol-deficient ELCs are grown in the bottom wells. Transfer of glycosylphosphatidylinositol-anchored proteins occurs depending on the incubation time, age, and differentiation state of the donor cells and is monitored by chip-based biosensing of isolated PMs prepared from the acceptor cells (see <b><a href="#fig003">Figures 3</a></b> and <b><a href="#fig004">4</a></b>). Addition of phosphoinositolglycans to the incubation medium prevents the sequestration of glycosylphosphatidylinositol-anchored proteins by glycosylphosphatidylinositol-anchored protein binding serum proteins. Transfer is blocked by serum proteins that bind to the glycan core of glycosylphosphatidylinositol-anchored proteins; bacterial phosphatidylinositol-specific phospholipase C, which cleaves the GPI anchor; antibodies against glycosylphosphatidylinositol-anchored proteins; and α-toxin, which interacts with the glycan core of glycosylphosphatidylinositol-anchored proteins.</h4></div> <img alt="media/image8.png" src="https://journals.academia-photos.com/10/7401/image8.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig006"></a><h5 class="sap__label">Figure 6</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Hypothetical model for the biosynthesis of glycosylphosphatidylinositol-anchored proteins at the endoplasmic reticulum and their translocation to lipid droplets in donor cells (A), their transfer from the lipid droplets of donor cells to the endoplasmic reticulum of acceptor cells (B), and their transfer from exogenous micelle-like complexes to the lipid droplets of acceptor cells resulting in phenotypic switching (C).</h4> <p id="id19">(<b>Aa</b>) The polypeptide portion of GPI-APs is synthesized as a pre-protein and transported across the endoplasmic reticulum (ER) membrane into the ER lumen, where the prefabricated GPI anchor becomes coupled to the carboxy terminus of the polypeptide moiety. Finally, the complete GPI-AP is translocated across the ER membrane with orientation toward the cytosolic face under the assistance of a still unidentified translocase (arrow). This translocase may operate in a similar fashion to the one responsible for reorientating the initial GPI anchor precursors from the cytosolic to the luminal face. Simultaneously, neutral lipids, predominantly triacylglycerol (TAG), are produced through the concerted action of TAG-synthesizing enzymes, including glycerol-3-phosphate acyltransferase 4 (GPAT4) and diacylglycerol acyltransferase 1 (DGAT1) at the ER. These lipids then accumulate between the cytosolic and luminal faces of the ER phospholipid bilayer membrane. TAG is highly mobile within the bilayer and may spontaneously form clusters due to thermal fluctuations and ionic interactions with polytopic (e.g., DGAT1) and monotopic (e.g., GPAT4) membrane proteins and other neutral lipids.</p> <p id="id20">(<b>Ab</b>) In the course of exceeding a certain critical local concentration of TAG, an oil “lens” will arise as the TAG molecules coalesce into a single oil phase or droplet, displaying membrane proteins that “fit” into the single phospholipid monolayer and are ultimately derived from the cytosolic face of the ER phospholipid bilayer, based on short membrane insertion domains (class I, e.g., GPAT4) or the GPI anchor (which, by nature, spans only a monolayer, such as GPI-APs like CD73 and Gce1). The formation and growth of the “lens” are fostered by seipin during its complexation and generation of foci.</p> <p id="id21">(<b>Ac</b>) Upon the accumulation of additional TAG molecules at the “lens” and further growth, the phospholipid bilayer becomes deformed, and a nascent LD buds into the cytosol, which may be further promoted by a “de-wetting” mechanism. LD-associated GPI-APs are translocated to the phospholipid monolayer surface of the LDs, either during the formation of the oil “lens” (<b>Ab</b>) or during the subsequent budding process after the generation and transient maintenance of a membrane bridge. This enables their lateral movement from the ER to the LDs via a continuous phospholipid monolayer. In consequence, the expansion of LDs is managed by the relocalization of TAG-synthesizing enzymes from the ER (luminal catalytic orientation) to the LD (catalytic orientation toward the LD core). The activity of these anabolic enzymes and that of TAG-metabolizing lipases seems to be regulated in coordinated fashion by various mechanisms, including the degradation of cyclic adenosine monophosphate (cAMP) by the GPI-anchored cAMP-binding ectoprotein Gce1, which simultaneously operates as cAMP-specific phosphodiesterase, and the cleavage of the produced adenosine monophosphate to adenosine by the GPI-AP 5′-nucleotidase or CD73, overall leading to upregulated TAG synthesis.</p> <p id="id22">(<b>Ad</b>) The nascent LD is released from the cytosolic face of the ER phospholipid bilayer upon further expansion, during which it acquires specific proteins from the cytosol. These proteins are spontaneously targeted to and inserted into the phospholipid monolayer surrounding the LD and constituted by amphipathic helices or other short hydrophobic domains of class II proteins (e.g., perilipin). Finally, the emerging LD becomes completely separated from the ER.</p> <p id="id23">(<b>Ba</b>) The complex coatomer of the coat protein complex I (COPI) vesicle, which is responsible for transporting phospholipids from the Golgi apparatus to the ER and newly synthesized proteins from the cis- to the trans-Golgi stacks, manages to target and associate with the surface of mature LDs.</p> <p id="id24">(<b>Bb</b>) In the course of binding to the phospholipids of the LD monolayer and local polymerization, the COPI molecular apparatus expels very small, the so-called nano-LDs (on the nm scale) from mature LDs, which consequently lowers the total concentration of phospholipids at their surface.</p> <p id="id25">(<b>Bc</b>) This decrease in the phospholipid, particularly phosphatidylcholine, to TAG molar ratio presumably causes an upregulation of the surface tension of the LDs and thereby facilitates the interaction of their surface monolayer with that of the ER, compensating for the relative deficiency of phospholipids, particularly phosphatidylcholine, at the LD surface.</p> <p id="id26">(<b>Bd</b>) Following the formation of a transient membrane bridge, GPI-APs become translocated from LDs to the ER through lateral movement via the continuous phospholipid monolayer between the two organelles. Overall, the cell division mechanisms (<b>A</b>, <b>B</b>) in concert may lead to the transfer of GPI-APs from donor or mother cells to acceptor or daughter cells, aided by LDs as “transport vehicles” and their passage, loaded onto LDs, from the ER of the former cells to that of the latter cells. Principally, the operation of these hypothetical mechanisms is feasible for almost all cell types, as most of them contain at least tiny LDs. By contrast, mature adipocytes display a single huge, so-called unilocular LD exclusively. These LDs escape dispersion into smaller ones and thus distribution between donor and acceptor cells.</p> <p id="id27">(<b>C</b>) Furthermore and quite surprisingly, recent observations have strongly suggested that GPI-APs displayed on the cell surface of most eukaryotic cells, such as rat adipocytes, can be recovered with intracellular LDs. This specific localization argues for the existence of an endocytic mechanism specific to GPI-APs, which has potential implications for lipid metabolism, as detailed below [<a href="#ref54">54</a>]:</p> <p id="id28">(<b>Ca</b>) Incubation of cultured acceptor cells, such as human ELCs or adipose cells, which exhibit only limited synthesis of TAG and biogenesis of LDs, with micelle-like GPI-AP complexes,</p> <p id="id29">(<b>Cb</b>) led to insertion of the GPI-APs into the outer leaflet of the PM phospholipid bilayer (green color), either in a spontaneous or protein-mediated fashion, and thereby to their exposure to the extracellular environment.</p> <p id="id30">(<b>Cc</b>) Subsequent endocytosis of the GPI-APs presumably involves clathrin-independent carriers (CLIC) and the GPI-AP-enriched early endosomal compartment, the so-called GPI-anchored protein-enriched early endosomal compartment (GEEC). The apparent translocation of the GPI-APs from the extracellular (green color) to the cytosolic face of the endosomal phospholipid bilayer (brown color) may be mediated by a translocase (thin arrow) that might be similar or identical to that postulated to be active at the ER (see <b>Aa</b>).</p> <p id="id31">(<b>Cd</b>) Following the formation of a continuous membrane bridge between the cytosolic face of the endosomal bilayer (brown color) and the phospholipid outer surface shell of the LDs, GPI-APs migrate via that bridge from the endosomes to the LDs of the acceptor adipocytes, remaining exposed toward the cytosol.</p> <p id="id32">(<b>Ce</b>) The complete release from the endosomes will result in LDs that are equipped with typical LD-associated monotopic and polytopic membrane proteins of classes I and II, such as GPAT4, perilipin, and DGAT1, as well as the GPI-APs, Gce1, and CD73. Their operation in concert will cause LDs to expand during ongoing upregulated TAG synthesis based on cAMP degradation at the immediate LD surface era (see <b>Ac</b>).</p> <p id="id33">(<b>Cf</b>) In the course of cell division, the upregulated lipid-synthesizing phenotype is inherited from the mother cell to the daughter cell based on the transfer, i.e., donation and acceptance, of LDs by donor and acceptor cells, respectively. Since LDs do not follow the principle of self-assembly but rather acquire their specific protein complement through self-organizing biogenesis, the intercellular transfer of targeting, flux, and topological information, i.e., information about the spatial and temporal distribution of their constituting components, may be regarded as an example of structural inheritance or templating within the “poly-matter” conception of inheritance.</p> </div> <img alt="media/image9.png" src="https://journals.academia-photos.com/10/7401/image9.png"> </div> <p id="id34">By contrast, the putative endocrine transfer of GPI-APs from the adipose tissue bed to circulating blood cells, along with the accompanying upregulation of glycogen synthesis, as can be mimicked with the transwell coculture, is prevented by GPI-AP BSPs (e.g., albumin and other yet unidentified proteins) or by GPI-specific phospholipase D (GPLD1) [<a href="#ref55">55</a>] (<b><a href="#fig007">Figure 7</a></b>).</p> <p id="id35">In conclusion, paracrine transfer of GPI-APs seems to exert physiological functions, such as stimulation of glucose or energy storage as glycogen and lipid. By contrast, their endocrine transfer to circulating blood cells and possibly to tissue cells distant from the donor ones is probably prevented by the presence of GPI-AP BSPs. This protective mechanism may lead to the circumvention of aberrant targeting of GPI-APs to distant tissue depots, accompanied by the induction of unwanted “specific” catalytic effects or “unspecific” cell lysis.</p> <p id="id36">Importantly, the transfer of GPI-APs via micelle-like complexes between somatic cells is not restricted to fully differentiated ones. According to original findings [<a href="#ref33">33</a>], incubation of micelle-like GPI-AP complexes liberated from primary rat adipocytes with (commercially available) human induced pluripotent stem cells (iPSCs) or with differentiated human adipocytes in transwell coculture caused increases in phase shift upon injection of antibodies against the GPI-APs CD59, TNAP, CD73, and AChE but not CD55. These elevations depended on the amount of complexes used and/or the period of incubation, respectively, and thus are indicative of the transfer of full-length GPI-APs from the complexes or the donor adipocytes, respectively, to the acceptor iPSCs. By contrast, the phase shifts observed in the presence of anti-CD55 and anti-Glut1 antibodies remained constant with the amount of added complexes and time. This reflected that GPI-APs and transmembrane proteins, respectively, were synthesized in the iPSCs and not transferred from donor adipocytes. Apparently, transfer of GPI-APs occurs in a differential fashion.</p> <div class="sap__fig sap__figure_panel"> <a id="fig007"></a><h5 class="sap__label">Figure 7</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Hypothetical molecular model of the transfer of full-length glycosylphosphatidylinositol-anchored proteins between somatic cells and its (patho)physiological consequences (for details, see [<a href="#ref33">33</a>], with permission of the authors). The individual steps, represented by numbers, are as follows: (1) release of full-length glycosylphosphatidylinositol-anchored proteins from the surface of large differentiated adipocytes into micelle-like complexes and subsequent paracrine transfer to the surface of small preadipocytes; (2) insertion of glycosylphosphatidylinositol-anchored proteins into the plasma membranes of acceptor cells, mediated by micelle-like complexes; (3) stimulation of lipid synthesis; (4) stimulation of lipid droplet biogenesis; (5) maturation of small to large adipocytes occurring within the same adipose tissue depot (1–5); (6) release of full-length glycosylphosphatidylinositol-anchored proteins from the surface of large differentiated adipocytes in the form of micelle-like complexes and subsequent endocrine transfer to the surface of circulating blood cells; (7) serum proteins, such as bovine serum albumin, may bind to the glycosylphosphatidylinositol anchor of glycosylphosphatidylinositol-anchored proteins; (8) GPLD1, which is inactive in the absence of Ca<sup>2+</sup> (i.e., chelation of Ca<sup>2+</sup>), may cleave the glycosylphosphatidylinositol anchor of glycosylphosphatidylinositol-anchored proteins in the presence of Ca<sup>2+</sup> (9); (10) the lipolytically cleaved glycosylphosphatidylinositol-anchored proteins or glycosylphosphatidylinositol-anchored proteins bound to glycosylphosphatidylinositol-anchored protein binding and signaling proteins are not capable of being transferred to blood cells; (11) consequently, they do not support the upregulation of glycogen synthesis in blood cells, as has been demonstrated for human ELCs (12), which might represent model hybrid red and white blood cells; (13) the lipolytically cleaved glycosylphosphatidylinositol-anchored proteins, generated by the action of either bacterial phosphoinositide-specific phospholipase C [<a href="#ref56">56</a>] or mammalian GPLD1 [<a href="#ref57">57</a>], as well as synthetic phosphoinositolglycans (14), may act as competitors for the displacement of full-length glycosylphosphatidylinositol-anchored proteins from binding to the binding and signaling proteins, such as bovine serum albumin or inactive GPLD1 [<a href="#ref15">15</a>, <a href="#ref58">58</a>]. Upon displacement, the full-length glycosylphosphatidylinositol-anchored proteins are transferred to the surface of circulating blood cells (16), leading to the stimulation of glycogen synthesis and the accompanying deposition of glycogen granules (17).</h4></div> <img alt="media/image10.png" src="https://journals.academia-photos.com/10/7401/image10.png"> </div> <p id="id37">As observed for somatic cells, the transfer of the GPI-APs was found to be associated with considerable upregulation of lipid synthesis in the acceptor iPSCs. The use of complexes reconstituted with only a single GPI-AP, such as either AChE or CD73, instead of complexes displaying the complete panel of adipocyte GPI-APs, or incubation in the absence of donor cells did not induce any significant stimulation of lipid synthesis in the iPSCs.</p> </div> <div class="sap__section"> <a id="sec5"></a><h2 class="sap__main-title">5. Hypotheses on the intercellular inheritance of non-DNA matter</h2> <p id="id38">A model for the transfer of non-DNA matter from mature somatic donor cells to immature somatic cells or iPSCs, which relies on the concept of membrane environment landscapes (MELs) being critical for phenotypic switching rather than solely on GPI-APs, is presented (<b><a href="#fig008">Figure 8</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig008"></a><h5 class="sap__label">Figure 8</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Hypothetical model for the MEL-based intercellular transfer of non-DNA matter (for details, see the text). LDs, lipid droplets; N, nucleus; MEL, membrane environment landscape (only glycosylphosphatidylinositol-anchored proteins are depicted as typical representative of all proteinaceous components; pink color indicates the typical set of (lyso)phospholipids and cholesterol); E, environmental factors; EVs, extracellular vesicles; iPSCs, induced pluripotent stem cells.</h4> <p id="id39">(<b>a</b>) Differentiated large human adipocytes, as donor cells for non-DNA matter, express considerable amounts of GPI-APs with their GPI anchor inserted into the outer phospholipid leaflet of the PMs, as originally described for various eukaryotic organisms ranging from yeast to trypanosomes to mammalian cells (Ferguson and Cross [<a href="#ref6">6</a>]; for a review, see [<a href="#ref59">59</a>, <a href="#ref60">60</a>]). Some of them are arranged in complex configurations, the so-called MELs (see <b><a href="#fig009">Figure 9</a></b>). These consist of (glyco/sphingo)phospholipids harboring saturated fatty acids, cholesterol, GPI-APs, transmembrane proteins, peripheral proteins, and intrinsically disordered proteins [<a href="#ref61">61</a>–<a href="#ref63">63</a>]. Some of them represent components of the intracellular cytoskeleton [<a href="#ref64">64</a>, <a href="#ref65">65</a>]. Environmental factors (E) that provoke mechanical distortion of PMs, such as increased pressure or turbulence in the bloodstream surrounding adipocyte tissue beds, may affect the molecular composition and/or spatial configuration of MELs [<a href="#ref66">66</a>, <a href="#ref67">67</a>]. Moreover, some GPI-APs are (also) located on the surface of LDs by the insertion of their GPI anchor into the cytoplasmic face of the surrounding phospholipid monolayer. Among these are the 5′-nucleotidase CD73 and the cAMP-binding ectoprotein and phosphodiesterase Gce1. These two GPI-APs are known to coordinate lipid synthesis and lipolysis in concert by regulating the concentration of cAMP at the immediate surface area of the LDs [<a href="#ref48">48</a>, <a href="#ref54">54</a>].</p> <p id="id40">(<b>b</b>) The donor adipocytes release GPI-APs into the tissue bed or circulation via EVs, through budding of PMs (microparticles) or exocytosis (exosomes, not depicted here), and/or via micelle-like complexes through local detachment of the outer leaflet from the bilayer of the PMs, preferably at areas equipped with MELs. Release of GPI-APs occurs at a low rate in the basal state but is significantly stimulated when donor adipocytes are challenged by E, such as mechanical stress or aging, which are often associated with elevated blood turbulence and pressure [<a href="#ref68">68</a>].</p> <p id="id41">(<b>c</b>) Transfer of MELs via “transport vehicles”, such as EVs or micelle-like complexes, from somatic donor cells to somatic acceptor cells or iPSCs, is affected by E, such as blood turbulence and pressure, due to alteration of the overall configuration—specifically the spatial arrangement, nature, and total composition of individual components—and thus the overall topology of the MELs [<a href="#ref38">38</a>] compared to their original state in the adipocytes.</p> <p id="id42">(<b>d</b>) MELs, displayed by EVs and micelle-like complexes, fuse with the phospholipid bilayer and its outer leaflet, respectively, of the PMs of differentiated small human adipocytes or iPSCs, which serve as the native acceptor cells [<a href="#ref36">36</a>, <a href="#ref37">37</a>].</p> <p id="id43">(<b>e</b>) The proper integration and distribution of the MELs along the PMs of the native acceptor cells, in concert with the subsequent translocation of GPI-APs from the PMs to the surface of LDs [<a href="#ref48">48</a>, <a href="#ref54">54</a>] and their insertion into the LD phospholipid monolayer, ultimately result in the stimulation of lipid synthesis and LD biogenesis in the acceptor cells, as a consequence of proper regulation of cAMP metabolism at the immediate surface area of the LDs.</p> </div> <img alt="media/image11.png" src="https://journals.academia-photos.com/10/7401/image11.png"> </div> <p id="id44">In conclusion, the transfer of non-DNA matter in the form of MELs from differentiated mature adipocytes to immature preadipocytes via EVs and micelle-like complexes leads to the conversion of the latter into adipocytes with upregulated lipid synthesis and LD biogenesis.</p> <p id="id45">On the basis of the data available, we believe that the transfer of a single specific GPI-AP from donor to acceptor cells is insufficient, as is the transfer of a more or less complete set of GPI-APs necessary, to elicit the switching of the acceptor cell phenotype to a lipogenic state in human and rat adipocytes (as summarized above) or to a glycogenic state in iPSCs (as demonstrated previously [<a href="#ref15">15</a>, <a href="#ref32">32</a>, <a href="#ref33">33</a>]). Unfortunately, experimental limitations, specifically the availability of recombinant full-length GPI-APs and anti-GPI-AP antibodies, have prevented rigorous testing of these two possibilities. Rather, we assume that specific sets of a limited number of GPI-APs and certain species of (lyso) phospholipids, in concert with cholesterol, form liquid-ordered nano-/microdomains/lipid rafts [<a href="#ref69">69</a>–<a href="#ref74">74</a>] that exhibit specific topological configurations, such as blebs, valleys, protuberances, and invaginations [<a href="#ref64">64</a>, <a href="#ref65">65</a>, <a href="#ref75">75</a>–<a href="#ref77">77</a>]. In the context of (i) transfer from donor to acceptor cells and (ii) phenotypic switching, MELs, which are amenable to E (see above), may constitute the smallest parcels or units of non-DNA matter of inheritance. In the context of (iii), replication could rely on self-organization or self-templating, which, however, represents mere speculation so far (<b><a href="#fig009">Figure 9</a></b>).</p> <p id="id46">It is important to stress that the postulated molecular mode of copying or replication of MELs critically depends on self-organization, i.e., the incorporation of newly fabricated and transferred components, such as proteins (e.g., GPI-APs) and lipids (e.g., (lyso)phospholipids and cholesterol), into preexisting structures, i.e., nano-/microdomains/lipid rafts/MELs, which operate as “attraction, assembly, or nucleation sites”. Self-assembly, i.e., the spontaneous aggregation de novo of all the components expressed in the functional structure without the aid of any extrinsic factors, such as binding, scaffolding, or templating proteins, which do not represent constituents of the final structure, is not sufficient. It will only enable the formation of proteoliposomes (using various biochemical methods of detergent removal) with a random distribution of the transmembrane and peripheral proteins. The resulting vesicles each exhibit both inwardly and outwardly oriented proteins (i.e., mixed type) rather than populations of either outside-in- or outside-out-oriented vesicles (<b><a href="#fig010">Figure 10</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig009"></a><h5 class="sap__label">Figure 9</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Model for the replication of membrane environment landscapes in acceptor cells through self-organization and the effect of environmental factors (see [<a href="#ref32">32</a>] with permission of the publisher). (a) Donor cells release membrane environment landscapes (MELs) composed of glycosylphosphatidylinositol-anchored proteins together with underlying peripheral cytoskeletal elements into extracellular vesicles (EVs). (b) Upon transfer to and (d) insertion into the plasma membranes of acceptor cells lacking membrane environment landscapes, (f) the membrane environment landscapes grow through the incorporation of newly synthesized glycosylphosphatidylinositol-anchored proteins and cytoskeletal elements during a self-organizing process. (i) Finally, this results in acceptor cells with fully developed and replicated membrane environment landscapes. (c) Environmental factors may distort the membrane environment landscapes. (e) Upon transfer to and insertion into the plasma membranes of acceptor cells lacking membrane environment landscapes, (g) the partially distorted membrane environment landscapes replicate through induced self-organization, (h) leading to stable inheritance of this environmentally altered, i.e., acquired, feature at the cell surface. It should be emphasized that the replication of membrane environment landscapes by (induced) self-organization is hypothetical (but see <b><a href="#fig019">Figure 19</a></b>).</h4></div> <img alt="media/image12.png" src="https://journals.academia-photos.com/10/7401/image12.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig010"></a><h5 class="sap__label">Figure 10</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Method of reconstitution of membrane proteins into proteoliposomes. Membrane phospholipids and integral as well as peripheral membrane proteins were prepared from native membranes upon solubilization by incubation with cold (nonionic) detergent. After (partial) purification of the solubilized proteins, proteoliposomes become reconstituted using one of the following methods for drastic reduction of the detergent concentration (i.e., below the so-called critical micellar concentration), such as dialysis, treatment with Ca<sup>2+</sup> in combination with ethylenediaminetetraacetic acid, gel chromatography, dilution, and adsorption to polystyrene beads (adapted from [<a href="#ref78">78</a>, <a href="#ref79">79</a>]). The protein constituents of the reconstituted proteoliposomes do not display a specific topology but rather mixtures of outside-in and outside-out orientations. Consequently, the constituents of biological membranes fail to self-assemble into functional plasma membranes, organelles, and other membranous cellular structures.</h4></div> <img alt="media/image13.png" src="https://journals.academia-photos.com/10/7401/image13.png"> </div> <p id="id47">Thus, the molecular mechanism of replication or copying of non-DNA matter resembles the biogenesis of typical biological membrane systems, such as mitochondria [<a href="#ref80">80</a>–<a href="#ref82">82</a>], ER [<a href="#ref83">83</a>–<a href="#ref86">86</a>], and animal DNA and RNA viruses, rather than that of certain macromolecular complexes of proteins and nucleic acids, such as ribosomes [<a href="#ref87">87</a>–<a href="#ref89">89</a>], signal recognition particle (SRP) [<a href="#ref90">90</a>, <a href="#ref91">91</a>], and bacteriophages. Clearly, the involvement of biological membranes in the constitution of the former makes the difference: (i) with the defined topological orientation of their protein constituents; (ii) as a cause or consequence of the asymmetry between the two leaflets concerning the type, saturation, and packing of their phospholipid constituents [<a href="#ref74">74</a>]; and (iii) with the determination of the interior–exterior boundary of cells. Certainly, a combination of self-organization and self-assembly is conceivable as a mechanism for the replication or copying of non-DNA matter (for a comparison, see <b><a href="#fig011">Figure 11</a></b>), as is apparently operative for the biogenesis of mitochondria, with the self-organization of their membranes requiring a complex multicomponent machinery and the self-assembly of mitochondrial ribosomes.</p> <div class="sap__fig sap__figure_panel"> <a id="fig011"></a><h5 class="sap__label">Figure 11</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Comparison of the principles of self-organization and self-assembly as exemplified by eukaryotic cells (a) and non-membranous viruses, such as bacteriophages and the plant tobacco mosaic virus (shown here, b) (adapted from [<a href="#ref3">3</a>, <a href="#ref32">32</a>]).</h4></div> <img alt="media/image14.png" src="https://journals.academia-photos.com/10/7401/image14.png"> </div> <p id="id48">Clearly, for the replication and copying of non-DNA matter, including MELs, the specificity of proteins and the operation of self-assembly mechanisms are not sufficient. Instead, it critically depends on the persistence of structural information, i.e., three-dimensional biochemical landscapes, to channel or template assembly. This principle of self-organization may be interpreted in terms of autopoiesis and structural coupling as introduced by the systems theories for living [<a href="#ref92">92</a>–<a href="#ref94">94</a>] and societal [<a href="#ref95">95</a>–<a href="#ref97">97</a>] systems. Accordingly, organisms, as well as societies, do not arise de novo due to the agency of the individual “members” and their specific hierarchical assemblies or subsystems, such as subcellular structures, organelles, cells, tissues, and organs and citizens, schools, universities, unions, parties, companies, hospitals, administrations, and governments, respectively. Rather, they grow and expand based on the capability of new “members” to become integrated and assembled into the already existing living and societal (sub)systems. In conclusion, the transfer of non-DNA matter through the donation by donor cells and acceptance by acceptor cells as MELs via micelle-like complexes and EVs harboring GPI-APs is not restricted to the cell surface and PMs (i.e., extracellular transfer or vertical inheritance) but must be extended to organelles and intracellular structures (i.e., intracellular transfer or horizontal/lateralinheritance) (<b><a href="#fig012">Figure 12</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig012"></a><h5 class="sap__label">Figure 12</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Extra- and intracellular transfer or inheritance of non-DNA matter between mother and daughter cells, gametes and zygotes, and donor and acceptor cells, following division or fusion of cells, including the consequences of environmental factors acting on glycosylphosphatidylinositol-anchored proteins within micelle-like complexes and extracellular vesicles (for details, see [<a href="#ref32">32</a>] with copyright permission of the publisher). (a) Membrane environment landscapes at the cell surface, as well as intracellular organelles eventually equipped with structures resembling membrane environment landscapes, are transferred from mother or donor cells via cell division (b, black arrows) and from gametes to zygote via cell fusion (c, yellow arrows). In addition, the effect of environmental factors on the arrangement of micelle-like glycosylphosphatidylinositol-anchored protein complexes, the topology of extracellular vesicles harboring glycosylphosphatidylinositol-anchored proteins, and the configuration of membrane environment landscapes in extracellular vesicles are indicated.</h4></div> <img alt="media/image15.png" src="https://journals.academia-photos.com/10/7401/image15.png"> </div> </div> <div class="sap__section"> <a id="sec6"></a><h2 class="sap__main-title">6. Hypotheses on the transgenerational inheritance of non-DNA matter</h2> <p id="id49">It is tempting to extend the demonstrated intercellular transfer of non-DNA matter, along with the resulting phenotypic switching, as demonstrated by us for micelle-like GPI-AP complexes with somatic cells [<a href="#ref33">33</a>, <a href="#ref39">39</a>] and iPSCs [<a href="#ref15">15</a>] and as shown by others for EVs with reproductive cells within mammalian gonadal tissues operating as donor and acceptor cells within the same tissue depot [<a href="#ref98">98</a>–<a href="#ref105">105</a>], to transgenerational sexual inheritance. Curiously, the latter may be interpreted in terms of Darwin’s “Pangenesis” theory [<a href="#ref106">106</a>–<a href="#ref109">109</a>]. Darwin strongly supported Lamarck’s theory of the inheritance of acquired traits and suggested as the underlying mechanism the operation of the so-called gemmules. These are small particles that are liberated from each tissue or organ of the donor organisms and represent specific and distinct features of each tissue and organ. Gemmules are transported via body fluids, such as interstitial fluids and blood, to the gonads. At that site, e.g., in the vicinity of eggs, they become concentrated and assembled to transferable functional units, tissues, and organs, due to the action of some ill-characterized attractive forces.</p> <p id="id50">Following transfer to the acceptor organism, i.e., children, gemmules reassemble or reassociate into the same type of functional unit, tissue, or organ from which they had been liberated in the donor organism, i.e., the mother, driven by certain, at those times unknown, molecular processes of self-assembly and/or self-organization. Importantly, a number of E which mediate (i) the expression of serum proteins, (ii) the operation of hormones, (iii) the action of drugs, (iv) the effects of mechanical pressure, or (v) the turnover of metabolites manage to affect the composition, topology, and overall configuration of non-DNA matter, i.e., MELs at micelle-like complexes or EVs, as well as the efficacy of their liberation from donor cells and transfer to acceptor cells, tissues, and organs. For instance, the plasma levels of micelle-like GPI-AP complexes were found to be considerably decreased in hyperinsulinemic high-fat diet fed, as well as genetically obese rats, and in type 2 diabetic and obese humans. This decline was even more pronounced in the cases of accompanying hyperglycemia [<a href="#ref36">36</a>–<a href="#ref38">38</a>] or elevated age [<a href="#ref68">68</a>]. The paradoxical lowering of the plasma levels of micelle-like GPI-AP complexes, despite their elevated liberation from donor cells, tissues, or organs under the corresponding nutritional or genetic states, is best explained by stimulation of serum GPLD1. Its activation leads to a decrease in the steady-state concentrations of full-length GPI-APs compared to normal. This “over-compensatory” mechanism may prevent the detrimental actions of full-length GPI-APs released into the bloodstream during their endocrine transfer to distant acceptor cells, tissues, or organs [<a href="#ref15">15</a>]. Importantly, as mentioned above, paracrine transfer of micelle-like GPI-AP complexes, liberated upon challenge by certain E, may cause phenotypic effects in proximal acceptor cells within the same tissue bed [<a href="#ref33">33</a>]. Taken together, the transfer and copying of non-DNA matter, altered in its amount and/or structure in response to E, at the tissues and organs of acceptor organisms lead to the development of new phenotypes and may thus be regarded as transgenerational inheritance of acquired traits.</p> <p id="id51">An important role in the replication of MELs may also be exerted by intrinsically disordered proteins (for a review, see [<a href="#ref62">62</a>, <a href="#ref63">63</a>, <a href="#ref110">110</a>]), which do not acquire a defined three-dimensional conformation. Rather, they become folded only upon interaction with other proteins of defined structure [<a href="#ref111">111</a>, <a href="#ref112">112</a>]. Folding of intrinsically disordered proteins could also happen following their incorporation into MELs. Consequently, intrinsically disordered proteins have been attributed a role in the emergence and inheritance of biological traits [<a href="#ref113">113</a>].</p> </div> <div class="sap__section"> <a id="sec7"></a><h2 class="sap__main-title">7. Structural inheritance</h2> <p id="id52">Structural inheritance refers to the transmission of alternative three-dimensional structures in a living organism through self-perpetuating spatial templating. A variant structure in a donor or mother cell guides the formation of a similar structure in an acceptor to daughter cell, leading to the transmission of the architectural variant. An early example was the inheritance of variations in the cortical structures of ciliates [<a href="#ref114">114</a>, <a href="#ref115">115</a>]. This contrasts with the transmission of DNA sequences as a form of digital information [<a href="#ref116">116</a>], which is responsible for the propagation of a major portion of polymorphisms and mutations. Structural inheritance has been described for the topological orientation of the cilia in protists, such as <i>Tetrahymena</i> and <i>Paramecium</i> [<a href="#ref117">117</a>], as well as the “handedness” of the spiral of the cell in <i>Tetrahymena</i> and the shells of snails [<a href="#ref118">118</a>]. Moreover, certain organelles provoke structural inheritance, such as the centriole, and most importantly, the cell itself, as it is surrounded by PMs, can be regarded as a complex arrangement of (PM) molecules in MELs that becomes transferred through structural inheritance.</p> <p id="id53">In greater detail, more than 60 years ago, the American biologist Tracy M. Sonneborn introduced the ciliate <i>Paramecium caudatum</i> as a genetic model organism [<a href="#ref119">119</a>]. Based on a variety of different spontaneous or experimentally induced “mutations” in the cortical organization of <i>Paramecium</i>, he succeeded in demonstrating their hereditary persistence throughout cellular continuity. This was not associated with any change in the DNA-encoded information. Sonneborn interpreted this observation of “cortical inheritance” in terms of the concepts of “cytotaxis”, “structural templating”, or “structural inheritance”. It reflected the critical role of preexisting structures and organization in the assembly of novel structures [<a href="#ref120">120</a>–<a href="#ref122">122</a>]. The conception of cortical inheritance was introduced approximately at the same time that discussions about the scrapie agent began, which represents a non-DNA-based entity and a novel non-DNA-based mode of inheritance [<a href="#ref123">123</a>].</p> <p id="id54">In summary: (i) there is no one-to-one correspondence between genotype and cellular architecture, as the genotype of <i>Paramecium</i> manages to stably acquire a variety of distinct configurations derived from its wild type. (ii) The directing role of the preexisting structures on the organization and assembly of new structures argues for the transfer of a novel type of information that is based on non-DNA matter. At that time, Sonneborn and his colleagues did not introduce the term of protein-based inheritance, but they insisted that DNA in the basal bodies or other cortical components was not responsible for the observations on cortical inheritance. Rather, they did not seem to rely on the overall characteristics of the basal bodies or associated components but on alterations in the three-dimensional arrangement of those elementary structures, which themselves remain unchanged at the molecular level [<a href="#ref114">114</a>]. (iii) During his investigation of <i>Paramecium</i> in the late 1930s, Sonneborn found that the structure of the cortex did not depend on genes or the cytoplasm but was severely affected by the cortical surface structure of the ciliates [<a href="#ref114">114</a>, <a href="#ref124">124</a>]. The structure of preexisting cell surfaces represented a template that was transmitted from one generation to the next for many generations. Sonneborn concluded that the specific configuration of surface structures within macromolecular complexes is inherited. The molecular basis of cortical inheritance is still not entirely clear, but it seems to be based on self-templating of complex molecular structures, similar to the transmission of the characteristics of already existing macronuclei to future new macronuclei [<a href="#ref125">125</a>].</p> <p id="id55">Since then, a large body of evidence has accumulated over the past century for the only major surviving concrete examples of the so-called nongenetic cytoplasmic inheritance, i.e., the experimental evidence of inheritance without genes, as exemplified by cortical inheritance in ciliates, such as <i>Paramecium</i> and <i>Tetrahymena</i>. In fact, geneticists have long been aware of the mechanisms responsible for the inheritance of cortical patterns but have downplayed their significance and frequency as exceptions to the general rule of DNA-based inheritance. By contrast, embryologists, who are predominantly interested in the development of organisms rather than (solely) the transmission of genes between them, do not agree with the hegemony of genetics over cytoplasmic non-DNA-based inheritance. Consequently, Grimes has postulated that both DNA and cortical inheritance represent components of “directed assembly, wherein the timing and placement of new structures are organized according to a template of preexisting structures”. Based on the identification of “cortical mutants” displaying inverted patterns of their cortex, which become stably inherited for hundreds of generations, it has been recognized that the genes encoding the cortical proteins are the same across generations, but that the cortical proteins are organized in different configurations. Thus, the validity of the conception of cortical inheritance cannot be questioned, since developmental biologists, including Sonneborn, Nanney, Beisson and their colleagues, did an excellent job in convincing other researchers of the operation of cortical inheritance based on successful experiments in protozoa. This has led to the urgent question of whether protozoa represent exceptions to or examples of the general rule. Do protozoa behave “normally” or “exceptionally”? According to Grimes and Aufderheide [<a href="#ref126">126</a>], all biological membranes are of a composite, mosaic, and complex nature, based on the insertion of novel constituent components into preexisting membrane structures. Thus, it is tempting to speculate about the extrapolation of the inheritance principle realized in ciliates to eukaryotic cells in general. However, the fluid mosaic model proposed for the membranes of metazoa [<a href="#ref1">1</a>] must not be confused with the highly structured and complex cortex at the cytoplasmic periphery underlying the PMs of ciliates. Consequently, Gilbert [<a href="#ref127">127</a>] summarized the state of the exception-rule debate at that time and concluded that “until stably inherited membrane structures are discovered in such metazoan cells (and not merely transient organizations….), cortical inheritance is likely to remain at the periphery of discussions on inheritance and development”.</p> </div> <div class="sap__section"> <a id="sec8"></a><h2 class="sap__main-title">8. Extended heredity: inheritance of features versus inheritance of differences</h2> <p id="id56">In contrast to the canonical view of biological inheritance and in accordance with a more fundamental interpretation attributed to the phenomenon of cortical inheritance, as well as of other nongenetic processes, “the fundamental reproductive unit of life is not a nucleic acid molecule but the remarkable versatile, intact, living cell” [<a href="#ref128">128</a>]. Further analysis of the phenomenon of structural inheritance has meanwhile been incorporated into the theory of extended heredity and evolutionary synthesis [<a href="#ref129">129</a>–<a href="#ref131">131</a>]. In line with this conception, Alfonso Martinez Arias [<a href="#ref132">132</a>] has recently substituted the “blueprint” analogy often applied in the context of DNA matter with a “hardware store catalog” image in a published book. He argued that genetic information has to be interpreted as the catalog used by the individual cell to order the building plans for its constituent proteins. In contrast to the common view of the role of genes in the biogenesis of (sub)cellular structures, such as the cortex and the centriole, Martinez Arias states that genes are utilized by cells to produce the building blocks necessary for forming three-dimensional structures of any complexity, including the cortex and the centriole. According to his perspective, genes alone per se do not provide a plan for spatial and temporal organization or for the management to sense and control putative deficits or abundance [<a href="#ref132">132</a>]. In the present manuscript, the assumption that only the information for protein synthesis is encoded by genes has been extended to MELs, including those displayed by PMs and organelles. These structures also contain information for the topological and functional arrangement of their constituent polypeptides, as well as for their replication through self-organization, in addition.</p> <p id="id57">In this context, the demonstration of the transfer of GPI-APs, assembled together with other transmembrane and peripheral membrane proteins, cytoskeletal elements, and (lyso)phospholipids in micelle-like complexes from the PMs of donor to acceptor mammalian cells—accompanied by the induction of metabolic switches in the latter, which seems to be transmitted to subsequent generations of cells—may be of considerable relevance. As suggested above, the transferred micelle-like complexes may be capable of provoking the emergence of novel MELs upon their insertion into the PMs of metazoa. Apparently, these complexes are causative for the induction of novel phenotypes and are inherited between PMs, similar to the specific patterns of the cortical structures and their inheritance in ciliates.</p> <p id="id58">With regard to the exception-rule debate, an additional aspect of great relevance is the problem of morphogenesis. It remains to be clarified how the various parts that constitute an organism, such as organs, tissues, cells, proteins, lipids, carbohydrates, and genes, manage to assemble in a regular fashion in space and time to form a complete, functional, and replicating living individuum. A number of developmental biologists have argued that there must be a fundamental principle of spatial organization, which manifests as structural patterns intrinsic to the cytoplasm of mother cells during asexual or parasexual reproduction (as seen in bacteria and protozoa), as well as in eggs during parthenogenetic or sexual reproduction (in metazoa), prior to cell division, autoinduction, or fertilization, respectively. The relevant spatial organization may represent a crude structural, organismal, or body plan, which is manifested in the cytoplasm or protoplasm of the mother cell or egg, respectively, and is successful in guiding the early stages of development. According to this view, Mendelian traits may “just” determine those features of the organisms that enable (i) their classification into species, order, class, or phylum and (ii) their differentiation from other members of the same species, order, class, or phylum.</p> <p id="id59">Strikingly, developmental stages encompassing the morula, blastula, and gastrula (along with the accompanying formation of the gut and the main body plan) do not appear to depend considerably on the input from nuclear genes transferred from the fertilizing sperm to the egg. Edward Conklin ([<a href="#ref133">133</a>]) described this “job sharing” of developmental potential between the egg cytoplasm and its genome as the emerging difference between the fundamental “body” organization and the individual traits of the “body” formed by that organism: “We are vertebrates because our mothers were vertebrates and produced eggs of the vertebrate pattern; but the colour of our skin and hair and eyes, our sex, stature and mental peculiarities were determined by the sperm as well as by the egg from which we came. There is evidence that the chromosomes of the egg and sperm are the seat of the differential factors or determiners for Mendelian characters while the general polarity, symmetry and pattern of the embryo are determined by the cytoplasm of the egg”.</p> <p id="id60">Similarly, Wilhelm Johannsen [<a href="#ref134">134</a>] concluded, more than a decade later, that the inheritance of Mendelian traits was “mostly operating with ‘characters’ which are rather superficial, in comparison with the fundamental Specific or Generic nature of the organism”. Moreover, the <i>Drosophila</i> genetics school, led by Thomas Hunt Morgan [<a href="#ref135">135</a>], focused on explaining the expression of (very) minor differences between individual flies, far from an understanding of the driving forces behind <i>Drosophila</i> species’ morphogenesis. Consequently, Johannsen interpreted this apparent lack of evolutionary substance [<a href="#ref134">134</a>]: “The Pomace-flies in Morgan’s splendid experiments continue to be Pomace flies even if they lose all ‘good’ genes necessary for a normal fly-life”. He also concluded that “a great central ‘something’ as yet not divisible into separate factors” must be expressed in the cytoplasm of Pomace fly eggs [<a href="#ref135">135</a>]. In addition, the French developmental biologist Maurice Caullery [<a href="#ref136">136</a>]) shared his perspective: “The properties of the characters to which Mendelism applies are limited, in an almost absolute way, to variations which do not extend beyond the framework of the species”.</p> <p id="id61">The following considerations concerning the differences in the number and structure of genes between species may shed some light on the putative contribution of genes versus the cytoplasmic “something” in relation to differences between nonliving and living matters, prokaryotes and eukaryotes, protozoa and metazoa, fungi and plants, plants and animals, lower and higher organismal kingdoms up to animal species, and animals versus humans. Moreover, insights are also given with regard to interindividual differences within a given species, for example pea plants (<i>Pisum sativum</i>), in terms of the shape of ripe seeds (round or roundish; with shallow or wrinkled surface) or the color of the seed coat (white, gray, or brown; with or without violet spotting), and in humans, in terms of traits such as the eye color or inborn errors of metabolism.</p> <div class="sap__list"> <a id="id62"></a><ol style="list-style-type: lower-roman"> <li><p id="id63">According to top-to-bottom approaches for the construction of organisms with a minimal genome, <i>Mycoplasma genitalium</i> has been demonstrated to harbor the smallest genome of any organism that can be grown in pure culture. The reported data suggest that a genome constructed to encode 387 protein-coding and 43 structural RNA genes may sustain a viable synthetic cell [<a href="#ref137">137</a>, <a href="#ref138">138</a>]. Does this mean that living matter is separated from nonliving matter by the operation of a limited number of (“just” 430) genes?</p></li> <li><p id="id64">The genomes of the yeast <i>Saccharomyces cerevisiae</i> and <i>Homo sapiens sapiens</i> are composed of 6,081 and 22,184 nonredundant open reading frames [<a href="#ref139">139</a>, <a href="#ref140">140</a>]. Does this mean that human beings are separated from baker’s yeast by the expression of (“just”) the three- to fourfold number of genes? In general, there is no (strict) positive correlation between the number of genes or the size of the genome and the relative phylogenic distance between both closely related and unrelated species.</p></li> <li><p id="id65">The sequences of many genes expressed in organisms phylogenetically as distant as yeast and humans are often highly conserved. For instance, the comparison of the sequences of the long-chain fatty acid transport proteins (FATPs) along a 311-amino acid FATP “signature sequence”, corresponding to amino acids 246–557, has revealed long stretches with >90% amino acid identity from mycobacteria to humans [<a href="#ref141">141</a>]. Do these pronounced sequence homologies in a given gene mean that the minor amino acid deviations between them are sufficient to explain interspecies differences?</p></li> </ol> </div> <p id="id66">Taken together, it seems more plausible that the distinction between nonliving and living matters, the classification into order, class, or phylum, and the differentiation between members of the same order, class, or phylum, which share early developmental processes, rely on cytoplasmic mechanisms rather than on Mendelian genes, which provide the basis for “subtle” differences within a given species.</p> </div> <div class="sap__section"> <a id="sec9"></a><h2 class="sap__main-title">9. Poly-matter conception</h2> <p id="id67">We would like to suggest a design for a “Frederick Griffith Experiment 2.0” for the putative demonstration of the inheritance of phenotypic alterations that does rely on the inheritance of both DNA and non-DNA matter, and thereby extends our “DNA-centric view” to “structural templating” and a poly-matter conception which includes materials capable of replication, intercellular transfer, and phenotypic switching, independent of DNA. First, the original and epochal experimental design, as realized by Frederick Griffith [<a href="#ref142">142</a>], is briefly explained for a better understanding of the consequences exerted by the altered design (<b><a href="#fig013">Figure 13</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig013"></a><h5 class="sap__label">Figure 13</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Design of Frederick Griffith experiment 1.0 (adapted from [<a href="#ref143">143</a>], with copyright permission and considerable modifications by G.A. Müller). To demonstrate the putative transition of pneumococci (<i>Diplococcus</i> or<i> Streptococcus pneumoniae</i>) from the avirulent rough serotype (which lacks a highly variable glycopolymer capsule anchored at the peptidoglycan layer; for a review, see [<a href="#ref144">144</a>–<a href="#ref146">146</a>]) (b) to the virulent pathogenic smooth serotype (which displays <i>O</i>-acetylated capsular polysaccharides for evasion from phagocytosis; for a review, see [<a href="#ref147">147</a>, <a href="#ref148">148</a>]) (a), the former were injected together with the latter smooth pneumococci after massive attenuation of their virulence by culturing in blood broth in the presence of anti-smooth serum (c) into mice, which resulted in their death (d). This experimental design [<a href="#ref142">142</a>] was per se open (i.e., inclusive) for the identification of both multiple substances or matter (e.g., DNA, protein, lipids, carbohydrates) and forms or structures (e.g., PMs, outer membranes, nano- and microdomains). The injection of heat-treated smooth form, which does not affect the viability of mice (e), together with the viable rough form again caused their death (f). However, in contrast to the original experimental setup (d), this latter design was apparently excluding for both heat-labile matter (e.g., proteins) and structures (e.g., membranes), putatively underlying inheritance between pneumococci, albeit the conditions used (80°C, one hour) did not enable unequivocal discrimination between DNA on one side and proteins, lipids, and membranes on the other (f). Thereafter, this differentiation was achieved by preparing a cell-free extract from the smooth form and subsequently purifying its DNA (chloroform extraction) in combination with enzymic treatment (nuclease or protease) prior to incubation with the rough form [<a href="#ref149">149</a>]. Injection of the incubation mixture (containing DNA) into mice was compatible with their survival (in case of incubation with nuclease) or led to their death (in the case of incubation with protease), respectively (g).</h4> <p id="id68">This experimental design led to the selection of DNA as the hereditary matter while simultaneously excluding other—material and structural—options, such as proteins, lipids and membranes, domains, respectively (see <b><a href="#fig016">Figure 16</a></b>). There is no doubt that DNA is required for the switch from the rough to the smooth phenotype of pneumococci, and the protease treatment is apparently in conflict with the involvement of proteins, though not glycolipids and membranes, as additional heredity matter. Moreover, other (more important) features of pneumococci which are not selected and assayed by the transformation experiment (e.g., <i>Diplococcus</i> morphology) could be inherited through different types of genes, consisting of proteins, glycolipids, membranes, or nano-/microdomains.</p> </div> <img alt="media/image16.png" src="https://journals.academia-photos.com/10/7401/image16.png"> </div> <p id="id69">The Frederick Griffith experiment 2.0 has been designed to address the question as to whether bacteria, specifically <i>Streptococcus pneumoniae</i> as the model organism enabling a large number of “test tubes”, manage to switch from the avirulent non-pathogenic rough (R) form to the virulent pathogenic smooth (S) form, as can be easily assayed under appropriate selection conditions, meaning that there is intercellular transfer of non-DNA matter and structures in prokaryontes. As a type of “mutagenic” agent (i.e., E), mechanical stress, such as shearing forces and distortion, will be applied in order to induce the release of putatively heritable materials from the bacteria, such as outer-membrane vesicles or micelle-like complexes consisting of lipopolysaccharides and other proteinaceous constituents (the expression of which has recently been reported [<a href="#ref150">150</a>–<a href="#ref154">154</a>] and their arrangement in MELs remains to be demonstrated in the future, respectively), which may subsequently be transferred from donor to acceptor bacteria (<b><a href="#fig014">Figure 14</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig014"></a><h5 class="sap__label">Figure 14</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Putative outcome of a putative Frederick Griffith experiment 2.0. The production of extracellular donor vesicles from the outer membranes of donor bacteria (a), in the course of specific exocytotic or budding mechanisms (b), has been amply documented (for a review, see [<a href="#ref151">151</a>, <a href="#ref153">153</a>–<a href="#ref157">157</a>]). Outer-membrane vesicles that may be released in response to environmental factors, such as mechanical stress, specifically harbor the glycolipids determining the smooth (S) phenotype (capsule) of the donor pneumococci, resist the enzymic attacks from both nuclease and protease, and upon transfer to rough (R) acceptor pneumococci (c), fuse with their outer membranes (d). By contrast, the released vesicles are removed by centrifugation (as 100,000×<i>g</i>-pellet), solubilized by extraction with chloroform, and degraded by phospholipase digestion, or destroyed by heat treatment (80°C, one hour; but see <b><a href="#fig013">Figure 13</a></b>) (e). In the course of fusion of the vesicles donating the smooth (S) glycolipid [<a href="#ref144">144</a>–<a href="#ref146">146</a>] to the outer membranes of rough (R) acceptor pneumococci (d) and subsequent replication by a molecular mechanism that may resemble the so-called plasma membrane memory (see <b><a href="#fig019">Figure 19</a></b>) for micelle-like GPI-AP complexes and membrane environment landscapes (g), the acceptor pneumococci gradually switch their phenotype from rough (R) to smooth (S), till completion of the transformation (h).As already mentioned (see <b><a href="#fig013">Figure 13</a></b>), more complex (e.g., morphological) features of pneumococci others than those mediating the smooth (S) phenotype and not assayed by the transformation experiment 1.0 may be inherited by outer-membrane vesicles, exhibiting micelle-like GPI-Ap complexes and membrane environment landscapes of higher complexity.</h4></div> <img alt="media/image17.png" src="https://journals.academia-photos.com/10/7401/image17.png"> </div> <p id="id70">The emergence of colonies displaying the smooth (S) phenotype will indicate its stable inheritance. Sequencing of the whole genome from individual colonies of the <i>Streptococci</i> will indicate whether some bacteria succeeded in acquiring the smooth (S) phenotype in the absence of any mutations in the (epi)genome. This may be accomplished in the donor bacteria by the spatial reconfiguration, rearrangement, and reorientation of MELs in response to mechanical stress. As indicated above, those MELs could be constituted by subsets of membrane (lyso) phospholipids and membrane proteins, capable of shaping or “materializing” the specific smooth (S) phenotype. Following their transfer to and insertion into the membranes of acceptor bacteria, the transferred MELs of the smooth (S) phenotype could trigger the spatial reconfiguration, rearrangement, and reorientation of preexisting ones, reflecting the rough (R) phenotype of the acceptor bacteria, and result in the new smooth (S) phenotype of the next-generation bacteria.</p> <p id="id71">Importantly, phenotypic switching between bacteria cannot only be provoked by transformation, but it may also result from the transport of some heritable substance and/or form from donor to acceptor cells, a process known as chromosome transfer (<b><a href="#fig015">Figure 15</a></b>).</p> <p id="id72">In conclusion, positive outcomes of the Frederick Griffith experiment 2.0, as well as those of the unbiased version 2.0 of the Lederberg Zinder experiment, selecting total pathways rather than simple features (not outlined here in greater detail), could be explained by a poly-matter conception of inheritance only, i.e., by the transfer of information as both DNA (for the synthesis of the membrane constituents, i.e., their proteins and lipids) and membranes (for the assembly, shaping, or templating of membraneous structures), i.e., operation of DNA and MELs as information carriers, in concert with the “physical” transfer of materials as MELs for the generation and propagation of a novel phenotype and the production of the corresponding narratives (<b><a href="#fig016">Figure 16</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig015"></a><h5 class="sap__label">Figure 15</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Exchange of hereditary matter and/or structure between bacteria in the course of chromosome transfer to support interbacterial parasexuality and recombination, as first described by Tatum and Lederberg [<a href="#ref158">158</a>], Lederberg et al. [<a href="#ref159">159</a>], and Zinder and Lederberg [<a href="#ref160">160</a>]. (a) Morphological linkage between a bacterial acceptor cell (<i>Escherichia coli</i> K-12) displaying a low rate of recombination (F<sup>−</sup>) and a donor cell capable of recombination at a high rate (Hfr) occurs through a tubular structure, the sexual pilus, which originates from the donor. For better visualization of specific cell surface structures of the donor by electron microscopy, it has been decorated by the adsorption of appropriate fili-like RNA phages. For a clear discrimination between acceptor and donor cells, a mutant of the former has been used, characterized by a shortened, stocky cell shape in contrast to the elongated, thin, <i>E. coli</i>-typical shape of the latter [<a href="#ref161">161</a>]. (b) Linkage between <i>E. coli</i> K-12 cells of the donor Hfr and acceptor F<sup>−</sup> type occurs through a cytoplasm–plasma membrane bridge in the course of chromosome transfer, as visualized by electron microscopy [<a href="#ref162">162</a>]. (c) Schematic interpretation of the process of chromosome transfer from Hfr- to F<sup>−</sup>-partners of the bacterial pair, as depicted in (b) (adapted from [<a href="#ref143">143</a>], with copyright permission and modifications by G.A. Müller). (d) Schematic details of the mechanism of DNA replication during the process of chromosome transfer from Hfr- to F<sup>−</sup>-partners of a bacterial pair. Based on the so-called “rolling-circle” mode of DNA replication, only the (+) strand of the DNA becomes transferred, which, prior to transfer, has been replicated in the Hfr donor cell (broken line), with the complete intact (−) strand operating as matrix for copying. Following the transfer, the newly arrived (+) strand is supplemented by de novo synthesis of the complementary (−) strand (broken line) to yield the complete DNA double helix in the F<sup>−</sup>-acceptor cell. Whereas the mechanism of “rolling-circle” replication of the transferred DNA has been proven experimentally, the unequivocal demonstration of continuity of the PMs (outer membranes) between Hfr- and F<sup>−</sup>-cells during chromosome transfer has remained a matter of debate thus far.</h4> <p id="id73">There is no doubt that approximation and initial contact between bacterial Hfr- and F<sup>−</sup>-cells require the formation of a pilus-like structure between them, which enables the directed movement of the DNA during the initial stage of chromosome transfer, at least (<b>a</b>). The expression of rather simple features (see <b>c</b>), such as resistance against azide (Az<sup>r</sup>) and resistance against phage T1 (T1<sup>r</sup>), but not yet for the metabolism of lactose (Lac) and galactose (Gal), in acceptor F<sup>−</sup>-cells mutated to auxotrophy for exactly those phenotypes, depends on the duration period of the (un)interrupted chromosome transfer (simply provoked by extensive mixing of the incubation mixture containing the “mating” bacteria with a Waring blender) and is perfectly explained by the time-dependent movement of DNA through the pili.</p> <p id="id74">However, it cannot be excluded that during the later stages, the approximated Hfr- and F<sup>−</sup>-cells manage to build up a thin bridge of cytoplasm due to the local fusion of their PMs at a strictly limited area (<b>b</b>). Matter, such as proteins and lipids, as well as structures, such as membranes, rafts, MELs, could be exchanged via the cytoplasm and PMs, respectively, between Hfr- and F<sup>−</sup>-cells, and may be responsible for the inheritance, i.e., transfer, replication, and expression, of more complex features, such as the typical morphology of <i>E. coli</i>. The selection procedures used for successful chromosome transfer (in analogy to the Frederick Griffith experiment 1.0) may have been designed to demonstrate the operation of transfer of the matter DNA exclusively (<b>c</b>), thus preventing the detection of the inheritance of other substances and structures.</p> </div> <img alt="media/image18.png" src="https://journals.academia-photos.com/10/7401/image18.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig016"></a><h5 class="sap__label">Figure 16</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Narratives of biological inheritance leading to the dichotomies between substance and form, as well as DNA and other matter, as manifested in the current DNA-centric view rather than in the extended heredity or poly-matter network (for details, see text), are presented in the boxes enclosed by green and blue lines, respectively. Some major representatives for the various narratives are provided (however, by nature, this list is far from being complete). The year dates and periods indicate key experiments, findings, and theories supporting those narratives.</h4> <p id="id75">Of central importance for the initial fixation of the dichotomies were experiments performed with bacteria, i.e., transformation and chromosome transfer, for the demonstration of parasexual processes operating between them rather than of the stability of bacteria (which had remained unclear to up to those studies). Both transformation, successfully performed in the period 1928–1944 (see <b><a href="#fig013">Figure 13</a></b>), and chromosome transfer, starting in 1951 (see <b><a href="#fig015">Figure 15</a></b>), were initially designed as unbiased experiments that per se do not exclude either the substance (materiality) or the form (three-dimensional structure) as the unique and sole foundation of inheritance or do they predetermine its material basis. However, with regard to transformation, during the relevant period, the use of cell-free extracts, chloroform extraction, purified DNA, and enzymic treatments caused a shift from an open including design (see <b><a href="#fig013">Figure 13a</a></b>–<b><a href="#fig013">d</a></b>) to an intermediate design (see <b><a href="#fig013">Figure 13e</a></b> and <b><a href="#fig013">f</a></b>) and finally, to a closed excluding experimental design (see <b><a href="#fig013">Figure 13g</a></b>), with final agreement upon DNA as the only matter of inheritance rather than, for instance, membranes as structure of inheritance, in addition. The identification of the (f)actors (causally) involved in this apparent twofold shift from 1928 to 1944 should be the theme of future science and technology studies (STS) (see below), with special emphasis on agential realism (AR) (see [<a href="#ref163">163</a>]).</p> <p id="id76">With the identification of DNA as the principle transforming rough- into smooth-type pneumococci in 1944 by Avery and coworkers, the narrative of DNA as the sole matter of inheritance was set into motion, ultimately culminating in current DNA-centric views. Those are manifested in conceptions of the (i) operation of “egoistic genes” [<a href="#ref164">164</a>], (ii) creation of artificial cells (for a review, see [<a href="#ref165">165</a>]), (iii) medical benefits of personalized or precision medicine (for a review, see [<a href="#ref166">166</a>, <a href="#ref167">167</a>]), (iv) usefulness of forensic DNA phenotyping (for a review, see [<a href="#ref168">168</a>, <a href="#ref169">169</a>]), and (v) value of gene testing for an ever-expanding range of diseases, including Parkinson’s disease and skeletal disorders (for a review, see [<a href="#ref170">170</a>, <a href="#ref171">171</a>]). Alternative, i.e., including narratives addressing biological inheritance failed to gain broad acceptance at all within the scientific community during the second half of the past century, or were criticized to varying degrees depending on their scientific claims. The nonscientific cultural, societal, political, and economic (f)actors that prevented the inclusion of these narratives into the frameworks of “extended heredity” from 1976 onward and the “poly-matter network” presented here remain to be explored in future STS efforts, with an emphasis on the actor–network theory (see [<a href="#ref172">172</a>]).</p> </div> <img alt="media/image19.png" src="https://journals.academia-photos.com/10/7401/image19.png"> </div> <p id="id77">Starting with Sir Archibald Garrod’s description of alkaptonuria as “inborn error of metabolism” in 1902 till the search for the molecular basis of inheritance in nonhuman organisms, such as <i>Drosophila melanogaster, Epilobium,</i> and sea urchin, in the 1930s, most biologists examined their test subjects using Mendelian genetics, which were aimed exclusively at recording nuclear genes. The cytoplasm was not considered to play a primary role in heredity. It was the time of the nucleus monopoly of heredity. At variance, Peter Michaelis succeeded in “transferring the largely homozygous nucleus into an alien cytoplasm”, thus providing decisive proof that “the plasma had retained its independent genetic properties over eight generations”. Heinz Brücher also strengthened the general opinion that in addition to the cell nucleus, the cytoplasm plays a critical role as a carrier of hereditary constituents localized in the plasmon, a collective term for all extrachromosomal inherited cellular elements. Fritz von Wettstein understood the plasmon as ensuring the correct arrangement of the various cellular components in space and time.</p> <p id="id78">Here we argue for the broadening of the use of the term plasmon to combine the principles of structural inheritance and inheritance based on non-DNA matter, such as prions, intrinsically disordered proteins, and micelle-like GPI-AP complexes in association with MELs. Accordingly, the poly-matter network is considered as the concerted action between DNA and the plasmon to enable replication, transfer, and phenotypic consequences of both shapes and substances. The term rhizene, a neologism between rhizome, which is based on the epochal philosophy of “Différence et Répétition” from Gilles Deleuze and Felíx Guattari, and gene, was introduced to characterize the rhizome-like continuity, cooperation, and “intra-action” of DNA and plasmon, that will be discussed in detail in a future essay.</p> <p id="id79">Certainly, the carriers of the various types of “information transferred” from donor to acceptor organisms have a physical basis, which per se represents a trivial proposition but must be distinguished from the term “material transferred”, as used in the sense of “materialized” features: (i) DNA, as the information for the synthesis of proteins, consists of nucleotides which, from a chemical point of view, are completely unrelated to amino acids as the building blocks of polypeptides. Consequently, DNA must be considered as information without meaning (with regard to the material nature of the “encoded product”). (ii) Following fragmentation into vesicles and their vertical transfer from donor to acceptor cells, membranous structures, such as mitochondria and ER, grow and expand during the incorporation of new polypeptides into the prefabricated organelles. This results in a continuous flux of material constituents across generations of cells while maintaining the corresponding specific mitochondrial or ER phenotypes. However, this type of (vertical) matter flux along the membranome, caused by structural templating or inheritance [<a href="#ref173">173</a>, <a href="#ref174">174</a>], must be distinguished from that associated with the (vertical or horizontal) transfer of EVs, bacterial outer-membrane vesicles, or MELs. In fact, only the transfer of the latter materials guarantees the emergence of novel features and phenotypes in acceptor organisms. Certain structural features with unique topology and configuration may be generated which differ from their initial arrangement in the donor organisms, putatively in response to E. This distinction separates the information transfer driven by structural inheritance, as included in the “Extended Heredity” [<a href="#ref126">126</a>, <a href="#ref175">175</a>–<a href="#ref179">179</a>], from the transfer of materialized features. Examples of the latter include transformation of prokaryotes (Frederick Griffith experiment 2.0), cortical inheritance in ciliates, and phenotypic switching via MELs in adipocytes and ELCs, which are now considered under the “poly-matter conception of inheritance” (<b><a href="#fig017">Figure 17</a></b>).</p> <p id="id80">In this article, it is hypothesized that both the intercellular and the transgenerational transfers of non-DNA matter, i.e., of MELs delivered as EVs or micelle-like GPI-AP complexes, supplement the repertoire of epigenetic mechanisms and thereby contribute to a better understanding of the phenomena of phenotypic plasticity and the inheritance of acquired features. Albeit the concept of “genetic information” is, in fact, of only limited theoretical value and does not contribute much to the practice of experimental research, the questioning of the “DNA-centric (environment-centric or epigenetics-centric)” conception(s) of inheritance by the “poly-matter conception” does not rely on overemphasizing the problems with the term “information”.</p> <p id="id81">Importantly, the conceptions of both structural and poly-matter inheritance raise serious doubts about the assumption that the organization of cells relies solely on direct genetic control, which ultimately represents a mere consequence of the central dogma of molecular biology. Accordingly, the characteristics of proteins per se completely explain their self-assembly into subcellular assemblies and structures of the next higher level of complexity, such as ribosomes, together with their constituing RNAs. However, the conception of self-assembly necessitates the acquisition of a stable equilibrium by the components involved, as is true for the assembly of ribosomes. It does not explain the dynamics of the cytoskeleton after its initial assembly, which routinely fails to achieve a stable equilibrium (<b><a href="#fig018">Figure 18</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig017"></a><h5 class="sap__label">Figure 17</h5> <div class="sap__caption"><h4 class="sap__subsection-title">Principal classification or interpretation of the inheritance phenomenon as the transfer of information (A) or material (B). In the donor organisms F<sub>0</sub>, three basic types of information are replicated by “stoichiometric” mechanisms: information for protein synthesis, three-dimensional structure, and gradient formation of morphogenic substances. These are encoded by self-organizing DNA, membranes, organelles, EVs, MELs, cortical structures, cytoskeleton, etc., during cell division and development in the acceptor organisms F<sub>1</sub> (A). In parallel, materials are (“catalytically”) synthesized, encompassing building blocks and “materialized” traits that undergo self-assembly, such as the spontaneous folding of proteins (B). In the F<sub>2</sub> acceptor organisms, the resulting effect or phenotype is maintained following ongoing replication of the transferred information, whereas it becomes attenuated as a consequence of the dilution of the materials that are directly transferred. The “poly-matter conception” includes the transfer of the three types of information rather than solely that encoded by DNA.</h4></div> <img alt="media/image20.png" src="https://journals.academia-photos.com/10/7401/image20.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig018"></a><h5 class="sap__label">Figure 18</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Synopsis of the various types of information transferred from parents (F<sub>0</sub>) to offspring (F<sub>1</sub>) during inheritance. The sole transfer of the primary gene sequence, which ultimately determines the tertiary and quaternary structures of the encoded polypeptide, corresponds to the conception of “hard/gene-centric” inheritance. The transfer of the spatial<b>–</b>temporal distribution of regulatory factors and epigenetic marks corresponds to the conception of “epigenetic–extended” inheritance. Finally, the transfer of the spatial distribution of membrane and cytoskeletal constituents at the various subcellular compartments and structures, during their correct targeting to and proper orientation at the membranes or cytoskeleton, results in functional topology and biogenesis, aligning with the conception of “structural–poly-matter” inheritance. The effect of environmental factors of different types (e.g., oxidative stress, mechanical pressure and distortion, and UV light) on the spatial<b>–</b>temporal distribution of regulatory factors and epigenetic marks, as well as on the configuration of organelles and the cytoskeleton, is indicated. According to a systems-theoretic conception of inheritance, the information transferred from parents (F<sub>0</sub>) to offspring (F<sub>1</sub>) is ultimately responsible for their self-preservation and self-care, provoked by the operation of self-organization or autopoiesis. However, this conception leaves open the problem of aging (F<sub>1</sub>′).</h4> <p id="id82">The open boxes surrounded by orange color indicate types of information without meaning in the sense of their materiality being totally unrelated to the nature of the encoded agent or action, i.e., DNA and amino acid sequences, hormones (e.g., insulin), signaling proteins (e.g., IR substrate), transcription factors (e.g., insulin-responsive element), and the regulation of the corresponding physiological processes (e.g., stimulation of glucose transport), as well as epigenetic modifications (e.g., methylation of chromatin) and the regulation of gene expression (stimulation or inhibition of transcription). The open box surrounded by blue color indicates the type of information with meaning in the sense of its materiality being critical for the nature of the encoded agent or action, i.e., apparatuses for correct targeting, orientation, topology, and biogenesis of organelles and PMs (e.g., presequences of mitochondrial and ER membrane proteins and their interaction with outer-membrane proteins and SRP, respectively; the amphipathic structure of GPI-APs and their assembly into micelle-like complexes; and subsequent incorporation into acceptor cells, e.g., arrangement of cytoskeletal elements into cilia and their division). The boxes surrounded by blue color and filled with pink color of increasing intensity indicate the preservation of the shape or form but a change of the substance or matter in the course of inheritance from parents (F<sub>0</sub>) to offspring (F<sub>1</sub>) as a consequence of self-organization or autopoiesis.</p> </div> <img alt="media/image21.png" src="https://journals.academia-photos.com/10/7401/image21.png"> </div> </div> <div class="sap__section"> <a id="sec10"></a><h2 class="sap__main-title">10. Facilitated variation</h2> <p id="id83">Instead, the characteristic versatility of cytoskeletal assemblies in vivo best fits the conception of self-organization, as it is compatible with both the stability and dynamics of the newly assembled structures [<a href="#ref180">180</a>–<a href="#ref182">182</a>]. Nevertheless, although the specific characteristics of the constituting components and the dynamics of their self-organization into polymeric cytoskeletal assemblies may be responsible for the induction of endogenous polarity, as well as the variability in the resulting patterns, the intrinsic properties of proteins, in concert with their capability for self-assembly, do not provide an adequate explanation for the intracellular three-dimensional arrangement and configuration of the cytoskeletal network. Rather, the organization of the microtubular networks, which are the most prominent cytoskeletal components, seems to be critically controlled by the operation of the so-called microtubule-organizing centers, with their terminal nucleation sites determining both the initiation of assembly and the polarity of the microtubules [<a href="#ref183">183</a>].</p> <p id="id84">Consequently, the spatial arrangement of the microtubule bundles seems to rely on the simultaneously dynamic and instable state inherent in these polymers. Continuous changes between periods of expansion and retraction seem to enable fixation of certain cytoskeletal patterns by chance in the course of stabilizing the terminal assembly ends, i.e., the distal nucleation sites. This mechanism of the so-called dynamic instability enables the cytoskeleton to form not only a single (genetically) fixed configuration but also multiple configurations that are not under the direct control of genetic information. Rather, they are determined by the spatial positioning of the microtubule-organizing center relative to preexisting distal structures, such as kinetochores, membranes, and cortex [<a href="#ref184">184</a>]. This variability of pattern formation and the accompanying freedom in differentiating between distinct cellular organization forms hint at the limitation of genetic control and concomitantly emphasize the critical role of preexisting three-dimensional assemblies in the mother or donor cell for the biogenesis of novel subcellular structures in the daughter or acceptor cell.</p> <p id="id85">In analogy to the role of the microtubule-organizing center in the inheritance and biogenesis of cytoskeletal structures, MELs harboring GPI-APs, transmembrane and peripheral proteins, cholesterol, and (lyso)phospholipids in specific arrangements and spatial configurations in donor membranes may induce the formation of similar or identical structures in acceptor membranes upon their intercellular transfer. The corresponding assemblies at the acceptor membranes, along with their associated phenotypes, may either be permanently retained in the specific arrangement and spatial configuration, even if the original MELs become physically lost from the acceptor membranes and transferred to the next acceptor cell. This apparently reflects their “replication” and stable expression, along with corresponding phenotypic switching. In the case of “non-infectiousness”, i.e., only a single transfer event from donor to acceptor membranes, MELs may gradually become lost due to “dilution” or degradation, thereby manifesting the transient nature of the phenotypic expression.</p> <p id="id86">It is proposed that the transferred components, particularly GPI-APs, membrane proteins, and cytoskeletal elements, alone or in concert as micelle-like complexes, become incorporated into specific areas of the PMs, such as lipid rafts and membrane nanoclusters [<a href="#ref185">185</a>]. These precursor structures operate as nucleation sites for the rearrangement of the components into specific MELs. As previously demonstrated (see above), the latter are characterized by unique topological orientation and three-dimensional configuration, provoking specific phenotypic alterations in the acceptor cells. These alterations are elicited neither solely by the precursor structures nor solely by the transferred components, with the aid of specific molecular mechanisms (which remain to be elucidated). After reduction of the concentration of the transferred components below a certain threshold concentration, e.g., during membrane enlargement or further transfer to daughter cells and their consequent dilution, or alternatively, degradation, two alternative pathways are conceivable: </p> <div class="sap__list"> <a id="id87"></a><ol style="list-style-type: lower-roman"> <li><p id="id88">The specific MEL switches back to the original topology and configuration before the rearrangement is induced by the transferred components, accompanied by an attenuation of the specific phenotype expressed in the acceptor cells in response to the transfer. Those cells will then be prepared for the initiation of the next cycle of insertion of inheritance materials, with accompanying phenotypic consequences.</p></li> <li><p id="id89">The specific MEL generated upon the transfer of components and the accompanying phenotypic consequences are retained even after their loss from the corresponding membrane areas (e.g., lipid rafts). The components will then be transferred to appropriate membrane areas presented by the same or another cell, which will cause the intra- and intercellular propagation of that specific MEL and concomitantly, the associated phenotype. This pathway resembles that engaged by prion proteins upon physical interaction of their scrapie and cellular versions, inducing a conformational change in the latter, which, together with the mutant phenotype, will persist even after termination of the interaction. Thereby, both prion proteins and MELs succeed in propagating their spatial topology, specific configuration, and conformation, respectively, in the absence of de novo synthesis of their constituent components, e.g., GPI-APs, transmembrane proteins, (lyso) phospholipids, and prion proteins, respectively. Consequently, in addition to prions, MELs may be regarded as the matter of inheritance that, after its initial emergence, is capable of self-replication without the aid of DNA.</p></li> </ol> </div> <p id="id90">“Dynamic instability” may also link the phenomena of development and inheritance and underlie the Frederick Griffith experiment 2.0 (see <b><a href="#fig016">Figure 16</a></b>). It resembles the concept of “weak linkage” and “facilitated variation”, as introduced by John Gerhart and Marc Kirschner [<a href="#ref186">186</a>]. This concept provides an explanation for the evolution of animals under conserving their physiological integrity (for a review, see [<a href="#ref187">187</a>]). Accordingly, core components and molecular mechanisms engaged in the development of embryos, such as organelles, cytoskeletal elements, lipid rafts, membrane biogenesis, regulated secretion, signal transduction, and metabolism, are connected to a limited degree by weak linkage and are therefore easily prone to reconfiguration and rearrangement. This provides the basis for the production of phenotypic variation and the emergence of novel features. Ultimately, this conception relies on groundbreaking ideas of Edward E. Just regarding “independent irritability” [<a href="#ref188">188</a>, <a href="#ref189">189</a>] (“The egg as a living cell is self-acting, self-regulating and self-realizing—an independently irritable system…like many other living cell—nerve or muscle, for example—possesses…the full capacity for development”) and of Johannes Holtfreter concerning “autoinduction” [<a href="#ref190">190</a>] (“The results indicated that the treatments merely operated like an unspecific trigger, setting in motion a preexisting, pent-up mechanism, which, through unknown chain of events, led to neural differentiation”). These two researchers argued that the “competence” of the responding cells or tissues is critical for the induction of early development, with the instructive power provoked by the inducing signal being rather low. The competent cells are apparently prepared for an adequate action (not reaction). They follow selected cell-intrinsic pathways under the minimal guidance of the inducing signal. Thus, competent cells are capable of responding to a multitude of nonspecific (and rather simple) signals in the course of selecting a certain predetermined fixed pathway [<a href="#ref191">191</a>].</p> <p id="id91">In an effort to reconcile the conception of facilitated variation and the “poly-matter conception” of inheritance, MELs are postulated to operate as the core components and molecular mechanisms that are connected by weak linkage. The structural information for their biogenesis is transferred from mother cells or the egg to daughter cells along cell division (vertical inheritance) or through the release and fusion of EVs (horizontal and vertical inheritance, respectively), thereby “poising” the daughter cells to follow certain daughter cell-intrinsic pathways upon minimal instruction by a simple nonspecific trigger. This trigger may be represented by E or, alternatively, by materials concomitantly transferred from the donor to the acceptor cells, such as GPI-APs, integral and peripheral membrane proteins, cytoskeletal and cortical proteins arranged in micelle-like complexes, along with their subsequent incorporation into MELs. For instance, this may provide an explanation for the observation that incubation of cultured human adipocytes or ELCs with micelle-like GPI-AP complexes stimulates lipid and glycogen synthesis, respectively [<a href="#ref32">32</a>]. In general, signaling pathways, including the one engaged by insulin for LD biogenesis, consist of a complex cascade of weak linkages. Molecular pathways of this type may be initiated several times with the aid of limited adjustments, thereby enabling mixing and fitting to result in distinct outputs. A prerequisite for this intermingling and matching is the lack of instructive nature in the signal, i.e., signal and response are not coupled. The signal provoked by the micelle-like GPI-AP complexes merely initiates latent, independent pathways that preexist in the daughter or acceptor cells, i.e., that stimulate lipid and glycogen synthesis in adipocytes and ELCs, respectively.</p> <p id="id92">The important point, as stressed by Gerhart and Kirschner [<a href="#ref186">186</a>], is that core components and mechanisms are coupled by weak linkages, which support their rearrangement to produce new anatomical and physiological traits throughout evolution. Weak linkage “pervades development and physiology”, thereby abolishing the requirement for “multiple complex instructions and precise stereochemical complementarity” to be fulfilled by the inducer. Consequently, this enables the emergence of novel features, making weak linkage [<a href="#ref186">186</a>] “the most important biochemical and cellular strategy used in biology, and the most unique to it”.</p> <p id="id93">Research on the phenomenon of transdifferentiation, which refers to the conversion of one differentiated cell type, e.g., fibroblasts, to a different differentiated type, e.g., adipocytes, has raised doubts about whether “the differentiation potential of different cell types can still be allocated to a hierarchic model…rather than a flat system in which pluripotency merely represents one of many equally attainable states” [<a href="#ref192">192</a>]. In fact, transdifferentiation argues for the validity of a “primus inter pares (first among equals)” model, which does not lead to a preference for one of the alternate cell fates, i.e., fibroblast versus adipocytes, but rather presents them “as dents along the circumference of a flat disk” [<a href="#ref193">193</a>]. The conversion of one fate to another may be provoked by the torsion of a disk-like MEL at a certain angle in a specific direction in response to E, such as mechanic distortion. Alternatively, the incorporation of materials, such as (lyso)phospholipids, GPI-APs, and membrane proteins typically assembled into micelle-like complexes, transmembrane and peripheral proteins, and cytoskeletal and cortical proteins, into MELs could provoke altered cell fate. Thereby, the converted, i.e., tilted state of the disk or MEL may be stably maintained, or it may be attenuated and then gradually lost from that state, reversing to the original fate. In both models, one explaining insulin-like signal transduction in insulin-responsive cells and the other explaining transdifferentiation, distinct “states” are coupled by weak linkage, and the transformation of one state to another is elicited by E as a non-instructive inducer or signal.</p> <p id="id94">A similar explanation may hold true for the phenomenon of phenotypic plasticity, which is based on the selection of varying hidden developmental pathways depending on the existing environmental conditions faced by the embryo. This selection necessitates the capability of producing extended phenotypic changes that “already exist in the organism in self-inhibited alternative states, and [one or another of] these can be elicited by simple signals” [<a href="#ref186">186</a>]. Such a selection procedure, rather than mere “pressure” from certain E, may ultimately lead to pronounced changes during evolution, even in the absence of any alterations to the (epi)genome.</p> <p id="id95">Supported by the above conceptions of structural inheritance, extended heredity, poly-matter networks, facilitated variation, and self-inhibition, the following speculative model for the replication, transfer, and phenotypic expression of MELs as non-DNA matter is proposed (<b><a href="#fig019">Figure 19</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig019"></a><h5 class="sap__label">Figure 19</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">Hypothetical model of “plasma membrane memory” for the replication and transfer of membrane environment landscapes and the accompanying phenotypic consequences.</h4> <p id="id96">(<b>a</b>) Involvement of particulate micelle-like GPI-AP complexes. Step A: Micelle-like complexes consisting of GPI-APs, transmembrane and peripheral proteins, GPI-BSPs, and (lyso)phospholipids, which float in the culture medium or blood, become transferred to the PMs of acceptor cells. Step B: Micelle-like GPI-AP complexes (spontaneously) insert into the (raft domains of) acceptor PMs. Step C: Preexisting cytoskeletal–cortical elements residing at the cytoplasmic rim immediately below the PMs of the acceptor cells are arranged around the previously inserted micelle-like GPI-AP complexes, which causes the formation of MELs with specific configuration, composition, and topology. Thus, the complexes and those elements may be considered as a “three-dimensional positive picture” and “negative image” or “foot and footprint”, respectively. While the biogenesis of the complexes, i.e., the “foot”, relies on self-assembly, the formation of the cytoskeletal–cortical elements, the “footprint”, and consequently, that of the total MELs, critically depends on self-organization. Importantly, the interaction between the complexes and the cytoskeletal–cortical elements leads to the inactivation of the (newly) formed MELs. Therefore, the complexes, i.e., the “foot”, may be regarded as inhibitors of the cytoskeletal–cortical elements, i.e., the “footprint”, compatible with self- or autoinhibited phenotypic switching or the absence of a (new) phenotype. Step D: Micelle-like GPI-AP complexes are released from the MELs into the culture medium or blood in response to E. The resulting unoccupied MELs, i.e., the “footprint”, are relieved from self- or autoinhibition, thereby inducing a specific (new) phenotype. Step E: The components constituting the micelle-like complexes, such as GPI-APs, are synthesized de novo and self-assembled, leading to the restoration of the autoinhibited MELs and the gradual disappearance of the newly induced phenotype over time. Step F: In response to E, micelle-like GPI-AP complexes synthesized de novo and self-assembled are released from the MELs into the pool of previously released complexes (Step D). Together, these complexes are primed to initiate the next cycle of non-DNA matter inheritance. E (e.g., mechanical distortion and oxidative stress) may affect the configuration and topology of MELs directly at the PMs of donor cells and/or indirectly within the culture medium or blood.</p> <p id="id97">(<b>b</b>) Involvement of direct contacts been between donor and acceptor PMs. Step A: GPI-APs, transmembrane, and peripheral proteins, probably along with (lyso)phospholipids, are (spontaneously) translocated to the (raft domains of) PMs of acceptor cells, even in the absence of particulate micelles. Step B: Preexisting cytoskeletal and cortical elements located at the cytoplasmic rim just below the PMs of the acceptor cells are arranged around the previously translocated GPI-APs and transmembrane proteins, leading to the formation of MELs with a specific configuration and topology (as described in Step C above). E (e.g., mechanical distortion and oxidative stress) may affect the configuration and topology of MELs directly at the PMs of donor cells and/or within the culture medium or blood. Step C: GPI-APs and transmembrane proteins are translocated from the MELs to PMs of other acceptor cells in response to E. The resulting unoccupied MELs are relieved from autoinhibition, thereby inducing a specific (new) phenotype (as described in Step D above).</p> <p id="id98">The mutual exchange of transmembrane proteins and GPI-APs between the surfaces of adjacent cells, such as those within a tissue, via direct cell-to-cell contact with corresponding functional consequences, is referred to as trogocytosis (for a review, see [<a href="#ref194">194</a>–<a href="#ref198">198</a>]).</p> <p id="id99">The formation of MELs in the course of self-organization with preexisting components of cytoskeletal–cortical elements (a, Step C; b, Step B), as well as through self-assembly with de novo synthesized components of micelle-like GPI-AP complexes (a, Step E; b, Step B), may rely on weak linkages and in consequence, enable facilitated variation.GPI-APs seem to be predominantly prone to trogocytosis involving their translocation between the outer leaflets of the PMs of adjacent cells due to the nature of their anchorage via glycolipidic GPI only, as has previously been demonstrated for intermembrane protein transfer between erythrocytes and liposomes [<a href="#ref199">199</a>–<a href="#ref201">201</a>], as well as through electrostatic interactions between their protein moiety and the charged phospholipid headgroups at the PM surface, as has previously been shown for recombinant GPI-anchored green fluorescent protein and artificial planar lipid mono- and bilayers [<a href="#ref202">202</a>]. Moreover, the GPI anchor may induce “hemifusion” of PMs, i.e., the merging of the proximal but not distal, leaflets of the two juxtaposed lipid bilayers, as has previously been revealed for recombinant GPI-anchored trimeric influenza hemagglutinin and erythrocytes [<a href="#ref203">203</a>].</p> <p id="id100">By analogy, the “PM memory” of this model may resemble the “water memory”, as proposed recently as a molecular mechanism for the homeopathic principle [<a href="#ref204">204</a>–<a href="#ref209">209</a>], with the drug molecules operating as micelle-like GPI-AP complexes and the (lyso)phospholipids, in combination with the preexisting cytoskeletal and cortical elements, serving as water molecules. However, there is a major difference between the “PM and water memories”. Based on the various types of mutual interactions, rather than mere hydrogen bonding, only the constituents of PMs manage to form three-dimensional liquid crystalline networks, such as raft domains, which, in a certain sense, may behave like “plasticine” and enable the non-DNA matter to leave a footprint.</p> </div> <img alt="media/image22.png" src="https://journals.academia-photos.com/10/7401/image22.png"> </div> </div> <div class="sap__section"> <a id="sec11"></a><h2 class="sap__main-title">11. Conclusions: philosophical implications of “noncentric” conceptions of inheritance</h2> <p id="id101">It is our personal opinion that the possibility of phenotypic plasticity and the inheritance of acquired features by non-DNA matter and non-(epi)genetic mechanisms have not gained adequate consideration so far, both in general and in research on the (patho)physiology of common complex diseases, such as metabolic diseases, in particular. In fact, during the past century of analyzing transmission and developmental genetics, extraordinary attention has been paid by both scientists and laypeople to the information-driven mechanistic reductionist conception alone, rather than to a materialistic, holistic, or organicistic one [<a href="#ref210">210</a>]. This shift in focus has only begun to be recognized, acknowledged, and studied in the past two to three decades, also with the application of STS (for initial studies, see also Müller [<a href="#ref211">211</a>, <a href="#ref212">212</a>]). This neglect is presumably in part caused by adherence to the DNA-/gene-centric conception of inheritance for almost the total past century. As a consequence, MELs may have escaped acknowledgment as non-DNA matter in relevant studies. It will be interesting and important to identify and characterize the network of human and nonhuman (f)actors that have been or even are still responsible for the exclusion of non-DNA matter from the agents of biological inheritance and consequently, for the exclusion of acquired features from the material-discursive (scientific) practice of cellular and transgenerational inheritance. The following questions have to be analyzed:</p> <p id="id102">(i) What (f)actor(s) performed this so-called agential cut to separate genetic matter, i.e., DNA from non-DNA matter and MELs; (ii) which method(s) were used to accomplish this “agential cut”; (iii) what was the rationale, motivation, and reason at the scientific, cultural, societal, economic, and political level that provoked this “agential cut”?</p> <p id="id103">For circumvention of the problem of the emergence of typical exclusions, differences, and dichotomies (<b><a href="#fig020">Figure 20</a></b>), successful transdisciplinary cooperation is urgently required between natural science, i.e., here molecular, cell, and developmental biology, genetics, and biochemistry on one side and STS on the other. The latter encompasses, in particular, the application of the actor<b>–</b>network theory, as originally developed by Bruno Latour [<a href="#ref172">172</a>, <a href="#ref213">213</a>], Michel Callon [<a href="#ref214">214</a>], and John Law [<a href="#ref215">215</a>] (for a review, see Mathar [<a href="#ref216">216</a>]), AR as introduced by Karen Barad [<a href="#ref163">163</a>, <a href="#ref217">217</a>, <a href="#ref218">218</a>] (for a review, see [<a href="#ref219">219</a>]), and the seminal contributions of Donna Haraway [<a href="#ref220">220</a>, <a href="#ref221">221</a>] to both STS and developmental biology [<a href="#ref222">222</a>]. Importantly, the mere description of the (f)actors constituting the corresponding apparatuses of observation, such as researchers, cells, chemicals, media, centrifuges, gel chambers, chip-based biosensors, computers, plotters, databases, and journals at the scientific level, may be sufficient, as those are cutting things together apart and apart together in the corresponding experimental studies. The delineation of the causal relationship between those (f)actors is not required and typically cannot be accomplished by both STS and AR (<b><a href="#fig021">Figure 21</a></b>).</p> <p id="id104">In addition or alternatively, the concept of unconceived alternatives, as introduced by P. Kyle Stanford to explain the genesis of scientific theories in general [<a href="#ref223">223</a>, <a href="#ref224">224</a>] (<b><a href="#fig021">Figure 21</a></b>), and former ideas about inheritance, such as Pangenesis in particular [<a href="#ref225">225</a>], may be useful for characterizing the reasons for the acceptance of the “DNA-/gene-centric” conceptions versus other alternatives and the rejection of the latter (<b><a href="#fig022">Figures 22</a></b> and <b><a href="#fig023">23</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig020"></a><h5 class="sap__label">Figure 20</h5> <div class="sap__caption"><h4 class="sap__subsection-title">A synopsis of typical dichotomies or binaries relevant to our thinking about the phenomenon of biological inheritance.</h4></div> <img alt="media/image23.png" src="https://journals.academia-photos.com/10/7401/image23.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig021"></a><h5 class="sap__label">Figure 21</h5> <div class="sap__caption"><h4 class="sap__subsection-title">A synopsis of reasons why science and technology studies may contribute to both a broader and deeper understanding of the phenomenon of biological inheritance.</h4></div> <img alt="media/image24.png" src="https://journals.academia-photos.com/10/7401/image24.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig022"></a><h5 class="sap__label">Figure 22</h5> <div class="sap__caption"><h4 class="sap__subsection-title">A synopsis of some dichotomies commonly used for exclusion from scientific theories.</h4></div> <img alt="media/image25.png" src="https://journals.academia-photos.com/10/7401/image25.png"> </div> <div class="sap__fig sap__figure_panel"> <a id="fig023"></a><h5 class="sap__label">Figure 23</h5> <div class="sap__caption"><h4 class="sap__subsection-title">A synopsis of narratives commonly used for the exclusion of non-DNA matter as hereditary material.</h4></div> <img alt="media/image26.png" src="https://journals.academia-photos.com/10/7401/image26.png"> </div> <p id="id105">It is important to note that the hypothesis presented in this manuscript does not involve merely substituting the “DNA-/gene-centric” conception with another “centric” model, such as a “protein-, membrane-, or MEL-centric” conception. The reasons for avoiding such a “re-narrowing” have been extensively discussed [<a href="#ref211">211</a>, <a href="#ref212">212</a>].</p> <p id="id106">Rather than focusing on the exclusion of “hard/gene-centric expression” or the inclusion of “soft/Lamarckian” [<a href="#ref222">222</a>] or “epigenetic/structural/extended inter-action” [<a href="#ref226">226</a>, <a href="#ref227">227</a>], a “pluralistic/including/poly-matter/rhizenic intra-action” of inheritance is suggested (<b><a href="#fig024">Figure 24</a></b>).</p> <div class="sap__fig sap__figure_panel"> <a id="fig024"></a><h5 class="sap__label">Figure 24</h5> <div class="sap__caption"> <h4 class="sap__subsection-title">A synopsis of various contrasting conceptions of biological inheritance: (A) “Mendelian” inheritance is mediated by the transmission of DNA (i.e., “hard” gene mutations and polymorphisms) from parents (F<sub>0</sub>) to offspring (F<sub>1</sub>), unaffected by environmental factors. (B) “Lamarckian” inheritance is mediated by the transmission of DNA, with germ line cells amenable to certain mutations initiated in the somatic cell line in response to environmental factors, thereby mediating the “soft” inheritance of acquired traits. (C) “Extended” inheritance is mediated by the transmission of DNA alongside a multitude of specific regulatory (i.e., signals of epigenetic modification, such as methylation, acetylation, ubiquitination, and phosphorylation) or positional factors (e.g., transcription factors, hormones, and signaling proteins) initiated in the somatic cell line in response to environmental factors, thus enabling the “epigenetic” (in the narrow sense) inheritance of acquired traits. In parallel to gene transmission, a multitude of structures (or templates), such as plasma membranes, organelles, and cytoskeletal elements (e.g., cortex and cilia), are transferred, having originated in somatic cell lines and then been modified in response to environmental factors. This process enables the “structural” inheritance of acquired traits. (D) “Poly-matter” inheritance encompasses the mode of “extended” inheritance, plus “pluralistic” and “including” inheritance, involving the replication, transfer, and phenotypic switching of MELs. While the conceptions of “Lamarckian” and “extended” inheritance rely on the “inter-actions” between environmental factors–somatic cell lines and environmental factors–regulatory factors or environmental factors–structures, respectively, the “poly-matter” conception emphasizes the importance for “intra-actions” among environmental factors–regulatory factors, environmental factors–structures, environmental factors–membrane environment landscapes, and membrane environment landscapes–DNA. (The critical difference between “inter-action” and “intra-action”, according to Barad, is explained below; figure adapted from Bonduriansky [<a href="#ref178">178</a>], Elsevier, Amsterdam, The Netherlands, with modifications. The “structural” and “poly-matter” conceptions of inheritance have been introduced into this synopsis by the author.)</h4> <p id="id107">The “intra-actions” MELs–DNA and structures–DNA apparently prevent the calculation of the relative contribution of structures and MELs, respectively, to “poly-matter” in comparison to “DNA-centric” inheritance conceptions. By contrast, analogous calculations of the relative contributions of DNA versus E or DNA versus epigenetic mechanisms may be feasible or even useful concerning the corresponding “inter-actions” prevalent in “Lamarckian” and “extended” inheritance, respectively.</p> </div> <img alt="media/image27.png" src="https://journals.academia-photos.com/10/7401/image27.png"> </div> <p id="id108">The use of STS, in general, and AR, in particular, for the analysis of biological inheritance leads to the description of a multitude of actors and actions encompassing but not restricted to DNA, genes, proteins, lipids, PMs, organelles, MELs, E, donor and acceptor organisms, researchers, and laboratory and experimental setups, such as the SAW biosensing instrument, scientific journals, text books, and so on. These actors and actions, in concert, contribute to the generation of apparatuses for both the production and observation of a specific phenomenon of heredity. Accordingly, the donor and acceptor organisms, as well as the subject and object of a measurement—here the SAW biosensor and transwell cell coculture—should be interpreted as only agentially separable rather than as distinct preexisting separated entities. The consideration of the meaning and agency of agential cuts and the parallel shift from the Cartesian to Bohr’s and Barad’s views of representation [<a href="#ref228">228</a>–<a href="#ref230">230</a>] may facilitate or even provide considerable advantages for the future investigation of the (patho)physiology of common complex diseases in general and metabolic diseases in particular, beyond the scope of typical classifications as DNA, E, nutrition, or lifestyle driven and their, nevertheless very important, epigenetic analyses.</p> <p id="id109">Gary Grimes and Karl Aufderheide [<a href="#ref126">126</a>] were among the first to note that structural inheritance and prions share an important aspect of their nature: a given gene product may be expressed as two (or more) distinct conformations, with shifting between these by chance, which leads to alternate cycles of infectious phenotypes driven by non-DNA matter. By contrast, both structural and poly-matter inheritance do not rely on the differential conformation of proteins but rather on the variation in the configuration of subcellular components and their three-dimensional arrangement. Nevertheless, these two phenomena critically depend on similar processes of nucleation and expansion of fibrous components to foster their assembly into three-dimensional structures. Consequently, the configuration of molecules, macromolecules, and subcellular structures cannot be regarded as being solely determined by the information contained in DNA matter. Rather, the inheritance of new configurations, as varied and assembled by chance, broadens our conception of phenotypic variation, which is determined by a certain genotype, as well as its adaptation to E and effect on evolution [<a href="#ref231">231</a>].</p> <p id="id110">Considering the history and philosophy of biological science in general and research on biological inheritance in particular, it is striking to see that the initial publication of the studies on <i>Paramecium</i> during 1963–1965 was hardly accompanied by considerable acceptance of the conception of structural inheritance. Rather, variants of the cortical structure in <i>Paramecium</i> were predominantly interpreted as curios zoological peculiarities with minor scientific significance. Despite strong evidence from genetic analysis, the demonstration of a critical role for preexisting and preassembled cellular structures in cellular heredity, i.e., cortical inheritance, was faced with preconceived opinions and ideological hindrances of similar type. After 20 years, the experimentally based acknowledgment of the operation of prions as “protein genes” was confronted with similar skepticism. In analogy, MELs—i.e., three-dimensional assemblies of micelle-like complexes of GPI-APs, transmembrane proteins, cytoskeletal elements, and (lyso)phospholipids as non-DNA matter of inheritance—have been neglected in the scientific community over the past decade. The lack of integration of non-DNA matter in heredity research, with its resulting narrowing to Mendelian inheritance (see, e.g., [<a href="#ref232">232</a>, <a href="#ref233">233</a>]), may provide a partial explanation for the low number of well-explored and documented examples of both structural and poly-matter inheritance. Molecular and subcellular structures or assemblies, such as prions, cortex, membranes, and MELs, typically fail to be recognized as (even short-term acting) matter of inheritance in the processes of growth, differentiation, and development. Rather, their formation and biogenesis are conceived of as transient steps in the course of a linear sequence of events initiated by genes.</p> <p id="id111">It should be expected that with the renewed interest in epigenetics (for a review, see [<a href="#ref234">234</a>–<a href="#ref241">241</a>]) and the enormous potential of “omics” technologies in combination with the tools of artificial intelligence for functional analysis, the number of newly identified cases of structural and poly-matter inheritance will increase steadily. Nevertheless, prerequisite for this admittedly major scientific progress seems to be the development of an adequate understanding of the philosophical, cultural, societal, political, and economic reasons for the exclusion of non-DNA matter from biological inheritance and for the narrowing to DNA-based inheritance, which should be fostered by future STS. One of the research areas newly opened by the poly-matter conception and its analysis by STS is synthetic biology, which aims at creating (bacterial and protozoal) cells. These cells will display unique and specific morphological features and metabolic phenotypes not observed or used (for biotechnological applications) so far and should exceed the (mere, albeit) total exchange of DNA matter (for previously designed bacterial strategies, see [<a href="#ref137">137</a>, <a href="#ref242">242</a>, <a href="#ref243">243</a>]; for a review, see [<a href="#ref165">165</a>, <a href="#ref244">244</a>]) for the creation 0f prokaryotic [<a href="#ref245">245</a>] or eukaryotic microorganisms [<a href="#ref246">246</a>].</p> </div> </div> <div id="article-back" class="sap__back"> <div class="sap__back-section"> <a id="abbreviations1"></a><h4 class="sap__block-title">Abbreviations</h4> <div class="sap__def-list"> <a id="id112"></a><div class="sap__def-list sap__table"> <div class="sap__def-item sap__row" id="id113"><div class="sap__def-term sap__cell" id="id114"><p>AChE: acetylcholinesterase</p></div></div> <div class="sap__def-item sap__row" id="id115"><div class="sap__def-term sap__cell" id="id116"><p>AR: agential realism</p></div></div> <div class="sap__def-item sap__row" id="id117"><div class="sap__def-term sap__cell" id="id118"><p>BSA: bovine serum albumin</p></div></div> <div class="sap__def-item sap__row" id="id119"><div class="sap__def-term sap__cell" id="id120"><p>Cs: cytosines</p></div></div> <div class="sap__def-item sap__row" id="id121"><div class="sap__def-term sap__cell" id="id122"><p>E: environmental factor(s)</p></div></div> <div class="sap__def-item sap__row" id="id123"><div class="sap__def-term sap__cell" id="id124"><p>ELCs: erythroleukemia cells</p></div></div> <div class="sap__def-item sap__row" id="id125"><div class="sap__def-term sap__cell" id="id126"><p>ER: endoplasmic reticulum</p></div></div> <div class="sap__def-item sap__row" id="id127"><div class="sap__def-term sap__cell" id="id128"><p>EVs: extracellular vesicles</p></div></div> <div class="sap__def-item sap__row" id="id129"><div class="sap__def-term sap__cell" id="id130"><p>Glut1/4: glucose transporter-1/4</p></div></div> <div class="sap__def-item sap__row" id="id131"><div class="sap__def-term sap__cell" id="id132"><p>GPI: glycosylphosphatidylinositol</p></div></div> <div class="sap__def-item sap__row" id="id133"><div class="sap__def-term sap__cell" id="id134"><p>GPI-AP BSPs: GPI-AP binding serum proteins</p></div></div> <div class="sap__def-item sap__row" id="id135"><div class="sap__def-term sap__cell" id="id136"><p>GPI-AP(s): GPI-anchored protein(s)</p></div></div> <div class="sap__def-item sap__row" id="id137"><div class="sap__def-term sap__cell" id="id138"><p>GPI-PLC/D(1): GPI-specific phospholipase C/D(1)</p></div></div> <div class="sap__def-item sap__row" id="id139"><div class="sap__def-term sap__cell" id="id140"><p>iPSC(s): induced pluripotent stem cell(s)</p></div></div> <div class="sap__def-item sap__row" id="id141"><div class="sap__def-term sap__cell" id="id142"><p>IR: insulin receptor</p></div></div> <div class="sap__def-item sap__row" id="id143"><div class="sap__def-term sap__cell" id="id144"><p>LD(s): lipid droplet(s)</p></div></div> <div class="sap__def-item sap__row" id="id145"><div class="sap__def-term sap__cell" id="id146"><p>MEL(s): membrane environment landscape(s)</p></div></div> <div class="sap__def-item sap__row" id="id147"><div class="sap__def-term sap__cell" id="id148"><p>mßCD: methyl-ß-cyclodextrin</p></div></div> <div class="sap__def-item sap__row" id="id149"><div class="sap__def-term sap__cell" id="id150"><p>PIGs: phosphoinositolglycans</p></div></div> <div class="sap__def-item sap__row" id="id151"><div class="sap__def-term sap__cell" id="id152"><p>PI-PLC: phosphatidylinositol-specific phospholipase C</p></div></div> <div class="sap__def-item sap__row" id="id153"><div class="sap__def-term sap__cell" id="id154"><p>PM(s): plasma membrane(s)</p></div></div> <div class="sap__def-item sap__row" id="id155"><div class="sap__def-term sap__cell" id="id156"><p>SAW: surface acoustic waves</p></div></div> <div class="sap__def-item sap__row" id="id157"><div class="sap__def-term sap__cell" id="id158"><p>SRP: signal recognition particle</p></div></div> <div class="sap__def-item sap__row" id="id159"><div class="sap__def-term sap__cell" id="id160"><p>STS: science and technology studies</p></div></div> <div class="sap__def-item sap__row" id="id161"><div class="sap__def-term sap__cell" id="id162"><p>TAG: triacylglycerol</p></div></div> <div class="sap__def-item sap__row" id="id163"><div class="sap__def-term sap__cell" id="id164"><p>TNAP: tissue nonspecific alkaline phosphatase</p></div></div> </div> </div> </div> <div class="sap__back-section"> <a id="sec12"></a><h2 class="sap__main-title">Funding</h2> <p id="id165">The author declares no financial support for the authorship or publication of this article. The scientific research performed by the author and reviewed in this article was funded by the Institute of Diabetes and Obesity (IDO) at Helmholtz Center Munich, German Research Center for Environmental Health, Oberschleissheim, Germany.</p> </div> <div class="sap__back-section"> <a id="sec13"></a><h2 class="sap__main-title">Author contributions</h2> <p id="id166">The author confirms sole responsibility for this work. The author approves of this work and takes responsibility for its integrity.</p> </div> <div class="sap__back-section"> <a id="id168"></a><h2 class="sap__main-title">Conflict of interest</h2> <p id="id167">The author declares no conflict of interest.</p> </div> <div class="sap__back-section"> <a id="sec14"></a><h2 class="sap__main-title">Data availability statement</h2> <p id="id169">Data supporting these findings are available within the article, at <a target="xrefwindow" href="https://doi.org/10.20935/AcadMolBioGen7401" id="id170">https://doi.org/10.20935/AcadMolBioGen7401</a>, or upon request.</p> </div> <div class="sap__back-section"> <a id="sec15"></a><h2 class="sap__main-title">Institutional review board statement</h2> <p id="id171">Not applicable.</p> </div> <div class="sap__back-section"> <a id="sec16"></a><h2 class="sap__main-title">Informed consent statement</h2> <p id="id172">Not applicable.</p> </div> <div class="sap__back-section"> <a id="sec17"></a><h2 class="sap__main-title">Publisher’s note</h2> <p id="id173">Academia.edu Journals stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p> </div> <div id="article-reference-list" class="sap__section"><div class="sap__back-section"> <a id="id174"></a><div class="sap__back-section sap__ref-list"> <a id="id174"></a><h2 class="sap__main-title">References</h2> <div class="sap__ref-list sap__table"> <a id="ref1"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id175"></a>1</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id176"></a>Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science. 1972;175:720–31. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.175.4023.720" id="id177">10.1126/science.175.4023.720</a></p></div> </div> <a id="ref2"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id178"></a>2</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id179"></a>Jelokhani-Niaraki M. Membrane proteins: structure, function and motion. Int J Mol Sci. 2023;24:468. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms24010468" id="id180">10.3390/ijms24010468</a></p></div> </div> <a id="ref3"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id181"></a>3</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id182"></a>Stryer L. Biochemistry. San Francisco, USA: W.H. Freeman and Company; 1975.</p></div> </div> <a id="ref4"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id183"></a>4</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id184"></a>Singer SJ. The molecular organization of membranes. Annu Rev Biochem. 1974;43:805–33. doi: <a target="xrefwindow" href="https://doi.org/10.1146/annurev.bi.43.070174.004105" id="id185">10.1146/annurev.bi.43.070174.004105</a></p></div> </div> <a id="ref5"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id186"></a>5</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id187"></a>Müller GA. Glycosylphosphatidylinositol-anchored proteins and their release from cells – from phenomenon to meaning. New York: Nova Science Publishers - Biochemistry Research Trends; 2018. p. 104–15.</p></div> </div> <a id="ref6"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id188"></a>6</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id189"></a>Ferguson MAJ, Haldar K, Cross GAM. <i>Trypanosoma brucei</i> variant surface glycoprotein has a <i>sn</i>-1,2-dimyristyl glycerol membrane anchor at its COOH terminus. J Biol Chem. 1985;260:4963–8. PMID: 3988741</p></div> </div> <a id="ref7"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id190"></a>7</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id191"></a>Eisenhaber B, Bork P, Eisenhaber B. Post-translational GPI lipid anchor modification of proteins in kingdoms of life: analysis of protein sequence data from complete genomes. Protein Eng. 2001;14:17–25. doi: <a target="xrefwindow" href="https://doi.org/10.1093/protein/14.1.17" id="id192">10.1093/protein/14.1.17</a></p></div> </div> <a id="ref8"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id193"></a>8</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id194"></a>Poisson G, Chauve C, Chen X, Bergeron A. FragAnchor: a large-scale predictor of glycosylphosphatidylinositol anchors in eukaryote protein sequences by qualitative scoring. Genom Proteom Bioinform. 2007;5:121–30. doi: <a target="xrefwindow" href="https://doi.org/10.1016/S1672-0229(07)60022-9" id="id195">10.1016/S1672-0229(07)60022-9</a></p></div> </div> <a id="ref9"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id196"></a>9</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id197"></a>Fujihara Y, Ikawa M. GPI-AP release in cellular, developmental, and reproductive biology. J Lipid Res. 2016;57:538–45. doi: <a target="xrefwindow" href="https://doi.org/10.1016/S1672-0229(07)60022-9" id="id198">10.1016/S1672-0229(07)60022-9</a></p></div> </div> <a id="ref10"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id199"></a>10</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id200"></a>Kinoshita T. Biosynthesis and biology of mammalian GPI-anchored proteins. Open Biol. 2020;10:190290. doi: <a target="xrefwindow" href="https://doi.org/10.1098/rsob.190290" id="id201">10.1098/rsob.190290</a></p></div> </div> <a id="ref11"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id202"></a>11</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id203"></a>Müller GA. Membrane insertion and intracellular transfer of glycosylphosphatidylinositol-anchored proteins: potential therapeutic applications. Arch Physiol Biochem. 2020; 126:139–56. doi: <a target="xrefwindow" href="https://doi.org/10.1080/13813455.2018.1498904" id="id204">10.1080/13813455.2018.1498904</a></p></div> </div> <a id="ref12"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id205"></a>12</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id206"></a>Albert B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Membrane proteins in molecular biology of the cell. New York: Garland Science/Taylor & Francis; 2002. p. 1525.</p></div> </div> <a id="ref13"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id207"></a>13</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id208"></a>Dobson L, Reményi GE, Tusnády GE. The human transmembrane proteome. Biol Direct. 2015;10:31. doi: <a target="xrefwindow" href="https://doi.org/10.1186/s13062-015-0061-x" id="id209">10.1186/s13062-015-0061-x</a></p></div> </div> <a id="ref14"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id210"></a>14</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id211"></a>Bausch-Fluck D, Goldmann U, Müller S, van Oostrum M, Müller M, Schubert OT, et al. The in silico human surfaceome. Proc Natl Acad Sci USA. 2018;115:E10988–97. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.1808790115" id="id212">10.1073/pnas.1808790115</a></p></div> </div> <a id="ref15"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id213"></a>15</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id214"></a>Müller GA, Müller TD. (Patho)Physiology of glycosylphosphatidylinositol-anchored proteins II: intercellular transfer of matter (inheritance?) that matters. Biomolecules. 2023;13:994. doi: <a target="xrefwindow" href="https://doi.org/10.3390/biom13060994" id="id215">10.3390/biom13060994</a></p></div> </div> <a id="ref16"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id216"></a>16</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id217"></a>Müller GA, Müller TD. (Patho)Physiology of glycosylphosphatidylinositol-anchored proteins I: localization at plasma membranes and extracellular compartments. Biomolecules. 2023;13:855. doi: <a target="xrefwindow" href="https://doi.org/10.3390/biom13050855" id="id218">10.3390/biom13050855</a></p></div> </div> <a id="ref17"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id219"></a>17</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id220"></a>Trams EG, Lauter CJ, Salem N Jr, Heine U. Exfoliation of membrane ecto-enzymes in the form of microvesicles. Biochim Biophys Acta. 1981;645:63–70. doi: <a target="xrefwindow" href="https://doi.org/10.1016/0005-2736(81)90512-5" id="id221">10.1016/0005-2736(81)90512-5</a></p></div> </div> <a id="ref18"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id222"></a>18</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id223"></a>Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000; 113:3365–74. doi: <a target="xrefwindow" href="https://doi.org/10.1242/jcs.113.19.3365" id="id224">10.1242/jcs.113.19.3365</a></p></div> </div> <a id="ref19"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id225"></a>19</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id226"></a>Johnstone RM. Revisiting the road to the discovery of exosomes. Blood Cells Molec Dis. 2005;34:214–9. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.bcmd.2005.03.002" id="id227">10.1016/j.bcmd.2005.03.002</a></p></div> </div> <a id="ref20"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id228"></a>20</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id229"></a>Müller G. Microvesicles/Exosomes as potential novel biomarkers for metabolic diseases. Diabet Metabol Synd Obes Targets Therap. 2012;5:247–82. doi: <a target="xrefwindow" href="https://doi.org/10.2147/DMSO.S32923" id="id230">10.2147/DMSO.S32923</a></p></div> </div> <a id="ref21"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id231"></a>21</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id232"></a>Hargett LA, Bauer NN. On the origin of microparticles: from “platelet dust” to mediators of intercellular communication. Pulmon Circ. 2013;3:329–40. doi: <a target="xrefwindow" href="https://doi.org/10.4103/2045-8932.114760" id="id233">10.4103/2045-8932.114760</a></p></div> </div> <a id="ref22"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id234"></a>22</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id235"></a>Harrison P, Gardiner C, Sargent IL. Extracellular vesicles in health and disease. Singapore: Pan Stanford Publishing, CRC Press; 2014.</p></div> </div> <a id="ref23"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id236"></a>23</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id237"></a>Cocucci E, Meldolesi J. Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 2015;25:364–72. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.tcb.2015.01.004" id="id238">10.1016/j.tcb.2015.01.004</a></p></div> </div> <a id="ref24"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id239"></a>24</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id240"></a>Clemmens H, Lambert DW. Extracellular vesicles: translational challenges and opportunities. Biochem Soc Transact. 2018;46:1073–82. doi: <a target="xrefwindow" href="https://doi.org/10.1042/BST20180112" id="id241">10.1042/BST20180112</a></p></div> </div> <a id="ref25"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id242"></a>25</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id243"></a>Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428–45. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.cell.2019.02.029" id="id244">10.1016/j.cell.2019.02.029</a></p></div> </div> <a id="ref26"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id245"></a>26</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id246"></a>Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nature Cell Biol. 2019;21:9–17. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41556-018-0250-9" id="id247">10.1038/s41556-018-0250-9</a></p></div> </div> <a id="ref27"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id248"></a>27</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id249"></a>Raposo G, Stahl PD. Extracellular vesicles: a new communication paradigm? Nature Rev Molec Cell Biol. 2019;20:509–10. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41580-019-0158-7" id="id250">10.1038/s41580-019-0158-7</a></p></div> </div> <a id="ref28"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id251"></a>28</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id252"></a>Couch Y, Buzas EI, Di Vizio D, Gho YS, Harrison P, Hill AF, et al. A brief history of nearly everything – the rise and rise of extracellular vesicles. J Extracell Vesic. 2021;10:e12144. doi: <a target="xrefwindow" href="https://doi.org/10.1002/jev2.12144" id="id253">10.1002/jev2.12144</a></p></div> </div> <a id="ref29"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id254"></a>29</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id255"></a>Panakova D, Sprong H, Marois E, Thiele C, Eaton S. Lipoprotein particles are required for Hedgehog and Wingless signalling. Nature. 2005;435:58–65. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nature03504" id="id256">10.1038/nature03504</a></p></div> </div> <a id="ref30"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id257"></a>30</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id258"></a>Neumann S, Harterink M, Sprong H. Hitch-hiking between cells on lipoprotein particles. Traffic. 2007;8: 331–8. doi: <a target="xrefwindow" href="https://doi.org/10.1111/j.1600-0854.2006.00532.x" id="id259">10.1111/j.1600-0854.2006.00532.x</a></p></div> </div> <a id="ref31"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id260"></a>31</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id261"></a>Eaton S. Multiple roles for lipids in the Hedgehog signalling pathway. Nat Rev Mol Cell Biol. 2008;9:437–45. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nrm2414" id="id262">10.1038/nrm2414</a></p></div> </div> <a id="ref32"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id263"></a>32</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id264"></a>Müller GA, Müller TD. Transfer of membrane(s) matter(s) – non-genetic inheritance of (metabolic) phenotypes? Front Mol Biosci. 2024;11:1347397. doi: <a target="xrefwindow" href="https://doi.org/10.3389/fmolb.2024.1347397" id="id265">10.3389/fmolb.2024.1347397</a></p></div> </div> <a id="ref33"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id266"></a>33</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id267"></a>Müller GA, Müller TD. Transfer of proteins from cultured human adipose to blood cells and induction of anabolic phenotype are controlled by serum, insulin and sulfonylurea drugs. Int J Mol Sci. 2023;24:482. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms24054825" id="id268">10.3390/ijms24054825</a></p></div> </div> <a id="ref34"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id269"></a>34</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id270"></a>Gronewold TMA, Glass S, Quandt E, Famulok M. Monitoring complex formation in the blood-coagulation cascade using aptamer-coated SAW sensors. Biosens Bioelectron. 2005;20:2044–52. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.bios.2004.09.007" id="id271">10.1016/j.bios.2004.09.007</a></p></div> </div> <a id="ref35"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id272"></a>35</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id273"></a>Andrä J, Böhling A, Gronewold TMA, Schlecht U, Perpeet M, Gutsmann T. Surface acoustic wave biosensor as a tool to study the interaction of antimicrobial peptides with phospholipid and lipopolysaccaride model membranes. Langmuir. 2008;24:9148–53. doi: <a target="xrefwindow" href="https://doi.org/10.1021/la801252t" id="id274">10.1021/la801252t</a></p></div> </div> <a id="ref36"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id275"></a>36</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id276"></a>Müller GA, Lechner A, Tschöp MH, Müller TD. Interaction of full-length glycosylphosphatidylinositol-anchored proteins with serum proteins and their translocation to cells in vitro depend on the (pre-)diabetic state in rats and humans. Biomedicines. 2021;9:277. doi: <a target="xrefwindow" href="https://doi.org/10.3390/biomedicines9030277" id="id277">10.3390/biomedicines9030277</a></p></div> </div> <a id="ref37"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id278"></a>37</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id279"></a>Müller GA, Tschöp MH, Müller TD. Chip-based sensing of the intercellular transfer of cell surface proteins: regulation by the metabolic state. Biomedicines. 2021; 9:1452. doi: <a target="xrefwindow" href="https://doi.org/10.3390/biomedicines9101452" id="id280">10.3390/biomedicines9101452</a></p></div> </div> <a id="ref38"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id281"></a>38</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id282"></a>Müller GA, Herling AW, Stemmer K, Lechner A, Tschöp MH. Chip-based sensing for release of unprocessed cell surface proteins in vitro and in serum and its (patho)physiological relevance. Am J Physiol Endocrinol Metab. 2019;317:E212–33. doi: <a target="xrefwindow" href="https://doi.org/10.1152/ajpendo.00079.2019" id="id283">10.1152/ajpendo.00079.2019</a></p></div> </div> <a id="ref39"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id284"></a>39</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id285"></a>Müller GA, Müller TD. Biological role of the intercellular transfer of glyosylphosphatidylinositol-anchored proteins: stimulation of lipid and glycogen synthesis. Int J Mol Sci. 2022;23:7418. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms23137418" id="id286">10.3390/ijms23137418</a></p></div> </div> <a id="ref40"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id287"></a>40</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id288"></a>Hirose S, Mohney RP, Mutka SC, Ravi L, Singleton DR, Perry G, et al. Derivation and characterization of glycoinositol-phospholipid anchor-defective human K562 cell clones. J Biol Chem. 1992;267:5272–8. PMID: 1371997</p></div> </div> <a id="ref41"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id289"></a>41</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id290"></a>Lazar DF, Knez JJ, Medof ME, Cuatrecasas P, Saltiel AR. Stimulation of glycogen synthesis by insulin in human erythroleukemia cells requires the synthesis of glycosylphosphatidylinositol. Proc Natl Acad Sci USA. 1994;91:9665–9. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.91.21.9665" id="id291">10.1073/pnas.91.21.9665</a></p></div> </div> <a id="ref42"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id292"></a>42</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id293"></a>Ilangumaran S, Hoessli DC. Effects of cholesterol depletion by cyclodextrin on the sphingolipid microdomains of the plasma membrane. Biochem J. 1998;335:433–40. doi: <a target="xrefwindow" href="https://doi.org/10.1042/bj3350433" id="id294">10.1042/bj3350433</a></p></div> </div> <a id="ref43"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id295"></a>43</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id296"></a>Wong YW, Low MG. Biosynthesis of glycosylphosphatidylinositol-anchored human placental alkaline phosphatase: evidence for a phospholipase C-sensitive precursor and its post-attachment conversion into a phospholipase C-resistant form. Biochem J. 1994; 301:205–9. doi: <a target="xrefwindow" href="https://doi.org/10.1042/bj3010205" id="id297">10.1042/bj3010205</a></p></div> </div> <a id="ref44"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id298"></a>44</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id299"></a>Dolezal S, Hester S, Kirby PS, Nairn A, Pierce M, Abbott KL. Elevated levels of glycosylphosphatidylinositol (GPI) anchored proteins in plasma from human cancers detected by C. septicum alpha toxin. Cancer Biomark. 2014;14:55–62. doi: <a target="xrefwindow" href="https://doi.org/10.3233/CBM-130377" id="id300">10.3233/CBM-130377</a></p></div> </div> <a id="ref45"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id301"></a>45</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id302"></a>Huang K, Park S. Affinity purification of glycosylphosphatidylinositol-anchored proteins by alpha-toxin. Methods Mol Biol. 2022;2303:251–7. doi: <a target="xrefwindow" href="https://doi.org/10.1007/978-1-0716-1398-6_20" id="id303">10.1007/978-1-0716-1398-6_20</a></p></div> </div> <a id="ref46"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id304"></a>46</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id305"></a>Pan YT, Kamitani T, Bhuvaneswaran C, Hallag Y, Warren CD, Yeh ET, et al. Inhibition of glycosylphosphatidylinositol anchor formation by mannosamine. J Biol Chem. 1992;267:21250–5. PMID: 1400435</p></div> </div> <a id="ref47"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id306"></a>47</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id307"></a>Sevlever D, Rosenberry TL. Mannosamine inhibits the synthesis of putative glycoinositol phosphplipid anchor precursors in mammalian cells without incorporating into an accumulated intermediate. J Biol Chem. 1993;268:10938–45. PMID: 8496158</p></div> </div> <a id="ref48"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id308"></a>48</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id309"></a>Müller G, Wied S, Jung C, Straub J. Coordinated regulation of esterification and lipolysis by palmitate, H<sub>2</sub>O<sub>2</sub> and the antidiabetic sulfonylurea drug, glimepiride, in rat adipocytes. Eur J Pharmacol. 2008;597:6–18. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.ejphar.2008.08.034" id="id310">10.1016/j.ejphar.2008.08.034</a></p></div> </div> <a id="ref49"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id311"></a>49</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id312"></a>Wilfling F, Haas JT, Walther TC, Farese RV. Lipid droplet biogenesis. Curr Opin Cell Biol. 2014;29:39–45. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.ceb.2014.03.008" id="id313">10.1016/j.ceb.2014.03.008</a></p></div> </div> <a id="ref50"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id314"></a>50</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id315"></a>Chorlay A, Monticelli L, Verissimo Ferreira J, Ben M’barek K, Ajjaji D, Wang S, et al. Membrane asymmetry imposes directionality on lipid droplet emergence from the ER. Dev Cell. 2019;50:25–42. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.devcel.2019.05.003" id="id316">10.1016/j.devcel.2019.05.003</a></p></div> </div> <a id="ref51"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id317"></a>51</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id318"></a>Chung J, Wu X, Lambert TJ, Lai ZW, Walther TC, Farese RV Jr. LDAF1 and seipin form a lipid droplet assembly complex. Dev Cell. 2019;51:551–63. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.devcel.2019.10.006" id="id319">10.1016/j.devcel.2019.10.006</a></p></div> </div> <a id="ref52"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id320"></a>52</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id321"></a>Choudhary V, Schneiter R. A unique junctional interface at contact sites between the endoplasmic reticulun and lipid droplets. Front Cell Dev Biol. 2021;9:650186. doi: <a target="xrefwindow" href="https://doi.org/10.3389/fcell.2021.650186" id="id322">10.3389/fcell.2021.650186</a></p></div> </div> <a id="ref53"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id323"></a>53</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id324"></a>Kumari RM, Khatri A, Chaudhary R, Choudhary V. Concept of lipid droplet biogenesis. Eur J Cell Biol. 2023;102:151362. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.ejcb.2023.151362" id="id325">10.1016/j.ejcb.2023.151362</a></p></div> </div> <a id="ref54"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id326"></a>54</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id327"></a>Müller G, Wied S, Jung C, Over S. Hydrogen peroxide-induced translocation of glycolipid-anchored (c)AMP-hydrolases to lipid droplets mediates inhibition of lipolysis in rat adipocytes. Br J Pharmacol. 2008;154: 901–13. doi: <a target="xrefwindow" href="https://doi.org/10.1038/bjp.2008.146" id="id328">10.1038/bjp.2008.146</a></p></div> </div> <a id="ref55"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id329"></a>55</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id330"></a>Huang K-S, Li S, Fung W-JC, Hulmes JD, Reik L, Pan YCE, et al. Purification and characterization of glycosyl-phosphatidylinositol-specific phospholipase D. J Biol Chem. 1990;265:17738–45. PMID: 2170394</p></div> </div> <a id="ref56"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id331"></a>56</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id332"></a>Davitz MA, Low MG, Nussenzweig V. Release of decay-accelerating factor (DAF) from the cell membrane by phosphatidylinositol-specific phospholipase C (PIPLC). selective modification of a complement regulatory protein. J Exp Med. 1986;163:1150–61. doi: <a target="xrefwindow" href="https://doi.org/10.1084/jem.163.5.1150" id="id333">10.1084/jem.163.5.1150</a></p></div> </div> <a id="ref57"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id334"></a>57</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id335"></a>Stieger S, Diem S, Jakob A, Brodbeck U. Enzymatic properties of phosphatidylinositol-glycan-specific phospholipase C from rat liver and phosphatidylinositol-glycan-specific phospholipase D from rat serum. Eur J Biochem. 1991;197:67–73. doi: <a target="xrefwindow" href="https://doi.org/10.1111/j.1432-1033.1991.tb15883.x" id="id336">10.1111/j.1432-1033.1991.tb15883.x</a></p></div> </div> <a id="ref58"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id337"></a>58</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id338"></a>Li J-Y, Hollfelder K, Huang K-S, Low MG. Structural features of GPI-specific phospholipase D revealed by proteolytic fragmentation and Ca<sup>2+</sup> binding studies. J Biol Chem. 1994;269:28963–71. PMID: 7961859</p></div> </div> <a id="ref59"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id339"></a>59</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id340"></a>Liu Y-S, Fujita M. Mammalian GPI-anchor modifications and the enzymes involved. Biochem Soc Trans. 2020;48:1129–38. doi: <a target="xrefwindow" href="https://doi.org/10.1042/BST20191142" id="id341">10.1042/BST20191142</a></p></div> </div> <a id="ref60"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id342"></a>60</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id343"></a>Komath SS, Fujita M, Hart GW, Ferguson MAJ, Kinoshita T. Glycosylphosphatidylinositol anchors. In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al., editors. Essentials of glycobiology. Chapter 12. Cold Spring Harbor: Cold Spring Harbor Laboratory Press; 2023.</p></div> </div> <a id="ref61"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id344"></a>61</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id345"></a>Uversky VN. Disorder in the lifetime of a protein. Intrinsic Disord Proteins. 2013;1:e26782. doi: <a target="xrefwindow" href="https://doi.org/10.4161/idp.26782" id="id346">10.4161/idp.26782</a></p></div> </div> <a id="ref62"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id347"></a>62</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id348"></a>Uversky VN. The multifaceted roles of intrinsic disorder in protein complexes. FEBS Lett. 2015;589:2498–506. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.febslet.2015.06.004" id="id349">10.1016/j.febslet.2015.06.004</a></p></div> </div> <a id="ref63"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id350"></a>63</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id351"></a>Milles S, Salvi N, Blackledge M, Jensen MR. Characterization of intrinsically disordered proteins and their dynamic complexes: from in vitro to cell-like environments. Prog Nucl Magn Reson Spectrosc. 2018; 109:79–100. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.pnmrs.2018.07.001" id="id352">10.1016/j.pnmrs.2018.07.001</a></p></div> </div> <a id="ref64"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id353"></a>64</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id354"></a>Sharonov GV, Balatskaya MN, Tkachuk VA. Glycosylphosphatidylinositol-anchored proteins as regulators of cortical cytoskeleton. Biochemistry (Moscow). 2016; 81:636–50. doi: <a target="xrefwindow" href="https://doi.org/10.1134/S0006297916060110" id="id355">10.1134/S0006297916060110</a></p></div> </div> <a id="ref65"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id356"></a>65</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id357"></a>Mayor S, Bhat A, Kusumi A. A survey of models of cell membranes: toward a new understanding of membrane organization. Cold Spring Harb Perspect Biol. 2023;15:a041394. doi: <a target="xrefwindow" href="https://doi.org/10.1101/cshperspect.a041394" id="id358">10.1101/cshperspect.a041394</a></p></div> </div> <a id="ref66"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id359"></a>66</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id360"></a>Caseli L, Oliveira RG, Masui DC, Furriel RP, Leone FA, Zaniquelli ME, et al. Rat osseous plate alkaline phosphatase as La ngmuir monolayer – an infrared study at the air-water interface. J Colloid Interface Sci. 2008;320:476–82. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.jcis.2008.01.043" id="id361">10.1016/j.jcis.2008.01.043</a></p></div> </div> <a id="ref67"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id362"></a>67</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id363"></a>Müller GA, Tschöp MH, Müller TD. Upregulated phospholipase D activity toward glycosylphosphatidylinositol-anchored proteins in micelle-like serum complexes in metabolically deranged rats and humans. Am J Physiol Endocrinol Metabol. 2020;318:E462–79. doi: <a target="xrefwindow" href="https://doi.org/10.1152/ajpendo.00504.2019" id="id364">10.1152/ajpendo.00504.2019</a></p></div> </div> <a id="ref68"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id365"></a>68</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id366"></a>Müller GA, Ussar S, Tschöp MH, Müller TD. Age-dependent membrane release and degradation of full-length glycosylphosphatidylinositol-anchored proteins in rats. Mech Age Dev. 2020;190:111307. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.mad.2020.111307" id="id367">10.1016/j.mad.2020.111307</a></p></div> </div> <a id="ref69"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id368"></a>69</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id369"></a>Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010;327:46–50. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.1174621" id="id370">10.1126/science.1174621</a></p></div> </div> <a id="ref70"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id371"></a>70</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id372"></a>Levental KR, Surma MA, Skinkle AD, Lorent JH, Zhou Y, Klose C, et al. Omega-3 polyunsaturated fatty acids direct differentiation of the membrane phenotype in mesenchymal stem cells to potentiate osteogenesis. Sci Adv. 2010;3:eaao1193. doi: <a target="xrefwindow" href="https://doi.org/10.1126/sciadv.aao1193" id="id373">10.1126/sciadv.aao1193</a></p></div> </div> <a id="ref71"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id374"></a>71</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id375"></a>Levental KR, Lorent JH, Lin X, Skinkle AD, Surma MA, Stockenbojer EA, et al. Polyunsaturated lipids regulate membrane domain stability by tuning membrane order. Biophys J. 2016;110:1800–10. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.bpj.2016.03.012" id="id376">10.1016/j.bpj.2016.03.012</a></p></div> </div> <a id="ref72"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id377"></a>72</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id378"></a>Garcia-Parajo MF, Cambi A, Torreno-Pina JA, Thompson N, Jacobson K. Nanoclustering as a dominant feature of plasma membrane organization. J Cell Sci. 2014;127:4995–5005. doi: <a target="xrefwindow" href="https://doi.org/10.1242/jcs.146340" id="id379">10.1242/jcs.146340</a></p></div> </div> <a id="ref73"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id380"></a>73</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id381"></a>Lorent JH, Diaz-Rohrer B, Lin X, Spring K, Gorfe AA, Levental KR, et al. Structural determinants and functional consequences of protein affinity for membrane rafts. Nat Commun. 2017;8:1219. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41467-017-01328-3" id="id382">10.1038/s41467-017-01328-3</a></p></div> </div> <a id="ref74"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id383"></a>74</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id384"></a>Lorent JH, Levental KR, Ganesan L, Rivera-Longsworth G, Sezgin E, Doktorova M, et al. Plasma membranes are asymmetric in lipid unsaturation, packing, and protein shape. Nat Chem Biol. 2020;16:644–52. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41589-020-0529-6" id="id385">10.1038/s41589-020-0529-6</a></p></div> </div> <a id="ref75"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id386"></a>75</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id387"></a>Jacobson K, Liu P, Lagerholm C. The lateral organization and mobility of plasma membrane components. Cell. 2019;177:806–19. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.cell.2019.04.018" id="id388">10.1016/j.cell.2019.04.018</a></p></div> </div> <a id="ref76"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id389"></a>76</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id390"></a>Kalappurakkal JM, Sil P, Mayor S. Toward a new picture of the living plasma membrane. Protein Sci. 2020;29:1355–65. doi: <a target="xrefwindow" href="https://doi.org/10.1002/pro.3874" id="id391">10.1002/pro.3874</a></p></div> </div> <a id="ref77"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id392"></a>77</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id393"></a>Saltukoglu D, Özdemir B, Holtmannspötter M, Reski R, Piehler J, Kurre R, et al. Plasma membrane topography governs the 3D dynamic localization of IgM B cell antigen receptor clusters. EMBO J. 2023;42:e112030. doi: <a target="xrefwindow" href="https://doi.org/10.15252/embj.2022112030" id="id394">10.15252/embj.2022112030</a></p></div> </div> <a id="ref78"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id395"></a>78</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id396"></a>Banerjee RK, Datta AG. Proteoliposomes as the model for the study of membrane-bound enzymes and transport proteins. Mol Cell Biochem. 1983;50:3–15. doi: <a target="xrefwindow" href="https://doi.org/10.1007/BF00225276" id="id397">10.1007/BF00225276</a></p></div> </div> <a id="ref79"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id398"></a>79</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id399"></a>Rigaud JL, Levy D. Reconstitution of membrane proteins into liposomes. Methods Enzymol. 2003;372:65–86. doi: <a target="xrefwindow" href="https://doi.org/10.1016/S0076-6879(03)72004-7" id="id400">10.1016/S0076-6879(03)72004-7</a></p></div> </div> <a id="ref80"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id401"></a>80</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id402"></a>Grevel A, Pfanner N, Becker T. Coupling of import and assembly pathways in mitchondrial protein biogenesis. Biol Chem. 2019;401:117–29. doi: <a target="xrefwindow" href="https://doi.org/10.1515/hsz-2019-0310" id="id403">10.1515/hsz-2019-0310</a></p></div> </div> <a id="ref81"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id404"></a>81</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id405"></a>Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins: from biogenesis to functional networks. Nat Rev Mol Cell Biol. 2019;50:267–84. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41580-018-0092-0" id="id406">10.1038/s41580-018-0092-0</a></p></div> </div> <a id="ref82"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id407"></a>82</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id408"></a>Moulin C, Caumont-Sarcos A, Ieva R. Mitochondrial presequence import: multiple regulatory knobs fine-tuning mitochondrial biogenesis and homeostasis. Biochim Biophys Acta Mol Cell Res. 2019;1866:930–44. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.bbamcr.2019.02.012" id="id409">10.1016/j.bbamcr.2019.02.012</a></p></div> </div> <a id="ref83"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id410"></a>83</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id411"></a>Hsieh H-H, Shan S-O. Fidelity of cotranslational protein targeting to the endoplasmic reticulum. Int J Mol Sci. 2021;23:281. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms23010281" id="id412">10.3390/ijms23010281</a></p></div> </div> <a id="ref84"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id413"></a>84</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id414"></a>Tirincsi A, Sicking M, Hadzibeganovic D, Haßdenteufel S, Lang S. The molecular biodiversity of protein targeting and protein transport related to the endoplasmic reticulum. Int J Mol Sci. 2021;23:143. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms23010143" id="id415">10.3390/ijms23010143</a></p></div> </div> <a id="ref85"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id416"></a>85</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id417"></a>O’Keefe S, Pool MR, High S. Membrane protein biogenesis at the ER: the highways and byways. FEBS J;2022;289:6835–62. doi: <a target="xrefwindow" href="https://doi.org/10.1111/febs.15905" id="id418">10.1111/febs.15905</a></p></div> </div> <a id="ref86"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id419"></a>86</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id420"></a>Lang S, Nguyen D, Bhadra P, Jung M, Helms V, Zimmermann R. Signal peptide features determining the substrate specificities of targeting and translocation components in human ER protein import. Front Physiol. 2022;13:833540. doi: <a target="xrefwindow" href="https://doi.org/10.3389/fphys.2022.833540" id="id421">10.3389/fphys.2022.833540</a></p></div> </div> <a id="ref87"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id422"></a>87</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id423"></a>Hilander T, Jackson CB, Robciuc M, Bashir T, Zhao H. The roles of assembly factors in mammalian mitoribosome biogenesis. Mitochondrion. 2021;60:70–84. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.mito.2021.07.008" id="id424">10.1016/j.mito.2021.07.008</a></p></div> </div> <a id="ref88"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id425"></a>88</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id426"></a>Pecoraro A, Pagano M; Russo G, Russo A. Ribosome biogenesis and cancer: overview on ribosomal proteins. Int J Mol Sci. 2021;22:5496. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms22115496" id="id427">10.3390/ijms22115496</a></p></div> </div> <a id="ref89"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id428"></a>89</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id429"></a>Gahura O, Chauhan P, Zikova A. Mechanisms and players of mitoribosomal biogenesis revealed in trypanosomatids. Trends Parasitol. 2022;38:1053–67. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.pt.2022.08.010" id="id430">10.1016/j.pt.2022.08.010</a></p></div> </div> <a id="ref90"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id431"></a>90</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id432"></a>Massenet S. In vivo assembly of eukaryotic signal recognition particle: a still enigmatic process involving the SMN complex. Biochimie. 2019;164:99–104. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.biochi.2019.04.007" id="id433">10.1016/j.biochi.2019.04.007</a></p></div> </div> <a id="ref91"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id434"></a>91</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id435"></a>Jung M, Zimmermann R. Quantitative mass spectrometry characterizes client spectra of components for targeting of membrane proteins to and their insertion the membrane of the human ER. Int J Mol Sci. 2023;24:14166. doi: <a target="xrefwindow" href="https://doi.org/10.3390/ijms241814166" id="id436">10.3390/ijms241814166</a></p></div> </div> <a id="ref92"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id437"></a>92</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id438"></a>Varela F. Principles of biological autonomy. New York: Appleton & Lange; 1979.</p></div> </div> <a id="ref93"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id439"></a>93</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id440"></a>Varela F, Maturana H. Autopoiesis and cognition. The realization of the living. Dordrecht, Boston, London: D. Reidel Publishing; 1980.</p></div> </div> <a id="ref94"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id441"></a>94</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id442"></a>Varela F, Maturana H. Der Baum der Erkenntnis. Munich: Goldmann; 1987.</p></div> </div> <a id="ref95"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id443"></a>95</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id444"></a>Luhmann N. Soziale systeme. Grundriß einer allgemeinen theorie. Frankfurt a.M.: Suhrkamp; 1984.</p></div> </div> <a id="ref96"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id445"></a>96</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id446"></a>Luhmann N. Die Gesellschaft der Gesellschaft. Frankfurt a.M.: Suhrkamp; 1997.</p></div> </div> <a id="ref97"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id447"></a>97</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id448"></a>Reese-Schäfer W. Niklas Luhmann – Eine Einführung. Hamburg: Junius; 2001.</p></div> </div> <a id="ref98"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id449"></a>98</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id450"></a>Rooney IA, Heuser JE, Atkinson JP. GPI-anchored complement regulatory proteins in seminal plasma. An analysis of their physical conditions and the mechanisms of their binding to exogenous cells. J Clin Invest. 1996;97:1675–86. doi: <a target="xrefwindow" href="https://doi.org/10.1172/JCI118594" id="id451">10.1172/JCI118594</a></p></div> </div> <a id="ref99"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id452"></a>99</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id453"></a>Kirchhoff C, Pera I, Derr P, Yeung CH, Cooper T. The molecular biology of the sperm surface. Post-testicular membrane remodelling. Adv Exp Med Biol. 1997;424:221–32. doi: <a target="xrefwindow" href="https://doi.org/10.1007/978-1-4615-5913-9_40" id="id454">10.1007/978-1-4615-5913-9_40</a></p></div> </div> <a id="ref100"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id455"></a>100</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id456"></a>Babiker AA, Ronquist G, Nilsson UR, Nilsson B. Transfer of prostasomal CD59 to CD59-deficient red blood cells results in protection against complement-mediated hemolysis. Am J Reprod Immunol. 2002;47:183–92. doi: <a target="xrefwindow" href="https://doi.org/10.1034/j.1600-0897.2002.1o023.x" id="id457">10.1034/j.1600-0897.2002.1o023.x</a></p></div> </div> <a id="ref101"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id458"></a>101</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id459"></a>Babiker AA, Nilsson B, Ronquist G, Carlsson L, Ekdahl KN. Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attack. Prostate. 2005;62:105–14. doi: <a target="xrefwindow" href="https://doi.org/10.1002/pros.20102" id="id460">10.1002/pros.20102</a></p></div> </div> <a id="ref102"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id461"></a>102</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id462"></a>Eckdahl KN, Ronquist G, Nilsson B, Babiker AA. Possible immunoprotective and angiogenesis promoting roles for malignant cell-derived prostasomes: a new paradigm for prostatic cancer? Adv Exp Med Biol. 2006;586:107–19. doi: <a target="xrefwindow" href="https://doi.org/10.1007/0-387-34134-X_8" id="id463">10.1007/0-387-34134-X_8</a></p></div> </div> <a id="ref103"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id464"></a>103</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id465"></a>Vickram AS, Samad HA, Latheef SK, Chakraborty S, Dhama K, Sridharan TB, et al. Human prostasomes as extracellular vesicles – Biomarkers for male infertility and prostate cancer: the journey from identification to current knowledge. Int J Biol Macromol. 2020;146:946–58. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.ijbiomac.2019.09.218" id="id466">10.1016/j.ijbiomac.2019.09.218</a></p></div> </div> <a id="ref104"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id467"></a>104</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id468"></a>Griffiths GS, Galileo DS, Reese K, Martin-Deleon PA. Investigating the role of murine epididymosomes and uterosomes in GPI-linked protein transfer to sperm using SPAM1 as a model. Mol Reprod Dev. 2008; 75:1627–36. doi: <a target="xrefwindow" href="https://doi.org/10.1002/mrd.20907" id="id469">10.1002/mrd.20907</a></p></div> </div> <a id="ref105"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id470"></a>105</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id471"></a>Griffiths GS, Miller KA, Galileo DS, Martin-DeLeon PA. SPAM1 is secreted by the estrous murine uterus and oviduct in a form which can bind to sperm during capacitation: Acquisition enhances hyaluronic acid-binding ability and cumulus penetration efficiency. Reproduction. 2008;135:293–301. doi: <a target="xrefwindow" href="https://doi.org/10.1530/REP-07-0340" id="id472">10.1530/REP-07-0340</a></p></div> </div> <a id="ref106"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id473"></a>106</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id474"></a>Darwin C. On the origin of species by means of natural selection. London: John Murray; 1859.</p></div> </div> <a id="ref107"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id475"></a>107</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id476"></a>Darwin C. The variation of animals and plants under domestication. London: John Murray; 1868.</p></div> </div> <a id="ref108"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id477"></a>108</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id478"></a>Darwin C. Pangenesis: Mr. Darwin’s reply to Professor Delphino scientific opinion: a weekly record of scientific progress at home & abroad. London: John Murray; 1869. p. 426.</p></div> </div> <a id="ref109"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id479"></a>109</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id480"></a>Darwin C. Pangenesis. Nature. 1871;3:502–3.</p></div> </div> <a id="ref110"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id481"></a>110</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id482"></a>Höglsperger F, Vos BF, Hofemeier AD, Seyfried MD, Stövesand B, Alavizargar A, et al. Rapid and reversible optical switching of cell membrane area by an amphiphilic azobenzene. Nat Commun. 2023;14:3760. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41467-023-39032-0" id="id483">10.1038/s41467-023-39032-0</a></p></div> </div> <a id="ref111"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id484"></a>111</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id485"></a>Necci M, Piovesan D, CAID Predictors, DisProt Curators, Tosatto SCE. Critical assessment of protein intrinsic disorder prediction. Nat Methods. 2021;18:472–81. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41592-021-01117-3" id="id486">10.1038/s41592-021-01117-3</a></p></div> </div> <a id="ref112"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id487"></a>112</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id488"></a>Paladino A, Vitagliano L, Graziano G. The action of chemical denaturants: from globular to intrinsically disordered proteins. Biology. 2023;12:754. doi: <a target="xrefwindow" href="https://doi.org/10.3390/biology12050754" id="id489">10.3390/biology12050754</a></p></div> </div> <a id="ref113"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id490"></a>113</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id491"></a>Chakrabortee S, Byers JS, Jones S, Garcia DM, Bhullar B, Chang A, et al. Intrinsically disordered proteins drive emergence and inherence of biological traits. Cell. 2016;167:369–81. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.cell.2016.09.017" id="id492">10.1016/j.cell.2016.09.017</a></p></div> </div> <a id="ref114"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id493"></a>114</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id494"></a>Beisson J, Sonneborn T. Cytoplasmic inheritance of the organization of the cell cortex in Paramecium aurelia. Proc Natl Acad Sci USA. 1965;53:275–82. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.53.2.275" id="id495">10.1073/pnas.53.2.275</a></p></div> </div> <a id="ref115"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id496"></a>115</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id497"></a>Ruiz F, Krzywicka A, Klotz C, Keller A, Cohen J, Koll F, Balavoine G, Beisson J. The SM19 gene, required for duplication of basal bodies in Paramecium, encodes a novel tubulin, eta-tubulin. Curr Biol. 2000;10:1451–4. doi: <a target="xrefwindow" href="https://doi.org/10.1016/s0960-9822(00)00804-6" id="id498">10.1016/s0960-9822(00)00804-6</a></p></div> </div> <a id="ref116"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id499"></a>116</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id500"></a>Dickins TE. The role of information in evolutionary biology. Acta Biotheor. 2023;71:17. doi: <a target="xrefwindow" href="https://doi.org/10.1007/s10441-023-09468-4" id="id501">10.1007/s10441-023-09468-4</a></p></div> </div> <a id="ref117"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id502"></a>117</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id503"></a>Frankel J. Structural inheritance. Pattern formation: ciliate studies and models. Oxford: Oxford University Press; 1989. p. 69–93.</p></div> </div> <a id="ref118"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id504"></a>118</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id505"></a>Nelsen EA, Frankel J, Jenkins LM. Non-genetic inheritance of cellular handedness. Development. 1989;105:447–56. doi: <a target="xrefwindow" href="https://doi.org/10.1242/dev.105.3.447" id="id506">10.1242/dev.105.3.447</a></p></div> </div> <a id="ref119"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id507"></a>119</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id508"></a>Sonneborn TM. Does preformed cell structure play an essential role in cell heredity? In: Allen JM, editor. The nature of biological diversity. New York: McGraw-Hill; 1963. p. 165–222.</p></div> </div> <a id="ref120"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id509"></a>120</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id510"></a>Sonneborn TM. Partners of the genes. Sci Am. 1950;183:30–9. doi: <a target="xrefwindow" href="https://doi.org/10.1038/SCIENTIFICAMERICAN1150-30" id="id511">10.1038/SCIENTIFICAMERICAN1150-30</a></p></div> </div> <a id="ref121"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id512"></a>121</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id513"></a>Sonneborn TM. The differentiation of cells. Proc Natl Acad Sci USA. 1964;51:915–29. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.51.5.915" id="id514">10.1073/pnas.51.5.915</a></p></div> </div> <a id="ref122"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id515"></a>122</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id516"></a>Beisson J. Preformed cell structure and cell heredity. Prion. 2008;2:1–8. doi: <a target="xrefwindow" href="https://doi.org/10.4161/pri.2.1.5063" id="id517">10.4161/pri.2.1.5063</a></p></div> </div> <a id="ref123"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id518"></a>123</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id519"></a>Griffith JS. Self-replication and scrapie. Nature. 1967;215: 1043–4. doi: <a target="xrefwindow" href="https://doi.org/10.1038/2151043a0" id="id520">10.1038/2151043a0</a></p></div> </div> <a id="ref124"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id521"></a>124</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id522"></a>Preer JR Jr. Whatever happened to paramecium genetics? Genetics. 1997;145:217–25. doi: <a target="xrefwindow" href="https://doi.org/10.1093/genetics/145.2.217" id="id523">10.1093/genetics/145.2.217</a></p></div> </div> <a id="ref125"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id524"></a>125</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id525"></a>Preer JR Jr. Sonneborn and the cytoplasm. Genetics. 2006;172:1373–7. doi: <a target="xrefwindow" href="https://doi.org/10.1093/genetics/172.3.1373" id="id526">10.1093/genetics/172.3.1373</a></p></div> </div> <a id="ref126"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id527"></a>126</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id528"></a>Grimes GW, Aufderheide KJ. Cellular aspects of pattern formation: the problem of assembly. In: Monographs in developmental biology. Vol. 22. Basel: S. Karger; 1991. p. 1–94.</p></div> </div> <a id="ref127"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id529"></a>127</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id530"></a>Gilbert SF. Cytoplasmic action in development. Quart Rev Biol. 1991;66:309–16. doi: <a target="xrefwindow" href="https://doi.org/10.1086/417245" id="id531">10.1086/417245</a></p></div> </div> <a id="ref128"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id532"></a>128</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id533"></a>Bonduriansky R, Day T. Extended heredity: a new understanding of inheritance and evolution. Princeton, Oxford: Princeton University Press; 2018.</p></div> </div> <a id="ref129"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id534"></a>129</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id535"></a>Pigliucci M. Do we need an extended evolutionary synthesis? Evolution. 2007;61:2743–9. doi: <a target="xrefwindow" href="https://doi.org/10.1111/j.1558-5646.2007.00246.x" id="id536">10.1111/j.1558-5646.2007.00246.x</a></p></div> </div> <a id="ref130"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id537"></a>130</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id538"></a>Danchin E, Charmantier A, Champagne FA, Mesoudi A, Pujol B, Blanchet S. Beyond DNA: integrating inclusive inheritance into an extended theory of evolution. Nat Rev Genet. 2011;12:475–86. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nrg3028" id="id539">10.1038/nrg3028</a></p></div> </div> <a id="ref131"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id540"></a>131</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id541"></a>Laland KN, Uller T, Feldman MW, Sterelny K, Müller GB, Moczek A, et al. The extended evolutionary synthesis: its structure, assumptions and predictions. Proc Royal Soc B Biol Sci. 2015;282:20151019. doi: <a target="xrefwindow" href="https://doi.org/10.1098/rspb.2015.1019" id="id542">10.1098/rspb.2015.1019</a></p></div> </div> <a id="ref132"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id543"></a>132</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id544"></a>Martinez Arias A. Master builder. how the new science of the cell is rewriting the story of life. London: Basic Books; 2023.</p></div> </div> <a id="ref133"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id545"></a>133</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id546"></a>Conklin E. The cultural value of zoology. Science. 1915;41:333–7. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.41.1053.333" id="id547">10.1126/science.41.1053.333</a></p></div> </div> <a id="ref134"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id548"></a>134</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id549"></a>Johannsen WL. Elemente der exakten Erblichkeitslehre. Jena: Gustav Fischer Verlag; 1926. p. 137.</p></div> </div> <a id="ref135"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id550"></a>135</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id551"></a>Morgan TH. An attempt to analyze the constitution of the chromosomes on the basis of sex-limited inheritance in Drososphila. J Exp Zool. 1911;11:365–413. doi: <a target="xrefwindow" href="https://doi.org/10.1002/jez.1400110404" id="id552">10.1002/jez.1400110404</a></p></div> </div> <a id="ref136"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id553"></a>136</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id554"></a>Caullery M. The present state of the problem of evolution. Science. 1916;XLIII:547–58. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.43.1112.547" id="id555">10.1126/science.43.1112.547</a></p></div> </div> <a id="ref137"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id556"></a>137</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id557"></a>Moger-Reischer RZ, Glass JI, Wise KS, Bittencourt DMC, Lehmkuhl BK, Schoolmaster DR Jr, et al. Evolution of a minimal cell. Nature. 2023;620:122–7. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41586-023-06288-x" id="id558">10.1038/s41586-023-06288-x</a></p></div> </div> <a id="ref138"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id559"></a>138</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id560"></a>Glass JI, Merryman C, Wise KS, Hutchison III CA, Smith HO. Minimal cells – real and imaged. Cold Spring Harb Perspect Biol. 2017;9:a023861. doi: <a target="xrefwindow" href="https://doi.org/10.1101/cshperspect.a023861" id="id561">10.1101/cshperspect.a023861</a></p></div> </div> <a id="ref139"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id562"></a>139</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id563"></a>Mackiewicz P, Kowalczuk M, Mackiewicz D, Nowicka A, Dudkiewicz M, Laskiewicz A, et al. How many protein-coding genes are there in the Saccharomyces cerevisiae genome? Comp St. 2002;19:619–29. doi: <a target="xrefwindow" href="https://doi.org/10.1002/yea.865" id="id564">10.1002/yea.865</a></p></div> </div> <a id="ref140"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id565"></a>140</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id566"></a>Southan C. Has the yo-yo stopped? An assessment of human protein-coding gene number. Proteomics. 2004;4:1712–26. doi: <a target="xrefwindow" href="https://doi.org/10.1002/pmic.200300700" id="id567">10.1002/pmic.200300700</a></p></div> </div> <a id="ref141"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id568"></a>141</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id569"></a>Hirsch D, Stahl A, Lodish HF. A family of fatty acid transporters conserved from mycobacterium to man. Proc Natl Acad Sci USA. 1998;95:8625–9. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.95.15.8625" id="id570">10.1073/pnas.95.15.8625</a></p></div> </div> <a id="ref142"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id571"></a>142</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id572"></a>Griffith F. The significance of pneumococcal types. J Hyg. 1928;27:113–59. doi: <a target="xrefwindow" href="https://doi.org/10.1017/s0022172400031879" id="id573">10.1017/s0022172400031879</a></p></div> </div> <a id="ref143"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id574"></a>143</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id575"></a>Kaudewitz F. Molekular- und Mikroben-Genetik. Berlin, Heidelberg, New York, Germany, USA: Springer; 1973. p. 7–9.</p></div> </div> <a id="ref144"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id576"></a>144</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id577"></a>Rajagopal M, Walker S. Envelope structures of gram-positive bacteria. Curr Top Microbiol Immunol. 2017;404:1–44. doi: <a target="xrefwindow" href="https://doi.org/10.1007/82_2015_5021" id="id578">10.1007/82_2015_5021</a></p></div> </div> <a id="ref145"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id579"></a>145</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id580"></a>Vollmer W, Massidda O, Tomasz A. The cell wall of <i>Streptococcus pneumoniae</i>. Microbiol Spectrum. 2019;7:GPP3-0018-2018. doi: <a target="xrefwindow" href="https://doi.org/10.1128/microbiolspec.GPP3-0018-2018" id="id581">10.1128/microbiolspec.GPP3-0018-2018</a></p></div> </div> <a id="ref146"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id582"></a>146</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id583"></a>Briaud P, Carroll RK. Extracellular vesicle biogenesis and functions in gram-positive bacteria. Infect Immun. 2020;88:e00433–20. doi: <a target="xrefwindow" href="https://doi.org/10.1128/IAI.00433-20" id="id584">10.1128/IAI.00433-20</a></p></div> </div> <a id="ref147"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id585"></a>147</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id586"></a>Calix JJ, Brady AM, Du VY, Saad JS, Nahm MH. Spectrum of pneumococcal serotype 11A variants results from incomplete loss of capsule <i>O</i>-acetylation. J Clin Microbiol. 2014;52:758–65. doi: <a target="xrefwindow" href="https://doi.org/10.1128/JCM.02695-13" id="id587">10.1128/JCM.02695-13</a></p></div> </div> <a id="ref148"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id588"></a>148</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id589"></a>O’Riordan K, Lee JC. <i>Staphylococcus aureus</i> capsular polysaccharides. Clin Microbiol Rev. 2004;17:218–34. doi: <a target="xrefwindow" href="https://doi.org/10.1128/CMR.17.1.218-234.2004" id="id590">10.1128/CMR.17.1.218-234.2004</a></p></div> </div> <a id="ref149"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id591"></a>149</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id592"></a>Avery OT, MacLeod CM, McCarty M. Studies on the chemical nature of the substance inducing transformation of pneumococcal types Type III. J Exp Med. 1944;79:137–58. doi: <a target="xrefwindow" href="https://doi.org/10.1084/jem.79.2.137" id="id593">10.1084/jem.79.2.137</a></p></div> </div> <a id="ref150"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id594"></a>150</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id595"></a>Kulp A, Kuehn MJ. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu Rev Microbiol. 2010;64:163–84. doi: <a target="xrefwindow" href="https://doi.org/10.1146/annurev.micro.091208.073413" id="id596">10.1146/annurev.micro.091208.073413</a></p></div> </div> <a id="ref151"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id597"></a>151</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id598"></a>Schwechheimer C, Kuehn MJ. Outer-membrane vesicles from gram-negative bacteria: biogenesis and function. Nat Rev. 2015;13:605–19. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nrmicro3525" id="id599">10.1038/nrmicro3525</a></p></div> </div> <a id="ref152"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id600"></a>152</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id601"></a>Nagakubo T, Nomura N, Toyofuku M. Cracking open bacterial membrane vesicles. Front Microbiol. 2020;10:3026. doi: <a target="xrefwindow" href="https://doi.org/10.3389/fmicb.2019.03026" id="id602">10.3389/fmicb.2019.03026</a></p></div> </div> <a id="ref153"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id603"></a>153</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id604"></a>Sartorio MG, Pardue EJ, Feldman MF, Haurat MF. Bacterial outer membrane vesicles: from discovery to applications. Annu Rev Microbiol. 2021;75:609–30. doi: <a target="xrefwindow" href="https://doi.org/10.1146/annurev-micro-052821-031444" id="id605">10.1146/annurev-micro-052821-031444</a></p></div> </div> <a id="ref154"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id606"></a>154</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id607"></a>Juodeikis R, Carding SR. Outer membrane vesicles: biogenesis, function, and issues. Microbiol Mol Biol Rev. 2022;86:1–28. doi: <a target="xrefwindow" href="https://doi.org/10.1128/mmbr.00032-22" id="id608">10.1128/mmbr.00032-22</a></p></div> </div> <a id="ref155"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id609"></a>155</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id610"></a>Lee J, Kim OY, Gho YS. Proteomic profiling of gram-negative bacterial outer membrane vesicles: current perspectives. Proteomics. 2016;10:897–909. doi: <a target="xrefwindow" href="https://doi.org/10.1002/prca.201600032" id="id611">10.1002/prca.201600032</a></p></div> </div> <a id="ref156"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id612"></a>156</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id613"></a>Dineshkumar K, Aparna V, Wu L, Abdelaziz MH, Su Z, Wang S, et al. Bacterial bug-out bags: outer membrane vesicles and their proteins and functions. J Microbiol. 2020;58:531–42. doi: <a target="xrefwindow" href="https://doi.org/10.1007/s12275-020-0026-3" id="id614">10.1007/s12275-020-0026-3</a></p></div> </div> <a id="ref157"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id615"></a>157</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id616"></a>Toyofuku M, Schild S, Kaparakis-Liaskos M, Eberl L. Composition and functions of bacterial membrane vesicles. Nat Rev Microbiol. 2023;21:415–30. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41579-023-00875-5" id="id617">10.1038/s41579-023-00875-5</a></p></div> </div> <a id="ref158"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id618"></a>158</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id619"></a>Tatum EL, Lederberg J. Gene recombination in the bacterium Escherichia coli. J Bact. 1947;53:673–8. doi: <a target="xrefwindow" href="https://doi.org/10.1128/jb.53.6.673-684.1947" id="id620">10.1128/jb.53.6.673-684.1947</a></p></div> </div> <a id="ref159"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id621"></a>159</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id622"></a>Lederberg J, Lederberg EM, Zinder ND, Lively ER. Recombination analysis of bacterial heredity. Cold Spr Harb Symp Quant Biol. 1951;16:413–21. doi: <a target="xrefwindow" href="https://doi.org/10.1101/sqb.1951.016.01.030" id="id623">10.1101/sqb.1951.016.01.030</a></p></div> </div> <a id="ref160"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id624"></a>160</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id625"></a>Zinder ND, Lederberg J. Genetic exchange in Salmonella. J Bact. 1952;64:679–85. doi: <a target="xrefwindow" href="https://doi.org/10.1128/jb.64.5.679-699.1952" id="id626">10.1128/jb.64.5.679-699.1952</a></p></div> </div> <a id="ref161"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id627"></a>161</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id628"></a>Watanabe T. Infectious drug resistance. Sci Am. 1967; 217(6):19–26. doi: <a target="xrefwindow" href="https://doi.org/10.1038/scientificamerican1267-19" id="id629">10.1038/scientificamerican1267-19</a></p></div> </div> <a id="ref162"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id630"></a>162</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id631"></a>Anderson TF, Wollman EL, Jacob F. Sur les processus de conjugaison et de recombination génétique chez <i>E. coli</i>. III. Aspects morphologiques en microscopie électronique. Ann Inst Pasteur. 1957;93:450–8. PMID: 13470467</p></div> </div> <a id="ref163"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id632"></a>163</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id633"></a>Barad K. Meeting the universe halfway. Quantum physics and the entanglement of matter and meaning; 2007. Durham: Duke University Press.</p></div> </div> <a id="ref164"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id634"></a>164</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id635"></a>Dawkins R. The selfish gene. Oxford: Oxford University Press; 1976.</p></div> </div> <a id="ref165"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id636"></a>165</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id637"></a>Venter JC, Glass JI, Hutchinson CA 3rd, Vashee S. Synthetic chromosomes, genomes, viruses, and cells. Cell. 2022; 185:2708–24. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.cell.2022.06.046" id="id638">10.1016/j.cell.2022.06.046</a></p></div> </div> <a id="ref166"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id639"></a>166</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id640"></a>Ho D, Quake SR, McCabe ERB, Chng WJ, Chow EK, Ding X, et al. Enabling technologies for personalized and precision medicine. Trends Biotechnol. 2020;38:497–518. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.tibtech.2019.12.021" id="id641">10.1016/j.tibtech.2019.12.021</a></p></div> </div> <a id="ref167"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id642"></a>167</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id643"></a>Braig ZV. Personalized medicine: from diagnostic to adaptive. Biomed J. 2022;45:132–42. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.bj.2019.05.004" id="id644">10.1016/j.bj.2019.05.004</a></p></div> </div> <a id="ref168"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id645"></a>168</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id646"></a>Kayser M, Branicki W, Parson W, Phillips C. Recent advances in forensic DNA phenotyping of appearance, ancestry and age. Forensic Sci Int Genet. 2023;65: 102870. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.fsigen.2023.102870" id="id647">10.1016/j.fsigen.2023.102870</a></p></div> </div> <a id="ref169"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id648"></a>169</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id649"></a>Dabas P, Jain S, Khajuria H, Nayak BP. Forensic DNA phenotyping: inferring phenotypic traits from crime scene DNA. J Forensic Leg Med. 2022;88:102351. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.jflm.2022.102351" id="id650">10.1016/j.jflm.2022.102351</a></p></div> </div> <a id="ref170"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id651"></a>170</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id652"></a>Cook L, Schulze J, Naito A, Alcalay RN. The role of genetic testing for Parkinson’s disease. Curr Neurol Neurosci Rep. 2021;21:17. doi: <a target="xrefwindow" href="https://doi.org/10.1007/s11910-021-01100-7" id="id653">10.1007/s11910-021-01100-7</a></p></div> </div> <a id="ref171"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id654"></a>171</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id655"></a>Hannan FM, Newey PJ, Whyte MP, Thakker RV. Genetics of skeletal disorders. Handb Exp Pharmacol. 2020;262:325–51. doi: <a target="xrefwindow" href="https://doi.org/10.1007/164_2020_350" id="id656">10.1007/164_2020_350</a></p></div> </div> <a id="ref172"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id657"></a>172</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id658"></a>Latour B. On actor-network theory. A few clarifications. Soziale Welt. 1996;47:369–81. Corpus ID: 9623434</p></div> </div> <a id="ref173"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id659"></a>173</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id660"></a>Kuroiwa T, Uchida H. Organelle division and cytoplasmic inheritance. BioScience. 1996;46:827–35. doi: <a target="xrefwindow" href="https://doi.org/10.2307/1312968" id="id661">10.2307/1312968</a></p></div> </div> <a id="ref174"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id662"></a>174</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id663"></a>Cavalier-Smith T. Genomes and eukaryotic phylogeny. In: Hirt RP, Horner DS, editors. Organelles, genomes and eukaryote phylogeny: an evolutionary synthesis in the age of genomics. London: Taylor & Francis; 2004. p. 335–51.</p></div> </div> <a id="ref175"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id664"></a>175</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id665"></a>Jablonka E, Lamb MJ. Evolution in four dimensions. genetic, epigenetic, behavioral, and symbolic variation in the history of life. Cambridge, Massachusetts, London: MIT Press; 2005.</p></div> </div> <a id="ref176"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id666"></a>176</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id667"></a>Jablonka E, Lamb MJ. The evolution of information in the major transitions. J Theor Biol. 2006;239:236–46. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.jtbi.2005.08.038" id="id668">10.1016/j.jtbi.2005.08.038</a></p></div> </div> <a id="ref177"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id669"></a>177</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id670"></a>Jablonka E, Lamb MJ. Transgenerational epigenetic inheritance. In: Pigliucci M, Müller GB, editors. Evolution – the extended synthesis. Cambridge, Massachusetts, London: MIT Press; 2010. p. 135–74.</p></div> </div> <a id="ref178"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id671"></a>178</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id672"></a>Bonduriansky R. Rethinking heredity, again. Trends Ecol Evol. 2012;27:330–6. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.tree.2012.02.003" id="id673">10.1016/j.tree.2012.02.003</a></p></div> </div> <a id="ref179"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id674"></a>179</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id675"></a>Bonduriansky R, Day T. Nongenetic inheritance and its evolutionary implications. Annu Rev Ecol Evol Syst. 2009;40:103–25. doi: <a target="xrefwindow" href="https://doi.org/10.1146/annurev.ecolsys.39.110707.173441" id="id676">10.1146/annurev.ecolsys.39.110707.173441</a></p></div> </div> <a id="ref180"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id677"></a>180</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id678"></a>Kushner DJ. Self-assembly of biological structures. Bacteriol Rev. 1969;33:302–45. doi: <a target="xrefwindow" href="https://doi.org/10.1128/br.33.2.302-345.1969" id="id679">10.1128/br.33.2.302-345.1969</a></p></div> </div> <a id="ref181"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id680"></a>181</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id681"></a>Kirschner M, Mitchison T. Beyond self-assembly: from microtubules to morphogenesis. Cell. 1986;45:329–42. doi: <a target="xrefwindow" href="https://doi.org/10.1016/0092-8674(86)90318-1" id="id682">10.1016/0092-8674(86)90318-1</a></p></div> </div> <a id="ref182"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id683"></a>182</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id684"></a>Kirschner M, Gerhart JC, Mitchison T. Molecular “vitalism”. Cell. 2000;100:79–88. doi: <a target="xrefwindow" href="https://doi.org/10.1016/s0092-8674(00)81685-2" id="id685">10.1016/s0092-8674(00)81685-2</a></p></div> </div> <a id="ref183"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id686"></a>183</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id687"></a>Feldman JL, Geimer S, Marshall WF. The mother centriole plays an instructive role in defining cell geometry. PLoS Biol. 2007;5:e149. doi: <a target="xrefwindow" href="https://doi.org/10.1371/journal.pbio.0050149" id="id688">10.1371/journal.pbio.0050149</a></p></div> </div> <a id="ref184"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id689"></a>184</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id690"></a>Kirschner M, Gerhart JC. The plausibility of life: resolving Darwin’s dilemma. New Haven: Yale University Press; 2005.</p></div> </div> <a id="ref185"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id691"></a>185</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id692"></a>Sezgin E, Davis SJ, Eggeling C. Membrane nanoclusters – tails of the unexpected. Cell. 2015;161:433–4. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.cell.2015.04.008" id="id693">10.1016/j.cell.2015.04.008</a></p></div> </div> <a id="ref186"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id694"></a>186</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id695"></a>Gerhart J, Kirschner M. The theory of facilitated variation. Proc Natl Acad Sci USA. 2007;104:8582–9. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.0701035104" id="id696">10.1073/pnas.0701035104</a></p></div> </div> <a id="ref187"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id697"></a>187</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id698"></a>Byrnes WM. Ernest Everett Just, Johannes Holtfreter, and the origin of certain concepts in embryo morphogenesis. Mol Reprod Dev. 2009;76:912–21. doi: <a target="xrefwindow" href="https://doi.org/10.1002/mrd.21081" id="id699">10.1002/mrd.21081</a></p></div> </div> <a id="ref188"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id700"></a>188</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id701"></a>Just EE. The biology of the cell surface. Philadelphia: Blakiston’s Son & Co Inc.; 1939.</p></div> </div> <a id="ref189"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id702"></a>189</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id703"></a>Just EE. Basic methods for experiments on eggs of marine animals. Philadelphia: Blakiston’s Son & Co Inc.; 1939.</p></div> </div> <a id="ref190"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id704"></a>190</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id705"></a>Holtfreter J. Reminiscences on the life and work of Johannes Holtfreter. In: Gilbert SF, editor. A conceptual history of modern embryology. Baltimore; John Hopkins University Press; 1991. p. 109–27.</p></div> </div> <a id="ref191"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id706"></a>191</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id707"></a>Newman SA. E.E. Just’s “independent irritability” revisited: the activated egg as excitable soft matter. Mol Reprod Dev. 2009;76:966–74. doi: <a target="xrefwindow" href="https://doi.org/10.1002/mrd.21094" id="id708">10.1002/mrd.21094</a></p></div> </div> <a id="ref192"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id709"></a>192</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id710"></a>Ladewig J, Koch P, Brüstle O. Leveling Waddington: the emergence of direct programming and the loss of cell fate hierarchies. Nat Rev Mol Cell Biol. 2013;14:225–36. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nrm3543" id="id711">10.1038/nrm3543</a></p></div> </div> <a id="ref193"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id712"></a>193</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id713"></a>Byrnes WM. E.E. Just’s broad, yet hidden, influence on modern cell and developmental biology. Mol Reprod Dev. 2020;87:380–91. doi: <a target="xrefwindow" href="https://doi.org/10.1002/mrd.23270" id="id714">10.1002/mrd.23270</a></p></div> </div> <a id="ref194"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id715"></a>194</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id716"></a>Dance A. Cells nibble one another via the under-appreciated process of trogocytosis. Proc Natl Acad Sci USA. 2019;116:17608–10. doi: <a target="xrefwindow" href="https://doi.org/10.1073/pnas.1912252116" id="id717">10.1073/pnas.1912252116</a></p></div> </div> <a id="ref195"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id718"></a>195</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id719"></a>Lin A, Yan W-H. Intercellular transfer of HLA-G: its potential in cancer immunology. Clin Translat Immunol. 2019;8:e1077. doi: <a target="xrefwindow" href="https://doi.org/10.1002/cti2.1077" id="id720">10.1002/cti2.1077</a></p></div> </div> <a id="ref196"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id721"></a>196</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id722"></a>Miyake K, Karasuyama H. The role of trogocytosis in the modulation of immune cell functions. Cells. 2021; 10:1255. doi: <a target="xrefwindow" href="https://doi.org/10.3390/cells10051255" id="id723">10.3390/cells10051255</a></p></div> </div> <a id="ref197"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id724"></a>197</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id725"></a>Nakada-Tsukui K, Nozaki T. Trogocytosis in unicellular eukaryotes. Cells. 2021;10:2975. doi: <a target="xrefwindow" href="https://doi.org/10.3390/cells10112975" id="id726">10.3390/cells10112975</a></p></div> </div> <a id="ref198"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id727"></a>198</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id728"></a>Park S, Kim J, Shin JH. Intercellular transfer of immune regulatory molecules via trogocytosis. Results Probl Cell Differ. 2024;73:131–46. doi: <a target="xrefwindow" href="https://doi.org/10.1007/978-3-031-62036-2_6" id="id729">10.1007/978-3-031-62036-2_6</a></p></div> </div> <a id="ref199"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id730"></a>199</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id731"></a>Huestis WH, Newton AC. Intermembrane protein transfer, band 3, the erythrocyte anion transporter, transfer in native orientation from human red blood cells into the bilayer of phospholipid vesicles. J Biol Chem. 1986; 261:16274–8. PMID: 3782118</p></div> </div> <a id="ref200"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id732"></a>200</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id733"></a>Waters SI, Sen R, Brunauer LS, Huestis WH. Physical determinants of intermembrane protein transfer. Biochemistry. 1996;35:4002–8. doi: <a target="xrefwindow" href="https://doi.org/10.1021/bi950433s" id="id734">10.1021/bi950433s</a></p></div> </div> <a id="ref201"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id735"></a>201</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id736"></a>Suzuki K, Okumura Y. Mechanism of selective release of membrane proteins from human erythrocytes in the presence of liposomes. Arch Biochem Biophys. 2000;379:344–52. doi: <a target="xrefwindow" href="https://doi.org/10.1006/abbi.2000.1891" id="id737">10.1006/abbi.2000.1891</a></p></div> </div> <a id="ref202"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id738"></a>202</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id739"></a>Banerjee P, Lipowsky R, Santer M. Coarse-grained molecular model for the glycosylphosphatidylinositol anchor with and wihout protein. J Chem Theory Comput. 2020;16:3889–903. doi: <a target="xrefwindow" href="https://doi.org/10.1021/acs.jctc.0c00056" id="id740">10.1021/acs.jctc.0c00056</a></p></div> </div> <a id="ref203"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id741"></a>203</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id742"></a>Kemble GW, Danieli T, White JM. Lipid-anchored influenza hemagglutinin promotes hemifusion, not complete fusion. Cell. 1994;76:383–91. doi: <a target="xrefwindow" href="https://doi.org/10.1016/0092-8674(94)90344-1" id="id743">10.1016/0092-8674(94)90344-1</a></p></div> </div> <a id="ref204"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id744"></a>204</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id745"></a>Bali P. Memory of water’ biologist dies after heart surgery. Nature. 2004;431:729. doi: <a target="xrefwindow" href="https://doi.org/10.1038/431729b" id="id746">10.1038/431729b</a></p></div> </div> <a id="ref205"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id747"></a>205</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id748"></a>Teixeira J. Can water possibly have a memory? A sceptical view. Homeopathy. 2007;96:158–62. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.homp.2007.05.001" id="id749">10.1016/j.homp.2007.05.001</a></p></div> </div> <a id="ref206"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id750"></a>206</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id751"></a>Thomas Y. The history of the memory of water. Homeopathy. 2007;96:151–7. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.homp.2007.03.006" id="id752">10.1016/j.homp.2007.03.006</a></p></div> </div> <a id="ref207"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id753"></a>207</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id754"></a>Yamabhai M, Chumseng S, Yoohat K, Srila W. Diverse biological effects of electromagnetic-treated water. Homeopathy. 2014;103:186–92. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.homp.2013.11.004" id="id755">10.1016/j.homp.2013.11.004</a></p></div> </div> <a id="ref208"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id756"></a>208</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id757"></a>Ullman D. Exploring possible mechanisms of hormesis and homeopathy in the light of nanopharmacology and ultra-high dilutions. Dose-response. Int J. 2021;2021:1–13. doi: <a target="xrefwindow" href="https://doi.org/10.1177/15593258211022983" id="id758">10.1177/15593258211022983</a></p></div> </div> <a id="ref209"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id759"></a>209</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id760"></a>Shahabi S, Borneman JP. The electrostatic model of homeopathy: the mechanism of physicochemical activities of homeopathic medicines. Homeopathy. 2022;111:210–6. doi: <a target="xrefwindow" href="https://doi.org/10.1055/s-0041-1732306" id="id761">10.1055/s-0041-1732306</a></p></div> </div> <a id="ref210"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id762"></a>210</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id763"></a>Gilbert SF, Sarkar S. Embracing complexity: organicism for the 21st century. Dev Dyn. 2000;219:1–9. doi: <a target="xrefwindow" href="https://doi.org/10.1002/1097-0177(2000)9999:9999<::AID-DVDY1036>3.0.CO%3B2-A" id="id764">10.1002/1097-0177(2000)9999:9999<::AID-DVDY1036>3.0.CO;2-A</a></p></div> </div> <a id="ref211"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id765"></a>211</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id766"></a>Müller GA. Donation and acceptance in biological inheritance: the long path from Darwin’s gemmules, DNA and membranes to uniqueness and kinship. Adv Hist Stud. 2024;13:26–72. doi: <a target="xrefwindow" href="https://doi.org/10.4236/ahs.2024.132003" id="id767">10.4236/ahs.2024.132003</a></p></div> </div> <a id="ref212"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id768"></a>212</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id769"></a>Müller GA. “Centric” and “excluding” conceptions of biological inheritance. Adv Hist Stud. 2024;13:122–55. doi: <a target="xrefwindow" href="https://doi.org/10.4236/ahs.2024.132007" id="id770">10.4236/ahs.2024.132007</a></p></div> </div> <a id="ref213"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id771"></a>213</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id772"></a>Latour B, Woolgar S. Laboratory life. The social construction of scientific facts. London: Sage; 1979.</p></div> </div> <a id="ref214"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id773"></a>214</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id774"></a>Callon M. Einige Elemente einer Soziologie der Übersetzung. Die Domestikation der Kammmuscheln und der Fischer der St. Brieuc-Bucht. In: Bellinger A, Krieger DJ, editors. ANThology. Ein einführendes Handbuch zur Akteur-Netzwerk-Theorie. Transcript, Bielefeld; 1986/2006. p. 135–74.</p></div> </div> <a id="ref215"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id775"></a>215</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id776"></a>Law J. After method: mess in social science research. London: Routledge; 2004.</p></div> </div> <a id="ref216"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id777"></a>216</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id778"></a>Mathar T. Akteur-Netzwerk theorie. In: Beck S, Niewöhner J, Sorensen E, editors. Science and technology studies. Bielefeld: Transcript; 2012. p. 173–90.</p></div> </div> <a id="ref217"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id779"></a>217</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id780"></a>Barad K. Reconceiving scientific literacy as agential literacy. In: Reid R, Trawee S, editors. New York: Doing Science + Culture; 2000. p. 221–58.</p></div> </div> <a id="ref218"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id781"></a>218</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id782"></a>Barad K. How material-discursive practices matter. Signs – J Women Culture Soc. 2003;28(3):803–31. doi: <a target="xrefwindow" href="https://doi.org/10.1086/345321" id="id783">10.1086/345321</a></p></div> </div> <a id="ref219"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id784"></a>219</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id785"></a>Hoppe K, Lemke T. Performativer Materialismus: Karen Barad und die Macht der Phänomene. In: Hoppe K, Lemke T, editors. Neue Materialismen zur Einführung. Hamburg: Junius Verlag; 2018. p. 59–80.</p></div> </div> <a id="ref220"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id786"></a>220</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id787"></a>Haraway DJ. Mice into wormholes: a technoscience fugue in two parts. In: Haraway DJ, editor. Modest_Witness@ Second_Millenium. FemaleMan<sup>©</sup>_Meets_OncoMouse<sup>TM</sup>. Routledge, New York, London, USA; 1997. p. 49–118.</p></div> </div> <a id="ref221"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id788"></a>221</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id789"></a>Haraway DJ. Monströse Versprechen. Eine Erneuerungspolitik für un/an/geeignete Andere. In: Haraway DJ, editor. Monströse Versprechen. Die gender- und technologie-essays. Hamburg: Argument; 2017. p. 35–123.</p></div> </div> <a id="ref222"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id790"></a>222</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id791"></a>Harraway DJ. Crystals, fabrics, and fields. metaphors that shape embryos. Berkeley: North Atlantic Books; 1976.</p></div> </div> <a id="ref223"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id792"></a>223</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id793"></a>Stanford PK. Darwin’s pangenesis and the problem of unconceived alternatives. Brit J Phil Sci. 2006;57:121–44. doi: <a target="xrefwindow" href="https://doi.org/10.1093/bjps/axi158" id="id794">10.1093/bjps/axi158</a></p></div> </div> <a id="ref224"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id795"></a>224</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id796"></a>Stanford PK. Scientific realism, the atomic theory, and the catch-all hypothesis: can we test fundamental theories against all serious alternatives. Brit J Phil Sci. 2009;60:253–69. doi: <a target="xrefwindow" href="https://doi.org/10.1093/bjps/axp003" id="id797">10.1093/bjps/axp003</a></p></div> </div> <a id="ref225"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id798"></a>225</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id799"></a>Stanford PK. Exceeding our grasp. Science, history, and the problem of unconceived alternatives. New York: Oxford University Press; 2006.</p></div> </div> <a id="ref226"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id800"></a>226</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id801"></a>Jablonka E, Lamb MJ, Avital E. Lamarckian’ mechanisms in Darwinian evolution. Trends Ecol Evol. 1998;13:206–10. doi: <a target="xrefwindow" href="https://doi.org/10.1016/S0169-5347(98)01344-5" id="id802">10.1016/S0169-5347(98)01344-5</a></p></div> </div> <a id="ref227"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id803"></a>227</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id804"></a>Jablonka E, Lamb MJ. Epigenetic inheritance and evolution: the lamarckian case. Oxford: Oxford University Press; 1995.</p></div> </div> <a id="ref228"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id805"></a>228</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id806"></a>Barad K. Quantum entanglements and the hauntological relations of inheritance: dis/continuities, space/time enfoldings, and justice-to-come. Derrida Today. 2010;3(2):240–68. doi: <a target="xrefwindow" href="https://doi.org/10.3366/E1754850010000813" id="id807">10.3366/E1754850010000813</a></p></div> </div> <a id="ref229"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id808"></a>229</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id809"></a>Barad K. Erasers and erasures: pinch’s unfortunate ‘uncertainty principle’. Soc Stud Sci. 2011;41:443–54. doi: <a target="xrefwindow" href="https://doi.org/10.1177/0306312711406317" id="id810">10.1177/0306312711406317</a></p></div> </div> <a id="ref230"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id811"></a>230</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id812"></a>Barad K. Diffracting diffraction. Cutting together-apart. Parallax. 2014;20(3):168–87. doi: <a target="xrefwindow" href="https://doi.org/10.1080/13534645.2014.927623" id="id813">10.1080/13534645.2014.927623</a></p></div> </div> <a id="ref231"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id814"></a>231</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id815"></a>Shorter J, Lindquist S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet. 2005;6:435–50. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nrg1616" id="id816">10.1038/nrg1616</a></p></div> </div> <a id="ref232"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id817"></a>232</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id818"></a>Crouch DJM, Bodmer WF. Evolution by natural selection is a scientific law and not just a theory. Acad Biol. 2024;2:6158. doi: <a target="xrefwindow" href="https://doi.org/10.20935/AcadBiol6158" id="id819">10.20935/AcadBiol6158</a></p></div> </div> <a id="ref233"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id820"></a>233</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id821"></a>van Wijnen AJ, Lewallen EA. Natural selection and evolution: evolving concepts. Acad Biol. 2024;2:6245. doi: <a target="xrefwindow" href="https://doi.org/10.20935/AcadBiol6158" id="id822">10.20935/AcadBiol6158</a></p></div> </div> <a id="ref234"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id823"></a>234</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id824"></a>Zoghbi HY, Beaudet AL. Epigenetics and human disease. Cold Spring Harb Perspect. Biol. 2016;8:a019497. doi: <a target="xrefwindow" href="https://doi.org/10.1101/cshperspect.a019497" id="id825">10.1101/cshperspect.a019497</a></p></div> </div> <a id="ref235"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id826"></a>235</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id827"></a>Tabatabaiefar MA, Sajjadi RS, Narrei S. Epigenetics and common non communicable disease. Adv Exp Med Biol. 2019;1121:7–20. doi: <a target="xrefwindow" href="https://doi.org/10.1007/978-3-030-10616-4_2" id="id828">10.1007/978-3-030-10616-4_2</a></p></div> </div> <a id="ref236"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id829"></a>236</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id830"></a>Bhattarai K, Maharjan B, Acharya S, Bigyan KC, Pandit R, Regmi R, et al. Epigenetic modifications and its basic mechanism. J Inn Agric. 2021;8:19–25. doi: <a target="xrefwindow" href="https://doi.org/10.37446/jinagri/ra/8.1.2021.19-25" id="id831">10.37446/jinagri/ra/8.1.2021.19-25</a></p></div> </div> <a id="ref237"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id832"></a>237</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id833"></a>Chen Q, Yan M, Cao Z, Li X, Zhang Y, Shi J, et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science. 2016;351:397–400. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.aad7977" id="id834">10.1126/science.aad7977</a></p></div> </div> <a id="ref238"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id835"></a>238</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id836"></a>Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Sem Reprod Med. 2012;27:351–7. doi: <a target="xrefwindow" href="https://doi.org/10.1055/s-0029-1237423" id="id837">10.1055/s-0029-1237423</a></p></div> </div> <a id="ref239"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id838"></a>239</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id839"></a>Feil R, Fraga M. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012;13:97–109. doi: <a target="xrefwindow" href="https://doi.org/10.1038/nrg3142" id="id840">10.1038/nrg3142</a></p></div> </div> <a id="ref240"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id841"></a>240</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id842"></a>Ooi STK, Bestor TH. Cytosine methylation: remaining faithful. Curr Biol. 2008;18:R174–6. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.cub.2007.12.045" id="id843">10.1016/j.cub.2007.12.045</a></p></div> </div> <a id="ref241"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id844"></a>241</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id845"></a>Vukic M, Wu H, Daxinger L. Making headway towards understanding how epigenetic mechanisms contribute to early-life effects. Philos Trans R Soc Lond B Biol Sci. 2019;374:20180126. doi: <a target="xrefwindow" href="https://doi.org/10.1098/rstb.2018.0126" id="id846">10.1098/rstb.2018.0126</a></p></div> </div> <a id="ref242"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id847"></a>242</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id848"></a>Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang RY, Algire MA, et al. Creation of a bacterial cell controlled by a chemically synthesized genome. Science. 2010;329: 52–6. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.1190719" id="id849">10.1126/science.1190719</a></p></div> </div> <a id="ref243"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id850"></a>243</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id851"></a>Hutchison CA 3rd, Chuang RY, Noskov VN, Assad-Garcia N, Deerinck TJ, Ellisman MH, et al. Design and synthesis of a minimal bacterial genome. Science. 2016; 351: aad6253. doi: <a target="xrefwindow" href="https://doi.org/10.1126/science.aad6253" id="id852">10.1126/science.aad6253</a></p></div> </div> <a id="ref244"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id853"></a>244</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id854"></a>Pelletier JF, Glass JI, Strychalski EA. Cellular mechanics during division of a genomically minimal cell. Trends Cell Biol. 2022;32:900–7. doi: <a target="xrefwindow" href="https://doi.org/10.1016/j.tcb.2022.06.009" id="id855">10.1016/j.tcb.2022.06.009</a></p></div> </div> <a id="ref245"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id856"></a>245</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id857"></a>Toyofuku M, Nomura N, Eberl I. Types and origins of bacterial membrane vesicles. Nat Rev Microbiol. 2019;17:13–24. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s41579-018-0112-2" id="id858">10.1038/s41579-018-0112-2</a></p></div> </div> <a id="ref246"></a><div class="sap__ref-container"> <div class="sap__ref-labels"><p class="sap__citation"><a id="id859"></a>246</p></div> <div class="sap__ref-content"><p class="sap__citation"><a id="id860"></a>Zhao K, Bleackley M, Chisanga D, Gangoda L, Fonseka P, Liem M, et al. Extracellular vesicles secreted by <i>Saccharomyces cerevisiae</i> are involved in cell wall remodelling. Commun Biol. 2019;2:305. doi: <a target="xrefwindow" href="https://doi.org/10.1038/s42003-019-0538-8" id="id861">10.1038/s42003-019-0538-8</a></p></div> </div> </div> </div> </div></div> </div> </div> <div class="sap__spacer"></div> </div> <div id="article-keywords" class="sap__sub-section"> <h3 class="sap__section-title"> Keywords </h3> <div class="sap__title sap__display-row">cellular heredity, extracellular vesicles, glycosylphosphatidylinositol-anchored protein, inheritance of acquired traits, membrane biogenesis, phenotypic plasticity, structural inheritance</div> </div> </div></body> </html> </div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/collapse-45805421cf446ca5adf7aaa1935b08a3a8d1d9a6cc5d91a62a2a3a00b20b3e6a.js"], function() { // from javascript_helper.rb }); </script> <script>(() => { document.addEventListener('DOMContentLoaded', () => { const tableOfContents = document.querySelector('#article-table-of-contents'); // const mobileTableOfContents = document.querySelector('#sap__header-mobile-toc-body'); // const articleRootContainer = document.querySelector('#article-root-container'); const articleRoot = document.querySelector('#article-root'); // Move table of contents above #article-text const articleContainer = document.querySelector('#article-container'); const articleText = document.querySelector('#article-text'); articleContainer.appendChild(tableOfContents); const articleFrontContainer = document.querySelector('#article-front-container'); const metadataSidebar = document.querySelector('#article-metadata-sidebar'); articleFrontContainer.appendChild(metadataSidebar); const articleFrontColumn = document.querySelector('#article-front-column'); const articleFront = document.querySelector('#article-front'); const articleMetadata = document.querySelector('#article-metadata'); articleFront.prepend(articleMetadata); // Move header into article front const articleHeader = document.querySelector('#article-header'); articleFront.after(articleHeader); const articleStats = document.querySelector('#article-stats'); articleHeader.after(articleStats); const authors = document.querySelector('#article-author-affiliations'); if (authors) { articleFrontColumn.appendChild(authors); } const articlePodcast = document.querySelector('#article-podcast'); if (articlePodcast) { articleFrontColumn.appendChild(articlePodcast); } const articleBack = document.querySelector('#article-back'); const articleReferenceList = document.querySelector('#article-reference-list'); const articleAppendices = document.querySelector('#article-appendices'); const articleAbout = document.querySelector('#article-about'); const articleKeywords = document.querySelector('#article-keywords'); const relatedArticles = document.querySelector('#related-articles'); if (articleKeywords) { articleAbout.appendChild(articleKeywords); } if (articleAppendices) { articleReferenceList.after(articleAppendices); } articleBack.appendChild(articleAbout); // articleBack.prepend(articleReferenceList); articleBack.appendChild(relatedArticles); // const articleBody = document.querySelector('#article-root-body'); const headers = document.querySelectorAll('#article-body > .sap__section > h2, .sap__back-section > h2, #article-back > .sap__section > h2'); // Add a link to the table of contents for each header for (const header of headers) { const sectionLink = header.parentNode.querySelector('a'); if (!sectionLink) { continue; } const sectionId = sectionLink.getAttribute('id'); const link = document.createElement('a'); link.setAttribute('href', `#${sectionId}`); link.textContent = header.textContent; const div = document.createElement('div'); div.setAttribute('class', 'sap__table-of-contents-item'); div.appendChild(link); tableOfContents.appendChild(div); } let showMoreOpen = false; document.querySelector('#article-metadata-show-more').addEventListener('click', () => { const extra = document.querySelector('#article-metadata-extra'); const showMore = document.querySelector('#article-metadata-show-more'); showMore.classList.toggle('open'); extra.classList.toggle('active'); showMoreOpen = !showMoreOpen; }); // Handle lower download button window.addEventListener('scroll', () => { const articleDownloadContainer = document.querySelector('#article-download-container'); if (showMoreOpen) { if (window.scrollY > 1300) { articleDownloadContainer.classList.add("mobile-visible"); } else { articleDownloadContainer.classList.remove("mobile-visible"); } } else { if (window.scrollY > 700) { articleDownloadContainer.classList.add("mobile-visible"); } else { articleDownloadContainer.classList.remove("mobile-visible"); } } if (window.scrollY > 500) { articleDownloadContainer.classList.add("visible"); } else { articleDownloadContainer.classList.remove("visible"); } }); }); document.getElementById('affiliation-list-link')?.addEventListener('click', () => { var icon = document.querySelector('#chevron'); icon.classList.toggle('rotate'); }); document.getElementById('open-access-link')?.addEventListener('click', () => { var icon = document.querySelector('#chevron-open-access'); icon.classList.toggle('rotate'); }); document.getElementById('sap__supplementary-dropdown-link')?.addEventListener('click', () => { var icon = document.querySelector('.sap__supplementary-expand-icon'); icon.classList.toggle('rotate'); }); /* Click to copy citation */ document.getElementById('js--cite-paper')?.addEventListener('click', () => { var node = document.querySelector('#sap__paper-citation'); var tempTextarea = document.createElement('textarea'); tempTextarea.value = node.innerText; document.body.appendChild(tempTextarea); tempTextarea.select(); document.execCommand('copy'); document.body.removeChild(tempTextarea); Components.Utils.showToast( Components.Toasts.BasicToast, { text: 'Citation copied to clipboard' }, { timeMs: 3000, color: '' } ); }); })();</script> </div> <style type="text/css">html{font-size:16px !important}.ds-grid-container{display:grid;height:100%;grid-auto-rows:max-content;justify-content:center;column-gap:24px;padding:0 24px;grid-template-columns:repeat(6, 1fr)}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-container{column-gap:48px;padding:0 40px;grid-template-columns:repeat(6, 1fr)}}@media(min-width: 1280px){.ds-grid-container{column-gap:48px;padding:0 64px;grid-template-columns:repeat(12, 50px)}}.ds-grid-container--stretch-large{display:grid;height:100%;grid-auto-rows:max-content;justify-content:center;column-gap:24px;padding:0 24px;grid-template-columns:repeat(6, 1fr)}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-container--stretch-large{column-gap:48px;padding:0 40px;grid-template-columns:repeat(6, 1fr)}}@media(min-width: 1280px){.ds-grid-container--stretch-large{column-gap:48px;padding:0 64px;grid-template-columns:repeat(12, minmax(0, 116px))}}@media(max-width: 567px){.ds-grid-column-small-hidden{display:none}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-hidden{display:none}}@media(min-width: 1280px){.ds-grid-column-large-hidden{display:none}}@media(max-width: 567px){.ds-grid-column-small-1{grid-column:span 1}}@media(max-width: 567px){.ds-grid-column-small-2{grid-column:span 2}}@media(max-width: 567px){.ds-grid-column-small-3{grid-column:span 3}}@media(max-width: 567px){.ds-grid-column-small-4{grid-column:span 4}}@media(max-width: 567px){.ds-grid-column-small-5{grid-column:span 5}}@media(max-width: 567px){.ds-grid-column-small-6{grid-column:span 6}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-1{grid-column:span 1}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-2{grid-column:span 2}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-3{grid-column:span 3}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-4{grid-column:span 4}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-5{grid-column:span 5}}@media(min-width: 568px)and (max-width: 1279px){.ds-grid-column-medium-6{grid-column:span 6}}@media(min-width: 1280px){.ds-grid-column-large-1{grid-column:span 1}}@media(min-width: 1280px){.ds-grid-column-large-2{grid-column:span 2}}@media(min-width: 1280px){.ds-grid-column-large-3{grid-column:span 3}}@media(min-width: 1280px){.ds-grid-column-large-4{grid-column:span 4}}@media(min-width: 1280px){.ds-grid-column-large-5{grid-column:span 5}}@media(min-width: 1280px){.ds-grid-column-large-6{grid-column:span 6}}@media(min-width: 1280px){.ds-grid-column-large-7{grid-column:span 7}}@media(min-width: 1280px){.ds-grid-column-large-8{grid-column:span 8}}@media(min-width: 1280px){.ds-grid-column-large-9{grid-column:span 9}}@media(min-width: 1280px){.ds-grid-column-large-10{grid-column:span 10}}@media(min-width: 1280px){.ds-grid-column-large-11{grid-column:span 11}}@media(min-width: 1280px){.ds-grid-column-large-12{grid-column:span 12}}.journals-footer-container{background:var(--background-black, #070A15);color:var(--text-white, #FFF);padding:var(--spacing-lg-80, 80px) 0 var(--spacing-md-48, 48px) 0}.journals-footer-container .footer-grid{display:grid;height:100%;grid-auto-rows:max-content;justify-content:center;column-gap:24px;padding:0 24px;grid-template-columns:repeat(6, minmax(0, 40px));height:auto}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .footer-grid{column-gap:48px;padding:0 40px;grid-template-columns:repeat(6, minmax(40px, 88px))}}@media(min-width: 1280px){.journals-footer-container .footer-grid{column-gap:48px;padding:0 64px;grid-template-columns:repeat(12, 50px)}}.journals-footer-container .journals-row{display:grid;height:100%;grid-auto-rows:max-content;justify-content:center;grid-template-columns:subgrid;height:auto;border-top:1px solid var(--stroke-white, #FFF);padding-top:var(--spacing-md-40, 40px);padding-bottom:var(--spacing-page-section, 80px)}@media(max-width: 567px){.journals-footer-container .journals-row{grid-column:span 6}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .journals-row{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .journals-row{grid-column:span 12}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .journals-row{padding-bottom:var(--spacing-page-section, 104px)}}@media(min-width: 1280px){.journals-footer-container .journals-row{padding-bottom:var(--spacing-page-section, 152px)}}.journals-footer-container .journals-row .text-column{padding-bottom:var(--spacing-md-48, 48px)}@media(max-width: 567px){.journals-footer-container .journals-row .text-column{grid-column:span 6}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .journals-row .text-column{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .journals-row .text-column{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .journals-row .text-column{padding-bottom:0}}.journals-footer-container .journals-row .text-column h3{margin:0 0 var(--spacing-sm-24, 24px);font-family:var(--type-font-family-serif, "Georgia"),"Times New Roman",serif;font-style:normal;font-weight:400;font-size:var(--type-serif-md-size, 34px);line-height:var(--type-serif-md-line-height, 44px);font-weight:var(--type-serif-md-font-weight, 400)}.journals-footer-container .journals-row .text-column p{margin:0;font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-lg-size, 20px);line-height:var(--type-body-lg-line-height, 32px);font-weight:var(--type-body-lg-font-weight, 400)}.journals-footer-container .journals-row ul{list-style-type:none;margin:0;padding:0;font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-lg-size, 20px);line-height:var(--type-body-lg-line-height, 32px);font-weight:var(--type-body-lg-font-weight, 400)}.journals-footer-container .journals-row ul li{margin:0 0 var(--spacing-sm-24, 24px)}.journals-footer-container .academia-row{border-top:1px solid var(--stroke-white, #FFF);padding-top:var(--spacing-md-40, 40px);display:grid;height:100%;grid-auto-rows:max-content;justify-content:center;grid-template-columns:subgrid}@media(max-width: 567px){.journals-footer-container .academia-row{grid-column:span 6}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .academia-row{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .academia-row{grid-column:span 12}}.journals-footer-container .academia-row .academia-logo{padding-bottom:var(--spacing-sm-24, 24px)}@media(max-width: 567px){.journals-footer-container .academia-row .academia-logo{grid-column:span 6}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .academia-row .academia-logo{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .academia-row .academia-logo{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .academia-row .academia-logo{padding-bottom:0}}.journals-footer-container .two-column-container{display:grid;height:100%;grid-auto-rows:max-content;justify-content:center;grid-template-columns:subgrid}@media(max-width: 567px){.journals-footer-container .two-column-container{grid-column:span 6}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .two-column-container{grid-column:span 6}}@media(min-width: 1280px){.journals-footer-container .two-column-container{grid-column:span 6}}@media(max-width: 567px){.journals-footer-container .two-column-container .single-column{grid-column:span 3}}@media(min-width: 568px)and (max-width: 1279px){.journals-footer-container .two-column-container .single-column{grid-column:span 3}}@media(min-width: 1280px){.journals-footer-container .two-column-container .single-column{grid-column:span 3}}.journals-footer-container .two-column-container.academia{font-family:var(--type-font-family-sans-serif, "Roboto"),Helvetica,Arial,sans-serif;font-style:normal;font-weight:400;font-size:var(--type-body-md-size, 16px);line-height:var(--type-body-md-line-height, 24px);font-weight:var(--type-body-md-font-weight, 400)}.journals-footer-container a{color:var(--text-white, #FFF);text-decoration:none}.journals-footer-container a:hover{color:var(--text-white, #FFF);text-decoration:underline;cursor:pointer}.journals-footer-container a.inverse{text-decoration:underline}.journals-footer-container a.inverse:hover{text-decoration:none}</style><div class="journals-footer-container"><div class="footer-grid"><div class="journals-row"><div class="text-column"><a href="https://www.academia.edu/journals?source=publishing-footer"><h3>Academia.edu Journals</h3></a><p>A diverse collection of peer-reviewed journals empowering researchers to accelerate progress in science and medicine. Powered by <a class="inverse" href="https://www.academia.edu/">Academia.edu</a></p></div><div class="two-column-container"><ul class="single-column"><li><a href="https://www.academia.edu/journals/all?source=publishing-footer">All journals</a></li><li><a href="https://www.academia.edu/journals/articles?source=publishing-footer">All articles</a></li><li><a href="https://www.academia.edu/about?source=publishing-footer">About Academia</a></li></ul><ul class="single-column"><li><a href="https://www.academia.edu/careers?source=publishing-footer">Careers</a></li><li><a href="https://www.academia.edu/journals/about/contact-us?source=publishing-footer">Contact us</a></li></ul></div></div><div class="academia-row"><div class="academia-logo"><a href="https://www.academia.edu/?source=publishing-footer"><img alt="Academia" src="//a.academia-assets.com/images/design_system/academia_logo_white.svg" /></a></div><div class="two-column-container academia"><div class="single-column"><div>580 California St., Suite 400</div><div>San Francisco, CA, 94104</div></div><div class="single-column"><div><a href="https://www.academia.edu/copyright?source=publishing-footer">© 2024 Academia. All rights reserved</a></div></div></div></div></div></div> <div id='overlay_background'></div> <div id='bootstrap-modal-container' class='bootstrap'></div> <div id='ds-modal-container' class='bootstrap DesignSystem'></div> <div id='full-screen-modal'></div> </div> </body> </html>