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value="clinpract" > Clinics and Practice </option> <option value="clockssleep" > Clocks & Sleep </option> <option value="coasts" > Coasts </option> <option value="coatings" > Coatings </option> <option value="colloids" > Colloids and Interfaces </option> <option value="colorants" > Colorants </option> <option value="commodities" > Commodities </option> <option value="complications" > Complications </option> <option value="compounds" > Compounds </option> <option value="computation" > Computation </option> <option value="csmf" > Computer Sciences & Mathematics Forum </option> <option value="computers" > Computers </option> <option value="condensedmatter" > Condensed Matter </option> <option value="conservation" > Conservation </option> <option value="constrmater" > Construction Materials </option> <option value="cmd" > Corrosion and Materials Degradation (CMD) </option> <option value="cosmetics" > Cosmetics </option> <option value="covid" > COVID </option> <option value="crops" > Crops </option> <option value="cryo" > Cryo </option> <option value="cryptography" > Cryptography </option> <option value="crystals" > Crystals </option> <option value="cimb" > Current Issues in Molecular Biology (CIMB) </option> <option value="curroncol" > Current Oncology </option> <option value="dairy" > Dairy </option> <option value="data" > Data </option> <option value="dentistry" > Dentistry Journal </option> <option value="dermato" > Dermato </option> <option value="dermatopathology" > Dermatopathology </option> <option value="designs" > Designs </option> <option value="diabetology" > Diabetology </option> <option value="diagnostics" > Diagnostics </option> <option value="dietetics" > Dietetics </option> <option value="digital" > Digital </option> <option value="disabilities" > Disabilities </option> <option value="diseases" > Diseases </option> <option value="diversity" > Diversity </option> <option value="dna" > DNA </option> <option value="drones" > Drones </option> <option value="ddc" > Drugs and Drug Candidates (DDC) </option> <option value="dynamics" > Dynamics </option> <option value="earth" > Earth </option> <option value="ecologies" > Ecologies </option> <option value="econometrics" > Econometrics </option> <option value="economies" > Economies </option> <option value="education" > Education Sciences </option> <option value="electricity" > Electricity </option> <option value="electrochem" > Electrochem </option> <option value="electronicmat" > Electronic Materials </option> <option value="electronics" > Electronics </option> <option value="ecm" > Emergency Care and Medicine </option> <option value="encyclopedia" > Encyclopedia </option> <option value="endocrines" > Endocrines </option> <option value="energies" > Energies </option> <option value="esa" > Energy Storage and Applications (ESA) </option> <option value="eng" > Eng </option> <option value="engproc" > Engineering Proceedings </option> <option value="entropy" > Entropy </option> <option value="environsciproc" > Environmental Sciences Proceedings </option> <option value="environments" > Environments </option> <option value="epidemiologia" > Epidemiologia </option> <option value="epigenomes" > Epigenomes </option> <option value="ebj" > European Burn Journal (EBJ) </option> <option value="ejihpe" > European Journal of Investigation in Health, Psychology and Education (EJIHPE) </option> <option value="fermentation" > Fermentation </option> <option value="fibers" > Fibers </option> <option value="fintech" > FinTech </option> <option value="fire" > Fire </option> <option value="fishes" > Fishes </option> <option value="fluids" > Fluids </option> <option value="foods" > Foods </option> <option value="forecasting" > Forecasting </option> <option value="forensicsci" > Forensic Sciences </option> <option value="forests" > Forests </option> <option value="fossstud" > Fossil Studies </option> <option value="foundations" > Foundations </option> <option value="fractalfract" > Fractal and Fractional (Fractal Fract) </option> <option value="fuels" > Fuels </option> <option value="future" > Future </option> <option value="futureinternet" > Future Internet </option> <option value="futurepharmacol" > Future Pharmacology </option> <option value="futuretransp" > Future Transportation </option> <option value="galaxies" > Galaxies </option> <option value="games" > Games </option> <option value="gases" > Gases </option> <option value="gastroent" > Gastroenterology Insights </option> <option value="gastrointestdisord" > Gastrointestinal Disorders </option> <option value="gastronomy" > Gastronomy </option> <option value="gels" > Gels </option> <option value="genealogy" > Genealogy </option> <option value="genes" > Genes </option> <option value="geographies" > Geographies </option> <option value="geohazards" > GeoHazards </option> <option value="geomatics" > Geomatics </option> <option value="geometry" > Geometry </option> <option value="geosciences" > Geosciences </option> <option value="geotechnics" > Geotechnics </option> <option value="geriatrics" > Geriatrics </option> <option value="glacies" > Glacies </option> <option value="gucdd" > Gout, Urate, and Crystal Deposition Disease (GUCDD) </option> <option value="grasses" > Grasses </option> <option value="hardware" > Hardware </option> <option value="healthcare" > Healthcare </option> <option value="hearts" > Hearts </option> <option value="hemato" > Hemato </option> <option value="hematolrep" > Hematology Reports </option> <option value="heritage" > Heritage </option> <option value="histories" > Histories </option> <option value="horticulturae" > Horticulturae </option> <option value="hospitals" > Hospitals </option> <option value="humanities" > Humanities </option> <option value="humans" > Humans </option> <option value="hydrobiology" > Hydrobiology </option> <option value="hydrogen" > Hydrogen </option> <option value="hydrology" > Hydrology </option> <option value="hygiene" > Hygiene </option> <option value="immuno" > Immuno </option> <option value="idr" > Infectious Disease Reports </option> <option value="informatics" > Informatics </option> <option value="information" > Information </option> <option value="infrastructures" > Infrastructures </option> <option value="inorganics" > Inorganics </option> <option value="insects" > Insects </option> <option value="instruments" > Instruments </option> <option value="iic" > Intelligent Infrastructure and Construction </option> <option value="ijerph" > International Journal of Environmental Research and Public Health (IJERPH) </option> <option value="ijfs" > International Journal of Financial Studies (IJFS) </option> <option value="ijms" > International Journal of Molecular Sciences (IJMS) </option> <option value="IJNS" > International Journal of Neonatal Screening (IJNS) </option> <option value="ijpb" > International Journal of Plant Biology (IJPB) </option> <option value="ijt" > International Journal of Topology 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Compos. Sci.) </option> <option value="jcp" > Journal of Cybersecurity and Privacy (JCP) </option> <option value="jdad" > Journal of Dementia and Alzheimer's Disease (JDAD) </option> <option value="jdb" > Journal of Developmental Biology (JDB) </option> <option value="jeta" > Journal of Experimental and Theoretical Analyses (JETA) </option> <option value="jfb" > Journal of Functional Biomaterials (JFB) </option> <option value="jfmk" > Journal of Functional Morphology and Kinesiology (JFMK) </option> <option value="jof" > Journal of Fungi (JoF) </option> <option value="jimaging" > Journal of Imaging (J. Imaging) </option> <option value="jintelligence" > Journal of Intelligence (J. Intell.) </option> <option value="jlpea" > Journal of Low Power Electronics and Applications (JLPEA) </option> <option value="jmmp" > Journal of Manufacturing and Materials Processing (JMMP) </option> <option value="jmse" > Journal of Marine Science and Engineering (JMSE) </option> <option value="jmahp" > Journal of Market Access & Health Policy (JMAHP) </option> <option value="jmp" > Journal of Molecular Pathology (JMP) </option> <option value="jnt" > Journal of Nanotheranostics (JNT) </option> <option value="jne" > Journal of Nuclear Engineering (JNE) </option> <option value="ohbm" > Journal of Otorhinolaryngology, Hearing and Balance Medicine (JOHBM) </option> <option value="jop" > Journal of Parks </option> <option value="jpm" > Journal of Personalized Medicine (JPM) </option> <option value="jpbi" > Journal of Pharmaceutical and BioTech Industry (JPBI) </option> <option value="jor" > Journal of Respiration (JoR) </option> <option value="jrfm" > Journal of Risk and Financial Management (JRFM) </option> <option value="jsan" > Journal of Sensor and Actuator Networks (JSAN) </option> <option value="joma" > Journal of the Oman Medical Association (JOMA) </option> <option value="jtaer" > Journal of Theoretical and Applied Electronic Commerce Research (JTAER) </option> <option value="jvd" > Journal of Vascular Diseases (JVD) </option> <option value="jox" > Journal of Xenobiotics (JoX) </option> <option value="jzbg" > Journal of Zoological and Botanical Gardens (JZBG) </option> <option value="journalmedia" > Journalism and Media </option> <option value="kidneydial" > Kidney and Dialysis </option> <option value="kinasesphosphatases" > Kinases and Phosphatases </option> <option value="knowledge" > Knowledge </option> <option value="labmed" > LabMed </option> <option value="laboratories" > Laboratories </option> <option value="land" > Land </option> <option value="languages" > Languages </option> <option value="laws" > Laws </option> <option value="life" > Life 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Med.) </option> <option value="resources" > Resources </option> <option value="rheumato" > Rheumato </option> <option value="risks" > Risks </option> <option value="robotics" > Robotics </option> <option value="ruminants" > Ruminants </option> <option value="safety" > Safety </option> <option value="sci" > Sci </option> <option value="scipharm" > Scientia Pharmaceutica (Sci. Pharm.) </option> <option value="sclerosis" > Sclerosis </option> <option value="seeds" > Seeds </option> <option value="sensors" > Sensors </option> <option value="separations" > Separations </option> <option value="sexes" > Sexes </option> <option value="signals" > Signals </option> <option value="sinusitis" > Sinusitis </option> <option value="smartcities" > Smart Cities </option> <option value="socsci" > Social Sciences </option> <option value="siuj" > Société Internationale d’Urologie Journal (SIUJ) </option> <option value="societies" > Societies </option> <option value="software" > Software </option> <option value="soilsystems" > Soil Systems </option> <option value="solar" > Solar </option> <option value="solids" > Solids </option> <option value="spectroscj" > Spectroscopy Journal </option> <option value="sports" > Sports </option> <option value="standards" > Standards </option> <option value="stats" > Stats </option> <option value="stresses" > Stresses </option> <option value="surfaces" > Surfaces </option> <option value="surgeries" > Surgeries </option> <option value="std" > Surgical Techniques Development </option> <option value="sustainability" > Sustainability </option> <option value="suschem" > Sustainable Chemistry </option> <option value="symmetry" > Symmetry </option> <option value="synbio" > SynBio </option> <option value="systems" > Systems </option> <option value="targets" > Targets </option> <option value="taxonomy" > Taxonomy </option> <option value="technologies" > Technologies </option> <option value="telecom" > Telecom </option> <option value="textiles" > Textiles </option> <option value="thalassrep" > Thalassemia Reports </option> <option value="therapeutics" > Therapeutics </option> <option value="thermo" > Thermo </option> <option value="timespace" > Time and Space </option> <option value="tomography" > Tomography </option> <option value="tourismhosp" > Tourism and Hospitality </option> <option value="toxics" > Toxics </option> 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value="women" > Women </option> <option value="world" > World </option> <option value="wevj" > World Electric Vehicle Journal (WEVJ) </option> <option value="youth" > Youth </option> <option value="zoonoticdis" > Zoonotic Diseases </option> </select> </div> <div class="large-2 medium-2 small-6 columns "> <div class=""> <div class="search-input-label">Article Type</div> </div> <select id="article_type" tabindex="4" name="article_type" class="chosen-select"> <option value="">All Article Types</option> <option value="research-article">Article</option> <option value="review-article">Review</option> <option value="rapid-communication">Communication</option> <option value="editorial">Editorial</option> <option value="abstract">Abstract</option> <option value="book-review">Book Review</option> <option value="brief-communication">Brief Communication</option> <option value="brief-report">Brief Report</option> <option value="case-report">Case Report</option> <option 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class="custom-accordion-for-small-screen-link " > <h2>Saved Queries</h2> </div> <div class="target-item custom-accordion-for-small-screen-content show-for-medium-up"> <div class="generic-item refind-item-wrap no-border last-item no-padding-top"> <a class="bold" href="/user/login">Sign in</a> to use this feature. </div> </div> </div> <div class="content__container " > <div class="custom-accordion-for-small-screen-link " data-callback=processResetAllVisibility> <h2> Search Filter <a href="#" class="remove-refines remove-refines-all link--red right">Reset All</a> </h2> </div> <div class="target-item custom-accordion-for-small-screen-content show-for-medium-up"> <div class="generic-item refind-item-wrap no-border no-padding-top"> <h3>Years</h3> <span>Between:</span> <input type="number" id="refine_year_from" style="display: inline-block; font-size: 12px;" name="year_from" value="1996" min="1996" max="2024"> - <input type="number" id="refine_year_to" style="display: inline-block; font-size: 12px;" name="year_to" value="2024" min="1996" max="2024"> <div id="year-range"></div> <div style="clear:both;"></div> </div> <div class="generic-item refind-item-wrap filter-container filter-container-featured" style="display: none;"> <h3>Feature Papers</h3> <div class="js-refinement-selections-container"> </div> <div class="filter-actions-container filter-actions-container--filled filter-actions-container--hidden"> <a class="js-refine-filter" data-reveal-id="refine-modal-featured" data-filter="featured"><strong>Add Feature Papers</strong></a> <a href="#" class="remove-refines link--red right" data-refineid="featured"><strong>Reset</strong></a> </div> <div class="filter-actions-container filter-actions-container--empty "> <a class="button button--color button--full-width js-refine-filter" href="#" data-reveal-id="refine-modal-featured" data-filter="featured" class="all">Select Feature Papers</a> </div> <div style="clear:both;"></div> <div id="refine-modal-featured" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2>Filter Feature Papers</h2> <input class="js-filter" type="text" form="temp" placeholder="Search for Feature Papers" style="width: 100%; max-width: 300px;" /> <p class="reveal-modal-new__description"> Select feature papers you want to add to your filter. </p> </div> <div class="js-refinement-values-container"> </div> </div> <div class="row"> <div class="small-12 columns"> <a class="button button--color js-filter-close" data-itemid="featured" onclick="$('#refine-modal-featured').foundation('reveal', 'close'); return false;">Add to Filter</a> <a class="button button--grey" onclick="$(this).closest('.reveal-modal').find('.close-reveal-modal').click(); return false;">Cancel</a> </div> </div> <input type="hidden" name="featured" id="refine_featured_field"> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div></div> <div class="generic-item refind-item-wrap filter-container filter-container-subjects" style=""> <h3>Subjects</h3> <div class="js-refinement-selections-container"> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_bio-life"> <i class="material-icons">remove_circle_outline</i> </a> <label> Biology & Life Sciences </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_med-pharma"> <i class="material-icons">remove_circle_outline</i> </a> <label> Medicine & Pharmacology </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_chem-materials"> <i class="material-icons">remove_circle_outline</i> </a> <label> Chemistry & Materials Science </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_health"> <i class="material-icons">remove_circle_outline</i> </a> <label> Public Health & Healthcare </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_environment"> <i class="material-icons">remove_circle_outline</i> </a> <label> Environmental & Earth Sciences </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_computer-math"> <i class="material-icons">remove_circle_outline</i> </a> <label> Computer Science & Mathematics </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_subjects_engineering"> <i class="material-icons">remove_circle_outline</i> </a> <label> Engineering </label> </div/> </div> <div class="filter-actions-container filter-actions-container--filled filter-actions-container--hidden"> <a class="js-refine-filter" data-reveal-id="refine-modal-subjects" data-filter="subjects"><strong>Add Subjects</strong></a> <a href="#" class="remove-refines link--red right" data-refineid="subjects"><strong>Reset</strong></a> </div> <div class="filter-actions-container filter-actions-container--empty "> <a class="button button--color button--full-width js-refine-filter" href="#" data-reveal-id="refine-modal-subjects" data-filter="subjects" class="all">Select Subjects</a> </div> <div style="clear:both;"></div> <div id="refine-modal-subjects" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2>Filter Subjects</h2> <input class="js-filter" type="text" form="temp" placeholder="Search for Subjects" style="width: 100%; max-width: 300px;" /> <p class="reveal-modal-new__description"> Select subjects you want to add to your filter. </p> </div> <div class="js-refinement-values-container"> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="biology & life sciences" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_bio-life" value="bio-life"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_bio-life">Biology & Life Sciences (23)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="medicine & pharmacology" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_med-pharma" value="med-pharma"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_med-pharma">Medicine & Pharmacology (23)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="chemistry & materials science" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_chem-materials" value="chem-materials"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_chem-materials">Chemistry & Materials Science (16)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="public health & healthcare" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_health" value="health"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_health">Public Health & Healthcare (3)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="environmental & earth sciences" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_environment" value="environment"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_environment">Environmental & Earth Sciences (2)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="computer science & mathematics" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_computer-math" value="computer-math"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_computer-math">Computer Science & Mathematics (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="engineering" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_subjects" id="refine_subjects_engineering" value="engineering"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_subjects_engineering">Engineering (1)</label> </div> </div> </div> </div> <div class="row"> <div class="small-12 columns"> <a class="button button--color js-filter-close" data-itemid="subjects" onclick="$('#refine-modal-subjects').foundation('reveal', 'close'); return false;">Add to Filter</a> <a class="button button--grey" onclick="$(this).closest('.reveal-modal').find('.close-reveal-modal').click(); return false;">Cancel</a> </div> </div> <input type="hidden" name="subjects" id="refine_subjects_field"> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div></div> <div class="generic-item refind-item-wrap filter-container filter-container-journals" style=""> <h3>Journals</h3> <div class="js-refinement-selections-container"> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_ijms"> <i class="material-icons">remove_circle_outline</i> </a> <label> IJMS </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_molecules"> <i class="material-icons">remove_circle_outline</i> </a> <label> Molecules </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_cells"> <i class="material-icons">remove_circle_outline</i> </a> <label> Cells </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_pharmaceutics"> <i class="material-icons">remove_circle_outline</i> </a> <label> Pharmaceutics </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_toxins"> <i class="material-icons">remove_circle_outline</i> </a> <label> Toxins </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_biomolecules"> <i class="material-icons">remove_circle_outline</i> </a> <label> Biomolecules </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_viruses"> <i class="material-icons">remove_circle_outline</i> </a> <label> Viruses </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_cancers"> <i class="material-icons">remove_circle_outline</i> </a> <label> Cancers </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_insects"> <i class="material-icons">remove_circle_outline</i> </a> <label> Insects </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_processes"> <i class="material-icons">remove_circle_outline</i> </a> <label> Processes </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_neuroglia"> <i class="material-icons">remove_circle_outline</i> </a> <label> Neuroglia </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_chemproc"> <i class="material-icons">remove_circle_outline</i> </a> <label> Chemistry Proceedings </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_journals_cimb"> <i class="material-icons">remove_circle_outline</i> </a> <label> CIMB </label> </div/> </div> <div class="filter-actions-container filter-actions-container--filled filter-actions-container--hidden"> <a class="js-refine-filter" data-reveal-id="refine-modal-journals" data-filter="journals"><strong>Add Journals</strong></a> <a href="#" class="remove-refines link--red right" data-refineid="journals"><strong>Reset</strong></a> </div> <div class="filter-actions-container filter-actions-container--empty "> <a class="button button--color button--full-width js-refine-filter" href="#" data-reveal-id="refine-modal-journals" data-filter="journals" class="all">Select Journals</a> </div> <div style="clear:both;"></div> <div id="refine-modal-journals" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2>Filter Journals</h2> <input class="js-filter" type="text" form="temp" placeholder="Search for Journals" style="width: 100%; max-width: 300px;" /> <p class="reveal-modal-new__description"> Select journals you want to add to your filter. </p> </div> <div class="js-refinement-values-container"> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="ijms" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_ijms" value="ijms"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_ijms">IJMS (9)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="molecules" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_molecules" value="molecules"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_molecules">Molecules (3)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="cells" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_cells" value="cells"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_cells">Cells (3)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="pharmaceutics" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_pharmaceutics" value="pharmaceutics"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_pharmaceutics">Pharmaceutics (2)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="toxins" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_toxins" value="toxins"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_toxins">Toxins (2)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="biomolecules" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_biomolecules" value="biomolecules"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_biomolecules">Biomolecules (2)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="viruses" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_viruses" value="viruses"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_viruses">Viruses (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="cancers" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_cancers" value="cancers"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_cancers">Cancers (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="insects" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_insects" value="insects"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_insects">Insects (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="processes" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_processes" value="processes"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_processes">Processes (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="neuroglia" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_neuroglia" value="neuroglia"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_neuroglia">Neuroglia (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="chemistry proceedings" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_chemproc" value="chemproc"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_chemproc">Chemistry Proceedings (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="cimb" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_journals" id="refine_journals_cimb" value="cimb"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_journals_cimb">CIMB (1)</label> </div> </div> </div> </div> <div class="row"> <div class="small-12 columns"> <a class="button button--color js-filter-close" data-itemid="journals" onclick="$('#refine-modal-journals').foundation('reveal', 'close'); return false;">Add to Filter</a> <a class="button button--grey" onclick="$(this).closest('.reveal-modal').find('.close-reveal-modal').click(); return false;">Cancel</a> </div> </div> <input type="hidden" name="journals" id="refine_journals_field"> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div></div> <div class="generic-item refind-item-wrap filter-container filter-container-article_types" style=""> <h3>Article Types</h3> <div class="js-refinement-selections-container"> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_article_types_research-article"> <i class="material-icons">remove_circle_outline</i> </a> <label> Article </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_article_types_review-article"> <i class="material-icons">remove_circle_outline</i> </a> <label> Review </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_article_types_rapid-communication"> <i class="material-icons">remove_circle_outline</i> </a> <label> Communication </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_article_types_proceedings"> <i class="material-icons">remove_circle_outline</i> </a> <label> Proceeding Paper </label> </div/> </div> <div class="filter-actions-container filter-actions-container--filled filter-actions-container--hidden"> <a class="js-refine-filter" data-reveal-id="refine-modal-article_types" data-filter="article_types"><strong>Add Article Types</strong></a> <a href="#" class="remove-refines link--red right" data-refineid="article_types"><strong>Reset</strong></a> </div> <div class="filter-actions-container filter-actions-container--empty "> <a class="button button--color button--full-width js-refine-filter" href="#" data-reveal-id="refine-modal-article_types" data-filter="article_types" class="all">Select Article Types</a> </div> <div style="clear:both;"></div> <div id="refine-modal-article_types" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2>Filter Article Types</h2> <input class="js-filter" type="text" form="temp" placeholder="Search for Article Types" style="width: 100%; max-width: 300px;" /> <p class="reveal-modal-new__description"> Select article types you want to add to your filter. </p> </div> <div class="js-refinement-values-container"> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="article" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_article_types" id="refine_article_types_research-article" value="research-article"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_article_types_research-article">Article (17)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="review" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_article_types" id="refine_article_types_review-article" value="review-article"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_article_types_review-article">Review (7)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="communication" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_article_types" id="refine_article_types_rapid-communication" value="rapid-communication"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_article_types_rapid-communication">Communication (3)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="proceeding paper" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_article_types" id="refine_article_types_proceedings" value="proceedings"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_article_types_proceedings">Proceeding Paper (1)</label> </div> </div> </div> </div> <div class="row"> <div class="small-12 columns"> <a class="button button--color js-filter-close" data-itemid="article_types" onclick="$('#refine-modal-article_types').foundation('reveal', 'close'); return false;">Add to Filter</a> <a class="button button--grey" onclick="$(this).closest('.reveal-modal').find('.close-reveal-modal').click(); return false;">Cancel</a> </div> </div> <input type="hidden" name="article_types" id="refine_article_types_field"> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div></div> <div class="generic-item refind-item-wrap filter-container filter-container-countries" style=""> <h3>Countries / Regions</h3> <div class="js-refinement-selections-container"> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_GERMANY"> <i class="material-icons">remove_circle_outline</i> </a> <label> Germany </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_UNITED_STATES"> <i class="material-icons">remove_circle_outline</i> </a> <label> USA </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_ITALY"> <i class="material-icons">remove_circle_outline</i> </a> <label> Italy </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_UNITED_KINGDOM"> <i class="material-icons">remove_circle_outline</i> </a> <label> UK </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_FRANCE"> <i class="material-icons">remove_circle_outline</i> </a> <label> France </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_RUSSIAN_FEDERATION"> <i class="material-icons">remove_circle_outline</i> </a> <label> Russia </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_ALGERIA"> <i class="material-icons">remove_circle_outline</i> </a> <label> Algeria </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_AUSTRIA"> <i class="material-icons">remove_circle_outline</i> </a> <label> Austria </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_CANADA"> <i class="material-icons">remove_circle_outline</i> </a> <label> Canada </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_CHINA"> <i class="material-icons">remove_circle_outline</i> </a> <label> China </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_GREECE"> <i class="material-icons">remove_circle_outline</i> </a> <label> Greece </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_JAPAN"> <i class="material-icons">remove_circle_outline</i> </a> <label> Japan </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_KENYA"> <i class="material-icons">remove_circle_outline</i> </a> <label> Kenya </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_MEXICO"> <i class="material-icons">remove_circle_outline</i> </a> <label> Mexico </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_NETHERLANDS"> <i class="material-icons">remove_circle_outline</i> </a> <label> The Netherlands </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_PORTUGAL"> <i class="material-icons">remove_circle_outline</i> </a> <label> Portugal </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_SOUTH_AFRICA"> <i class="material-icons">remove_circle_outline</i> </a> <label> South Africa </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_TAIWAN"> <i class="material-icons">remove_circle_outline</i> </a> <label> Taiwan </label> </div/> <div class="remove-filter-container remove-filter-container--hidden"> <a href="#" class="remove-filter-link link--red " data-filterid="refine_countries_KOREA_REPUBLIC_OF"> <i class="material-icons">remove_circle_outline</i> </a> <label> Republic of Korea </label> </div/> </div> <div class="filter-actions-container filter-actions-container--filled filter-actions-container--hidden"> <a class="js-refine-filter" data-reveal-id="refine-modal-countries" data-filter="countries"><strong>Add Countries / Regions</strong></a> <a href="#" class="remove-refines link--red right" data-refineid="countries"><strong>Reset</strong></a> </div> <div class="filter-actions-container filter-actions-container--empty "> <a class="button button--color button--full-width js-refine-filter" href="#" data-reveal-id="refine-modal-countries" data-filter="countries" class="all">Select Countries / Regions</a> </div> <div style="clear:both;"></div> <div id="refine-modal-countries" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2>Filter Countries / Regions</h2> <input class="js-filter" type="text" form="temp" placeholder="Search for Countries / Regions" style="width: 100%; max-width: 300px;" /> <p class="reveal-modal-new__description"> Select countries / regions you want to add to your filter. </p> </div> <div class="js-refinement-values-container"> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="germany" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_GERMANY" value="GERMANY"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_GERMANY">Germany (6)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="usa" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_UNITED_STATES" value="UNITED_STATES"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_UNITED_STATES">USA (6)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="italy" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_ITALY" value="ITALY"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_ITALY">Italy (4)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="uk" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_UNITED_KINGDOM" value="UNITED_KINGDOM"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_UNITED_KINGDOM">UK (3)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="france" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_FRANCE" value="FRANCE"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_FRANCE">France (2)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="russia" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_RUSSIAN_FEDERATION" value="RUSSIAN_FEDERATION"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_RUSSIAN_FEDERATION">Russia (2)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="algeria" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_ALGERIA" value="ALGERIA"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_ALGERIA">Algeria (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="austria" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_AUSTRIA" value="AUSTRIA"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_AUSTRIA">Austria (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="canada" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_CANADA" value="CANADA"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_CANADA">Canada (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="china" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_CHINA" value="CHINA"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_CHINA">China (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="greece" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_GREECE" value="GREECE"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_GREECE">Greece (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="japan" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_JAPAN" value="JAPAN"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_JAPAN">Japan (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="kenya" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_KENYA" value="KENYA"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_KENYA">Kenya (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="mexico" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_MEXICO" value="MEXICO"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_MEXICO">Mexico (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="the netherlands" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_NETHERLANDS" value="NETHERLANDS"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_NETHERLANDS">The Netherlands (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="portugal" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_PORTUGAL" value="PORTUGAL"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_PORTUGAL">Portugal (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="south africa" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_SOUTH_AFRICA" value="SOUTH_AFRICA"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_SOUTH_AFRICA">South Africa (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="taiwan" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_TAIWAN" value="TAIWAN"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_TAIWAN">Taiwan (1)</label> </div> </div> <div class="large-6 medium-6 small-12 columns end js-data-filter" data-filter="republic of korea" style="padding-top: 0px; padding-bottom: 0px; margin-top: 0;" > <div> <input type="checkbox" class="refine_checkbox refine_countries" id="refine_countries_KOREA_REPUBLIC_OF" value="KOREA_REPUBLIC_OF"> <label class="search_refine_label" style="margin-bottom: 10px;" for="refine_countries_KOREA_REPUBLIC_OF">Republic of Korea (1)</label> </div> </div> </div> </div> <div class="row"> <div class="small-12 columns"> <a class="button button--color js-filter-close" data-itemid="countries" onclick="$('#refine-modal-countries').foundation('reveal', 'close'); return false;">Add to Filter</a> <a class="button button--grey" onclick="$(this).closest('.reveal-modal').find('.close-reveal-modal').click(); return false;">Cancel</a> </div> </div> <input type="hidden" name="countries" id="refine_countries_field"> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div></div> <div class="generic-item last-item refind-item-wrap"> <a class="button button--grey button--full-width refineSearch" href="javascript:void(0);" title="Refine">Update Search</a> </div> </div> </div> </form> </div> </div> <div id="middle-column" class="content__column large-9 medium-9 small-12 columns end middle-bordered"> <div class="middle-column__help"> <div class="middle-column__help__fixed show-for-medium-up"> <a href="#" class="UA_ShareButton" data-reveal-id="main-share-modal" title="Share"> <i class="material-icons">share</i> </a> <a href="#" data-reveal-id="main-help-modal" title="Help"> <i class="material-icons">announcement</i> </a> </div> <div id="main-help-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 style="margin: 0;">Need Help?</h2> </div> <div class="small-6 columns"> <h3>Support</h3> <p> Find support for a specific problem in the support section of our website. </p> <a target="_blank" href="/about/contactform" class="button button--color button--full-width"> Get Support </a> </div> <div class="small-6 columns"> <h3>Feedback</h3> <p> Please let us know what you think of our products and services. </p> <a target="_blank" href="/feedback/send" class="button button--color button--full-width"> Give Feedback </a> </div> <div class="small-6 columns end"> <h3>Information</h3> <p> Visit our dedicated information section to learn more about MDPI. </p> <a target="_blank" href="/authors" class="button button--color button--full-width"> Get Information </a> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> </div> <div class="middle-column__main "> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/jquery-ui-1.10.4.custom.min.css?80647d88647bf347?1732286508"> <div class="content__container content__container--overflow-initial"> <h1> Search Results (28) </h1> <p> Search Parameters: <br/> <b>Keywords</b> = large extracellular loop </p> <div class="article-listing"> <form id="exportArticles" method="post" action="/export"> <input type="hidden" name="_token" value="lgzDvf-P_-OjbxtY4WkSlVZDtwMAe2t1gZSle9KoPjM"> <input type="hidden" name="sort" value="pubdate"> <input type="hidden" name="page_count" value="50"> <input type="hidden" name="year_from" value="1996"> <input type="hidden" name="year_to" value="2024"> <input type="hidden" name="q" value="large extracellular loop"> <script type="text/x-mathjax-config"> MathJax.Hub.Config({ "HTML-CSS": { availableFonts: ["TeX"], preferredFonts: "TeX", webFont:"TeX", imageFont:"TeX", undefinedFamily:"'Arial Unicode MS',serif", scale: 80, linebreaks: { automatic: true, width: "container" } }, "TeX": { extensions: ["noErrors.js"], noErrors: { inlineDelimiters: ["",""], multiLine: true, style: { "font-size": "90%", "text-align": "left", "color": "black", "padding": "1px 3px", "border": "1px solid" } } } }); MathJax.Hub.Register.StartupHook("End",function () { $(".art-abstract").css("display", "block"); }); </script> <script type="text/javascript" src="https://pub.mdpi-res.com/bundles/mathjax/MathJax.js?config=TeX-AMS-MML_HTMLorMML"></script> <div class="ui-tabs-panel article-listing" style="padding: 0px;border: 0;"> <div class="header listing-header"> <div class="listing-display-options1" id="selectView"> <div class="row generic-item indented1"> <input type="hidden" name="sort" value="pubdate"> <input type="hidden" name="page_count" value="50"> <input type="hidden" name="year_from" value="1996"> <input type="hidden" name="year_to" value="2024"> <input type="hidden" name="q" value="large extracellular loop"> <div class="large-4 medium-4 small-12 columns"> <div class="listing-option__label"> Order results </div> <div class="listing-option__options"> <select class="chosen-select" name="sort" onchange="$('#articleBrowserView').click(); return false;"> <option value="bibliographic" >Bibliographic</option> <option value="relevance" >Relevance</option> <option value="pubdate" selected = 'selected'>Publication Date</option> <option value="reference_citedby_number_max" >Times Cited</option> <option value="articles_stats_art_view_page" >Times Viewed</option> </select> </div> </div> <div class="large-4 medium-4 small-12 columns"> <div 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</div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/1422-0067/25/11/6121">The Development of Robust Antibodies to Sarcospan, a Dystrophin- and Integrin-Associated Protein, for Basic and Translational Research</a> <div class="authors"> by <span class="inlineblock "><strong>Ekaterina I. Mokhonova</strong>, </span><span class="inlineblock "><strong>Ravinder Malik</strong>, </span><span class="inlineblock "><strong>Hafsa Mamsa</strong>, </span><span class="inlineblock "><strong>Jackson Walker</strong>, </span><span class="inlineblock "><strong>Elizabeth M. Gibbs</strong> and </span><span class="inlineblock "><strong>Rachelle H. Crosbie</strong></span> </div> <div class="color-grey-dark"> <em>Int. J. Mol. Sci.</em> <b>2024</b>, <em>25</em>(11), 6121; <a href="https://doi.org/10.3390/ijms25116121">https://doi.org/10.3390/ijms25116121</a> - 1 Jun 2024 </div> Viewed by 1064 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of <a href="#" data-counterslink = "https://www.mdpi.com/1422-0067/25/11/6121/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Sarcospan (SSPN) is a 25-kDa transmembrane protein that is broadly expressed at the cell surface of many tissues, including, but not limited to, the myofibers from skeletal and smooth muscles, cardiomyocytes, adipocytes, kidney epithelial cells, and neurons. SSPN is a core component of the dystrophin–glycoprotein complex (DGC) that links the intracellular actin cytoskeleton with the extracellular matrix. It is also associated with integrin α7β1, the predominant integrin expressed in skeletal muscle. As a tetraspanin-like protein with four transmembrane spanning domains, SSPN functions as a scaffold to facilitate protein–protein interactions at the cell membrane. Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy are caused by the loss of dystrophin at the muscle cell surface and a concomitant loss of the entire DGC, including SSPN. SSPN overexpression ameliorates Duchenne muscular dystrophy in the <i>mdx</i> murine model, which supports SSPN being a viable therapeutic target. Other rescue studies support SSPN as a biomarker for the proper assembly and membrane expression of the DGC. Highly specific and robust antibodies to SSPN are needed for basic research on the molecular mechanisms of SSPN rescue, pre-clinical studies, and biomarker evaluations in human samples. The development of SSPN antibodies is challenged by the presence of its four transmembrane domains and limited antigenic epitopes. To address the significant barrier presented by limited commercially available antibodies, we aimed to generate a panel of robust SSPN-specific antibodies that can serve as a resource for the research community. We created antibodies to three SSPN protein epitopes, including the intracellular N- and C-termini as well as the large extracellular loop (LEL) between transmembrane domains 3 and 4. We developed a panel of rabbit antibodies (poly- and monoclonal) against an N-terminal peptide fragment of SSPN. We used several assays to show that the rabbit antibodies recognize mouse SSPN with a high functional affinity and specificity. We developed mouse monoclonal antibodies against the C-terminal peptide and the large extracellular loop of human SSPN. These antibodies are superior to commercially available antibodies and outperform them in various applications, including immunoblotting, indirect immunofluorescence analysis, immunoprecipitation, and an ELISA. These newly developed antibodies will significantly improve the quality and ease of SSPN detection for basic and translational research. <a href="/1422-0067/25/11/6121">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/ijms/sections/biochemistry">Biochemistry</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1422-0067/25/11/6121/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1407080"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1407080"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1407080" data-cycle-prev="#prev1407080" data-cycle-progressive="#images1407080" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1407080-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g001-550.jpg?1717232406" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1407080" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g002-550.jpg?1717232410'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g003-550.jpg?1717232413'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g004-550.jpg?1717232415'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g005-550.jpg?1717232416'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g006-550.jpg?1717232419'><p>Figure 6</p></div> --- <div class='openpopupgallery' data-imgindex='6' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g007-550.jpg?1717232422'><p>Figure 7</p></div> --- <div class='openpopupgallery' data-imgindex='7' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g008-550.jpg?1717232425'><p>Figure 8</p></div> --- <div class='openpopupgallery' data-imgindex='8' data-target='article-1407080-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g009-550.jpg?1717232430'><p>Figure 9</p></div></script></div></div><div id="article-1407080-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g001-550.jpg?1717232406" title=" <strong>Figure 1</strong><br/> <p>SSPN epitopes are used for antibody development. (<b>A</b>) Schematic diagram representing the predicted membrane topology of human SSPN protein and the corresponding epitopes of commercially available antibodies (in gray). (<b>B</b>) Summary of commercially available antibodies, their epitopes, applications, and limitations. (<b>C</b>) Schematic diagrams representing the predicted membrane topology of mouse (mSSPN) and human (hSSPN) SSPN proteins and the corresponding epitopes of newly developed antibodies (in gray). hSSPN has 243 amino acids, while mSSPN has 216, with the difference mostly being due to the longer N-terminus of hSSPN. (<b>D</b>) Comparison of the amino acid residues of hSSPN and mSSPN in the epitope regions used to immunize rabbits and mice. The amino acid sequence is shown in a single-letter code. Non-matching amino acids between hSSPN and mSSPN are labeled by gray in the amino acid sequence of mSSPN.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g002-550.jpg?1717232410" title=" <strong>Figure 2</strong><br/> <p>Testing rabbit immune response to mSSPN with the ELISA and immunoblotting. <b>Panels</b> (<b>A</b>,<b>D</b>,<b>G</b>,<b>J</b>,<b>M</b>): mSSPN-specific rabbit sera titration curves with the ELISA. The blood was collected seven days after the second (bleed I) and third (bleed II) booster doses. Serial dilutions of each rabbit serum were added to the ELISA plates coated with SUMO-tagged mSSPN N-terminus (MGRKPSPRAQELPEEEARTCCGCRF, U02487). HRP-conjugated goat anti-rabbit IgG was used to detect the mSSPN-specific rabbit IgG. TMB was used as a substrate for the HRP. The enzymatic reaction was stopped by 2 M of sulfuric acid, and the plates were read at 450 nm. <b>Panels</b> (<b>B</b>,<b>C</b>,<b>E</b>,<b>F</b>,<b>H</b>,<b>I</b>,<b>K</b>,<b>L</b>,<b>N</b>,<b>O</b>): Immunoblotting of bleeds I and II from each rabbit. Rabbit 8870—panels (<b>B</b>,<b>C</b>); rabbit 8871—panels (<b>E</b>,<b>F</b>); rabbit 8872—panels (<b>H</b>,<b>I</b>); rabbit 8873—panels (<b>K</b>,<b>L</b>); and rabbit 8874—panels (<b>N</b>,<b>O</b>). Immunoblotting of bleeds I and II with total muscle lysates from mice overexpressing mouse SSPN (mSSPN-TG, arrow) (lane 1), human SSPN (hSSPN-TG) (lane 2), wild type (lane 3), <span class="html-italic">mdx</span> (lane 4), and SSPN-null (lane 5). m-SSPN-TG, wild type, and <span class="html-italic">mdx</span> lysates were used for the evaluation of the specific immune response to mouse SSPN. h-SSPN-TG lysate was used for detection of possible cross-reactivity between the SSPN of mouse and human origins. The SSPN-null lysate was used to exclude rabbits generating a non-specific response. mSSPN was detected at 25 kDa (arrow) by immunoblotting. The skeletal muscle was solubilized using an RIPA buffer, and the protein samples (20 μg of total protein per line for all lines, except mSSPN-TG (lane 1) where 2 μg of total protein per line was loaded) were separated by SDS-PAGE and transferred to nitrocellulose membranes. Immunoblots were probed with crude non-purified rabbit sera diluted 1:150 (bleed I) or 1:600 (bleed II) in the blocking buffer. Arrows indicate the mSSPN. The ~27 kDa bands presenting in all muscle lysates (panels (<b>C</b>,<b>E</b>,<b>F</b>,<b>I</b>,<b>L</b>,<b>N</b>,<b>O</b>)) were not SSPN-related and may represent secondary antibody cross-reactivity with endogenous antibody light chains in the skeletal muscle protein lysates.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g003-550.jpg?1717232413" title=" <strong>Figure 3</strong><br/> <p>Validation of rabbit polyclonal antibodies to mouse SSPN N-terminus. (<b>A</b>) Validation of purified rabbit polyclonal antibodies with an ELISA. Terminal bleeds from rabbits #8870, #8871, #8872, and #8873 were purified by affinity chromatography. The titer of purified antibodies was estimated by the ELISA with SUMO-tagged mSSPN (MGRKPSPRAQELPEEEARTCCGCRF, U02487). HRP-conjugated goat anti-rabbit IgG was used to detect the mSSPN-specific rabbit IgG. TMB was used as a substrate for the HRP. The enzymatic reaction was stopped by 2 M of sulfuric acid, and the plates were read at 450 nm. (<b>B</b>) Immunoblotting of the total muscle lysates from the mSSPN-TG (lane 1), hSSPN-TG (lane 2), WT (lane 3), <span class="html-italic">mdx</span> (lane 4), and SSPN-null (lane 5) mice with purified rabbit polyclonal antibodies #8870. There was 20 μg of total protein per line for all lines, except mSSPN-TG where 2 μg of total protein per line was loaded. The arrow indicates the mSSPN. Film exposure time, 15 s. (<b>C</b>) Immunofluorescence images of the transverse cross-sections of the quadriceps muscles of the WT and SSPN-null mice and the human control (hamstring) stained with purified rabbit polyclonal antibodies #8870. The acquisition time for all muscle cross-sections was 0.8 s. Scale bar, 50 μm.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g004-550.jpg?1717232415" title=" <strong>Figure 4</strong><br/> <p>Validation of rabbit monoclonal antibodies to mouse SSPN N-terminus. (<b>A</b>) Immunoblotting of total muscle lysates from mSSPN-TG (lane 1), hSSPN-TG (lane 2), WT (lane 3), <span class="html-italic">mdx</span> (lane 4), and SSPN-null (lane 5) with newly developed rabbit monoclonal antibody 10B8. There was 20 μg of total protein per line for all lines, except mSSPN-TG where 2 μg of total protein per line was loaded. The arrow indicates the mSSPN. Film exposure time, 15 s. (<b>B</b>) Immunofluorescence images of transverse cross-sections of the quadriceps of WT and SSPN-null mice, WT hearts, and the human control hamstring stained with newly developed rabbit monoclonal antibody 10B8 and commercially available mouse monoclonal antibody E2 for comparison. The acquisition time for E2 was 1 s, and for 10B8, it was 0.8 s. Scale bar, 50 μm.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g005-550.jpg?1717232416" title=" <strong>Figure 5</strong><br/> <p>Reactivity of mouse sera to C-terminus and LEL fragment of human SSPN in an indirect ELISA. hSSPN-specific mouse IgG titration curves. Blood was collected seven days after the second (bleed I) booster dose. Serial dilutions of each mouse serum were added to the ELISA plates coated with a biotinylated peptide of hSSPN C-terminus (HRYQVFYVGVRICSLTASEGPQQKI, AF016028) (<b>A</b>) or with a biotinylated peptide of hSSPN LEL fragment (PSSEPLSRTFVYRDVTDCTS) (<b>B</b>). HRP-conjugated goat anti-mouse IgG was used to detect hSSPN-specific mouse IgG. TMB was used as a substrate for the HRP. The enzymatic reaction was stopped by 2 M of sulfuric acid, and the plates were read at 450 nm.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g006-550.jpg?1717232419" title=" <strong>Figure 6</strong><br/> <p>Validation of intermediate mouse hybridoma clones by immunoblotting and IFA. (<b>A</b>) mSSPN-TG (lane 1), hSSPN-TG (lane 2), WT (lane 3), <span class="html-italic">mdx</span> (lane 4), and SSPN-null (lane 5) with intermediate mouse clones 289-F15 and 290-F25 and commercially available mouse monoclonal antibody E2 (Santa Cruz). (There was 20 μg of total protein per line for all lines, except mSSPN where 2 μg of total protein per line was loaded. Film exposure time for all antibodies—2 min. (<b>B</b>) Immunofluorescence images of transverse cross-sections of the quadriceps muscle of the WT and SSPN-null mice and the human control (hamstring) stained with intermediate mouse clones 289-F15 and 290-F25 and mouse monoclonal antibody E2 (Santa Cruz). The acquisition time for all antibodies was 1 s. Scale bar, 50 μm.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g007-550.jpg?1717232422" title=" <strong>Figure 7</strong><br/> <p>Validation of final mouse monoclonal antibodies to C-terminus and LEL fragment of human SSPN by IFA. Immunofluorescence images of transverse cross-sections of human healthy control, human Becker muscular dystrophy (BMD) skeletal muscles, and mouse WT and mouse SSPN-null quadriceps stained with newly developed mouse monoclonal antibodies to hSSPN C-terminus (clones 289-17, 289-18), hSSPN LEL fragment (clones 290-4, 290-11), and commercially available mouse monoclonal antibody E2 for comparison. Newly developed mouse monoclonal antibodies to the hSSPN C-terminus are human-specific and do not cross-react with mouse SSPN. Clone 290-04, developed to the hSSPN LEL fragment, recognizes both mSSPN and hSSPN, and clone 290-11 is mouse-specific. All three human-specific clones shown in the figure recognize hSSPN in muscles from the BMD patient more efficiently than E2. The acquisition time for all antibodies was 1 s. Scale bar, 50 μm.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g008-550.jpg?1717232425" title=" <strong>Figure 8</strong><br/> <p>Affinity purification of SSPN by newly developed monoclonal antibodies. Quadricep muscle lysates from hSSPN-TG (lane 1), mSSPN-TG (lane 2), WT (lane 3), and SSPN-null (lane 4) were immunoprecipitated with the indicated rabbit (10B8) or mouse (290-04, 290-06, 289-17, and E2) monoclonal antibodies. Successful pull-down was assessed by immunoblotting equimolar amounts of lysates with E2 or 10B8 anti-SSPN antibodies. Lysates incubated with protein A/G PLUS-agarose beads without antibodies were used as a negative control (S.6). Black arrow: SSPN monomer (SSPN<sup>m</sup>); gray arrow: SSPN dimer (SSPN<sup>d</sup>); and IB: antibody used for immunoblotting. All blots were processed in parallel and developed with an identical film exposure time.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-06121/article_deploy/html/images/ijms-25-06121-g009-550.jpg?1717232430" title=" <strong>Figure 9</strong><br/> <p>Summary of development of rabbit and mouse antibodies to SSPN of mouse and human origin.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/11/6121'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1315697" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 15 pages, 4222 KiB   </span> <a href="/1422-0067/25/2/820/pdf?version=1704792159" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Analysis of Receptor-Type Protein Tyrosine Phosphatase Extracellular Regions with Insights from AlphaFold" data-journal="ijms"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Review</span></div> <a class="title-link" href="/1422-0067/25/2/820">Analysis of Receptor-Type Protein Tyrosine Phosphatase Extracellular Regions with Insights from AlphaFold</a> <div class="authors"> by <span class="inlineblock "><strong>Lina El Badaoui</strong> and </span><span class="inlineblock "><strong>Alastair J. Barr</strong></span> </div> <div class="color-grey-dark"> <em>Int. J. Mol. Sci.</em> <b>2024</b>, <em>25</em>(2), 820; <a href="https://doi.org/10.3390/ijms25020820">https://doi.org/10.3390/ijms25020820</a> - 9 Jan 2024 </div> Viewed by 1726 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> The receptor-type protein tyrosine phosphatases (RPTPs) are involved in a wide variety of physiological functions which are mediated via their diverse extracellular regions. They play key roles in cell–cell contacts, bind various ligands and are regulated by dimerization and other processes. Depending on <a href="#" data-counterslink = "https://www.mdpi.com/1422-0067/25/2/820/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> The receptor-type protein tyrosine phosphatases (RPTPs) are involved in a wide variety of physiological functions which are mediated via their diverse extracellular regions. They play key roles in cell–cell contacts, bind various ligands and are regulated by dimerization and other processes. Depending on the subgroup, they have been described as everything from ‘rigid rods’ to ‘floppy tentacles’. Here, we review current experimental structural knowledge on the extracellular region of RPTPs and draw on AlphaFold structural predictions to provide further insights into structure and function of these cellular signalling molecules, which are often mutated in disease and are recognised as drug targets. In agreement with experimental data, AlphaFold predicted structures for extracellular regions of R1, and R2B subgroup RPTPs have an extended conformation, whereas R2B RPTPs are twisted, reflecting their high flexibility. For the R3 PTPs, AlphaFold predicts that members of this subgroup adopt an extended conformation while others are twisted, and that certain members, such as CD148, have one or more large, disordered loop regions in place of fibronectin type 3 domains suggested by sequence analysis. <a href="/1422-0067/25/2/820">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/ijms/special_issues/4C3HDWPDUR ">The Role of Phosphatases in Human Health and Disease</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1422-0067/25/2/820/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1315697"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1315697"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1315697" data-cycle-prev="#prev1315697" data-cycle-progressive="#images1315697" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1315697-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g001-550.jpg?1704792244" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1315697" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1315697-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g002-550.jpg?1704792248'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1315697-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g003-550.jpg?1704792253'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1315697-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g004-550.jpg?1704792256'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-1315697-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g005-550.jpg?1704792257'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-1315697-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g006-550.jpg?1704792260'><p>Figure 6</p></div></script></div></div><div id="article-1315697-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g001-550.jpg?1704792244" title=" <strong>Figure 1</strong><br/> <p>Schematic representation of the RPTP family. Created with <a href="http://BioRender.com" target="_blank">BioRender.com</a>.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/2/820'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g002-550.jpg?1704792248" title=" <strong>Figure 2</strong><br/> <p>AlphaFold structural predictions of the extracellular domain for R1, R2A and R2B subgroup RPTPs. Images were generated using PyMol with structures coloured by spectrum (N-terminus, blue; C-terminus, yellow). Human structures were downloaded from: <a href="https://alphafold.ebi.ac.uk/" target="_blank">https://alphafold.ebi.ac.uk/</a> accessed on 10 November 2023.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/2/820'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g003-550.jpg?1704792253" title=" <strong>Figure 3</strong><br/> <p>AlphaFold predicted structures for the extracellular domain of R3 subgroup PTPs. Images were generated using PyMol with colouring by secondary structure (helix, red; sheet, yellow; loop, green) and by spectrum (N-terminus, blue; C-terminus, yellow/red). For clarity, the sequence preceding FN3-1 and from the predicted transmembrane domain onwards is not shown. Unstructured loops are indicated by an arrow.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/2/820'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g004-550.jpg?1704792256" title=" <strong>Figure 4</strong><br/> <p>The unstructured loop of CD148 extracellular domain. Images were generated using PyMol (<b>A</b>) Part of the AlphaFold predicted extracellular domain CD148 structure coloured by pLDDT colours (credit Konstantin Korotkov). (<b>B</b>) Superimposition of the AlphaFold predicted CD148 structure FN3-1 to FN3-3 (AF-Q12913-F1, green) with an X-ray crystal structure of CD148 FN3 domains 1 and 2 (PDB: 7U08, magenta) and the NMR solution structure of FN3-4 of CD148 (PDB: 2DLE, blue). (<b>C</b>) Superimposition of a section of the CD148 AlphaFold structure (green) and a Colabfold structure generated without templates (magenta). ColabFold (v1.5.2) was installed from <a href="https://github.com/YoshitakaMo/localcolabfold" target="_blank">https://github.com/YoshitakaMo/localcolabfold</a> on a Linux system and the structure was generated using amino acids 36–975 of human PTPRJ (Q12913) with the command “colabfold_batch colabfold_input outputdir/” accessed on 7 November 2023.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/2/820'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g005-550.jpg?1704792257" title=" <strong>Figure 5</strong><br/> <p>Location of missense SNPs in AlphaFold structures of CD148 and PTPRQ. Images were generated using PyMol with colouring by secondary structure (helix, red; sheet, yellow; loop, green) (<b>A</b>) Structure of a section of the AlphaFold CD148 extracellular domain showing the position of the SNPs (Q276P and R326Q). Ribbons for other domains have been removed for clarity. (<b>B</b>) Structure of a section of the AlphaFold PTPRQ extracellular domain showing the position of the SNP (R281G).</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/2/820'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-25-00820/article_deploy/html/images/ijms-25-00820-g006-550.jpg?1704792260" title=" <strong>Figure 6</strong><br/> <p>AlphaFold structures of the extracellular region of R5 and R8 subgroup PTPs. Structures are coloured by spectrum (N-terminus, blue; C-terminus, yellow/red). The structured carbonic anhydrase-like (CA) domain, single FN3-like (FN3) domain and long disordered spacer region are shown for the R5 group. SEA (sea urchin sperm protein, enterokinase, agrin) module.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/25/2/820'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1295569" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 13 pages, 3253 KiB   </span> <a href="/2218-273X/13/12/1757/pdf?version=1701932203" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Modelling and Molecular Dynamics Predict the Structure and Interactions of the Glycine Receptor Intracellular Domain" data-journal="biomolecules"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/2218-273X/13/12/1757">Modelling and Molecular Dynamics Predict the Structure and Interactions of the Glycine Receptor Intracellular Domain</a> <div class="authors"> by <span class="inlineblock "><strong>James R. E. Thompson</strong>, </span><span class="inlineblock "><strong>Christopher A. Beaudoin</strong> and </span><span class="inlineblock "><strong>Sarah C. R. Lummis</strong></span> </div> <div class="color-grey-dark"> <em>Biomolecules</em> <b>2023</b>, <em>13</em>(12), 1757; <a href="https://doi.org/10.3390/biom13121757">https://doi.org/10.3390/biom13121757</a> - 7 Dec 2023 </div> <a href="/2218-273X/13/12/1757#metrics">Cited by 1</a> | Viewed by 1436 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Glycine receptors (GlyRs) are glycine-gated inhibitory pentameric ligand-gated ion channels composed of α or α + β subunits. A number of structures of these proteins have been reported, but to date, these have only revealed details of the extracellular and transmembrane domains, with <a href="#" data-counterslink = "https://www.mdpi.com/2218-273X/13/12/1757/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Glycine receptors (GlyRs) are glycine-gated inhibitory pentameric ligand-gated ion channels composed of α or α + β subunits. A number of structures of these proteins have been reported, but to date, these have only revealed details of the extracellular and transmembrane domains, with the intracellular domain (ICD) remaining uncharacterised due to its high flexibility. The ICD is a region that can modulate function in addition to being critical for receptor localisation and clustering via proteins such as gephyrin. Here, we use modelling and molecular dynamics (MD) to reveal details of the ICDs of both homomeric and heteromeric GlyR. At their N and C ends, both the α and β subunit ICDs have short helices, which are major sites of stabilising interactions; there is a large flexible loop between them capable of forming transient secondary structures. The α subunit can affect the β subunit ICD structure, which is more flexible in a 4α<sub>2</sub>:1β than in a 4α<sub>1</sub>:1β GlyR. We also explore the effects of gephyrin binding by creating GlyR models bound to the gephyrin E domain; MD simulations suggest these are more stable than the unbound forms, and again there are α subunit-dependent differences, despite the fact the gephyrin binds to the β subunit. The bound models also suggest that gephyrin causes compaction of the ICD. Overall, the data expand our knowledge of this important receptor protein and in particular clarify features of the underexplored ICD. <a href="/2218-273X/13/12/1757">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/biomolecules/sections/MSD">Molecular Structure and Dynamics</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2218-273X/13/12/1757/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1295569"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1295569"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1295569" data-cycle-prev="#prev1295569" data-cycle-progressive="#images1295569" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1295569-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g001-550.jpg?1701932271" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1295569" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1295569-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g002-550.jpg?1701932273'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1295569-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g003-550.jpg?1701932276'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1295569-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g004-550.jpg?1701932278'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-1295569-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g005-550.jpg?1701932279'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-1295569-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g006-550.jpg?1701932282'><p>Figure 6</p></div> --- <div class='openpopupgallery' data-imgindex='6' data-target='article-1295569-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g007-550.jpg?1701932283'><p>Figure 7</p></div></script></div></div><div id="article-1295569-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g001-550.jpg?1701932271" title=" <strong>Figure 1</strong><br/> <p>A Clustal Omega sequence alignment of the ICD reveals low sequence similarity between human GlyR subunits and also between other human pLGIC subunits, such as the α<sub>7</sub> nAChR subunit. Residue identity and lone residues are shown in dark grey, and residues with similar chemical properties are shown in light grey. Residue numbers are GlyRα1: 299–444; α2: 306–439; β: 329–438; α3: 328–430; nAChRα7: 318–469.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g002-550.jpg?1701932273" title=" <strong>Figure 2</strong><br/> <p>GlyR models. Colours distinguish subunits, with light pink (leftmost subunit) representing β in heteromeric models.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g003-550.jpg?1701932276" title=" <strong>Figure 3</strong><br/> <p>Changes in ICD structures after MD simulations. (<b>A</b>) Example structures from before (left-hand side) and after (right-hand side) the simulation, viewed from the bottom of the receptor. Typical of 3–5 production runs. The maximal ICD width (measured between Cα in Å) is labelled in red, and the pore diameter (between Cα in Å) in black. (<b>B</b>) Pore (spots) and diameter (lines) distances before (white) and after (grey) the MD simulations. * = significantly different, Student’s <span class="html-italic">t</span> test, <span class="html-italic">p</span> &lt; 0.05. Data = mean ± SEM, <span class="html-italic">n</span> = 3.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g004-550.jpg?1701932278" title=" <strong>Figure 4</strong><br/> <p>Changes in ICD interactions during the MD simulation for each model. A range of different interactions were identified and are shown in different shades of colour. For the unbound GlyR models (5α<sub>1,</sub> 4α<sub>2</sub>:1β, and 4α<sub>2</sub>:1β), the number of interactions increased during the simulation, but there was no significant increase in interactions in the bound models (4α<sub>1</sub>:1β-gephE and 4α<sub>2</sub>:1β-gephE). This can be seen in the plot at the bottom right-hand side, which shows the total number of interactions at the start (white) and end (grey) of the simulations. * = significantly different to start, Student’s t test, <span class="html-italic">p</span> &lt; 0.05. Data = mean ± SEM, n = 3.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g005-550.jpg?1701932279" title=" <strong>Figure 5</strong><br/> <p>Comparison of Box–Cox transformed β subunit ICD RMSF values. The 4α<sub>2</sub>:1β GlyR model had a larger RMSF value than 4α<sub>1</sub>:1β and 4α<sub>1</sub>:1β-GephE GlyRs. * = significantly different at <span class="html-italic">p</span> &lt; 0.0001, n = 3.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g006-550.jpg?1701932282" title=" <strong>Figure 6</strong><br/> <p>The effect of GephE binding on ICD structure. Images of ICDs without (upper panel) and with (lower panel) bound GephE. Typical of 3 production runs. Maximal ICD width (red) and pore diameter (black) in Å are shown.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01757/article_deploy/html/images/biomolecules-13-01757-g007-550.jpg?1701932283" title=" <strong>Figure 7</strong><br/> <p>Residues involved in GephE binding may differ for 4α<sub>1</sub>:1β-GephE (<b>A</b>) and 4α<sub>2</sub>:1β-GephE (<b>B</b>). Potential interactions between gephyrin (blue) and the α subunit (orange) following a typical MD production run are shown as dashed yellow lines. More potential interactions are observed in the 4α<sub>2</sub>:1β-GephE model.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/12/1757'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1245225" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 16 pages, 1328 KiB   </span> <a href="/2218-273X/13/10/1431/pdf?version=1695354912" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Unraveling the Functional Significance of Unstructured Regions in G Protein-Coupled Receptors" data-journal="biomolecules"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Review</span></div> <a class="title-link" href="/2218-273X/13/10/1431">Unraveling the Functional Significance of Unstructured Regions in G Protein-Coupled Receptors</a> <div class="authors"> by <span class="inlineblock "><strong>Roberto Maggio</strong>, </span><span class="inlineblock "><strong>Irene Fasciani</strong>, </span><span class="inlineblock "><strong>Francesco Petragnano</strong>, </span><span class="inlineblock "><strong>Maria Francesca Coppolino</strong>, </span><span class="inlineblock "><strong>Marco Scarselli</strong> and </span><span class="inlineblock "><strong>Mario Rossi</strong></span> </div> <div class="color-grey-dark"> <em>Biomolecules</em> <b>2023</b>, <em>13</em>(10), 1431; <a href="https://doi.org/10.3390/biom13101431">https://doi.org/10.3390/biom13101431</a> - 22 Sep 2023 </div> <a href="/2218-273X/13/10/1431#metrics">Cited by 1</a> | Viewed by 2386 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Unstructured regions in functional proteins have gained attention in recent years due to advancements in informatics tools and biophysical methods. G protein-coupled receptors (GPCRs), a large family of cell surface receptors, contain unstructured regions in the form of the i3 loop and C-terminus. <a href="#" data-counterslink = "https://www.mdpi.com/2218-273X/13/10/1431/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Unstructured regions in functional proteins have gained attention in recent years due to advancements in informatics tools and biophysical methods. G protein-coupled receptors (GPCRs), a large family of cell surface receptors, contain unstructured regions in the form of the i3 loop and C-terminus. This review provides an overview of the functional significance of these regions in GPCRs. GPCRs transmit signals from the extracellular environment to the cell interior, regulating various physiological processes. The i3 loop, located between the fifth and sixth transmembrane helices, and the C-terminus, connected to the seventh transmembrane helix, are determinant of interactions with G proteins and with other intracellular partners such as arrestins. Recent studies demonstrate that the i3 loop and C-terminus play critical roles in allosterically regulating GPCR activation. They can act as autoregulators, adopting conformations that, by restricting G protein access, modulate receptor coupling specificity. The length and unstructured nature of the i3 loop and C-terminus provide unique advantages in GPCR interactions with intracellular protein partners. They act as “fishing lines”, expanding the radius of interaction and enabling GPCRs to tether scaffolding proteins, thus facilitating receptor stability during cell membrane movements. Additionally, the i3 loop may be involved in domain swapping between GPCRs, generating novel receptor dimers with distinct binding and coupling characteristics. Overall, the i3 loop and C-terminus are now widely recognized as crucial elements in GPCR function and regulation. Understanding their functional roles enhances our comprehension of GPCR structure and signaling complexity and holds promise for advancements in receptor pharmacology and drug development. <a href="/2218-273X/13/10/1431">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/biomolecules/sections/bio_molecular_biology">Molecular Biology</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2218-273X/13/10/1431/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1245225"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1245225"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1245225" data-cycle-prev="#prev1245225" data-cycle-progressive="#images1245225" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1245225-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g001-550.jpg?1695354984" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1245225" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1245225-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g002-550.jpg?1695354985'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1245225-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g003-550.jpg?1695354986'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1245225-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g004-550.jpg?1695354987'><p>Figure 4</p></div></script></div></div><div id="article-1245225-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g001-550.jpg?1695354984" title=" <strong>Figure 1</strong><br/> <p>This model, greatly influenced by the research of Heng et al. [<a href="#B19-biomolecules-13-01431" class="html-bibr">19</a>], illustrates how the dynamic movement of a long and flexible C-terminus can modulate the accessibility of GPCR to the G protein. In the inactive state, the C-terminus assumes diverse conformations, engaging interactions with both the intracellular loops and the transmembrane core of the receptor, as indicated by the dashed lines in the upper-left corner. This conformation, referred to as the “closed C-terminus”, serves to restrict the receptor’s accessibility to the G protein. Upon binding of an agonist (or a positive allosteric modulator) to the receptor, a conformational shift occurs, weakening the interaction between the C-terminus and the receptor’s cytoplasmic surface. This shift leads to the displacement of the C-terminal region, allowing the G protein access to the receptor, referred to as the “open C-terminus”. In this state, the G protein can bind and initiate signaling. The dynamic interplay between the open and closed states of the C-terminus constitutes a previously unrecognized mechanism by which GPCRs finely regulate their coupling to G proteins.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/10/1431'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g002-550.jpg?1695354985" title=" <strong>Figure 2</strong><br/> <p>This scheme illustrates some of the post-translational modifications that occur in GPCRs. The N-terminus can undergo N- or O-glycosylation at asparagine (N) or serine (S)/threonine (T) sites, respectively. Phosphorylation (P) takes place either on intracellular loop 3 (IL3) or on the C-terminus at serine/threonine sites. When clusters of 3 serine or threonine residues within a span of 7 or 8 amino acids are phosphorylated, they are recognized by arrestin. Palmitoylation (red zigzag line) occurs at cysteine (C) residues in the C-terminus, resulting in the formation of an additional α-helix structure (Helix 8). Ubiquitination (U) occurs on specific lysine (K) residues, promoting protein transport to the proteasome and subsequent receptor degradation, or determining a specific trafficking route for the receptor within the cells. For more detailed information on post-translational modifications, you can refer to the review authored by Patwardhan et al. [<a href="#B26-biomolecules-13-01431" class="html-bibr">26</a>].</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/10/1431'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g003-550.jpg?1695354986" title=" <strong>Figure 3</strong><br/> <p>This illustration represents the hypothetical mechanism underlying domain swapping between two GPCRs. This proposed mechanism primarily pertains to receptors within the same subtypes, such as dopamine D2 and D3, as well as muscarinic M2 and M3 receptors. The process involves the exchange of transmembrane regions VI and VII between these two receptors, visually portrayed by the interchange of the cylindrical segments in the diagram. This intriguing phenomenon can result in either a modification of drug selectivity, evident through the distinct colors denoting ligands bound to the receptors, or an alteration in G protein coupling selectivity. This selectivity shift is visualized by the differing colors representing G proteins bound to the receptors, whether in their monomeric or heterodimeric forms. It is worth noting that this model, as well as class A GPCR dimerization per se, is highly controversial. In fact, all structures of the complexes of GPCRs with G proteins, arrestins, and of rhodopsin with GRK1, reveal a single GPCR bound to one molecule of a signaling protein. Class C GPCRs are true dimers, but they function without domain swapping. Nevertheless, as indicated in the text, the phenomenon of domain swapping has been leveraged in vivo to rescue the function of defective GPCRs.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/10/1431'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/biomolecules/biomolecules-13-01431/article_deploy/html/images/biomolecules-13-01431-g004-550.jpg?1695354987" title=" <strong>Figure 4</strong><br/> <p>This picture illustrates how a long and flexible C-terminal can effectively anchor GPCRs to the underlying scaffolding proteins. In the upper-left of the illustration (<b>a</b>), a resting leukocyte is depicted as a round cell circulating in the bloodstream. In this state (upper-right), the two GPCRs can interact with the underlying actin filaments seamlessly due to their C-terminus and the PDZ domain protein bridging this interaction. Moving to the lower-left of the illustration (<b>b</b>), a leukocyte responds to a chemotactic stimulus and begins to cross the endothelial barrier of the blood stream. As the leukocyte crosses this barrier, its membrane must adapt to the narrow slit between endothelial cells, leading to its slow extravasation from the bloodstream. In the lower-right part of the illustration, the leukocyte’s membrane bends to form a loop that contains the two receptors. The flexibility and length of their C-terminus enable the receptors to stay firmly anchored to the actin filaments, maintaining the same spatial arrangement even after the leukocyte has crossed the endothelial barrier. It is worth noting that a tight fold or a shorter length of the C-terminus would have weakened the receptor’s interaction with the underlying scaffold, drastically altering the spatial compartmentalization of the GPCRs on the cell membrane. The illustration exaggerates the phenomenon but provides a representative understanding of the actual occurrence.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2218-273X/13/10/1431'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1165980" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 9 pages, 933 KiB   </span> <a href="/2072-6651/15/6/386/pdf?version=1686142347" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Transgenic Drosophila to Functionally Validate Fall Armyworm ABCC2 Mutations Conferring Bt Resistance" data-journal="toxins"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Communication</span></div> <a class="title-link" href="/2072-6651/15/6/386">Transgenic <i>Drosophila</i> to Functionally Validate Fall Armyworm ABCC2 Mutations Conferring Bt Resistance</a> <div class="authors"> by <span class="inlineblock "><strong>Rafaela Panteleri</strong>, </span><span class="inlineblock "><strong>Amalia Anthousi</strong>, </span><span class="inlineblock "><strong>Shane Denecke</strong>, </span><span class="inlineblock "><strong>Debora Boaventura</strong>, </span><span class="inlineblock "><strong>Ralf Nauen</strong> and </span><span class="inlineblock "><strong>John Vontas</strong></span> </div> <div class="color-grey-dark"> <em>Toxins</em> <b>2023</b>, <em>15</em>(6), 386; <a href="https://doi.org/10.3390/toxins15060386">https://doi.org/10.3390/toxins15060386</a> - 7 Jun 2023 </div> <a href="/2072-6651/15/6/386#metrics">Cited by 2</a> | Viewed by 2484 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> The fall armyworm (FAW), <i>Spodoptera frugiperda</i> (J.E. Smith; Lepidoptera: Noctuidae) is an invasive agricultural pest with a global distribution, causing major crop losses annually. Its control strategies largely rely on chemical insecticides and transgenic crops expressing <i>Bacillus thuringiensis</i> insecticidal proteins (Cry and Vip <a href="#" data-counterslink = "https://www.mdpi.com/2072-6651/15/6/386/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> The fall armyworm (FAW), <i>Spodoptera frugiperda</i> (J.E. Smith; Lepidoptera: Noctuidae) is an invasive agricultural pest with a global distribution, causing major crop losses annually. Its control strategies largely rely on chemical insecticides and transgenic crops expressing <i>Bacillus thuringiensis</i> insecticidal proteins (Cry and Vip toxins); however, the development of high resistance poses a significant issue. The ATP-binding cassette transporter C2 (ABCC2) has been linked to Cry toxin pore formation, acting as a receptor of some Cry toxins. Recently detected mutations in the SfABCC2 gene in extracellular loop 4 (ECL4) have been associated with Bt toxin resistance in FAW. In the present study, we expressed the SfABCC2 gene in <i>Drosophila melanogaster</i>, a species normally unaffected by the Bt toxins. We demonstrate that susceptibility can be introduced by the ectopic and tissue-specific expression of wildtype SfABCC2. Next, we introduced mutations into ECL4—both individually and in combination—that have been recently described in Brazilian FAW and functionally validated by toxicity bioassays against the foliar Bt product Xentari. Our results provide an efficient demonstration of the suitability of transgenic <i>Drosophila</i> for validating FAW ABCC2 resistance mutations in ECL4 against Bt toxins, and potential cross-resistance issues between closely related proteins that use ABCC2. <a href="/2072-6651/15/6/386">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/toxins/special_issues/9SWHQLJI77 ">Resistance to Insect-Killing Proteins from the <em>Bacillus thuringiensis</em> (Bt) Toxins</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2072-6651/15/6/386/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1165980"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1165980"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1165980" data-cycle-prev="#prev1165980" data-cycle-progressive="#images1165980" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1165980-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/toxins/toxins-15-00386/article_deploy/html/images/toxins-15-00386-ag-550.jpg?1686142417" alt="" style="border: 0;"><p>Graphical abstract</p></div><script id="images1165980" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1165980-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/toxins/toxins-15-00386/article_deploy/html/images/toxins-15-00386-g001-550.jpg?1686142416'><p>Figure 1</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1165980-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/toxins/toxins-15-00386/article_deploy/html/images/toxins-15-00386-g002-550.jpg?1686142414'><p>Figure 2</p></div></script></div></div><div id="article-1165980-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/toxins/toxins-15-00386/article_deploy/html/images/toxins-15-00386-ag-550.jpg?1686142417" title=" <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6651/15/6/386'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/toxins/toxins-15-00386/article_deploy/html/images/toxins-15-00386-g001-550.jpg?1686142416" title=" <strong>Figure 1</strong><br/> <p>Experimental flow of the current study. (<b>a</b>) The wild type allele of SfABCC2 and the mutant alleles (bearing the GY deletion and P799K substitution, alone and in combination) were cloned into pUAST-attB vectors. The four recombinant plasmids were injected into VK13 Drosophila embryos, which carry an attP landing site on the 3rd chromosome. Injected G0 flies were outcrossed with VK13 adult flies and G1 progeny was screened for w+ phenotypes, indicating the integration of the plasmid. The homozygous fly lines were established after a series of crosses. (<b>b</b>) PCR screening followed to test integration into the transgenic fly lines. Primer pair A (black and green arrows—3xP3_RFP_F and VK13_R) gives product when integration has not occurred, whereas Primer pair B (red and green arrows—SV40_F and VK13_R) gives product when integration has occurred. m: molecular weight marker, 1: ABCC2_GYdel, 2: ABCC2_P799K, 3: ABCC2_combo, 4: ABCC2_GYdel/+ (heterozygous), 5: ABCC2, 6: VK13, 7: no template control (NTC). (<b>c</b>) Eye phenotype of the VK13 line, the heterozygous state after transgene integration and the homozygous state.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6651/15/6/386'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/toxins/toxins-15-00386/article_deploy/html/images/toxins-15-00386-g002-550.jpg?1686142414" title=" <strong>Figure 2</strong><br/> <p>Discriminating dose larval bioassay. Comparison of the mortality (±SEM) at different Xentari doses of flies expressing the SfABCC2 transporter in different tissues (x ABCC2) and others not bearing the transporter (x VK13). ELAV-GAL4 is a neuronal cell specific driver, Myo-Gal4 drives expression in the midgut cells, while HR-GAL4 drives expression in the midgut, Malpighian tubules and fat body. Flies that do not carry the transporter (progeny of elav-GAL4 × VK13, Myo-GAL4 × VK13 and HR-GAL4 × VK13) are not affected by the Cry toxin mixture. The expression of he SfABCC2 transporter in the midgut renders the fly susceptible to the Cry toxin mixture, whereas the flies expressing it in their neuronal cells are not affected by the toxins—even in concentrations as high as 100 mg/L.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6651/15/6/386'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1117596" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 22 pages, 2680 KiB   </span> <a href="/2072-6694/15/7/2186/pdf?version=1680916272" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases" data-journal="cancers"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Review</span></div> <a class="title-link" href="/2072-6694/15/7/2186">Targeting of Tetraspanin CD81 with Monoclonal Antibodies and Small Molecules to Combat Cancers and Viral Diseases</a> <div class="authors"> by <span class="inlineblock "><strong>Christian Bailly</strong> and </span><span class="inlineblock "><strong>Xavier Thuru</strong></span> </div> <div class="color-grey-dark"> <em>Cancers</em> <b>2023</b>, <em>15</em>(7), 2186; <a href="https://doi.org/10.3390/cancers15072186">https://doi.org/10.3390/cancers15072186</a> - 6 Apr 2023 </div> <a href="/2072-6694/15/7/2186#metrics">Cited by 12</a> | Viewed by 4999 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also <a href="#" data-counterslink = "https://www.mdpi.com/2072-6694/15/7/2186/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Tetraspanin CD81 plays major roles in cell-cell interactions and the regulation of cellular trafficking. This cholesterol-embarking transmembrane protein is a co-receptor for several viruses, including HCV, HIV-1 and Chikungunya virus, which exploits the large extracellular loop EC2 for cell entry. CD81 is also an anticancer target implicated in cancer cell proliferation and mobility, and in tumor metastasis. CD81 signaling contributes to the development of solid tumors (notably colorectal, liver and gastric cancers) and has been implicated in the aggressivity of B-cell lymphomas. A variety of protein partners can interact with CD81, either to regulate attachment and uptake of viruses (HCV E2, claudin-1, IFIM1) or to contribute to tumor growth and dissemination (CD19, CD44, EWI-2). CD81-protein interactions can be modulated with molecules targeting the extracellular domain of CD81, investigated as antiviral and/or anticancer agents. Several monoclonal antibodies anti-CD81 have been developed, notably mAb 5A6 active against invasion and metastasis of triple-negative breast cancer cells. CD81-EC2 can also be targeted with natural products (trachelogenin and harzianoic acids A-B) and synthetic compounds (such as benzothiazole-quinoline derivatives). They are weak CD81 binders but offer templates for the design of new compounds targeting the open EC2 loop. There is no anti-CD81 compound in clinical development at present, but this structurally well-characterized tetraspanin warrants more substantial considerations as a drug target. <a href="/2072-6694/15/7/2186">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/cancers/sections/Cancer_Drug_Development">Cancer Drug Development</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2072-6694/15/7/2186/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1117596"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1117596"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1117596" data-cycle-prev="#prev1117596" data-cycle-progressive="#images1117596" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1117596-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g001-550.jpg?1680916352" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1117596" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1117596-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g002-550.jpg?1680916358'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1117596-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g003-550.jpg?1680916356'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1117596-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g004-550.jpg?1680916357'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-1117596-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g005-550.jpg?1680916355'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-1117596-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g006-550.jpg?1680916353'><p>Figure 6</p></div></script></div></div><div id="article-1117596-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g001-550.jpg?1680916352" title=" <strong>Figure 1</strong><br/> <p>CD81 domain organization and structure. (<b>a</b>) Schematic representation of CD81 architecture, with four transmembrane (TM) segments embedded in the membrane bilayer and sequestering a molecule of cholesterol, and two extracellular (EC) loops. The small loop EC1 (or SEL) and the large loop EC2 (or SEL). The disulfur bridges between cysteine residue in EC2 are represented, as well as a palmitoylated cysteine residue contributing the anchoring of the protein into the membrane bilayer. (<b>b</b>) A model of CD81, with EC2 in a closed conformation (based in PDB: 5TCX).</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6694/15/7/2186'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g002-550.jpg?1680916358" title=" <strong>Figure 2</strong><br/> <p>Representation of the clustering of tetraspanins to form microdomains at the plasma membrane, associating divers tetraspanins and partner proteins. The tetraspanin web is a dynamic structural organization at the cell surface, including promiscuous and specific interactions [<a href="#B32-cancers-15-02186" class="html-bibr">32</a>].</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6694/15/7/2186'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g003-550.jpg?1680916356" title=" <strong>Figure 3</strong><br/> <p>CD81 protein partners. (<b>a</b>) Multiple CD81-interacting proteins have been identified, including ten defined with the support of STRING database “<a href="https://cn.string-db.org/" target="_blank">https://cn.string-db.org/</a> (accessed on 1 March 2023)” and other additional proteins discovered through our own analysis of the scientific literature. (<b>b</b>) The partners include proteins interacting with the extracellular loops of CD81, such as proteins implicated in virus entry into cells and proteins involved in cancer cell growth and mobility, but also proteins interacting with the intracellular portions of CD81 for cell signaling.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6694/15/7/2186'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g004-550.jpg?1680916357" title=" <strong>Figure 4</strong><br/> <p>Different anti-CD81 antibodies (mAbs) have been discovered. They are used to study CD81 expression and/or function, notably to characterize membrane-bound CD81 on exosomes. Several anti-CD81 mAbs, such as QV-6A8-F2-C4, MT81, K04, K21 and JS-81 can be used to control virus entry into cells. The mAbs 2F7, Eat1 and Eat2 have been essentially used to study autoimmune encephalomyelitis and colitis, whereas mAb DSP-8250 has been tested against IBD. The lead mAb 5A6 displays marked antitumor activities, in murine models of B cell lymphoma and triple-negative breast cancer. A molecular model of the Fab fragment of 5A6 bound to CD81-EC2 is shown (PDB: 6U9S). 5A6 recognizes a conformational epitope on CD81 that is masked when CD81 is bound to CD19 [<a href="#B79-cancers-15-02186" class="html-bibr">79</a>].</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6694/15/7/2186'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g005-550.jpg?1680916355" title=" <strong>Figure 5</strong><br/> <p>Small molecules identified as CD-81 binders. The binding of these molecules to the large extracellular loop (EC2) of CD-81 has been evidenced experimentally and/or proposed on the basis of computational studies (see <a href="#cancers-15-02186-t002" class="html-table">Table 2</a>).</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6694/15/7/2186'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cancers/cancers-15-02186/article_deploy/html/images/cancers-15-02186-g006-550.jpg?1680916353" title=" <strong>Figure 6</strong><br/> <p>A representation of the drug binding cavity identified in the EC2 loop of CD81. The boraadamantane compound <b>5</b> and benzothiazole derivative <b>6</b> have been predicted to bind to CD81-EC2 on the basis of molecular docking and molecular dynamics simulation [<a href="#B146-cancers-15-02186" class="html-bibr">146</a>,<a href="#B148-cancers-15-02186" class="html-bibr">148</a>]. Specific interaction between the compound and the indicated amino-acid has been underlined. All compounds indicated in <a href="#cancers-15-02186-f005" class="html-fig">Figure 5</a> would fit into the binding cavity delineated by the indicated key residues.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6694/15/7/2186'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1106976" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 54 pages, 2623 KiB   </span> <a href="/1422-0067/24/7/6187/pdf?version=1679671754" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands" data-journal="ijms"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Review</span></div> <a class="title-link" href="/1422-0067/24/7/6187">Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands</a> <div class="authors"> by <span class="inlineblock "><strong>Alexander O. Shpakov</strong></span> </div> <div class="color-grey-dark"> <em>Int. J. Mol. Sci.</em> <b>2023</b>, <em>24</em>(7), 6187; <a href="https://doi.org/10.3390/ijms24076187">https://doi.org/10.3390/ijms24076187</a> - 24 Mar 2023 </div> <a href="/1422-0067/24/7/6187#metrics">Cited by 14</a> | Viewed by 5412 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR <a href="#" data-counterslink = "https://www.mdpi.com/1422-0067/24/7/6187/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail. <a href="/1422-0067/24/7/6187">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/ijms/special_issues/GPCR_Signaling ">G Protein-Coupled Receptors in Cell Signaling Transduction</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1422-0067/24/7/6187/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1106976"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1106976"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1106976" data-cycle-prev="#prev1106976" data-cycle-progressive="#images1106976" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1106976-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g001-550.jpg?1679671824" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1106976" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1106976-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g002-550.jpg?1679671822'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1106976-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g003-550.jpg?1679671819'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1106976-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g004-550.jpg?1679671821'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-1106976-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g005-550.jpg?1679671826'><p>Figure 5</p></div></script></div></div><div id="article-1106976-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g001-550.jpg?1679671824" title=" <strong>Figure 1</strong><br/> <p>The main group of allosteric regulators of GPCRs, including the homo- and heterodimerization, along with the main classes of allosteric regulators (ions, lipids, amino acids, peptides, proteins, steroid hormones, autoantibodies to extracellular regions of GPCRs), the heterotrimeric G proteins, β-arrestins, and RAMPs are shown, which form complexes with GPCRs during signal transduction acting allosterically on their functional activity. The allosteric effect of homo- and heterodi(oligo)merization of the receptors has also been shown, as demonstrated for class C GPCRs and some representatives of the class.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/7/6187'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g002-550.jpg?1679671822" title=" <strong>Figure 2</strong><br/> <p>Allosteric regulation of chemokine receptors. There are data on the allosteric regulation of a significant number of chemokine receptors, including CXCR1, CXCR2, CXCR3, CXCR4, CCR2, CCR5, CCR7, and CCR9. Allosteric sites in them can be located at different loci of the TMD: in the upper (outwardly oriented) portion of the transmembrane tunnel (interfaces including the membrane-proximal segments of ECLs and extracellular segments of TMs, as well as the outer vestibule of the transmembrane channel) (designated as AS-1), in the central part of the 7TM bundle (AS-2), and in the lower (oriented to the cytoplasm) portion of the transmembrane tunnel (interfaces, including the membrane-proximal segments of ICLs and the cytoplasmic endings of TMs) (AS-3). In each of these loci, there are several cavities in which allosteric sites can be located, both overlapping and spatially separated. Along with this, allosteric sites can be located in hydrophilic loops being targets for autoantibodies and synthetic pepducins. Endogenous allosteric regulators of the chemokine receptors are sodium (NAM) and zinc (PAM) ions, as well as cholesterol and membrane phospholipids (mainly with PAM activity). Synthetic small allosteric regulators interact with allosteric sites located at all three loci, AS-1, AS-2, and AS-3, while pepducins, lipidated derivatives of peptides corresponding to ICLs, are transported across the plasma membrane and interact with intracellular sites. <a href="#ijms-24-06187-f002" class="html-fig">Figure 2</a> shows the following small regulators interacting with the AS-1 locus: maraviroc (CCR5-selective NAM), reparixin, ladarixin and their analogs (CXCR1/CXCR2-selective NAMs and/or non-competitive allosteric antagonists), plerixafor (allosteric CXCR4-inhibitor), FAUC1036 (biased allosteric CXCR3-agonist), T140 and its analog TN14003 (biased allosteric CXCR4-antagonists), and the peptide X4-2-6 (TM2/ECL1 of CXCR4; allosteric CXCR4-antagonist). The following ligands bind specifically to the AS-2 locus: RAMX3 and its biased analogs 8-azaquinazolinone (8-AQ) derivative 1b, BD064, and BD103 (CXCR3-selective NAMs), DF2755A (noncompetitive allosteric CXCR1/CXCR2-antagonist). The following ligands bind specifically to the AS-3 locus: vercirnon and its analogs (allosteric CCR9-antagonists), navarixin (allosteric antagonist of CXCR1, CXCR2 and CCR7), CCR2-RA-[R] and Cmp2105 (allosteric CCR2-antagonists and/or NAMs). Pepducins, such as <span class="html-italic">N</span>-palmitoylated peptides X1/2pal-i3 (ICL3 of CXCR1/CXCR2; CXCR1/CXCR2-selective NAM), PZ-218 (ICL1 of CXCR4; CXCR4-selective NAM), and PZ-210 (ICL3 of CXCR4; CXCR4-selective NAM), as well as lithocholic acid-modified X1/2LCA-i1 (ICL1 CXCR1/CXCR2; allosteric CXCR1/CXCR2-inhibitor and/or NAM) and ATI-2341 (ICL1 of CXCR4; CXCR4-selective PAM) interact with intracellular sites involved in functional coupling with G proteins and β-arrestins. Antibodies against extracellular regions of chemokine receptors are able to interact with ECLs and the extracellular <span class="html-italic">N</span>-terminal domain, but their effects remain poorly understood. Allosteric regulators that increase receptor activity (full agonists) are placed in red squares, while allosteric regulators that decrease receptor activity (antagonists and NAMs) are placed in green squares.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/7/6187'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g003-550.jpg?1679671819" title=" <strong>Figure 3</strong><br/> <p>Allosteric regulation of proteinase-activated receptors. There is now evidence of allosteric regulation and localization of allosteric sites for PAR1, PAR2, and PAR4. As in the case of chemokine receptors (see <a href="#ijms-24-06187-f002" class="html-fig">Figure 2</a>), allosteric sites in PARs can be located at different TMD loci (AS-1, AS-2, and AS-3) in the ECLs where they are available for interaction with autoantibodies, as well as in the ICLs where they are targets for pepducins. The small compounds, such as GB83 (PAR1-selective PAM), AZ3451 (allosteric PAR2-inhibitor), I-191 (PAR2-selective NAM), and cross-linked heterobivalent allosteric PAR1/PAR2 inhibitor, RWJ-58259/imidazopyridazine (IZP) derivative), interact with allosteric sites located in the upper and central parts of the TM7 bundle. The low-molecular-weight parmodulins, including the PAR1-allosteric inhibitors ML161 (PM2) and JF5, as well as pepducins, interact with intracellular sites, including the AS-3 locus. The following pepducins have been obtained and have specific activity for PAR1, PAR2, and PAR4: Palm-SGRRYGHALR (P4pal-10) (ICL3 of PAR4, allosteric PAR4-antagonist and NAM and allosteric antagonist for the non-cognate receptors PAR1, FPR2, and FFAR2), Palm-ATGAPRLPST (P4pal-i1) (ICL1 of PAR4, allosteric PAR4-inhibitor), Palm-RCLSSSAVANRS (P1pal-12), Palm-RSLSSSAVANRS (P1pal-12S) and its analog P1pal-7 (PZ-128) (ICL3 of PAR1, allosteric PAR1-antagonists), Pal-RCLSSSAVANRSKKSRALF (P1pal-19), Palm-AVANRSKKSRALF (P1pal-13) (ICL3 of PAR1, full allosteric PAR1-agonists), and Palm-RSSAMDENSEKKRKSAIK<sup>270−287</sup> (P2pal-18S) and its analog PZ-235 (ICL3 of PAR2, allosteric PAR1/2-antagonists). Data on autoantibodies to PARs are fragmentary, but antibodies to extracellular regions of PAR1 in patients with systemic sclerosis have been shown to function as PAR1-specific allosteric full agonists and/or PAMs. Many of the effects of allosteric regulators are due to their effect on the stability of heterodimeric PAR1/PAR2 complexes, as shown for the heterobivalent PAR1/PAR2-inhibitor and pepducins P1pal-12S and P2pal-18S. Allosteric regulators that increase receptor activity (full agonists and PAMs) are placed in red squares, while allosteric regulators that decrease receptor activity (antagonists and NAMs) are placed in green squares.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/7/6187'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g004-550.jpg?1679671821" title=" <strong>Figure 4</strong><br/> <p>Allosteric regulators of thyroid-stimulating hormone receptor. The TSHR belongs to a family of class A GPCRs having a large extracellular domain in which an orthosteric site is located and which is a target for autoantibodies. Most of the small regulators of TSHR bind to allosteric sites located in the cavity of the AS-2 locus or slightly higher in the lower portions of the AS-1 locus. The following low-molecular-weight compounds specifically interact with allosteric sites in the AS-2 locus: compound C2, NCGC00168126-01 and its analog NCGC00165237-01 (full allosteric TSHR-agonists), MS437, MS438 (biased allosteric TSHR-agonists, did not affect G<sub>i</sub>-proteins), TPY3m (biased allosteric TSHR-agonist, mainly activates G<sub>s</sub>-proteins), MSq1 (biased allosteric TSHR-agonist, mainly activates G<sub>q/11</sub>-proteins), NCGC00379308 (biased PAM, predominantly activates β-arrestins), TPY1, NIDDK/CEB-52 and its analogs NCGC00242595 and NCGC00242364 (allosteric TSHR-antagonists), NCGC00161856, NCGC00229600, compound S37a, and TP48 (allosteric inverse TSHR-agonists). Pepducin 612–627(Palm) (ICL3 of TSHR) interacts with the intracellular allosteric site and functions as an allosteric TSHR-agonist. Stimulating TSHR autoantibodies (TSAb) interact with the LRR subdomain, hinge region, and ECLs. Blocking TSHR autoantibodies (TSBAb) mainly interact with the N-terminal and central portions of the LRR subdomain. Allosteric regulators that increase receptor activity (full agonists and PAMs) are placed in red squares, allosteric regulators with neutral antagonist activity are placed in green squares, while allosteric regulators with inverse agonist activity are placed in blue squares.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/7/6187'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-06187/article_deploy/html/images/ijms-24-06187-g005-550.jpg?1679671826" title=" <strong>Figure 5</strong><br/> <p>Allosteric regulators of the luteinizing hormone receptor. Like TSHR, LHR has a large extracellular domain in which an orthosteric site is located, and the small LHR regulators bind to allosteric sites located in the cavity of the AS-2 locus. The following low-molecular-weight compounds specifically interact with allosteric sites in the AS-2 locus: thieno[2,3-d]-pyrimidine derivatives Org41841, Org43553, TP03, TP04 and their analogs (allosteric LHR-agonists or ago-PAMs, predominantly activate G<sub>s</sub>-proteins), the derivatives of 1,3,5-pyrazole (compound 1) and terphenyl (LUF5771) (allosteric LHR-agonists), and thieno[2,3-d]-pyrimidine derivative TP31 (allosteric LHR-antagonists). Pepducin NKDTKIAKK-Nle-A(562–572)-K(Palm)A (ICL3 of LHR) interacts with the intracellular allosteric site and functions as an allosteric LHR agonist. Autoantibodies to the extracellular regions of LHR have been suggested but have not been characterized to date. Allosteric regulators that increase receptor activity (full agonists and ago-PAMs) are placed in red squares, while allosteric regulators with neutral antagonist activity are placed in green squares.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/7/6187'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1076464" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 16 pages, 10608 KiB   </span> <a href="/1422-0067/24/5/4339/pdf?version=1677119019" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="The Role of Bacteria–Mitochondria Communication in the Activation of Neuronal Innate Immunity: Implications to Parkinson’s Disease" data-journal="ijms"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/1422-0067/24/5/4339">The Role of Bacteria–Mitochondria Communication in the Activation of Neuronal Innate Immunity: Implications to Parkinson’s Disease</a> <div class="authors"> by <span class="inlineblock "><strong>João D. Magalhães</strong>, </span><span class="inlineblock "><strong>Ana Raquel Esteves</strong>, </span><span class="inlineblock "><strong>Emanuel Candeias</strong>, </span><span class="inlineblock "><strong>Diana F. Silva</strong>, </span><span class="inlineblock "><strong>Nuno Empadinhas</strong> and </span><span class="inlineblock "><strong>Sandra Morais Cardoso</strong></span> </div> <div class="color-grey-dark"> <em>Int. J. Mol. Sci.</em> <b>2023</b>, <em>24</em>(5), 4339; <a href="https://doi.org/10.3390/ijms24054339">https://doi.org/10.3390/ijms24054339</a> - 22 Feb 2023 </div> <a href="/1422-0067/24/5/4339#metrics">Cited by 8</a> | Viewed by 2600 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Mitochondria play a key role in regulating host metabolism, immunity and cellular homeostasis. Remarkably, these organelles are proposed to have evolved from an endosymbiotic association between an alphaproteobacterium and a primitive eukaryotic host cell or an archaeon. This crucial event determined that human <a href="#" data-counterslink = "https://www.mdpi.com/1422-0067/24/5/4339/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Mitochondria play a key role in regulating host metabolism, immunity and cellular homeostasis. Remarkably, these organelles are proposed to have evolved from an endosymbiotic association between an alphaproteobacterium and a primitive eukaryotic host cell or an archaeon. This crucial event determined that human cell mitochondria share some features with bacteria, namely cardiolipin, N-formyl peptides, mtDNA and transcription factor A, that can act as mitochondrial-derived damage-associated molecular patterns (DAMPs). The impact of extracellular bacteria on the host act largely through the modulation of mitochondrial activities, and often mitochondria are themselves immunogenic organelles that can trigger protective mechanisms through DAMPs mobilization. In this work, we demonstrate that mesencephalic neurons exposed to an environmental alphaproteobacterium activate innate immunity through toll-like receptor 4 and Nod-like receptor 3. Moreover, we show that mesencephalic neurons increase the expression and aggregation of alpha-synuclein that interacts with mitochondria, leading to their dysfunction. Mitochondrial dynamic alterations also affect mitophagy which favors a positive feedback loop on innate immunity signaling. Our results help to elucidate how bacteria and neuronal mitochondria interact and trigger neuronal damage and neuroinflammation and allow us to discuss the role of bacterial-derived pathogen-associated molecular patterns (PAMPs) in Parkinson’s disease etiology. <a href="/1422-0067/24/5/4339">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/ijms/special_issues/1AF84UT5M5 ">Mechanisms of Innate Immune Activation and Regulation in Health and Disease (Volume 2)</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1422-0067/24/5/4339/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1076464"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1076464"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1076464" data-cycle-prev="#prev1076464" data-cycle-progressive="#images1076464" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1076464-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g001-550.jpg?1677119088" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1076464" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1076464-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g002-550.jpg?1677119097'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1076464-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g003-550.jpg?1677119090'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1076464-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g004-550.jpg?1677119094'><p>Figure 4</p></div></script></div></div><div id="article-1076464-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g001-550.jpg?1677119088" title=" <strong>Figure 1</strong><br/> <p>Bacterial exposure activates neuronal innate immunity. Primary mesencephalic neuronal cultures from naive mice were exposed to 1 × 10<sup>6</sup>/mL bacteria for 48 hours (<b>a</b>) Representative immunoblot for TLR4. Blots were re-probed for β-Tubulin to confirm equal protein loading. (<b>b</b>) Densitometric analysis of the levels of TLR4 was normalized with β-Tubulin. Data are expressed relatively to untreated (Unt) neurons (<span class="html-italic">n</span> = 7, ** <span class="html-italic">p</span> = 0.0065). (<b>c</b>) Nuclear factor kappa-B (NF-κB) levels were calculated using NF-κB p65 ELISA kit. Data are expressed relatively to Unt neurons (<span class="html-italic">n</span> = 3, <span class="html-italic">p</span> = 0.0782). (<b>d</b>) Caspase-1 activation. Data are expressed relatively to Unt neurons (<span class="html-italic">n</span> = 3, * <span class="html-italic">p</span> = 0.0459). (<b>e</b>) IL-1β levels in the isolated cytosolic fraction was determined using an IL-1β ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 5–6, * <span class="html-italic">p</span> = 0.0399). (<b>f</b>) IL-1β levels released by neurons were determined using an IL-1β ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 4–5, * <span class="html-italic">p</span> = 0.0459). (<b>g</b>) TNFα levels in the isolated cytosolic fraction were determined using a TNFα ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 3, * <span class="html-italic">p</span> = 0.0353). (<b>h</b>) TNFα levels released by neurons were determined using a TNFα ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 3, * <span class="html-italic">p</span> = 0.0372). (<b>i</b>) IL-6 levels in the isolated cytosolic fraction were determined using an IL-6 ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 4, * <span class="html-italic">p</span> = 0.0301). (<b>j</b>) IL-6 levels released by neurons were determined using an IL-6 ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 4, * <span class="html-italic">p</span> = 0.0226). Data represent mean + SEM. Unpaired Student’s <span class="html-italic">t</span>-test was performed.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/5/4339'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g002-550.jpg?1677119097" title=" <strong>Figure 2</strong><br/> <p>Bacterial exposure promotes α-Syn expression and aggregation. (<b>a</b>) Representative immunoblot showing α-Syn monomer and oligomers in mesencephalic neuronal cultures infected with 1 × 10<sup>6</sup>/mL bacteria for 48 h. The blots were re-probed for β-Actin to confirm equal protein loading. (<b>b</b>) Densitometric analyses of the levels of α-Syn normalized against β-Actin. (<span class="html-italic">n</span> = 3, *** <span class="html-italic">p</span> = 0.0003). (<b>c</b>) Cytosolic α-Syn oligomeric levels from primary mesencephalic neuronal cultures exposed to 1 × 10<sup>6</sup>/mL bacteria for 48 h were calculated using an ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 4, * <span class="html-italic">p</span> = 0.0346). (<b>d</b>) Mitochondrial α-Syn oligomeric levels from primary mesencephalic neuronal cultures exposed to 1 × 10<sup>6</sup>/mL bacteria for 48 h were calculated using an ELISA kit. Values are pg/mL (<span class="html-italic">n</span> = 7, ** <span class="html-italic">p</span> = 0.0028). Data represent mean + SEM. Statistical analysis was performed using Unpaired Student’s <span class="html-italic">t</span>-test.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/5/4339'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g003-550.jpg?1677119090" title=" <strong>Figure 3</strong><br/> <p>Bacteria induce neuronal mitochondrial dysfunction and fragmentation. Primary mesencephalic neuronal cultures were exposed to 1 × 10<sup>6</sup>/mL bacteria (α-Proteobacteria) for 48 h. (<b>a</b>) Mitochondrial ROS production was assessed using the fluorescent dye MitoPY1 (<span class="html-italic">n</span> = 4, ** <span class="html-italic">p</span> = 0.0029). (<b>b</b>) Changes in mitochondrial membrane potential (ΔΨm) were assessed using the fluorescent cationic dye TMRM (<span class="html-italic">n</span> = 5, *** <span class="html-italic">p</span> = 0.0007). (<b>c</b>) Representative images of mitochondrial network of primary mesencephalic neurons immunostained with Tom20. (<b>d</b>,<b>e</b>) Alterations in mitochondrial network were calculated with an ImageJ Macro tool (16 images from <span class="html-italic">n</span> = 4). (<b>d</b>) Number of mitochondrial individuals (<span class="html-italic">n</span> = 4, ** <span class="html-italic">p</span> = 0.007). (<b>e</b>) Number of mitochondrial network branches (<span class="html-italic">n</span> = 4, ** <span class="html-italic">p</span> = 0.0043). (<b>f</b>) Representative immunoblot for phospho-Drp1 levels. The blots were re-probed for TOM20 to confirm equal protein loading and mitochondrial fraction purity. (<b>g</b>) Densitometric analysis of phospho-Drp1 levels. Data are expressed relatively to Unt neurons (<span class="html-italic">n</span> = 4–3, * <span class="html-italic">p</span> = 0.0270). Scale bars = 21 µm. Data represent mean + SEM. Statistical analysis was performed using Unpaired Student’s <span class="html-italic">t</span>-test.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/5/4339'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-24-04339/article_deploy/html/images/ijms-24-04339-g004-550.jpg?1677119094" title=" <strong>Figure 4</strong><br/> <p>Mitophagy is differentially affected by bacterial exposure. Primary mesencephalic neuronal cultures infected with 1 × 10<sup>6</sup>/mL bacteria for 48 h in the presence or absence of lysosomal inhibitors (NHCl + leupeptin; NL, last 4 h) were examined by immunoblotting. (<b>a</b>) Representative immunoblot for LC3B-I and II levels. (<b>b</b>) Autophagic vacuoles basal levels (LC3-II basal densitometric values) were determined (<span class="html-italic">n</span> = 4, Unt vs. NL,**** <span class="html-italic">p</span> &lt; 0.0001; Unt vs. αProteobact, * <span class="html-italic">p</span> = 0.0473). (<b>c</b>) Autophagic flux was determined (ratio of LC3-II densitometric value of NL-treated samples over the corresponding untreated samples (<span class="html-italic">n</span> = 4, Unt vs. αProteobact, **** <span class="html-italic">p</span> &lt; 0.0001). The blots were re-probed for α-tubulin to confirm equal protein loading. (<b>d</b>) Co-localization between autophagic vacuoles (labeled in green with LC3B antibody) and mitochondria (labeled in red with COXII antibody) was visualized by immunofluorescence (<span class="html-italic">n</span> = 6 images). Hoechst 33342-stained nuclei are in blue. (<b>e</b>) Percentage of LC3B and COXII co-localization was calculated using Image J as described in Material and Methods (<span class="html-italic">n</span> = 3, Unt vs. Unt + NL, *** <span class="html-italic">p</span> = 0.0009). (<b>f</b>) Assessment of LC3B and COXII co-localization as the ratio between +NL/-NL treatments (<span class="html-italic">n</span> = 3, * <span class="html-italic">p</span> = 0.0487). (<b>g</b>), Co-localization between mitochondria (labeled in green with Tom20 antibody) and lysosomes (labeled in red with Lamp1 antibody) was visualized by immunofluorescence (<span class="html-italic">n</span> = 6–8 images). Hoechst 33342- stained nuclei are in blue. (<b>h</b>) Percentage of Tom20 and Lamp1 co-localization was calculated using Image J as described in Material and Methods. (<span class="html-italic">n</span> = 3, Unt vs. NL, * <span class="html-italic">p</span> = 0.0352; Unt vs. α-Proteobact, * <span class="html-italic">p</span> = 0.0427). (<b>i</b>) Assessment of Tom20 and Lamp1 co-localization as the ratio between +NL/-NL treatments (<span class="html-italic">n</span> = 3, ** <span class="html-italic">p</span> = 0.0087). Data represent mean + SEM. Scale bars = 10 µm Statistical analysis was performed using Unpaired Student’s <span class="html-italic">t</span>-test to compare NL treatments vs. respective control group and untreated cells versus bacterial-exposed cells.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/24/5/4339'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="1007242" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 19 pages, 2891 KiB   </span> <a href="/1422-0067/23/24/16157/pdf?version=1671603564" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Cross-Linking and Functional Analyses for Dimerization of a Cysteine Mutant of Glycine Transporter 1" data-journal="ijms"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/1422-0067/23/24/16157">Cross-Linking and Functional Analyses for Dimerization of a Cysteine Mutant of Glycine Transporter 1</a> <div class="authors"> by <span class="inlineblock "><strong>Jingru Wang</strong>, </span><span class="inlineblock "><strong>Hanhe Liu</strong> and </span><span class="inlineblock "><strong>Yuan-Wei Zhang</strong></span> </div> <div class="color-grey-dark"> <em>Int. J. Mol. Sci.</em> <b>2022</b>, <em>23</em>(24), 16157; <a href="https://doi.org/10.3390/ijms232416157">https://doi.org/10.3390/ijms232416157</a> - 18 Dec 2022 </div> <a href="/1422-0067/23/24/16157#metrics">Cited by 1</a> | Viewed by 2265 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Glycine transporter 1 (GlyT1) is responsible for the reuptake of glycine, which regulates glutamate signaling as a co-agonist with N-methyl-D-aspartic acid (NMDA) receptors in the excitatory synapse and has been proposed to be a potential target in the development of therapies for a <a href="#" data-counterslink = "https://www.mdpi.com/1422-0067/23/24/16157/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Glycine transporter 1 (GlyT1) is responsible for the reuptake of glycine, which regulates glutamate signaling as a co-agonist with N-methyl-D-aspartic acid (NMDA) receptors in the excitatory synapse and has been proposed to be a potential target in the development of therapies for a broad range of disorders of the central nervous system. Despite significant progress in characterizing structure and transport mechanism of the transporter, the regulation of transport function through oligomerization remains to be understood. In the present work, association of two forms of GlyT1 into dimers and higher order oligomers was detected by coimmunoprecipitation. To investigate functional properties of dimers of a GlyT1 cysteine mutant L288C, we performed oxidative cross-linking of the positioned cysteine residues in extracellular loop 3 (EL3) near the extracellular end of TM6. By analyzing the effect of copper phenanthroline (CuP)-induced dimerization on transport function, cross-linking of L288C was found to inhibit transport activity. In addition, an intramolecular ion pair Lys286-Glu289 was revealed to be critical for stabilizing EL3 in a conformation that modulates CuP-induced dimerization and transport function of the GlyT1 L288C mutant. Furthermore, the influence of transporter conformation on GlyT1 L288C dimerization was investigated. The substrate glycine, in the presence of both Na<sup>+</sup> and Cl<sup>−</sup>, significantly reduced oxidative cross-linking, suggesting a large-scale rotation of the bundle domain during substrate transport impairs interfacial interactions between L288C protomers. The present study provides new insights into structural and functional elements regulating GlyT1 transport activity through its dimerization or oligomerization. <a href="/1422-0067/23/24/16157">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/ijms/sections/biochemistry">Biochemistry</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1422-0067/23/24/16157/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev1007242"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next1007242"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next1007242" data-cycle-prev="#prev1007242" data-cycle-progressive="#images1007242" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-1007242-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g001-550.jpg?1671603632" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images1007242" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g002-550.jpg?1671603635'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g003-550.jpg?1671603631'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g004-550.jpg?1671603642'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g005-550.jpg?1671603639'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g006-550.jpg?1671603628'><p>Figure 6</p></div> --- <div class='openpopupgallery' data-imgindex='6' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g007-550.jpg?1671603629'><p>Figure 7</p></div> --- <div class='openpopupgallery' data-imgindex='7' data-target='article-1007242-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g008-550.jpg?1671603637'><p>Figure 8</p></div></script></div></div><div id="article-1007242-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g001-550.jpg?1671603632" title=" <strong>Figure 1</strong><br/> <p>Association of two epitope-tagged GlyT1 forms. (<b>A</b>,<b>B</b>) Co-immunoprecipitation of FLAG-GlyT1 with GlyT1-HA. FLAG-tagged GlyT1 in total lysates of the cells co-expressing FLAG-GlyT1 with GlyT1-HA was pulled down by anti-FLAG agarose beads and subjected to separation by SDS-PAGE. The HA-tagged GlyT1 associated with FLAG-GlyT1 was then detected by immunoblot analysis with anti-HA antibody (<b>A</b>). After stripping, the immunoprecipitated FLAG-tagged GlyT1 was detected by re-probing the membrane with anti-FLAG antibody (<b>B</b>). (<b>C</b>,<b>D</b>) Co-immunoprecipitation of GlyT1-HA with FLAG-GlyT1. The HA-tagged GlyT1 was pulled down from cell lysates using anti-HA agarose beads and separated by SDS-PAGE. The FLAG-GlyT1 associated with GlyT1-HA was detected by immunoblot analysis with anti-FLAG antibody (<b>C</b>). Immunoprecipitation of the HA tagged GlyT1 was confirmed by anti-HA antibody (<b>D</b>). Graphs show representative blots, and experiments were performed more than three times with similar results.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g002-550.jpg?1671603635" title=" <strong>Figure 2</strong><br/> <p>Location of the cysteine replacing Leu288 in GlyT1 and CuP cross-linking of the L288C mutant. (<b>A</b>) The cysteine replacing Leu288 in the x-ray structure of GlyT1 in an inward open conformation (PDB accession code, 6ZPL) [<a href="#B26-ijms-23-16157" class="html-bibr">26</a>]. Cys288 (spheres) is located at EL3 near the extracellular end of TM6 in the GlyT1 structure. The bundle domain (TMs 1, 2, 6, and 7) and other part of the protein are colored in golden and gray, respectively. (<b>B</b>) Immunoblots of WT (right panel) and L288C (left panel) with or without CuP treatment. HEK293 cells stably expressing WT or L288C were treated with 100 μM CuP at 22 °C for 15 min and the cross-linking reaction was then quenched by incubating them with 10 mM N-ethylmaleimide for 15 min. FLAG-tagged GlyT1 in total cell lysates was detected by immunoblot analysis as described under “Materials and Methods”. Numbers on the right of each blot represent molecular masses in kDa of protein standards. (<b>C</b>) Quantification of dimer fraction in total GlyT1. The fully glycosylated dimers (−190 kDa) were considered to reside on the cell surface, whereas non-glycosylated dimers were within the cytoplasm. Dimer fraction was expressed as percentage of fully glycosylated dimers in total DAT integrated density value. Results are shown as mean ± SEM averaged from three independent experiments. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g003-550.jpg?1671603631" title=" <strong>Figure 3</strong><br/> <p>CuP concentration-dependent cross-linking and its influence on transport activity of GlyT1 L288C. (<b>A</b>) The representative immunoblot of CuP cross-linking of L288C. HEK-L288C cells were treated without or with CuP at indicated concentrations at 22 °C for 15 min and then lysed. The FLAG-tagged L288C in cell lysates were detected by immunoblot analysis using anti-FLAG antibody. (<b>B</b>) Relationship between CuP-induced dimer fraction of GlyT1 (◦) or glycine uptake (●) and CuP concentrations. After HEK-L288C cells were treated with varying concentrations of CuP, [<sup>3</sup>H]glycine uptake measurements and immunoblot analysis were parallelly performed. [<sup>3</sup>H]Glycine uptake was expressed as a percentage of the value obtained without CuP treatment and CuP-induced dimer fraction was expressed as an increased dimer percentage caused by CuP cross-linking after subtracting a spontaneously occurring dimer percentage of total GlyT1 integrated density value. All results are presented as mean ± SEM averaged from three independent experiments.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g004-550.jpg?1671603642" title=" <strong>Figure 4</strong><br/> <p>The intramolecular salt bridge in EL3 modulates dimeric interfacial interactions and transport activity of GlyT1 L288C. (<b>A</b>) Dimer docking of GlyT1 L288C with each protomer in an inward open conformation (PDB accession code, 6ZPL). An intramolecular salt bridge formed by Lys286-Glu289 in EL3 near the extracellular end of TM6 was shown in each protomer. The two protomers in a putative GlyT1 L288C dimer are colored in green and cyan, respectively. (<b>B</b>) A representative immunoblot of biotinylated L288C, K286A/L288C, and E289A/L288C. HEK293 cells stably expressing GlyT1 L288C, K286A/L288C, or E289A/L288C were treated with sulfo-NHS-SS-biotin at 4 °C for 20 min. After precipitation with streptavidin agarose, biotinylated GlyT1 was detected by immunoblot analysis as described under “Materials and Methods”. (<b>C</b>) Quantification of cell surface expression and transport activity of GlyT L288C, K286A/L288C, and E289A/L288C. Biotinylation and [<sup>3</sup>H]glycine uptake assays were performed in parallel to measure cell surface expression and transport activity of GlyT1 L288C, K286A/L288C, and E289A/L288C. Cell surface expression was expressed as a percentage of the integrated density value of GlyT1 L288C. Transport activity was expressed as a percentage of [<sup>3</sup>H]glycine uptake normalized to cell surface expression of GlyT1 L288C. The dotted line shows cell surface expression and transport activity of GlyT1 L288C. All results are presented as mean ± SEM averaged from three independent experiments. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01, compared to L288C. (<b>D</b>) A representative immunoblot of the E289A/L288C mutant with or without DTT treatment. HEK293 cells stably expressing E289A/L288C were lysed, and the cell lysates were then treated with or without 100 mM DTT at 22 °C for 1 h. GlyT1 E289A/L288C was detected by immunoblot analysis. (<b>E</b>) Quantification of dimer fraction of E289A/L288C with or without DTT treatment. Dimer fraction was expressed as a percentage of fully glycosylated dimers relative to total GlyT1 E289A/L288C. Results are presented as mean ± SEM averaged from three independent experiments. * <span class="html-italic">p</span> &lt; 0.05 compared to E289A/L288C without DTT treatment.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g005-550.jpg?1671603639" title=" <strong>Figure 5</strong><br/> <p>Influence of ion pair mutations on CuP cross-linking and transport activity of L288C. (<b>A</b>) A representative immunoblot of ion pair mutants with or without CuP treatment. HEK293 cells stably expressing GlyT1 L288C, K286A/L288C, or E289A/L288C were treated with 10 μM CuP at 22 °C for 15 min. After quenching, GlyT1 in cell lysates was detected by immunoblot analysis as described under “Materials and Methods”. (<b>B</b>) Quantification of dimer fractions of L288C, K286A/L288C, and E289A/L288C with or without CuP treatment. Dimer fraction was expressed as a percentage of fully glycosylated dimers in total GlyT1. Results are presented as mean ± SEM averaged from three independent experiments. * <span class="html-italic">p</span> &lt; 0.05 compared to each mutant without CuP treatment. (<b>C</b>) CuP-induced increase in dimer fraction and decrease in transport activity. Immunoblot analysis and [<sup>3</sup>H]glycine uptake were parallelly performed to examine CuP-induced changes in both dimer fraction and transport activity with HEK293 cells stably expressing GlyT1 L288C, K286A/L288C, and E289A/L288C as described under “Materials and Methods”. All results are presented as mean ± SEM averaged from at least three independent experiments. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the background construct, L288C.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g006-550.jpg?1671603628" title=" <strong>Figure 6</strong><br/> <p>Influence of Zn<sup>2+</sup> on CuP cross-linking and transport activity of L288C. (<b>A</b>) Influence of CuP on Zn<sup>2+</sup> induced decrease in transport activity of L288C. HEK293 cells stably expressing L288C were treated with ZnCl<sub>2</sub> at indicated concentrations in the absence or presence of 10 μM CuP at 22 °C for 15 min and [<sup>3</sup>H]glycine uptake was measured as described under “Materials and Methods”. The graph showed a representative experiment with triplicate measurements. The experiment was repeated twice with similar results. Glycine uptake was expressed as a percentage of glycine uptake of L288C without both CuP and ZnCl<sub>2</sub> treatments. (<b>B</b>) Influence of ZnCl<sub>2</sub> on CuP-induced cross-linking of L288C. HEK293 cells stably expressing L288C were treated with ZnCl<sub>2</sub> at indicated concentrations in the absence or presence of 10 μM CuP at 22 °C for 15 min. After quenching, L288C in cell lysates was detected by immunoblot analysis. A representative immunoblot was shown (inset). Dimer fraction was expressed as a percentage of fully glycosylated dimers in total L288C. All results are presented as mean ± SEM averaged from three independent experiments.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g007-550.jpg?1671603629" title=" <strong>Figure 7</strong><br/> <p>Influence of GlyT1 conformations on CuP cross-linking of L288C. (<b>A</b>) A representative immunoblot showing CuP cross-linking of L288C under different conditions. HEK293 cells stably expressing L288C were treated with 10 μM CuP in the absence or presence of the indicated cation (150 mM), glycine (200 μM), or ligand (10 μM) at 22 °C for 15 min. After quenching, L288C in total lysates was detected by immunoblot analysis. (<b>B</b>) Quantification of dimer fraction under indicated treatments. The fraction of dimers was expressed as a percentage of fully glycosylated dimers. All results are presented as mean ± SEM averaged from three independent experiments. ** <span class="html-italic">p</span> &lt; 0.01 compared to the value obtained with L288C under CuP treatment in the presence of 150 mM NMDGCl. Gly, glycine; BITOP, bitopertin; LY, LY2365109.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-23-16157/article_deploy/html/images/ijms-23-16157-g008-550.jpg?1671603637" title=" <strong>Figure 8</strong><br/> <p>Dimer docking of GlyT1 L288C with both protomers in an inward open (<b>A</b>) or an outward open conformation (<b>B</b>). Dimer docking was performed based on the crystal structure of GlyT1 in an inward open conformation (PDB accession code, 6ZPL) [<a href="#B26-ijms-23-16157" class="html-bibr">26</a>] and the GlyT1b model in an outward open conformation. The distance between two dimeric cysteines replacing Leu288 in the inward-open dimer and outward-open dimer are 5.5 and 6.2 Å, respectively. The bundle domains (TMs 1, 2, 6, and 7) and other part of the protein are colored in golden and gray, respectively.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/23/24/16157'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="975601" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 10 pages, 2237 KiB   </span> <a href="/1467-3045/44/11/387/pdf?version=1668679138" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Single-Step Protocol for Isolating the Recombinant Extracellular Domain of the Luteinizing Hormone Receptor from the Ovis aries Testis" data-journal="cimb"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Communication</span></div> <a class="title-link" href="/1467-3045/44/11/387">Single-Step Protocol for Isolating the Recombinant Extracellular Domain of the Luteinizing Hormone Receptor from the <i>Ovis aries</i> Testis</a> <div class="authors"> by <span class="inlineblock "><strong>José Luis Villalpando-Aguilar</strong>, </span><span class="inlineblock "><strong>Itzel López-Rosas</strong>, </span><span class="inlineblock "><strong>Arnulfo Montero-Pardo</strong>, </span><span class="inlineblock "><strong>Elisa Azuara-Liceaga</strong>, </span><span class="inlineblock "><strong>Javier de Jesús Valencia-Méndez</strong>, </span><span class="inlineblock "><strong>Cynthia R. Trejo-Muñoz</strong> and </span><span class="inlineblock "><strong>Carlos Kubli-Garfias</strong></span> </div> <div class="color-grey-dark"> <em>Curr. Issues Mol. Biol.</em> <b>2022</b>, <em>44</em>(11), 5718-5727; <a href="https://doi.org/10.3390/cimb44110387">https://doi.org/10.3390/cimb44110387</a> - 17 Nov 2022 </div> Viewed by 1916 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> The luteinizing hormone receptor (LHR) is a glycoprotein member of the G protein-coupled receptors superfamily. It participates in corpus luteum formation and ovulation in females and acts in testosterone synthesis and spermatogenesis in males. In this study, we extracted RNA from sheep testicles <a href="#" data-counterslink = "https://www.mdpi.com/1467-3045/44/11/387/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> The luteinizing hormone receptor (LHR) is a glycoprotein member of the G protein-coupled receptors superfamily. It participates in corpus luteum formation and ovulation in females and acts in testosterone synthesis and spermatogenesis in males. In this study, we extracted RNA from sheep testicles and synthetized the cDNA to amplify the gene <i>lhr-bed</i>. This gene consists of 762 bp and encodes 273 amino acids of the extracellular domain of LHR. The <i>lhr-bed</i> was cloned into pJET1.2/blunt, then subcloned into pCOLD II, and finally, transformed in <i>E. coli</i> BL21 (<i>DE</i>3) cells. Because the induced rLHR-Bed protein was found in the insoluble fraction, we followed a modified purification protocol involving induction at 25 °C, subjection to denaturing conditions, and on-column refolding to increase solubility. We confirmed rLHR-Bed expression by means of Western blot and mass spectrometry analysis. It is currently known that the structure stem-loop 5′UTR on pCOLD II vector is stable at 15 °C. We predicted and obtained RNAfold stability at 25 °C. We successfully obtained the recombinant LHR extracellular domain, with protein yields of 0.2 mg/L, and purity levels of approximately 90%, by means of a single chromatographic purification step. The method described here may be used to obtain large quantities of rLHR-Bed in the future. <a href="/1467-3045/44/11/387">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/cimb/sections/BMCB">Biochemistry, Molecular and Cellular Biology</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1467-3045/44/11/387/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev975601"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next975601"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next975601" data-cycle-prev="#prev975601" data-cycle-progressive="#images975601" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-975601-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-ag-550.jpg?1668679897" alt="" style="border: 0;"><p>Graphical abstract</p></div><script id="images975601" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-975601-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g001-550.jpg?1668679893'><p>Figure 1</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-975601-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g002-550.jpg?1668679896'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-975601-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g003-550.jpg?1668679890'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-975601-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g004-550.jpg?1668679894'><p>Figure 4</p></div></script></div></div><div id="article-975601-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-ag-550.jpg?1668679897" title=" <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1467-3045/44/11/387'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g001-550.jpg?1668679893" title=" <strong>Figure 1</strong><br/> <p>Purification protocol of LHR-Bed. The figure summarizes the four stages of the purification protocol. Stage I (green): lysis and fraction-obtaining. Stage II (red): Akta Prime preparation in manual mode. Stage III (yellow): refolding. Stage IV (purple): elution analysis.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1467-3045/44/11/387'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g002-550.jpg?1668679896" title=" <strong>Figure 2</strong><br/> <p>Genomic location of LHR gene in <span class="html-italic">Ovis aries.</span> (<b>A</b>) shows the LHR gene of 1965 bp length. Upstream and downstream of the LHR genes are the LOC114113602 and GTF2A1L gene loci encoded by 1484 bp and 1308bp, respectively. (<b>B</b>) Eleven exons encompass the LHR mRNA. Exons 1 to 10 encode the extracellular domain, while the long exon 11 encodes 7TMD and the carboxy terminal. (<b>C</b>) Arrangement of LHR predicted according to NCBI Batch CD-Search, showing 2 domains: a leucine-rich region (LRR) and seven-transmembrane helices characteristic of the GPCR superfamily. (<b>D</b>) Cloned <span class="html-italic">lhr</span>-<span class="html-italic">bed</span> gene. Characteristics of the store plasmid pJET.2/blunt cloning vector for <span class="html-italic">lhr</span>-<span class="html-italic">bed</span> are shown. (<b>E</b>) The amplicon (insert), of 762 bp, corresponding to <span class="html-italic">lhr-bed</span> (lane 2). (<b>F</b>) Map pCOLD-II expression vector. (<b>G</b>) Bands of the expressed vector pCOLD II (lane 3) and the insert of 762 bp yielding the pCOLD II-<span class="html-italic">lhr-bed</span> as product expression after digestion by NdeI and XhoI enzymes and ligation with T4 ligase (lane 2). The MW of the DNA marker (1 kb) is shown in B and C, lane 1.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1467-3045/44/11/387'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g003-550.jpg?1668679890" title=" <strong>Figure 3</strong><br/> <p>rLHR-Bed induction-solubilization-refolding-purification profile. (<b>A</b>) Lane 1 shows MW (molecular weight). Lanes 2–7 show non-induction (NIND) and induction (IND) for BL21 cells without transformation, Clone 2, and Clone 4, respectively. (<b>B</b>) Western blot (WB) SDS-PAGE shows rLHR-Bed profiles with detection signals between 25 and 37 kDa; this expression coincides clearly with rLHR-Bed (lane 7). The WB control was a 50 kDa protein with tag histidines (lane 10). Arrows indicate 50 and 28 kDa, respectively. (<b>C</b>) Solubility profile test of rLHR-Bed shows: MW (lane 1), non-soluble fraction (NSF) protein, (lane 2), and soluble fraction (SF) protein (lane 3). The arrow indicates rLHR-Bed. (<b>D</b>) Western Blot from a gel SDS-PAGE of the rLHR-Bed solubility profile. Lane 1 shows MW; lines 2 and 3 show NSF, and SF, respectively. The presence of rLHR-Bed can be observed in the non-soluble fraction at 28 kDa (lane 2). (<b>E</b>) Complete profile of rLHR-Bed purification and its WB detection. Lane 1 shows MW; lanes 2 and 3 show samples of NIND and IND, respectively; lines 4 and 5 show NSF and SF, respectively, lines 6–9 represent elutions 2–5. and 5; lane 10 shows the WB of elution 5.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1467-3045/44/11/387'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cimb/cimb-44-00387/article_deploy/html/images/cimb-44-00387-g004-550.jpg?1668679894" title=" <strong>Figure 4</strong><br/> <p>Secondary structure prediction of <span class="html-italic">cspA</span> 5′UTR of pCOLDl II under varying temperature conditions. The models were obtained using RNAfold (<a href="http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi" target="_blank">http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi</a>, accessed on 18 August 2022) and showed predictions with the following temperature parameters: (<b>A</b>) 15 °C; (<b>B</b>) 25 °C; and (<b>C</b>) 37 °C.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1467-3045/44/11/387'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="706562" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 17 pages, 6920 KiB   </span> <a href="/2073-4409/10/12/3594/pdf?version=1639995783" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin β1 Expression" data-journal="cells"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/2073-4409/10/12/3594">Targeting Chondroitin Sulfate Reduces Invasiveness of Glioma Cells by Suppressing CD44 and Integrin β1 Expression</a> <div class="authors"> by <span class="inlineblock "><strong>Yin-Hung Chu</strong>, </span><span class="inlineblock "><strong>Wen-Chieh Liao</strong>, </span><span class="inlineblock "><strong>Ying-Jui Ho</strong>, </span><span class="inlineblock "><strong>Chih-Hsien Huang</strong>, </span><span class="inlineblock "><strong>To-Jung Tseng</strong> and </span><span class="inlineblock "><strong>Chiung-Hui Liu</strong></span> </div> <div class="color-grey-dark"> <em>Cells</em> <b>2021</b>, <em>10</em>(12), 3594; <a href="https://doi.org/10.3390/cells10123594">https://doi.org/10.3390/cells10123594</a> - 20 Dec 2021 </div> <a href="/2073-4409/10/12/3594#metrics">Cited by 17</a> | Viewed by 4609 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor <a href="#" data-counterslink = "https://www.mdpi.com/2073-4409/10/12/3594/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Chondroitin sulfate (CS) is a major component of the extracellular matrix found to be abnormally accumulated in several types of cancer tissues. Previous studies have indicated that CS synthases and modification enzymes are frequently elevated in human gliomas and are associated with poor prognosis. However, the underlying mechanisms of CS in cancer progression and approaches for interrupting its functions in cancer cells remain largely unexplored. Here, we have found that CS was significantly enriched surrounding the vasculature in a subset of glioma tissues, which was akin to the perivascular niche for cancer-initiating cells. Silencing or overexpression of the major CS synthase, chondroitin sulfate synthase 1 (CHSY1), significantly regulated the glioma cell invasive phenotypes and modulated integrin expression. Furthermore, we identified CD44 as a crucial chondroitin sulfate proteoglycan (CSPG) that was modified by CHSY1 on glioma cells, and the suppression of CS formation on CD44 by silencing the CHSY1-inhibited interaction between CD44 and integrin β1 on the adhesion complex. Moreover, we tested the CS-specific binding peptide, resulting in the suppression of glioma cell mobility in a fashion similar to that observed upon the silencing of CHSY1. In addition, the peptide demonstrated significant affinity to CD44, promoted CD44 degradation, and suppressed integrin β1 expression in glioma cells. Overall, this study proposes a potential regulatory loop between CS, CD44, and integrin β1 in glioma cells, and highlights the importance of CS in CD44 stability. Furthermore, the targeting of CS by specific binding peptides has potential as a novel therapeutic strategy for glioma. <a href="/2073-4409/10/12/3594">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Section <a href="/journal/cells/sections/Cell_Microenvironment">Cell Microenvironment</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2073-4409/10/12/3594/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev706562"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next706562"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next706562" data-cycle-prev="#prev706562" data-cycle-progressive="#images706562" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-706562-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g001-550.jpg?1639995886" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images706562" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-706562-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g002-550.jpg?1639995886'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-706562-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g003-550.jpg?1639995886'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-706562-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g004-550.jpg?1639995886'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-706562-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g005-550.jpg?1639995886'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-706562-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g006-550.jpg?1639995886'><p>Figure 6</p></div></script></div></div><div id="article-706562-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g001-550.jpg?1639995886" title=" <strong>Figure 1</strong><br/> <p>Immunohistochemistry (IHC) analysis of CS56 expression in a tissue array containing primary glioma and non-tumorous brain tissues. (<b>A</b>) A total of 85 primary glioma cases and three non-tumor brain tissues on a tissue array were stained for CS56 expression by immunohistochemistry. Staining was visualized as a brown color using the 3, 3-diaminobenzidine (DAB) liquid substrate system. All sections were counterstained with hematoxylin. The CS56 and nuclei staining are depicted by brown and blue colored stains, respectively. Representative images of non-tumor brain (A1), perivascular CS56 staining in glioma tissues (A2), and the spread of CS56 staining in glioma tissue (A3) are shown. Amplified images are shown at right. Scale bars, 100 μm. (<b>B</b>) Classification of CS56 distribution patterns in different clinical stages of glioma tissue. Fisher exact test, * <span class="html-italic">p</span> &lt; 0.05. (<b>C</b>) CS56 staining intensities compared to different stages of glioma tissue. Staining of CS56 was graded by brown area, 0: negative, +1: &lt;20%, +2: 20–50%, +3: &gt;50%. A Mann–Whitney <span class="html-italic">U</span> Test was used. *** <span class="html-italic">p</span> &lt; 0.001.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/12/3594'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g002-550.jpg?1639995886" title=" <strong>Figure 2</strong><br/> <p>Correlation and modulation between CHSY1 and integrins in glioblastoma tissue and cells. (<b>A</b>) Gene expression of CHSY1 in comparison to related integrins. Data were collected from the cBioPortal database and analysed by Pearson’s correlation. (<b>B</b>) CHSY1, CHPF, and ITGB1 protein expressions in the glioblastoma cell lines GBM8401, Ln18, DBTRG, GBM8901, U251, A172, U118, and mouse glioblastoma cell line GL261. Each group was standardized with total protein. (<b>C</b>) ITGB1 protein expression upon overexpression or silencing of CHSY1 in glioma cells. Control siRNA (Ctr si) or CHSY1-siRNA (CHSY1 si). The red arrow indicates the mature form of ITGB1. (<b>D</b>) qPCR analysis of the gene expression of <span class="html-italic">ITGB1</span> and <span class="html-italic">CHSY1</span> in A172 and U118 cells with <span class="html-italic">CHSY1</span> siRNA knockdown. Statistical significance, *** <span class="html-italic">p</span> &lt; 0.001.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/12/3594'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g003-550.jpg?1639995886" title=" <strong>Figure 3</strong><br/> <p>CHSY1 regulates cell adhesion, migration, and invasion in glioma cells. (<b>A</b>) Effects of CHSY1 on cell adhesion, (<b>B</b>) transwell cell migration, and (<b>C</b>) matrigel invasion assays. Stable overexpression of CHSY1 was performed in GL261 cells, and siRNA-mediated knockdown of CHSY1 was performed in A172 and U118 cells. (Ctr si, Control-siRNA; CHSY1 si, CHSY1-siRNA; FN, fibronectin; BSA, bovine serum albumin; TCP, tissue culture plate). Representative micrographs are shown. All results are presented as the means ± SD from three independent experiments. Statistical significance, * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/12/3594'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g004-550.jpg?1639995886" title=" <strong>Figure 4</strong><br/> <p>CHSY1 modulates the CS chains on CD44. (<b>A</b>) List of peptide-to-spectrum matching (PSM) analysis of control A172 cell lysate (Ctr si) and CHSY1 silenced cell lysate (CHSY1 si) after immunoprecipitation by CS56 antibody. CSPG and focal adhesion-related protein are shown. (<b>B</b>) Western blots of CD44 on control (Ctr si) and CHSY1 silenced cell lysates (CHSY1 si) after treatment with chondroitinase ABC (Chase ABC) or heparinase. (<b>C</b>) Confocal microscopy analysis of ITGB1 (red) and CD44 (green) distribution around the cell surface. Scale bar, 8 μm. Amplified images are shown at right. (<b>D</b>) Immunoprecipitation (IP) of CD44 and immunoblots with ITGB1 and CD44 antibodies.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/12/3594'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g005-550.jpg?1639995886" title=" <strong>Figure 5</strong><br/> <p>Effects of CS-binding peptide (C6S-p) on glioma cells. (<b>A</b>) Immunocytochemistry of biotin staining with streptavidin-Alexa 594 (red) and nuclear with DAPI (blue). A172 cells were treated with PBS or C6S-p for 20 min or C6S-p for 120 min. Scale bar, 12.5 μm. Amplified images are shown at lower panel. (<b>B</b>) A CCK8 assay was used for detecting the effect of C6S-p on the viability of A172 cells. Treatment with different doses (10, 50, and 100 μg) of C6S-p or the control scrambled peptide for 24 h (left); and the time course treatment with 100 μg of C6S-p or control scrambled peptide for 24, 48, and 72 h (right). Cell viability is represented as percentage relative to the control group. (<b>C</b>) Scratch assays in GL261 and A172 glioma cells treated with C6S-p or the scrambled peptide; the average area of wound closure is shown as a percentage relative to control. (<b>D</b>) Matrigel invasion assays in GL261 and A172 glioma treated with C6S-p or the scrambled peptide; migrated cells are shown as the number of invaded cells per field. (<b>E</b>) Examining the ex vivo migration of A172 cells transfected with control siRNA (Ctr si) or CHSY1-siRNA (CHSY1 si, upper) and A172 cells treated with scrambled peptide or C6S-p (lower) on mouse brain tissue slice. The white circles indicate the original location of the cell seeding at day 0, and the red line indicates the cell moving edge after 72 h. Representative images are shown. Scale bars, 150 μm. The mean ± SD of area changes from four independent experiments were shown at bottom. Statistical significance, ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/12/3594'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-03594/article_deploy/html/images/cells-10-03594-g006-550.jpg?1639995886" title=" <strong>Figure 6</strong><br/> <p>C6S-p binds to CD44 and accelerates CD44 degradation. (<b>A</b>) Co-localization between CD44 and C6S-binding peptides. Peptides staining with biotin (red) and CD44 antibody (green). Scale bar 8 μm. Amplified images are shown. (<b>B</b>) Streptavidin beads pulldown assay isolated the CD44-C6S-p complex. A172 cell lysate was used for the biotinylated peptide pulldown assay. Protein levels of CD44 were analyzed by Western blotting. (<b>C</b>) Western blotting of CD44 degradation. A172 cells were treated with peptides and 20 μM cycloheximide (CHX) for 30, 60 and 120 min. Actin was used as the loading control. The relative protein levels are shown on the right. ** <span class="html-italic">p</span> &lt; 0.01. (<b>D</b>) Real-time PCR analysis of <span class="html-italic">ITGB1</span> mRNA expression after treatment with C6S-p and scramble peptide in A172 and U118 cells. *** <span class="html-italic">p</span> &lt; 0.001. (<b>E</b>) A proposed model illustrating the co-operation of CD44 with integrins to enhance glioma cell-invasive phenotypes. The model also demonstrates that the knockdown of CHSY1 or blocking CS on CD44 may promote the degradation of CD44 and suppress the expression of integrins in glioma cells.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/12/3594'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="633195" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 59 pages, 4027 KiB   </span> <a href="/2073-4409/10/9/2383/pdf?version=1631501280" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Effects of Extracellular Osteoanabolic Agents on the Endogenous Response of Osteoblastic Cells" data-journal="cells"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Review</span></div> <a class="title-link" href="/2073-4409/10/9/2383">Effects of Extracellular Osteoanabolic Agents on the Endogenous Response of Osteoblastic Cells</a> <div class="authors"> by <span class="inlineblock "><strong>Giulia Alloisio</strong>, </span><span class="inlineblock "><strong>Chiara Ciaccio</strong>, </span><span class="inlineblock "><strong>Giovanni Francesco Fasciglione</strong>, </span><span class="inlineblock "><strong>Umberto Tarantino</strong>, </span><span class="inlineblock "><strong>Stefano Marini</strong>, </span><span class="inlineblock "><strong>Massimo Coletta</strong> and </span><span class="inlineblock "><strong>Magda Gioia</strong></span> </div> <div class="color-grey-dark"> <em>Cells</em> <b>2021</b>, <em>10</em>(9), 2383; <a href="https://doi.org/10.3390/cells10092383">https://doi.org/10.3390/cells10092383</a> - 10 Sep 2021 </div> <a href="/2073-4409/10/9/2383#metrics">Cited by 9</a> | Viewed by 5468 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to <a href="#" data-counterslink = "https://www.mdpi.com/2073-4409/10/9/2383/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to note that the microstructure of bone depends not only on genetic determinants (which control the bone remodeling loop through autocrine and paracrine signals) but also, more importantly, on the continuous response of cells to external mechanical cues. In particular, bone cells sense mechanical signals such as shear, tensile, loading and vibration, and once activated, they react by regulating bone anabolism. Although several specific surrounding conditions needed for osteoblast cells to specifically augment bone formation have been empirically discovered, most of the underlying biomechanical cellular processes underneath remain largely unknown. Nevertheless, exogenous stimuli of endogenous osteogenesis can be applied to promote the mineral apposition rate, bone formation, bone mass and bone strength, as well as expediting fracture repair and bone regeneration. The following review summarizes the latest studies related to the proliferation and differentiation of osteoblastic cells, enhanced by mechanical forces or supplemental signaling factors (such as trace metals, nutraceuticals, vitamins and exosomes), providing a thorough overview of the exogenous osteogenic agents which can be exploited to modulate and influence the mechanically induced anabolism of bone. Furthermore, this review aims to discuss the emerging role of extracellular stimuli in skeletal metabolism as well as their potential roles and provide new perspectives for the treatment of bone disorders. <a href="/2073-4409/10/9/2383">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/cells/special_issues/Cellular_Mechanisms_Bone_Regeneration ">Cellular Mechanisms of Bone Regeneration</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2073-4409/10/9/2383/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev633195"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next633195"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next633195" data-cycle-prev="#prev633195" data-cycle-progressive="#images633195" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-633195-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-ag-550.jpg?1631520282" alt="" style="border: 0;"><p>Graphical abstract</p></div><script id="images633195" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g001-550.jpg?1631520282'><p>Figure 1</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g002-550.jpg?1631520282'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g003-550.jpg?1631520282'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='4' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g004-550.jpg?1631520282'><p>Figure 4</p></div> --- <div class='openpopupgallery' data-imgindex='5' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g005-550.jpg?1631520282'><p>Figure 5</p></div> --- <div class='openpopupgallery' data-imgindex='6' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g006-550.jpg?1631520282'><p>Figure 6</p></div> --- <div class='openpopupgallery' data-imgindex='7' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g007-550.jpg?1631520282'><p>Figure 7</p></div> --- <div class='openpopupgallery' data-imgindex='8' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g008-550.jpg?1631520282'><p>Figure 8</p></div> --- <div class='openpopupgallery' data-imgindex='9' data-target='article-633195-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g009-550.jpg?1631520282'><p>Figure 9</p></div></script></div></div><div id="article-633195-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-ag-550.jpg?1631520282" title=" <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g001-550.jpg?1631520282" title=" <strong>Figure 1</strong><br/> <p>The principal signaling networks and transcription factors regulating bone cell differentiation. (<b>a</b>) Osteoblastogenesis and osteogenesis. In boxes, transcriptional factors, which characterize each stage of osteogenic differentiation, are shown. The MSC population actively proliferates at the initial stages of osteogenesis. As MSCs commit to osteoblasts, their proliferation rate decreases while they start expressing osteogenic genes. Following mineralization, mature osteoblasts undergo apoptosis, revert back to a bone lining phenotype or become embedded in the mineralized matrix and differentiate into osteocytes. Lines with an arrowhead indicate a positive action, and lines with a bar indicate inhibition. (<b>b</b>) Osteoblast cytokines involved in osteoclastogenesis: osteoblasts produce chemokine MCP-1 (monocyte chemoattractant protein-1). In addition, osteoblasts express the master of osteoclastogenesis cytokines, i.e., CSF-1 (light blue sphere), RANKL (represented in dark blue) and OPG (yellow semicircle). Monocytes (differentiated from HSCs) evolve to osteoclast precursors and finally to active OC forms which are stimulated by RANKL. Together with the canonical Wnt signaling, the RANK/RANKL OPG signaling pathways control osteoclasts in response to the actual extracellular stimuli.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g002-550.jpg?1631520282" title=" <strong>Figure 2</strong><br/> <p>Molecular crosstalk in bone molecular unit (BMU): Paracrine actions of osteoblast-, osteocyte- and osteoclast-derived factors within the bone remodeling compartment. Osteoblasts respond to external signals generated by mechanically activated osteocytes or direct endocrine signals, recruit osteoclast precursors to the remodeling site, by expressing CSF, RANKL (represented in dark blue) and WNT (orange diamond), and inhibit osteoclast activity through OPG (yellow semicircle), a decoy receptor of RANKL (pictured in dark blue). Osteocyte-derived SOST (magenta oval) inhibits OB differentiation and stimulates osteoclastogenesis. The osteocyte expression levels of Wnt inhibitors (SOST and DKK (green oval)) temporally control the cycle of bone remodeling. Lines with an arrowhead indicate a positive action, and lines with a bar indicate inhibition.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g003-550.jpg?1631520282" title=" <strong>Figure 3</strong><br/> <p>(<b>a</b>) Representation of inside-out and outside-in mechanotransduction signals. Focal adhesions (FAs) serve as crucial sites for transferring forces in both directions. Integrins are coupled to the cytoskeleton via molecules such as vinculin, talin and α-actin. (<b>b</b>) Protein network clusters across the extracellular matrix, transmembrane proteins and cytoskeleton regions of a spread cell. On the right side, three nonlinear spring series conceptualize the mechanical linkage between the cytoskeleton, focal adhesion complex and extracellular matrix, with respective nonlinear spring constants: k<sub>CSK</sub>, k<sub>FA</sub>, k<sub>ECM</sub>. On the left side, a zoom of the membrane portion is represented. Mechanical signals perceived by membrane-bound receptors such as stretch-activated Ca<sup>2+</sup> channels, integrins, G proteins, IGF and TGFβ and/or BMP receptors are stimulated by mechanical forces and converted into a proper biological response (Table 2). The ECM and intracellular pathways are biochemically coupled by mechanotransduction pathways: mechanical resistance to intrinsic forces regulates the stability of focal adhesion complex that contains focal adhesion kinase (FAK), which phosphorylates and activates mechanoresponsive signaling elements. Line with an arrowhead indicates a positive action, and line with a bar indicates inhibition.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g004-550.jpg?1631520282" title=" <strong>Figure 4</strong><br/> <p>The regulation of Runx2 by mechanical and soluble ossification agents. Mechanical signals perceived by membrane-bound receptors such as lipoprotein-related protein (LRP) 5/6 and the frizzled (Fz) co-receptors, TGFβ and/or BMP receptors, integrins, FGF and G proteins (as an example, the PTH receptor is indicated) and stretch-activated Ca<sup>2+</sup> channels regulate Rnux2 activity. Major regulatory pathways are represented. Biochemical agents such as vitamin A, coenzyme Q10, resveratrol (RSV), vitamin D, zinc ion and exosomes (EXS) can affect Runx2 and thus osteoblast differentiation.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g005-550.jpg?1631520282" title=" <strong>Figure 5</strong><br/> <p>Scheme of direct actions of 1,25(OH)2D3/VDR on mature osteoblasts. 1,25(OH)2D3 acts via the VDR to regulate the osteoblast-related genes containing VDRE binding motifs. 1,25(OH)2D3 can both positively and negatively regulate expression of osteoblast phenotypic markers as a function of the proliferative and differentiated states of osteoblasts and the duration and concentration of exposure. SPP1, Secreted Phosphoprotein 1; BSP, bone sialoprotein; IBSP, integrin binding sialoprotein.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g006-550.jpg?1631520282" title=" <strong>Figure 6</strong><br/> <p>Effect of zinc intake (at high or low concentrations/doses) on the skeletal system.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g007-550.jpg?1631520282" title=" <strong>Figure 7</strong><br/> <p>Representation of the zinc transport process across membranes, mediated by specific importers and exporters, to Zrt- and Irt-like protein (ZIP) and the zinc transporter (ZnT). At the cytoplasmic level, zinc is important for the functionality of zinc finger transcription factors (ZF-TFs) that regulate the transcription of early and late genes in osteoblastic differentiation. Refer to the text for a detailed description.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g008-550.jpg?1631520282" title=" <strong>Figure 8</strong><br/> <p>Osteogenic effects of resveratrol in vitro. RSV influences estrogen-dependent and independent signal transduction pathways which modulate the gene expression of transcription factors Runx2 and osterix (OSX), regulating osteoblast differentiation and mineralization.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02383/article_deploy/html/images/cells-10-02383-g009-550.jpg?1631520282" title=" <strong>Figure 9</strong><br/> <p>Exosome biogenesis. Through endocytosis and plasma membrane invagination, fluid and extracellular constituents such as proteins, lipids, metabolites, small molecules and ions can enter cells. This process leads to the formation of early endosomes or the possible fusion of the gem with endosomes performed by the constituents of the endoplasmic reticulum and of the Golgi network. Early endosomes give rise to late endosomes. Late endosomes evolve to multivesicular bodies (MVBs) with a defined collection of intraluminal vesicles (future exosomes). MVBs can also fuse directly with lysosomes for degradation (not shown). MVBs that do not follow this pathway can be transported to the plasma membrane. Exocytosis follows and leads to the release of exosomes with a lipid bilayer orientation similar to that of the plasma membrane. Exosomes can contain different types of cell surface proteins, intracellular proteins, RNA, DNA, amino acids and metabolites.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/9/2383'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="626133" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 16 pages, 1160 KiB   </span> <a href="/1422-0067/22/17/9449/pdf?version=1630404362" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis" data-journal="ijms"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Review</span></div> <a class="title-link" href="/1422-0067/22/17/9449">Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis</a> <div class="authors"> by <span class="inlineblock "><strong>Davide Ferrari</strong>, </span><span class="inlineblock "><strong>Fabio Casciano</strong>, </span><span class="inlineblock "><strong>Paola Secchiero</strong> and </span><span class="inlineblock "><strong>Eva Reali</strong></span> </div> <div class="color-grey-dark"> <em>Int. J. Mol. Sci.</em> <b>2021</b>, <em>22</em>(17), 9449; <a href="https://doi.org/10.3390/ijms22179449">https://doi.org/10.3390/ijms22179449</a> - 31 Aug 2021 </div> <a href="/1422-0067/22/17/9449#metrics">Cited by 19</a> | Viewed by 4180 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still <a href="#" data-counterslink = "https://www.mdpi.com/1422-0067/22/17/9449/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques’ formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes’ inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments. <a href="/1422-0067/22/17/9449">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/ijms/special_issues/Psoriasis_Arthritis ">Psoriasis (PsO) and Psoriatic Arthritis (PsA)</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1422-0067/22/17/9449/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev626133"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next626133"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next626133" data-cycle-prev="#prev626133" data-cycle-progressive="#images626133" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-626133-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/ijms/ijms-22-09449/article_deploy/html/images/ijms-22-09449-g001-550.jpg?1630404458" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images626133" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-626133-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/ijms/ijms-22-09449/article_deploy/html/images/ijms-22-09449-g002-550.jpg?1630404458'><p>Figure 2</p></div></script></div></div><div id="article-626133-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/ijms/ijms-22-09449/article_deploy/html/images/ijms-22-09449-g001-550.jpg?1630404458" title=" <strong>Figure 1</strong><br/> <p>Purinergic signaling molecules. Intracellular adenine (ATP and ADP), uridine nucleotides (UTP and UDP), and nucleosides (ADO) play the role of cell-to-cell mediators once released, as a consequence of shear stress membrane damage, hypoxia, apoptosis, necrosis, and infections. They can be transported by specialized molecules (PANX1, CALHM1, VRAC, MAC, Connexin, and P2X7) and act as agonists at purinergic P2 (P2X and P2Y) or P1 (A<sub>1</sub>, A<sub>2A</sub>, A<sub>2B</sub>, and A<sub>3</sub>) receptors. ADO, which activates P1 receptors, can also be transported extracellularly or generated on the outer surface of the cell by the enzymatic conversion of ATP/ADP to AMP by the ectonucleoside triphosphate diphosphohydrolase CD39 and with the hydrolysis of AMP to ADO by the ecto-5′-nucleotidase CD73.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/22/17/9449'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/ijms/ijms-22-09449/article_deploy/html/images/ijms-22-09449-g002-550.jpg?1630404458" title=" <strong>Figure 2</strong><br/> <p>Hypothetical model for the early phase of psoriasis. An initial skin damaging event, caused by mechanical trauma, UV irradiation, or the accumulation of cell metabolites in the presence of susceptibility gene variants or epigenetic modifications, induce ATP release, both by cell membrane damage and connexin activation. Extracellular ATP may act as a chemotactic stimulus for immune cells and activate the inflammasome by binding the P2X7 receptor in keratinocytes and in CD103<sup>+</sup> dermal DCs. This stimulates the production of IL-1β and IL-18 and hyper migration of CD103<sup>+</sup> dermal DCs to the skin draining lymph-node, where they present antigens to CD4<sup>+</sup> and CD8<sup>+</sup> T lymphocytes.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1422-0067/22/17/9449'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="609578" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 9 pages, 1292 KiB   </span> <a href="/2073-4409/10/8/2005/pdf?version=1628243959" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Differences in a Single Extracellular Residue Underlie Adhesive Functions of Two Zebrafish Aqp0s" data-journal="cells"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/2073-4409/10/8/2005">Differences in a Single Extracellular Residue Underlie Adhesive Functions of Two Zebrafish Aqp0s</a> <div class="authors"> by <span class="inlineblock "><strong>Irene Vorontsova</strong>, </span><span class="inlineblock "><strong>James E. Hall</strong>, </span><span class="inlineblock "><strong>Thomas F. Schilling</strong>, </span><span class="inlineblock "><strong>Noriaki Nagai</strong> and </span><span class="inlineblock "><strong>Yosuke Nakazawa</strong></span> </div> <div class="color-grey-dark"> <em>Cells</em> <b>2021</b>, <em>10</em>(8), 2005; <a href="https://doi.org/10.3390/cells10082005">https://doi.org/10.3390/cells10082005</a> - 6 Aug 2021 </div> <a href="/2073-4409/10/8/2005#metrics">Cited by 3</a> | Viewed by 2355 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Aquaporin 0 (AQP0) is the most abundant lens membrane protein, and loss of function in human and animal models leads to cataract formation. AQP0 has several functions in the lens including water transport and adhesion. Since lens optics rely on strict tissue architecture <a href="#" data-counterslink = "https://www.mdpi.com/2073-4409/10/8/2005/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Aquaporin 0 (AQP0) is the most abundant lens membrane protein, and loss of function in human and animal models leads to cataract formation. AQP0 has several functions in the lens including water transport and adhesion. Since lens optics rely on strict tissue architecture achieved by compact cell-to-cell adhesion between lens fiber cells, understanding how AQP0 contributes to adhesion would shed light on normal lens physiology and pathophysiology. We show in an in vitro adhesion assay that one of two closely related zebrafish Aqp0s, Aqp0b, has strong auto-adhesive properties while Aqp0a does not. The difference appears to be largely due to a single amino acid difference at residue 110 in the extracellular C-loop, which is T in Aqp0a and N in Aqp0b. Similarly, P110 is the key residue required for adhesion in mammalian AQP0, highlighting the importance of residue 110 in AQP0 cell-to-cell adhesion in vertebrate lenses as well as the divergence of adhesive and water permeability functions in zebrafish duplicates. <a href="/2073-4409/10/8/2005">Full article</a> </div> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/2073-4409/10/8/2005/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev609578"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next609578"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next609578" data-cycle-prev="#prev609578" data-cycle-progressive="#images609578" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-609578-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g001-550.jpg?1628244037" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images609578" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-609578-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g002-550.jpg?1628244038'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-609578-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g003-550.jpg?1628244038'><p>Figure 3</p></div> --- <div class='openpopupgallery' data-imgindex='3' data-target='article-609578-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g004-550.jpg?1628244037'><p>Figure 4</p></div></script></div></div><div id="article-609578-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g001-550.jpg?1628244037" title=" <strong>Figure 1</strong><br/> <p>Zebrafish Aqp0b has adhesive properties. (<b>A</b>) Adherent cell percentages are shown for homotypic pairs of stable cell lines expressing positive control rat AQP0 (rAQP0), negative control rat AQP1 (rAQP1), zebrafish Aqp0a or Aqp0b, as well as cells transfected with an empty vector (L-(−)). Each lane represents <span class="html-italic">n</span> = 6–8. (<b>B</b>) Similar expression levels of rat AQP0 and zebrafish Aqp0 proteins shown by Western blotting using an anti-human C-terminus AQP0 antibody, and an anti-β-actin antibody as the loading control. Sample blot, top panel; quantification, bottom panel (<span class="html-italic">n</span> ≥ 3). (<b>C</b>) Heterotypic adhesion tested between zebrafish orthologs. Aqp0 plated first is indicated at the bottom. Statistical differences are shown as * having <span class="html-italic">p</span> &lt; 0.05 or as ** having <span class="html-italic">p</span> &lt; 0.01.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/8/2005'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g002-550.jpg?1628244038" title=" <strong>Figure 2</strong><br/> <p>Zoo protein alignments of AQP0 extracellular loops. Amino acid alignment of extracellular loops A, C, and E of AQP0 across selected mammalian and piscine species. RasMol coloring. Human (<span class="html-italic">Homo sapiens</span>), bovine (<span class="html-italic">Bos taurus</span>), mouse (<span class="html-italic">Mus musculus</span>), and rat (<span class="html-italic">Rattus norvegicus</span>) AQP0 (also known as MIP) are shown. The fish Aqp0s shown include MIPfun of killifish (<span class="html-italic">Fundulus heteroclitus</span>) and duplicated Aqp0s for zebrafish (<span class="html-italic">Danio rerio</span>) and Atlantic salmon (<span class="html-italic">Salmo salar</span>). Two amino acids of interest indicated as boxed sites 110 and 195 were mutated in this study.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/8/2005'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g003-550.jpg?1628244038" title=" <strong>Figure 3</strong><br/> <p>Mutational analysis reveals the importance of site 110 for adhesion of Aqp0b. (<b>A</b>) Adhesive properties were tested between homotypic pairs of stable cell lines expressing WT and mutant variants of Aqp0a and Aqp0b. Each lane represents <span class="html-italic">n</span> = 6–8. (<b>B</b>) Western blot analysis example showing equal expression of the protein between Aqp0 WT and mutant variants using zebrafish specific rabbit anti-Aqp0a and anti-Aqp0b sera quantified in (<b>C</b>) (<span class="html-italic">n</span> ≥ 3). Statistical differences are shown as ** having <span class="html-italic">p</span> &lt; 0.01.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/8/2005'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/cells/cells-10-02005/article_deploy/html/images/cells-10-02005-g004-550.jpg?1628244037" title=" <strong>Figure 4</strong><br/> <p>MIPfun’s adhesive properties are enhanced by an N110P mutation. (<b>A</b>) Adhesive properties were tested between homotypic pairs of stable cell lines expressing WT MIPfun and mutated variants. Each lane represents <span class="html-italic">n</span> = 6–8. (<b>B</b>) Western blot analysis example shows equal expression of the protein between WT and mutant variants using the rabbit anti-zebrafish Aqp0b sera quantified in (<b>C</b>) (<span class="html-italic">n</span> ≥ 3). Statistical differences are shown as ** having <span class="html-italic">p</span> &lt; 0.01.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2073-4409/10/8/2005'>Full article</a></strong> "></a></div> </div> </div> <div class="generic-item article-item"> <input class="article-list-checkbox export-element" type="checkbox" name="articles_ids[]" value="550297" data-select-all-name="article-listing"> <div class="article-content"> <div class="label right label__btn"> <span style="font-size: 12px; color: #1a1a1a;"> 18 pages, 6064 KiB   </span> <a href="/1999-4923/13/5/672/pdf?version=1620630854" class="UD_Listings_ArticlePDF" title="Article PDF" data-name="Polymer Particles Bearing Recombinant LEL CD81 as Trapping Systems for Hepatitis C Virus" data-journal="pharmaceutics"> <i class="material-icons custom-download"></i> </a> </div> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <a class="title-link" href="/1999-4923/13/5/672">Polymer Particles Bearing Recombinant LEL CD81 as Trapping Systems for Hepatitis C Virus</a> <div class="authors"> by <span class="inlineblock "><strong>Dmitry Polyakov</strong>, </span><span class="inlineblock "><strong>Ekaterina Sinitsyna</strong>, </span><span class="inlineblock "><strong>Natalia Grudinina</strong>, </span><span class="inlineblock "><strong>Mariia Antipchik</strong>, </span><span class="inlineblock "><strong>Rodion Sakhabeev</strong>, </span><span class="inlineblock "><strong>Viktor Korzhikov-Vlakh</strong>, </span><span class="inlineblock "><strong>Mikhail Shavlovsky</strong>, </span><span class="inlineblock "><strong>Evgenia Korzhikova-Vlakh</strong> and </span><span class="inlineblock "><strong>Tatiana Tennikova</strong></span> </div> <div class="color-grey-dark"> <em>Pharmaceutics</em> <b>2021</b>, <em>13</em>(5), 672; <a href="https://doi.org/10.3390/pharmaceutics13050672">https://doi.org/10.3390/pharmaceutics13050672</a> - 7 May 2021 </div> <a href="/1999-4923/13/5/672#metrics">Cited by 8</a> | Viewed by 2098 <div class="abstract-div"> <a href="#" onclick="$(this).next('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> <strong>Abstract </strong> </a> <div class="abstract-cropped inline"> Hepatitis C is one of the most common social diseases in the world. The improvements in both the early diagnostics of the hepatitis C and the treatment of acute viremia caused by hepatitis C virus are undoubtedly an urgent task. In present work, <a href="#" data-counterslink = "https://www.mdpi.com/1999-4923/13/5/672/more" onclick="$(this).parents('.abstract-cropped').toggleClass('inline').next('.abstract-full').toggleClass('inline'); return false;"> [...] Read more.</a> </div> <div class="abstract-full "> Hepatitis C is one of the most common social diseases in the world. The improvements in both the early diagnostics of the hepatitis C and the treatment of acute viremia caused by hepatitis C virus are undoubtedly an urgent task. In present work, we offered the micro- and nanotraps for the capturing of HCV. As a capturing moiety, we designed and synthesized in <i>E. coli</i> a fusion protein consisting of large extracellular loop of CD81 receptor and streptavidin as spacing part. The obtained protein has been immobilized on the surface of PLA-based micro- and nanoparticles. The developed trapping systems were characterized in terms of their physico-chemical properties. In order to illustrate the ability of developed micro- and nanotraps to bind HCV, E2 core protein of HCV was synthesized as a fusion protein with GFP. Interaction of E2 protein and hepatitis C virus-mimicking particles with the developed trapping systems were testified by several methods. <a href="/1999-4923/13/5/672">Full article</a> </div> </div> <div class="belongsTo" style="margin-bottom: 10px;"> (This article belongs to the Special Issue <a href=" /journal/pharmaceutics/special_issues/Protein_Therap ">Advances in Delivering Protein and Peptide Therapeutics</a>)<br/> </div> <a href="#" class="abstract-figures-show" data-counterslink = "https://www.mdpi.com/1999-4923/13/5/672/show" ><span >►</span><span style=" display: none;">▼</span> Show Figures </a><div class="abstract-image-preview "><div class="arrow left-arrow" id="prev550297"><i class="fa fa-caret-left"></i></div><div class="arrow right-arrow" id="next550297"><i class="fa fa-caret-right"></i></div><div class="absgraph cycle-slideshow manual" data-cycle-fx="scrollHorz" data-cycle-timeout="0" data-cycle-next="#next550297" data-cycle-prev="#prev550297" data-cycle-progressive="#images550297" data-cycle-slides=">div" data-cycle-log="false"><div class='openpopupgallery cycle-slide' data-imgindex='0' data-target='article-550297-popup'><span class="helper"></span><img src="data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=" data-src="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g001-550.jpg?1620630957" alt="" style="border: 0;"><p>Figure 1</p></div><script id="images550297" type="text/cycle" data-cycle-split="---"><div class='openpopupgallery' data-imgindex='1' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g002-550.jpg?1620630957'><p>Figure 2</p></div> --- <div class='openpopupgallery' data-imgindex='2' data-target='article-550297-popup'><span class="helper"></span><img 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src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g006a-550.jpg?1620630957'><p>Figure 6</p></div> --- <div class='openpopupgallery' data-imgindex='6' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g006b-550.jpg?1620630957'><p>Figure 6 Cont.</p></div> --- <div class='openpopupgallery' data-imgindex='7' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g007-550.jpg?1620630957'><p>Figure 7</p></div> --- <div class='openpopupgallery' data-imgindex='8' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g008-550.jpg?1620630957'><p>Figure 8</p></div> --- <div class='openpopupgallery' data-imgindex='9' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g009-550.jpg?1620630957'><p>Figure 9</p></div> --- <div class='openpopupgallery' data-imgindex='10' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g010-550.jpg?1620630957'><p>Figure 10</p></div> --- <div class='openpopupgallery' data-imgindex='11' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g011-550.jpg?1620630957'><p>Figure 11</p></div> --- <div class='openpopupgallery' data-imgindex='12' data-target='article-550297-popup'><span class="helper"></span><img src='https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g012-550.jpg?1620630957'><p>Figure 12</p></div></script></div></div><div id="article-550297-popup" class="popupgallery" style="display: inline; line-height: 200%"><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g001-550.jpg?1620630957" title=" <strong>Figure 1</strong><br/> <p>Scheme of possible application of trapping systems for virus capturing.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g002-550.jpg?1620630957" title=" <strong>Figure 2</strong><br/> <p>The amino acid sequence of the recombinant chimeric protein LEL CD81-SA. The blue color indicates the amino acid sequence of LEL (116–202 a.a.) of the CD81 protein, and the red color indicates the amino acid sequence of the SA protein.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g003-550.jpg?1620630957" title=" <strong>Figure 3</strong><br/> <p>SDS PAGE analysis of purified LEL CD81-SA: lane 1—SA solution boiled with addition of SDS, lane 2—SA solution boiled with addition of SDS and 2-mercaptoethanol, lane 3—LEL CD81-SA solution boiled with addition of SDS, lane 4—LEL CD81-SA solution boiled with addition of SDS and 2-mercaptoethanol, lane 5—LEL CD81-SA filtered through the membrane with MWCO of 50,000. Coomassie R-250 Staining.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g004-550.jpg?1620630957" title=" <strong>Figure 4</strong><br/> <p>Amino acid sequence of the E2-GFP fusion protein. E2 core (412–645) amino acid sequence is colored in violet.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g005-550.jpg?1620630957" title=" <strong>Figure 5</strong><br/> <p>PAGE analysis of E2-GFP isolated from inclusion bodies: (<b>a</b>) non-denaturing PAGE with fluorescence detection: lane 1—E2-GFP, lane 2—GFP; (<b>b</b>) SDS PAGE with Coomassie staining: lane 1—GFP; lane 2—protein markers; lanes 3–5—E2-GFP from different fractions.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g006a-550.jpg?1620630957" title=" <strong>Figure 6</strong><br/> <p>Confocal microscopy images of the Sepharose beads modified with LEL CD81-SA and contained affinity bound (<b>a</b>–<b>c</b>) or eluted (<b>d</b>–<b>f</b>) E2-GFP. Images (<b>a</b>,<b>d</b>) registered in the fluorescent mode (excitation at 488 nm); (<b>b</b>,<b>e</b>)—differential interference contrast (DIC); and (<b>c</b>,<b>f</b>) represent the combined images of (<b>b</b>,<b>c</b>), and (<b>d</b>,<b>e</b>), respectively.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g006b-550.jpg?1620630957" title=" <strong>Figure 6 Cont.</strong><br/> <p>Confocal microscopy images of the Sepharose beads modified with LEL CD81-SA and contained affinity bound (<b>a</b>–<b>c</b>) or eluted (<b>d</b>–<b>f</b>) E2-GFP. Images (<b>a</b>,<b>d</b>) registered in the fluorescent mode (excitation at 488 nm); (<b>b</b>,<b>e</b>)—differential interference contrast (DIC); and (<b>c</b>,<b>f</b>) represent the combined images of (<b>b</b>,<b>c</b>), and (<b>d</b>,<b>e</b>), respectively.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g007-550.jpg?1620630957" title=" <strong>Figure 7</strong><br/> <p>Scheme for modification of PEG-<span class="html-italic">b</span>-PLA nanoparticles with protein (LEL CD81-SA for preparation of nanotraps or E2-GFP for VMPs’ obtaining). The same approach was applied for the modification of PLA microparticles with LEL CD81-SA to prepare microtraps.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g008-550.jpg?1620630957" title=" <strong>Figure 8</strong><br/> <p>Results of DLS analysis of the neat PEG-<span class="html-italic">b</span>-PLA nanoparticles (<b>a</b>), PEG-<span class="html-italic">b</span>-PLA modified with the LEL CD81-SA-Cy3 conjugate (nanotraps) (<b>b</b>), and PEG-<span class="html-italic">b</span>-PLA modified with E2-GFP (HC VMPs) (<b>c</b>).</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g009-550.jpg?1620630957" title=" <strong>Figure 9</strong><br/> <p>Confocal microscopy images of the microtraps incubated with E2-GFP (<b>a</b>–<b>c</b>) and GFP as negative control (<b>d</b>–<b>f</b>). Images (<b>a</b>,<b>d</b>) registered in the fluorescent mode (excitation at 488 nm); (<b>b</b>,<b>e</b>)—differential interference contrast (DIC); and (<b>c</b>,<b>f</b>) represent the combined images of (<b>b</b>,<b>c</b>), and (<b>d</b>,<b>e</b>), respectively.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g010-550.jpg?1620630957" title=" <strong>Figure 10</strong><br/> <p>Confocal microscopy images of the microtraps modified with Cy3 and incubated with E2-GFP (<b>a</b>–<b>d</b>) and microparticles modified with SITR-Cy3 and incubated with E2-GFP (<b>e</b>–<b>h</b>). Images (<b>a</b>,<b>e</b>) and (<b>b</b>,<b>f</b>) registered in the fluorescent mode for Cy3 and GFP, respectively; (<b>c</b>,<b>g</b>)—differential interference contrast (DIC); and (<b>d</b>,<b>h</b>) represent the combined images of (<b>a</b>–<b>c</b>) and (<b>e</b>–<b>g</b>), respectively.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g011-550.jpg?1620630957" title=" <strong>Figure 11</strong><br/> <p>Monitoring of interaction between nanotraps and HC VMPs during time (DLS analysis).</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a><a href="https://pub.mdpi-res.com/pharmaceutics/pharmaceutics-13-00672/article_deploy/html/images/pharmaceutics-13-00672-g012-550.jpg?1620630957" title=" <strong>Figure 12</strong><br/> <p>Results of nanoparticle tracking analysis (NTA) of HC VMPs (<b>a</b>), nanotraps (<b>b</b>) and interaction between nanotraps and HC VMPs (<b>c</b>,<b>d</b>) for 5 and 20 min, respectively.</p> <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/1999-4923/13/5/672'>Full article</a></strong> "></a></div> </div> </div> <span class="more" style="display: none;"></span> </div> <div class="row footer"> <div class="listing-select-options"> <div class="columns small-12"> <div class="select generic-item"> <a href="#" class="export-options-show export-element export-expanded"> Show export options <i class="material-icons">expand_more</i> </a> <a href="#" class="export-options-show export-element"> Show export options <i class="material-icons">expand_less</i> </a> 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