{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:26:53Z","timestamp":1765949213607,"version":"3.48.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010724","name":"Health Systems Research Institute","doi-asserted-by":"publisher","award":["66-082"],"award-info":[{"award-number":["66-082"]}],"id":[{"id":"10.13039\/501100010724","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand","doi-asserted-by":"publisher","award":["N34A640419"],"award-info":[{"award-number":["N34A640419"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thailand Science Research and Innovation Fund"},{"name":"Chulalongkorn University Fundamental Fund","award":["HEA_FF_68_275_3000_041"],"award-info":[{"award-number":["HEA_FF_68_275_3000_041"]}]},{"name":"90th Anniversary of Chulalongkorn University Scholarship","award":["GCUGR1125671137M"],"award-info":[{"award-number":["GCUGR1125671137M"]}]},{"name":"Quick Win Research Project"},{"name":"Ratchadapiseksompotch Fund"},{"DOI":"10.13039\/501100002873","name":"Chulalongkorn University","doi-asserted-by":"publisher","award":["767006"],"award-info":[{"award-number":["767006"]}],"id":[{"id":"10.13039\/501100002873","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Development and Promotion of Science and Technology Talents Project Fund"},{"name":"Ratchadapiseksompotch Fund"},{"DOI":"10.13039\/100019603","name":"Faculty of Medicine","doi-asserted-by":"publisher","award":["RA60\/050"],"award-info":[{"award-number":["RA60\/050"]}],"id":[{"id":"10.13039\/100019603","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Long QT syndrome type 3 (LQTS3), caused by gain-of-function mutations in the SCN5A gene, encompasses a spectrum of clinical presentations, ranging from asymptomatic carriers to severe arrhythmic phenotypes, representing the \u201csilent killer\u201d and \u201cbrutal killer\u201d dichotomy. The p.I239V mutation is associated with mild symptoms and minimal arrhythmic events, whereas the newly identified p.M1487K mutation is linked to life-threatening arrhythmic storms. This study aimed to explore the electrophysiological properties of these mutations and their responses to sodium channel blockers to advance precision medicine in LQTS3 management. Genetic analysis identified rare SCN5A mutations in two LQTS3 patients. Site-directed mutagenesis was used to construct mutant SCN5A plasmids, which were expressed in HEK293 cells. Electrophysiological properties were analyzed using patch-clamp techniques, and pharmacological responses to flecainide, mexiletine, and ranolazine were evaluated. Electrophysiological recordings correlated with clinical presentations. Both mutations showed increased window INa and faster recovery from inactivation. The p.I239V mutation lacked sustained INa, while p.M1487K exhibited significantly increased sustained INa (2.3 \u00b1 2.15%, P &amp;lt; 0.0001). Mexiletine and ranolazine effectively reduced sustained INa by 76.15 \u00b1 5.83, and 77.63 \u00b1 9.41%, respectively, outperforming flecainide, aligning with clinical responses. This study highlights the role of sustained INa in LQTS3 severity and underscores the importance of mutation-specific treatments. By tailoring treatments to the electrophysiological characteristics of each mutation, precision medicine offers a promising approach to improving patient outcomes in LQTS3.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgaf379","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T14:28:27Z","timestamp":1765031307000},"source":"Crossref","is-referenced-by-count":0,"title":["Mutation-specific roles of sustained sodium current (INa) in guiding precision medicine for long QT syndrome type 3"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-034X","authenticated-orcid":false,"given":"Vichaya","family":"Auvichayapat","sequence":"first","affiliation":[{"name":"Science Program in Physiology, Graduate School, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Department of Physiology, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6601-5916","authenticated-orcid":false,"given":"Sarin","family":"Lekchuensakul","sequence":"additional","affiliation":[{"name":"Center of Excellence in Arrhythmia Research Chulalongkorn University, Department of Medicine, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Division of Cardiology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2676-0767","authenticated-orcid":false,"given":"Pharawee","family":"Wandee","sequence":"additional","affiliation":[{"name":"Center of Excellence in Arrhythmia Research Chulalongkorn University, Department of Medicine, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Mauleekoonphairoj","sequence":"additional","affiliation":[{"name":"Center of Excellence in Arrhythmia Research Chulalongkorn University, Department of Medicine, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2973-6816","authenticated-orcid":false,"given":"Sirikorn","family":"Vongseenin","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6820-4542","authenticated-orcid":false,"given":"Praewphan","family":"Ingrungruanglert","sequence":"additional","affiliation":[{"name":"Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Excellence Center for Stem Cell and Cell Therapy, King Chulalongkorn Memorial Hospital, Thai Red Cross Society , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1954-6567","authenticated-orcid":false,"given":"Nipan","family":"Israsena","sequence":"additional","affiliation":[{"name":"Center of Excellence for Stem Cell and Cell Therapy, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Excellence Center for Stem Cell and Cell Therapy, King Chulalongkorn Memorial Hospital, Thai Red Cross Society , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9424-3311","authenticated-orcid":false,"given":"Phichaya","family":"Suthivanich","sequence":"additional","affiliation":[{"name":"Science Program in Physiology, Graduate School, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Department of Physiology, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7203-5226","authenticated-orcid":false,"given":"Damrongsak","family":"Jinarat","sequence":"additional","affiliation":[{"name":"Center of Excellence in Arrhythmia Research Chulalongkorn University, Department of Medicine, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University , 110 Inthawarorot Rd., Sri Phum, Muang, Chiang Mai 50200 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5738-1738","authenticated-orcid":false,"given":"Apichai","family":"Khongphatthanayothin","sequence":"additional","affiliation":[{"name":"Center of Excellence in Arrhythmia Research Chulalongkorn University, Department of Medicine, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Division of Cardiology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Department of Cardiology, Bangkok Hospital , 2 Soi Soonvijai 7, New Petchburi Road, Huaykwang, Bangkok 10310 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-3568","authenticated-orcid":false,"given":"Saknan","family":"Bongsebandhu-phubhakdi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chulalongkorn University , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]},{"name":"Chula Neuroscience Center, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society , 1873 Rama IV Rd., Pathum Wan, Bangkok 10330 ,","place":["Thailand"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"2025121700212753600_pgaf379-B1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ccep.2023.04.007","article-title":"Personalized care in long QT syndrome: better management, more sports, and fewer devices","volume":"15","author":"MacIntyre","year":"2023","journal-title":"Card Electrophysiol Clin"},{"key":"2025121700212753600_pgaf379-B2","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/B978-0-12-378630-2.00133-X","volume-title":"Encyclopedia of biological chemistry","author":"Catterall","year":"2013","edition":"2nd ed"},{"key":"2025121700212753600_pgaf379-B3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00424-009-0761-0","article-title":"Cardiac sodium channelopathies","volume":"460","author":"Amin","year":"2010","journal-title":"Pflugers Arch"},{"key":"2025121700212753600_pgaf379-B4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jacep.2018.03.006","article-title":"Clinical spectrum of SCN5A mutations: long QT syndrome, Brugada syndrome, and cardiomyopathy","volume":"4","author":"Wilde","year":"2018","journal-title":"JACC Clin Electrophysiol"},{"key":"2025121700212753600_pgaf379-B5","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ipej.2017.10.011","article-title":"The congenital long QT syndrome type 3: an update","volume":"18","author":"P\u00e9rez-Riera","year":"2018","journal-title":"Indian Pacing Electrophysiol J"},{"key":"2025121700212753600_pgaf379-B6","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1080\/17431380410032689","article-title":"Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland","volume":"36","author":"Fodstad","year":"2004","journal-title":"Ann Med"},{"key":"2025121700212753600_pgaf379-B7","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1093\/europace\/euq184","article-title":"Abnormal repolarization dynamics revealed in exercise test in long QT syndrome mutation carriers with normal resting QT interval","volume":"12","author":"Hekkala","year":"2010","journal-title":"Europace"},{"key":"2025121700212753600_pgaf379-B8","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1136\/hrt.2009.190868","article-title":"A history of stressful life events, prolonged mental stress and arrhythmic events in inherited long QT syndrome","volume":"96","author":"Hintsa","year":"2010","journal-title":"Heart"},{"key":"2025121700212753600_pgaf379-B9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.ipej.2018.07.007","article-title":"Genotype and clinical characteristics of congenital long QT syndrome in Thailand","volume":"18","author":"Saprungruang","year":"2018","journal-title":"Indian Pacing Electrophysiol J"},{"key":"2025121700212753600_pgaf379-B10","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.3390\/cells11233714","article-title":"When the gates swing open only: arrhythmia mutations that target the fast inactivation gate of Na(v)1.5","volume":"11","author":"Gamal El-Din","year":"2022","journal-title":"Cells"},{"key":"2025121700212753600_pgaf379-B11","doi-asserted-by":"crossref","first-page":"10910","DOI":"10.1073\/pnas.89.22.10910","article-title":"A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation","volume":"89","author":"West","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025121700212753600_pgaf379-B12","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.ijcard.2009.04.023","article-title":"A novel SCN5A mutation associated with the linker between III and IV domains of Nav1.5 in a neonate with fatal long QT syndrome","volume":"145","author":"Yamamura","year":"2010","journal-title":"Int J Cardiol"},{"key":"2025121700212753600_pgaf379-B13","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1161\/CIRCULATIONAHA.106.646513","article-title":"Cardiac sodium channel dysfunction in sudden infant death syndrome","volume":"115","author":"Wang","year":"2007","journal-title":"Circulation"},{"key":"2025121700212753600_pgaf379-B14","doi-asserted-by":"crossref","first-page":"5123","DOI":"10.1113\/jphysiol.2012.235374","article-title":"The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity","volume":"590","author":"Song","year":"2012","journal-title":"J Physiol"},{"key":"2025121700212753600_pgaf379-B15","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1007\/s00424-008-0477-6","article-title":"Oxidation of multiple methionine residues impairs rapid sodium channel inactivation","volume":"456","author":"Kassmann","year":"2008","journal-title":"Pfl\u00fcgers Archiv"},{"key":"2025121700212753600_pgaf379-B16","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.pbiomolbio.2008.10.005","article-title":"SCN5A channelopathies\u2013an update on mutations and mechanisms","volume":"98","author":"Zimmer","year":"2008","journal-title":"Prog Biophys Mol Biol"},{"key":"2025121700212753600_pgaf379-B17","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.yjmcc.2011.12.003","article-title":"Pathophysiology of the cardiac late Na current and its potential as a drug target","volume":"52","author":"Moreno","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"2025121700212753600_pgaf379-B18","doi-asserted-by":"crossref","first-page":"580481","DOI":"10.3389\/fphar.2020.580481","article-title":"Ranolazine as an alternative therapy to flecainide for SCN5A V411M long QT syndrome type 3 patients","volume":"11","author":"Cano","year":"2020","journal-title":"Front Pharmacol"},{"key":"2025121700212753600_pgaf379-B19","doi-asserted-by":"crossref","first-page":"e004370","DOI":"10.1161\/CIRCEP.116.004370","article-title":"Ranolazine for congenital long-QT syndrome type III: experimental and long-term clinical data","volume":"9","author":"Chorin","year":"2016","journal-title":"Circ Arrhythm Electrophysiol"},{"issue":"10","key":"2025121700212753600_pgaf379-B20","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1093\/molehr\/gav038","article-title":"Sodium leak channel, non-selective contributes to the leak current in human myometrial smooth muscle cells from pregnant women","volume":"21","author":"Reinl","year":"2015","journal-title":"Mol Hum Reprod"},{"key":"2025121700212753600_pgaf379-B21","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1161\/hh0701.089668","article-title":"Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel","volume":"88","author":"Abriel","year":"2001","journal-title":"Circ Res"},{"key":"2025121700212753600_pgaf379-B22","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.cardiores.2005.01.017","article-title":"Substitution of a conserved alanine in the domain IIIS4-S5 linker of the cardiac sodium channel causes long QT syndrome","volume":"67","author":"Smits","year":"2005","journal-title":"Cardiovasc Res"},{"key":"2025121700212753600_pgaf379-B23","doi-asserted-by":"crossref","first-page":"e1258","DOI":"10.1371\/journal.pone.0001258","article-title":"A novel and lethal de novo LQT-3 mutation in a newborn with distinct molecular pharmacology and therapeutic response","volume":"2","author":"Bankston","year":"2007","journal-title":"PLoS One"},{"key":"2025121700212753600_pgaf379-B24","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1161\/CIRCRESAHA.110.218891","article-title":"Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3","volume":"106","author":"Ruan","year":"2010","journal-title":"Circ Res"},{"key":"2025121700212753600_pgaf379-B25","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1161\/01.CIR.0000014448.19052.4C","article-title":"Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes","volume":"105","author":"Yang","year":"2002","journal-title":"Circulation"},{"key":"2025121700212753600_pgaf379-B26","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1161\/CIRCULATIONAHA.107.736330","article-title":"Cardiac sodium channel gene variants and sudden cardiac death in women","volume":"117","author":"Albert","year":"2008","journal-title":"Circulation"},{"key":"2025121700212753600_pgaf379-B27","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/19336950.2019.1632670","article-title":"SCN5A mutation G615E results in Na(V)1.5 voltage-gated sodium channels with normal voltage-dependent function yet loss of mechanosensitivity","volume":"13","author":"Strege","year":"2019","journal-title":"Channels (Austin)"},{"key":"2025121700212753600_pgaf379-B28","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1113\/jphysiol.2013.256461","article-title":"Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects","volume":"591","author":"Remme","year":"2013","journal-title":"J Physiol"},{"key":"2025121700212753600_pgaf379-B29","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.gene.2015.08.062","article-title":"The cardiac sodium channel gene SCN5A and its gene product NaV1.5: role in physiology and pathophysiology","volume":"573","author":"Veerman","year":"2015","journal-title":"Gene"},{"key":"2025121700212753600_pgaf379-B30","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/B978-1-4377-0285-9.00082-X","volume-title":"Electrophysiological disorders of the heart","author":"Dobrev","year":"2012","edition":"2nd ed"},{"key":"2025121700212753600_pgaf379-B31","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.3389\/fphar.2020.01182","article-title":"Gating properties of mutant sodium channels and responses to sodium current inhibitors predict mexiletine-sensitive mutations of long QT syndrome 3","volume":"11","author":"Li","year":"2020","journal-title":"Front Pharmacol"},{"key":"2025121700212753600_pgaf379-B32","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.yjmcc.2022.01.009","article-title":"Increased atrial effectiveness of flecainide conferred by altered biophysical properties of sodium channels","volume":"166","author":"O' Brien","year":"2022","journal-title":"J Mol Cell Cardiol"},{"key":"2025121700212753600_pgaf379-B33","first-page":"1353","article-title":"Ranolazine (roche bioscience)","volume":"2","author":"Jones","year":"1999","journal-title":"IDrugs"},{"key":"2025121700212753600_pgaf379-B34","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1136\/hrt.2005.078782","article-title":"Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium\u2013calcium overload","volume":"92","author":"Noble","year":"2006","journal-title":"Heart"},{"key":"2025121700212753600_pgaf379-B35","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1111\/j.1540-8167.2008.01246.x","article-title":"Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome","volume":"19","author":"Moss","year":"2008","journal-title":"J Cardiovasc Electrophysiol"},{"key":"2025121700212753600_pgaf379-B36","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/376683a0","article-title":"Molecular mechanism for an inherited cardiac arrhythmia","volume":"376","author":"Bennett","year":"1995","journal-title":"Nature"},{"key":"2025121700212753600_pgaf379-B37","doi-asserted-by":"crossref","first-page":"11474","DOI":"10.1002\/anie.202102196","article-title":"Structural basis for pore blockade of the human cardiac sodium channel Nav1.5 by the antiarrhythmic drug quinidine","volume":"60","author":"Li","year":"2021","journal-title":"Angew Chem Int Ed Engl"}],"container-title":["PNAS Nexus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/pnasnexus\/advance-article-pdf\/doi\/10.1093\/pnasnexus\/pgaf379\/65788947\/pgaf379.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pnasnexus\/article-pdf\/4\/12\/pgaf379\/65788947\/pgaf379.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pnasnexus\/article-pdf\/4\/12\/pgaf379\/65788947\/pgaf379.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T05:21:52Z","timestamp":1765948912000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/pnasnexus\/article\/doi\/10.1093\/pnasnexus\/pgaf379\/8373347"}},"subtitle":[],"editor":[{"given":"Marenda","family":"Wilson-Pham","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":37,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1093\/pnasnexus\/pgaf379","relation":{},"ISSN":["2752-6542"],"issn-type":[{"type":"electronic","value":"2752-6542"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,12,1]]},"article-number":"pgaf379"}}