{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T02:35:53Z","timestamp":1789266953489,"version":"build-2803163510"},"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014942","name":"Novartis Gene Therapies","doi-asserted-by":"publisher","award":["NIH CRADA # C-073-2023_A1"],"award-info":[{"award-number":["NIH CRADA # C-073-2023_A1"]}],"id":[{"id":"10.13039\/100014942","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Niemann-Pick disease, type C (NPC), is an inherited fatal lysosomal storage disorder caused by a mutation in the\n                    <jats:italic>NPC1<\/jats:italic>\n                    or\n                    <jats:italic>NPC2<\/jats:italic>\n                    genes and characterized by impaired lysosomal cholesterol export. Previous studies have demonstrated that delivery of the\n                    <jats:italic>NPC1<\/jats:italic>\n                    gene to the central nervous system (CNS) via an adeno-associated virus (AAV) can substantially improve lifespan and mitigate signs of disease in\n                    <jats:italic>Npc1<\/jats:italic>\n                    -deficient mouse models of NPC. To determine the optimal parameters for an efficacious AAV-based gene therapy for NPC, we measured the survival and disease phenotypes of mice treated systemically as neonates or at weaning age, along with neonatal mice treated via intracerebroventricular (ICV) delivery, with a construct containing either a ubiquitous truncated EF1\u03b1 promoter or a truncated\n                    <jats:italic>Mecp2<\/jats:italic>\n                    promoter. While all constructs and delivery methods resulted in improvement compared with baseline, mice treated as neonates survived significantly longer and experienced slower disease progression compared with those treated systemically at weaning age. Systemic delivery to neonates was capable of increasing survival and phenotypic improvement comparable to that of ICV delivery, and neonatal systemic and ICV delivery were both similarly capable of near-total Purkinje cell rescue. We also found no difference between a ubiquitous EF1\u03b1-derived promoter and an\n                    <jats:italic>Mecp2<\/jats:italic>\n                    -derived promoter. Ultimately, early treatment with maximal access to the CNS, whether via systemic or direct CNS delivery, is key to the efficacy of gene therapy in treating NPC.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0331275","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:32:48Z","timestamp":1773250368000},"page":"e0331275","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparison of neonatal systemic and intracerebroventricular AAV9 gene therapy delivery demonstrating improved behavioral and phenotypic outcomes in a mouse model of Niemann-Pick disease, type C1"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5129-9044","authenticated-orcid":true,"given":"Benjamin E.","family":"Epstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle M.","family":"Soden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arturo A.","family":"Incao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avani","family":"Mylvara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Flynn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih","family":"Ozsolak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8281-5120","authenticated-orcid":true,"given":"William J.","family":"Pavan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"pone.0331275.ref001","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1016\/B978-0-444-59565-2.00041-1","article-title":"Niemann-Pick diseases","volume":"113","author":"MT Vanier","year":"2013","journal-title":"Handb Clin Neurol"},{"issue":"7","key":"pone.0331275.ref002","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.cell.2009.03.049","article-title":"Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol","volume":"137","author":"HJ Kwon","year":"2009","journal-title":"Cell"},{"key":"pone.0331275.ref003","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick disease type C","volume":"5","author":"MT Vanier","year":"2010","journal-title":"Orphanet J Rare Dis"},{"key":"pone.0331275.ref004","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bbalip.2004.08.007","article-title":"Structure and function of the NPC2 protein","volume":"1685","author":"MT Vanier","year":"2004","journal-title":"Biochim Biophys Acta"},{"issue":"40","key":"pone.0331275.ref005","doi-asserted-by":"crossref","first-page":"15287","DOI":"10.1073\/pnas.0807328105","article-title":"NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes","volume":"105","author":"RE Infante","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0331275.ref006","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/978-3-030-14265-0_8","article-title":"Insights into the Molecular Mechanisms of Cholesterol Binding to the NPC1 and NPC2 Proteins","volume":"1135","author":"SM Cologna","year":"2019","journal-title":"Adv Exp Med Biol"},{"issue":"3","key":"pone.0331275.ref007","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.ymgme.2012.03.012","article-title":"Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update","volume":"106","author":"MC Patterson","year":"2012","journal-title":"Mol Genet Metab"},{"key":"pone.0331275.ref008","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1186\/s12883-015-0511-1","article-title":"Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: A 5-year update from the UK clinical database","volume":"15","author":"J Imrie","year":"2015","journal-title":"BMC Neurol"},{"issue":"1","key":"pone.0331275.ref009","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1038\/s41598-022-06112-y","article-title":"Correlation of age of onset and clinical severity in Niemann-Pick disease type C1 with lysosomal abnormalities and gene expression","volume":"12","author":"LL Baxter","year":"2022","journal-title":"Sci Rep"},{"key":"pone.0331275.ref010","unstructured":"Miglustat in Niemann-Pick Type C Disease NCT00517153. https:\/\/www.clinicaltrials.gov\/study\/NCT00517153. 2002. Accessed 2025 August 6."},{"key":"pone.0331275.ref011","unstructured":"Application of Miglustat in Patients With Niemann-Pick Type C. https:\/\/www.clinicaltrials.gov\/study\/NCT01760564. 2008. Accessed 2025 August 6."},{"key":"pone.0331275.ref012","unstructured":"12. Adrabetadex to treat Niemann-Pick type C1 (NPC1) disease NCT02534844. https:\/\/www.clinicaltrials.gov\/study\/NCT04958642. 2015. Accessed 2025 August 6."},{"key":"pone.0331275.ref013","unstructured":"Niemann-Pick Type C Treatment With Adrabetadex for Symptoms of Brain and Nervous System. https:\/\/www.clinicaltrials.gov\/study\/NCT03643562. 2018. Accessed 2025 August 6."},{"key":"pone.0331275.ref014","unstructured":"Phase 3 study to evaluate intravenous Trappsol(R) Cyclo(TM) in pediatric and adult patients with Niemann-Pick disease type C1. https:\/\/www.clinicaltrials.gov\/study\/NCT04860960. 2021. Accessed 2025 August 6."},{"key":"pone.0331275.ref015","unstructured":"Arimoclomol Prospective Study in Participants Diagnosed With Niemann-Pick Disease Type C. https:\/\/www.clinicaltrials.gov\/study\/NCT02612129. 2016. Accessed 2025 August 6."},{"key":"pone.0331275.ref016","unstructured":"A pivotal study of N-acetyl-L-leucine on Niemann-Pick disease type C. https:\/\/www.clinicaltrials.gov\/study\/NCT05163288. 2025. Accessed 2025 August 6."},{"issue":"1","key":"pone.0331275.ref017","article-title":"FDA approval of Miplyffa and Aqneursa: A dual breakthrough for the treatment of Neimann-Pick disease type C","volume":"11","author":"M Jan","year":"2025","journal-title":"Alzheimers Dement (N Y)"},{"key":"pone.0331275.ref018","unstructured":"FDA Approves First Treatment for Niemann-Pick Disease, Type C. Silver Spring, MD: U.S. Food & Drug Administration. 2024. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-treatment-niemann-pick-disease-type-c"},{"key":"pone.0331275.ref019","unstructured":"FDA Approves New Drug to Treat Niemann-Pick Disease, Type C. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-new-drug-treat-niemann-pick-disease-type-c. 2024. Accessed 2025 June 11."},{"issue":"1","key":"pone.0331275.ref020","first-page":"52","article-title":"Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1","volume":"26","author":"RJ Chandler","year":"2017","journal-title":"Hum Mol Genet"},{"issue":"10","key":"pone.0331275.ref021","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.202101040","article-title":"Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice","volume":"4","author":"CD Davidson","year":"2021","journal-title":"Life Sci Alliance"},{"issue":"3","key":"pone.0331275.ref022","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1194\/jlr.M071274","article-title":"AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse NPC disease","volume":"58","author":"C Xie","year":"2017","journal-title":"J Lipid Res"},{"issue":"17","key":"pone.0331275.ref023","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1093\/hmg\/ddy212","article-title":"AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease","volume":"27","author":"MP Hughes","year":"2018","journal-title":"Hum Mol Genet"},{"key":"pone.0331275.ref024","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1089\/hum.2020.175","article-title":"Gene therapy in a mouse model of niemann-pick disease Type C1","volume":"32","author":"Y Kurokawa","year":"2021","journal-title":"Hum Gene Ther"},{"issue":"12","key":"pone.0331275.ref025","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.3390\/cells12121619","article-title":"A novel small NPC1 Promoter Enhances AAV-Mediated Gene Therapy in Mouse Models of Niemann-Pick Type C1 Disease","volume":"12","author":"MP Hughes","year":"2023","journal-title":"Cells"},{"issue":"4","key":"pone.0331275.ref026","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/gt.2009.157","article-title":"High AAV vector purity results in serotype- and tissue-independent enhancement of transduction efficiency","volume":"17","author":"E Ayuso","year":"2010","journal-title":"Gene Ther"},{"issue":"1","key":"pone.0331275.ref027","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1089\/hgtb.2011.034","article-title":"Universal real-time PCR for the detection and quantification of adeno-associated virus serotype 2-derived inverted terminal repeat sequences","volume":"23","author":"C Aurnhammer","year":"2012","journal-title":"Hum Gene Ther Methods"},{"issue":"93","key":"pone.0331275.ref028","doi-asserted-by":"crossref","DOI":"10.3791\/52037-v","article-title":"Intravenous injections in neonatal mice","author":"SE Gombash Lampe","year":"2014","journal-title":"J Vis Exp"},{"issue":"91","key":"pone.0331275.ref029","first-page":"51863","article-title":"Intracerebroventricular viral injection of the neonatal mouse brain for persistent and widespread neuronal transduction","author":"J-Y Kim","year":"2014","journal-title":"J Vis Exp"},{"issue":"4","key":"pone.0331275.ref030","doi-asserted-by":"crossref","DOI":"10.1242\/bio.059052","article-title":"Phenotype assessment for neurodegenerative murine models with ataxia and application to Niemann-Pick disease, type C1","volume":"11","author":"J Yerger","year":"2022","journal-title":"Biol Open"},{"issue":"7","key":"pone.0331275.ref031","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.micinf.2010.03.009","article-title":"Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology","volume":"12","author":"M Gulinello","year":"2010","journal-title":"Microbes Infect"},{"key":"pone.0331275.ref032","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.nbd.2016.09.006","article-title":"Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington\u2019s disease","volume":"96","author":"EE Arteaga-Bracho","year":"2016","journal-title":"Neurobiol Dis"},{"key":"pone.0331275.ref033","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.omtm.2020.10.011","article-title":"CNS Transduction Benefits of AAV-PHP.eB over AAV9 Are Dependent on Administration Route and Mouse Strain","volume":"19","author":"SN Mathiesen","year":"2020","journal-title":"Mol Ther Methods Clin Dev"},{"issue":"6","key":"pone.0331275.ref034","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nbt0617-491","article-title":"After Glybera\u2019s withdrawal, what\u2019s next for gene therapy?","volume":"35","author":"M Senior","year":"2017","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pone.0331275.ref035","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s40259-017-0234-5","article-title":"Adeno-Associated Virus (AAV) as a vector for gene therapy","volume":"31","author":"MF Naso","year":"2017","journal-title":"BioDrugs"},{"issue":"5","key":"pone.0331275.ref036","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-associated virus vector as a platform for gene therapy delivery","volume":"18","author":"D Wang","year":"2019","journal-title":"Nat Rev Drug Discov"},{"issue":"7","key":"pone.0331275.ref037","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1016\/j.xphs.2021.03.024","article-title":"Manufacturing challenges and rational formulation development for AAV Viral Vectors","volume":"110","author":"A Srivastava","year":"2021","journal-title":"J Pharm Sci"},{"key":"pone.0331275.ref038","doi-asserted-by":"crossref","first-page":"747726","DOI":"10.3389\/fnins.2021.747726","article-title":"A multifaceted approach to optimizing AAV delivery to the brain for the treatment of neurodegenerative diseases","volume":"15","author":"JM Fischell","year":"2021","journal-title":"Front Neurosci"},{"issue":"2","key":"pone.0331275.ref039","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/mt.2014.181","article-title":"The expression pattern of systemically injected AAV9 in the developing mouse retina is determined by age","volume":"23","author":"LC Byrne","year":"2015","journal-title":"Mol Ther"},{"issue":"2","key":"pone.0331275.ref040","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nbt.3440","article-title":"Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain","volume":"34","author":"BE Deverman","year":"2016","journal-title":"Nat Biotechnol"},{"issue":"1","key":"pone.0331275.ref041","doi-asserted-by":"crossref","DOI":"10.1016\/j.medj.2022.11.002","article-title":"Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression in the macaque CNS","volume":"4","author":"AC Stanton","year":"2023","journal-title":"Med"},{"issue":"1","key":"pone.0331275.ref042","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41593-021-00969-4","article-title":"AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset","volume":"25","author":"D Goertsen","year":"2022","journal-title":"Nat Neurosci"},{"issue":"10","key":"pone.0331275.ref043","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1038\/s41565-023-01419-x","article-title":"Adeno-associated viral vectors for functional intravenous gene transfer throughout the non-human primate brain","volume":"18","author":"MR Chuapoco","year":"2023","journal-title":"Nat Nanotechnol"},{"key":"pone.0331275.ref044","article-title":"Highly conserved brain vascular receptor ALPL mediates transport of engineered viral vectors across the blood-brain barrier","author":"TC Moyer","year":"2024","journal-title":"bioRxiv"},{"issue":"12","key":"pone.0331275.ref045","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1016\/j.ymthe.2023.10.005","article-title":"Redirecting AAV vectors to extrahepatic tissues","volume":"31","author":"A Asokan","year":"2023","journal-title":"Molecular Therapy"},{"issue":"7488","key":"pone.0331275.ref046","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/nature12875","article-title":"Selection and evaluation of clinically relevant AAV variants in a xenograft liver model","volume":"506","author":"L Lisowski","year":"2014","journal-title":"Nature"},{"issue":"23","key":"pone.0331275.ref047","doi-asserted-by":"crossref","first-page":"3709","DOI":"10.1093\/hmg\/ddi402","article-title":"A segment of the Mecp2 promoter is sufficient to drive expression in neurons","volume":"14","author":"M Adachi","year":"2005","journal-title":"Hum Mol Genet"},{"issue":"4","key":"pone.0331275.ref048","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/hep.20868","article-title":"Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease","volume":"42","author":"EP Beltroy","year":"2005","journal-title":"Hepatology"},{"issue":"2","key":"pone.0331275.ref049","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/jcb.21200","article-title":"Characterization of liver disease and lipid metabolism in the Niemann-Pick C1 mouse","volume":"101","author":"WS Garver","year":"2007","journal-title":"J Cell Biochem"},{"issue":"3","key":"pone.0331275.ref050","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2019.e01293","article-title":"Hepatic and neuronal phenotype of NPC1-\/- mice","volume":"5","author":"E Santiago-Mujica","year":"2019","journal-title":"Heliyon"},{"issue":"14","key":"pone.0331275.ref051","doi-asserted-by":"crossref","first-page":"5059","DOI":"10.3390\/ijms21145059","article-title":"Clinical and molecular features of early infantile niemann pick type C disease","volume":"21","author":"B Seker Yilmaz","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0331275.ref052","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/cne.10522","article-title":"Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease","volume":"456","author":"JR Sarna","year":"2003","journal-title":"J Comp Neurol"},{"issue":"1","key":"pone.0331275.ref053","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nbt.1515","article-title":"Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes","volume":"27","author":"KD Foust","year":"2009","journal-title":"Nat Biotechnol"},{"issue":"6","key":"pone.0331275.ref054","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0067680","article-title":"Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain","volume":"8","author":"P Chakrabarty","year":"2013","journal-title":"PLoS One"},{"issue":"3","key":"pone.0331275.ref055","article-title":"Gene Therapy for Spinal Muscular Atrophy (SMA): A Review of Current Challenges and Safety Considerations for Onasemnogene Abeparvovec (Zolgensma)","volume":"15","author":"T Ogbonmide","year":"2023","journal-title":"Cureus"},{"issue":"14","key":"pone.0331275.ref056","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1007\/s40265-023-01929-x","article-title":"Delandistrogene moxeparvovec: First approval","volume":"83","author":"SM Hoy","year":"2023","journal-title":"Drugs"},{"key":"pone.0331275.ref057","article-title":"ASPIRO Gene Therapy Trial in X-Linked Myotubular Myopathy (XLMTM): Update on Preliminary Efficacy and Safety Findings","author":"A Blaschek","year":"2021","journal-title":"Neuropediatrics"},{"key":"pone.0331275.ref058","doi-asserted-by":"crossref","first-page":"975803","DOI":"10.3389\/fimmu.2022.975803","article-title":"Immunogenicity and toxicity of AAV gene therapy","volume":"13","author":"HCJ Ertl","year":"2022","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0331275.ref059","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41434-023-00405-1","article-title":"Adeno-associated virus vectors and neurotoxicity-lessons from preclinical and human studies","volume":"32","author":"D Stone","year":"2025","journal-title":"Gene Ther"},{"issue":"3","key":"pone.0331275.ref060","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/mt.2014.210","article-title":"Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: A dose-response study in mice and nonhuman primates","volume":"23","author":"K Meyer","year":"2015","journal-title":"Mol Ther"},{"key":"pone.0331275.ref061","unstructured":"Newborn Screening - NNPDF. Fort Atkinson, WI: National Niemann-Pick Disease Foundation. 2023. https:\/\/nnpdf.org\/newborn-screening\/"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331275","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:33:05Z","timestamp":1773250385000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0331275"}},"subtitle":[],"editor":[{"given":"Kent","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,11]]},"references-count":61,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0331275","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,11]]}}}