{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T21:49:07Z","timestamp":1783633747454,"version":"3.55.0"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006087","name":"Direcci\u00f3n General de Asuntos del Personal Acad\u00e9mico, Universidad Nacional Aut\u00f3noma de M\u00e9xico","doi-asserted-by":"publisher","award":["IN202424"],"award-info":[{"award-number":["IN202424"]}],"id":[{"id":"10.13039\/501100006087","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003141","name":"Consejo Nacional de Ciencia y Tecnolog\u00eda","doi-asserted-by":"publisher","award":["Fellowship 788879"],"award-info":[{"award-number":["Fellowship 788879"]}],"id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cancer cells drive the increase in vascular permeability mediating tumor cell extravasation and metastatic seeding. VIAN-c4551, an antiangiogenic peptide analog of vasoinhibin, inhibits the growth and vascularization of melanoma tumors in mice. Because VIAN-c4551 is a potent inhibitor of vascular permeability, we evaluated whether its antitumor action extended to a reduction in metastasis generation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Circulating levels of vascular endothelial growth factor (VEGF), lung vascular permeability, melanoma cell extravasation, and melanoma pulmonary nodules were assessed in C57BL\/6J mice intravenously inoculated with murine melanoma B16-F10 cells after acute treatment with VIAN-c4551. VEGF levels, transendothelial electrical resistance, and transendothelial migration in cocultures of B16-F10 cells and endothelial cell monolayers supported the findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>B16-F10 cells increased circulating VEGF levels and elevated lung vascular permeability 2 hours after inoculation. VIAN-c4551 prevented enhanced vascular permeability and reduced melanoma cell extravasation after 2 hours and the number and size of macroscopic and microscopic melanoma tumors in lungs after 17 days. In vitro, VIAN-c4551 suppressed the B16-F10 cell-induced and VEGF mediated increase in endothelial cell monolayer permeability and the transendothelial migration of B16-F10 cells. No detrimental effect of VIAN-c4551 was observed on hematological, biochemical, and histological parameters after its intravenous administration in mice for 14 days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support the inhibition of distant vascular permeability for the prevention of tumor metastasis and unveil the anti-vascular permeability factor VIAN-c4551 as a potential and safe therapeutic drug able to prevent metastasis generation by lowering the extravasation of melanoma cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0316983","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T14:13:32Z","timestamp":1748441612000},"page":"e0316983","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["The antiangiogenic peptide VIAN-c4551 inhibits lung melanoma metastasis in mice by reducing pulmonary vascular permeability"],"prefix":"10.1371","volume":"20","author":[{"given":"Alma Lorena","family":"Perez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Bahena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Aramburo-Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elva","family":"Adan-Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Granados-Carrasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Bertsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1989-8645","authenticated-orcid":true,"given":"Jakob","family":"Triebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Martinez de la Escalera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Robles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Clapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"issue":"3","key":"pone.0316983.ref001","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41571-018-0134-8","article-title":"A framework for the development of effective anti-metastatic agents","volume":"16","author":"RL Anderson","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"issue":"8","key":"pone.0316983.ref002","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1111\/cas.14942","article-title":"Regulation of vascular permeability in cancer metastasis","volume":"112","author":"T Tomita","year":"2021","journal-title":"Cancer Sci"},{"key":"pone.0316983.ref003","doi-asserted-by":"crossref","first-page":"11017","DOI":"10.1038\/ncomms11017","article-title":"VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread","volume":"7","author":"X Li","year":"2016","journal-title":"Nat Commun"},{"issue":"1","key":"pone.0316983.ref004","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s10456-021-09800-x","article-title":"The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide","volume":"25","author":"JP Robles","year":"2022","journal-title":"Angiogenesis"},{"key":"pone.0316983.ref005","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/978-3-319-12114-7_4","article-title":"Regulation of blood vessels by prolactin and vasoinhibins","volume":"846","author":"C Clapp","year":"2015","journal-title":"Adv Exp Med Biol"},{"issue":"8","key":"pone.0316983.ref006","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1167\/iovs.05-0173","article-title":"Prolactins are natural inhibitors of angiogenesis in the retina","volume":"46","author":"J Aranda","year":"2005","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"9","key":"pone.0316983.ref007","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1242\/jcs.02887","article-title":"Matrix metalloproteases from chondrocytes generate an antiangiogenic 16\u2009kDa prolactin","volume":"119","author":"Y Macotela","year":"2006","journal-title":"J Cell Sci"},{"issue":"9","key":"pone.0316983.ref008","doi-asserted-by":"crossref","first-page":"994898","DOI":"10.3389\/fendo.2022.994898","article-title":"Prolactin and vasoinhibin are endogenous players in diabetic retinopathy revisited","volume":"13","author":"J Triebel","year":"2022","journal-title":"Front Endocrinol"},{"key":"pone.0316983.ref009","doi-asserted-by":"crossref","first-page":"905756","DOI":"10.3389\/fendo.2022.905756","article-title":"Dual Roles of Prolactin and Vasoinhibin in Inflammatory Arthritis","volume":"13","author":"C Clapp","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"3","key":"pone.0316983.ref010","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.cell.2006.12.036","article-title":"A cathepsin D-cleaved 16\u2009kDa form of prolactin mediates postpartum cardiomyopathy","volume":"128","author":"D Hilfiker-Kleiner","year":"2007","journal-title":"Cell"},{"issue":"10","key":"pone.0316983.ref011","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/labinvest.3700662","article-title":"Elevated vasoinhibins may contribute to endothelial cell dysfunction and low birth weight in preeclampsia","volume":"87","author":"C Gonz\u00e1lez","year":"2007","journal-title":"Lab Invest"},{"issue":"4","key":"pone.0316983.ref012","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1152\/physrev.00024.2009","article-title":"Peptide hormone regulation of angiogenesis","volume":"89","author":"C Clapp","year":"2009","journal-title":"Physiol Rev"},{"issue":"2","key":"pone.0316983.ref013","first-page":"386","article-title":"Antitumor activity of the 16-kDa prolactin fragment in prostate cancer","volume":"63","author":"J Kim","year":"2003","journal-title":"Cancer Res"},{"issue":"19","key":"pone.0316983.ref014","first-page":"7356","article-title":"Expression of the antiangiogenic factor 16K hPRL in human HCT116 colon cancer cells inhibits tumor growth in Rag1(-\/-) mice","volume":"61","author":"F Bentzien","year":"2001","journal-title":"Cancer Res"},{"issue":"2","key":"pone.0316983.ref015","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12672-010-0012-z","article-title":"16\u2009kDa prolactin reduces angiogenesis, but not growth of human breast cancer tumors in vivo","volume":"1","author":"JM Faupel-Badger","year":"2010","journal-title":"Horm Cancer"},{"issue":"12","key":"pone.0316983.ref016","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1038\/sj.mt.6300294","article-title":"Inhibition of tumor growth and metastasis establishment by adenovirus-mediated gene transfer delivery of the antiangiogenic factor 16K hPRL","volume":"15","author":"N-Q-N Nguyen","year":"2007","journal-title":"Mol Ther"},{"issue":"2","key":"pone.0316983.ref017","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.canlet.2009.04.030","article-title":"Antiangiogenic liposomal gene therapy with 16K human prolactin efficiently reduces tumor growth","volume":"284","author":"V Kinet","year":"2009","journal-title":"Cancer Lett"},{"key":"pone.0316983.ref018","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.pep.2019.04.011","article-title":"Sequence optimization and glycosylation of vasoinhibin: Pitfalls of recombinant production","volume":"161","author":"B Moreno-Carranza","year":"2019","journal-title":"Protein Expr Purif"},{"key":"pone.0316983.ref019","article-title":"Topical ophthalmic administration of vian-c4551 antiangiogenic peptide for diabetic macular edema: preclinical efficacy and ocular pharmacokinetics","author":"E Ad\u00e1n-Castro","year":"2024","journal-title":"bioRxiv"},{"issue":"1","key":"pone.0316983.ref020","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1078\/0171-9335-00213","article-title":"Immortalization of bovine umbilical vein endothelial cells: a model for the study of vascular endothelium","volume":"81","author":"M Cajero-Ju\u00e1rez","year":"2002","journal-title":"Eur J Cell Biol"},{"issue":"3","key":"pone.0316983.ref021","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nprot.2007.54","article-title":"A protocol for isolation and culture of human umbilical vein endothelial cells","volume":"2","author":"B Baudin","year":"2007","journal-title":"Nat Protoc"},{"issue":"3","key":"pone.0316983.ref022","doi-asserted-by":"crossref","first-page":"101695","DOI":"10.1016\/j.jbc.2022.101695","article-title":"The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin \u03b15\u03b21 and NF-\u03baB signaling","volume":"298","author":"JP Robles","year":"2022","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0316983.ref023","doi-asserted-by":"crossref","DOI":"10.1111\/jne.13091","article-title":"Sulpiride-induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats","volume":"34","author":"E Ad\u00e1n-Castro","year":"2022","journal-title":"J Neuroendocrinol"},{"key":"pone.0316983.ref024","article-title":"B16 as a mouse model for human melanoma","author":"WW Overwijk","year":"2001","journal-title":"Curr Protoc Immunol"},{"issue":"19","key":"pone.0316983.ref025","doi-asserted-by":"crossref","first-page":"7529","DOI":"10.1158\/0008-5472.CAN-08-4382","article-title":"Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis","volume":"69","author":"Y Huang","year":"2009","journal-title":"Cancer Res"},{"issue":"10","key":"pone.0316983.ref026","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/jnci\/84.10.797","article-title":"Early steps in hematogenous metastasis of B16F1 melanoma cells in chick embryos studied by high-resolution intravital videomicroscopy","volume":"84","author":"A Chambers","year":"1992","journal-title":"J Natl Cancer Inst"},{"issue":"2","key":"pone.0316983.ref027","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/2211068214561025","article-title":"Teer measurement techniques for in vitro barrier model systems","volume":"20","author":"B Srinivasan","year":"2015","journal-title":"SLAS Technol"},{"issue":"7","key":"pone.0316983.ref028","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0201231","article-title":"A functional siRNA screen identifies RhoGTPase-associated genes involved in thrombin-induced endothelial permeability","volume":"13","author":"J Amado-Azevedo","year":"2018","journal-title":"PLoS One"},{"issue":"11","key":"pone.0316983.ref029","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1038\/ncb1486","article-title":"VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin","volume":"8","author":"J Gavard","year":"2006","journal-title":"Nat Cell Biol"},{"issue":"14","key":"pone.0316983.ref030","doi-asserted-by":"crossref","first-page":"5277","DOI":"10.1073\/pnas.83.14.5277","article-title":"Experimental metastasis in nude mice of NIH 3T3 cells containing various ras genes","volume":"83","author":"MO Bradley","year":"1986","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0316983.ref031","doi-asserted-by":"crossref","first-page":"520","DOI":"10.3390\/ijms22020520","article-title":"Endothelial Cells as Tools to Model Tissue Microenvironment in Hypoxia-Dependent Pathologies","volume":"22","author":"A Majewska","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0316983.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3892\/ol.2023.13926","article-title":"MicroRNA expression profiles associated with the metastatic ability of MDA\u2011MB\u2011231 breast cancer cells","volume":"26","author":"P Phannasil","year":"2023","journal-title":"Oncol Lett"},{"issue":"6","key":"pone.0316983.ref033","first-page":"3147","article-title":"The Story of MCF-7 Breast Cancer Cell Line: 40 years of Experience in Research","volume":"35","author":"\u015e Com\u015fa","year":"2015","journal-title":"Anticancer Res"},{"key":"pone.0316983.ref034","author":"R Charles"},{"issue":"4","key":"pone.0316983.ref035","first-page":"375","article-title":"Clinical chemistry reference intervals for C57BL\/6J, C57BL\/6N, and C3HeB\/FeJ mice (Mus musculus)","volume":"55","author":"GP Otto","year":"2016","journal-title":"J Am Assoc Lab Anim Sci"},{"issue":"1","key":"pone.0316983.ref036","first-page":"115","article-title":"Hematological and plasma biochemical values in four specific pathogen-free mice strains produced in the animal facility at Cantacuzino Institute, Bucharest","author":"C Coman","year":"2018","journal-title":"Sci Works Ser C Vet Med"},{"key":"pone.0316983.ref037","doi-asserted-by":"crossref","first-page":"43","DOI":"10.4137\/CGM.S31244","article-title":"Cancer Metastases: Early Dissemination and Late Recurrences","volume":"8","author":"S Friberg","year":"2015","journal-title":"Cancer Growth Metastasis"},{"issue":"1","key":"pone.0316983.ref038","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.cell.2008.01.046","article-title":"Tgf\u03b2 primes breast tumors for lung metastasis seeding through angiopoietin-like 4","volume":"133","author":"D Padua","year":"2008","journal-title":"Cell"},{"issue":"7137","key":"pone.0316983.ref039","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/nature05760","article-title":"Mediators of vascular remodelling co-opted for sequential steps in lung metastasis","volume":"446","author":"GP Gupta","year":"2007","journal-title":"Nature"},{"issue":"6","key":"pone.0316983.ref040","first-page":"2291","article-title":"Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A\u2013dependent eNOS inactivation","volume":"118","author":"C Garc\u00eda","year":"2008","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0316983.ref041","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.molcel.2010.07.013","article-title":"S-nitrosylation of beta-catenin by eNOS-derived NO promotes VEGF-induced endothelial cell permeability","volume":"39","author":"S Thibeault","year":"2010","journal-title":"Mol Cell"},{"key":"pone.0316983.ref042","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3389\/fncel.2014.00333","article-title":"Vasoinhibins regulate the inner and outer blood-retinal barrier and limit retinal oxidative stress","volume":"8","author":"D Arredondo Zamarripa","year":"2014","journal-title":"Front Cell Neurosci"},{"issue":"6","key":"pone.0316983.ref043","doi-asserted-by":"crossref","DOI":"10.1186\/bcr2452","article-title":"Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients","volume":"11","author":"G Kallergi","year":"2009","journal-title":"Breast Cancer Res"},{"issue":"17","key":"pone.0316983.ref044","doi-asserted-by":"crossref","DOI":"10.1242\/jcs.231563","article-title":"Circulating tumor cells exit circulation while maintaining multicellularity, augmenting metastatic potential","volume":"132","author":"TA Allen","year":"2019","journal-title":"J Cell Sci"},{"key":"pone.0316983.ref045","first-page":"343","article-title":"Profile of ranibizumab: efficacy and safety for the treatment of wet age-related macular degeneration","volume":"8","author":"Y Chen","year":"2012","journal-title":"Ther Clin Risk Manag"},{"issue":"7","key":"pone.0316983.ref046","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/nm.3552","article-title":"PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin","volume":"20","author":"K Bajou","year":"2014","journal-title":"Nat Med"},{"issue":"3","key":"pone.0316983.ref047","first-page":"1380","article-title":"A specific, high affinity, saturable binding site for the 16-kilodalton fragment of prolactin on capillary endothelial cells","volume":"130","author":"C Clapp","year":"1992","journal-title":"Endocrinology"},{"issue":"5","key":"pone.0316983.ref048","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1530\/EC-18-0116","article-title":"16\u2009kDa vasoinhibin binds to integrin alpha5 beta1 on endothelial cells to induce apoptosis","volume":"7","author":"K Morohoshi","year":"2018","journal-title":"Endocr Connect"},{"issue":"2","key":"pone.0316983.ref049","doi-asserted-by":"crossref","DOI":"10.1210\/endocr\/bqad185","article-title":"Vasoinhibin\u2019s Apoptotic, Inflammatory, and Fibrinolytic Actions Are in a Motif Different From Its Antiangiogenic HGR Motif","volume":"165","author":"JP Robles","year":"2023","journal-title":"Endocrinology"},{"issue":"12","key":"pone.0316983.ref050","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1210\/en.2004-0647","article-title":"16K-prolactin inhibits activation of endothelial nitric oxide synthase, intracellular calcium mobilization, and endothelium-dependent vasorelaxation","volume":"145","author":"C Gonzalez","year":"2004","journal-title":"Endocrinology"},{"issue":"8","key":"pone.0316983.ref051","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/s41374-020-0432-5","article-title":"Vasoinhibin reduces joint inflammation, bone loss, and the angiogenesis and vasopermeability of the pannus in murine antigen-induced arthritis","volume":"100","author":"G Ortiz","year":"2020","journal-title":"Lab Invest"},{"issue":"12","key":"pone.0316983.ref052","doi-asserted-by":"crossref","first-page":"8944","DOI":"10.1167\/iovs.11-8190","article-title":"Vasoinhibin gene transfer by adenoassociated virus type 2 protects against vegf- and diabetes-induced retinal vasopermeability","volume":"52","author":"M Ram\u00edrez","year":"2011","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"6","key":"pone.0316983.ref053","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1210\/me.2007-0021","article-title":"The angiostatic 16K human prolactin overcomes endothelial cell anergy and promotes leukocyte infiltration via nuclear factor-kappaB activation","volume":"21","author":"SP Tabruyn","year":"2007","journal-title":"Mol Endocrinol"},{"key":"pone.0316983.ref054","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1186\/1471-2407-12-455","article-title":"Lfa-1 and icam-1 expression induced during melanoma-endothelial cell co-culture favors the transendothelial migration of melanoma cell lines in vitro","volume":"12","author":"S Ghislin","year":"2012","journal-title":"BMC Cancer"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316983","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T14:13:43Z","timestamp":1748441623000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316983"}},"subtitle":[],"editor":[{"given":"Mohamed","family":"Abdelkarim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,5,28]]},"references-count":54,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0316983","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.12.22.629954","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,28]]}}}