{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:29:26Z","timestamp":1787614166201,"version":"build-2736575974"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T00:00:00Z","timestamp":1719360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Science, Research and Innovation Fund (NSRF) and Prince of Songkla University","award":["SCI6701024S"],"award-info":[{"award-number":["SCI6701024S"]}]},{"name":"a Prince of Songkla University-Ph.D. Scholarship","award":["PSU_PHD2561-001"],"award-info":[{"award-number":["PSU_PHD2561-001"]}]},{"name":"a Prince of Songkla University-Ph.D. Scholarship","award":["PSU_PHD2565-002"],"award-info":[{"award-number":["PSU_PHD2565-002"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is an aggressive cancer originating from bile duct epithelium, particularly prevalent in Asian countries with liver fluke infections. Current chemotherapy for CCA often fails due to drug resistance, necessitating novel anticancer agents. This study investigates the potential of 5\u2019-deoxy-5\u2019-methylthioadenosine (MTA), a naturally occurring nucleoside, against CCA. While MTA has shown promise against various cancers, its effects on CCA remain unexplored. We evaluated MTA\u2019s anticancer activity in CCA cell lines and drug-resistant sub-lines, assessing cell viability, migration, invasion, and apoptosis. The potential anticancer mechanisms of MTA were explored through proteomic analysis using LC-MS\/MS and bioinformatic analysis. The results show a dose-dependent reduction in CCA cell viability, with enhanced effects on cancer cells compared to normal cells. Moreover, MTA inhibits growth, induces apoptosis, and suppresses cell migration and invasion. Additionally, MTA enhanced the anticancer effects of gemcitabine on drug-resistant CCA cells. Proteomics revealed the down-regulation of multiple proteins by MTA, affecting various molecular functions, biological processes, and cellular components. Network analysis highlighted MTA\u2019s role in inhibiting proteins related to mitochondrial function and energy derivation, crucial for cell growth and survival. Additionally, MTA suppressed proteins involved in cell morphology and cytoskeleton organization, important for cancer cell motility and metastasis. Six candidate genes, including ZNF860, KLC1, GRAMD1C, MAMSTR, TANC1, and TTC13, were selected from the top 10 most down-regulated proteins identified in the proteomics results and were subsequently verified through RT-qPCR. Further, KLC1 protein suppression by MTA treatment was confirmed through Western blotting. Additionally, based on TCGA data, KLC1 mRNA was found to be upregulated in the tissue of CCA patients compared to that of normal adjacent tissues. In summary, MTA shows promising anticancer potential against CCA by inhibiting growth, inducing apoptosis, and suppressing migration and invasion, while enhancing gemcitabine\u2019s effects. Proteomic analysis elucidates possible molecular mechanisms underlying MTA\u2019s anticancer activity, laying the groundwork for future research and development of MTA as a treatment for advanced CCA.<\/jats:p>","DOI":"10.1371\/journal.pone.0306060","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T17:36:12Z","timestamp":1719423372000},"page":"e0306060","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Quantitative proteomics analysis reveals possible anticancer mechanisms of 5\u2019-deoxy-5\u2019-methylthioadenosine in cholangiocarcinoma cells"],"prefix":"10.1371","volume":"19","author":[{"given":"Kankamol","family":"Kerdkumthong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5604-767X","authenticated-orcid":true,"given":"Sutthipong","family":"Nanarong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-8390","authenticated-orcid":true,"given":"Sittiruk","family":"Roytrakul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanawat","family":"Pitakpornpreecha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phonprapavee","family":"Tantimetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6800-1048","authenticated-orcid":true,"given":"Phanthipha","family":"Runsaeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3001-0563","authenticated-orcid":true,"given":"Sumalee","family":"Obchoei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,26]]},"reference":[{"issue":"9493","key":"pone.0306060.ref001","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/S0140-6736(05)67530-7","article-title":"Cholangiocarcinoma","volume":"366","author":"SA Khan","year":"2005","journal-title":"The Lancet"},{"issue":"9","key":"pone.0306060.ref002","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: the next horizon in mechanisms and management","volume":"17","author":"JM Banales","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"9","key":"pone.0306060.ref003","doi-asserted-by":"crossref","first-page":"3590","DOI":"10.1007\/s11695-020-04661-7","article-title":"Cholangiocarcinoma Following Bariatric Surgery: a Prospective Follow-Up Single-Center Audit","volume":"30","author":"N Beghdadi","year":"2020","journal-title":"Obes Surg"},{"issue":"3","key":"pone.0306060.ref004","doi-asserted-by":"crossref","first-page":"1073274817729245","DOI":"10.1177\/1073274817729245","article-title":"Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma","volume":"24","author":"NN Massarweh","year":"2017","journal-title":"Cancer Control"},{"issue":"5","key":"pone.0306060.ref005","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1634\/theoncologist.2015-0446","article-title":"Forty-year trends in cholangiocarcinoma incidence in the US: intrahepatic disease on the rise","volume":"21","author":"SK Saha","year":"2016","journal-title":"Oncologist"},{"issue":"4","key":"pone.0306060.ref006","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.idc.2010.07.006","article-title":"Cholangiocarcinoma: new insights into disease pathogenesis and biology","volume":"24","author":"C Braconi","year":"2010","journal-title":"Infect Dis Clin North Am"},{"issue":"6","key":"pone.0306060.ref007","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0002-9610(01)00628-6","article-title":"Predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma","volume":"181","author":"T Isa","year":"2001","journal-title":"Am J Surg"},{"issue":"5","key":"pone.0306060.ref008","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1021\/bi00405a003","article-title":"Effect of inhibitors of S-adenosylmethionine decarboxylase on polyamine content and growth of L1210 cells","volume":"27","author":"AE Pegg","year":"1988","journal-title":"Biochemistry"},{"issue":"3","key":"pone.0306060.ref009","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0006-2952(82)90171-X","article-title":"Trends in the biochemical pharmacology of 5\u2019-deoxy-5\u2019-methylthioadenosine","volume":"31","author":"HG Williams-Ashman","year":"1982","journal-title":"Biochem Pharmacol"},{"issue":"1","key":"pone.0306060.ref010","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1534\/g3.114.014555","article-title":"Expression of MTAP inhibits tumor-related phenotypes in HT1080 cells via a mechanism unrelated to its enzymatic function","volume":"5","author":"B Tang","year":"2015","journal-title":"G3-genes genom genet"},{"issue":"45","key":"pone.0306060.ref011","doi-asserted-by":"crossref","first-page":"78851","DOI":"10.18632\/oncotarget.20234","article-title":"S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting microRNA 34a\/b-methionine adenosyltransferase 2A\/2B axis","volume":"8","author":"ML Tomasi","year":"2017","journal-title":"Oncotarget"},{"issue":"7","key":"pone.0306060.ref012","doi-asserted-by":"crossref","first-page":"627","DOI":"10.4161\/cbt.11.7.14948","article-title":"Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies","volume":"11","author":"JR Bertino","year":"2011","journal-title":"Cancer Biol Ther"},{"issue":"1","key":"pone.0306060.ref013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-022-29397-z","article-title":"MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers","volume":"13","author":"O Alhalabi","year":"2022","journal-title":"Nat Commun"},{"issue":"2","key":"pone.0306060.ref014","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.euo.2021.10.006","article-title":"Integrative clinical and genomic characterization of MTAP-deficient metastatic urothelial cancer","volume":"6","author":"O Alhalabi","year":"2023","journal-title":"Eur Urol Oncol"},{"key":"pone.0306060.ref015","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1007\/s13577-020-00334-w","article-title":"Functional and genetic characterization of three cell lines derived from a single tumor of an Opisthorchis viverrini-associated cholangiocarcinoma patient","volume":"33","author":"B Sripa","year":"2020","journal-title":"Human cell"},{"issue":"3","key":"pone.0306060.ref016","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/01.TP.0000110292.73873.25","article-title":"Establishment of a highly differentiated immortalized human cholangiocyte cell line with SV40T and hTERT","volume":"77","author":"M Maruyama","year":"2004","journal-title":"Transplantation"},{"key":"pone.0306060.ref017","first-page":"1","article-title":"Two Recombinant Bacteriocins, Rhamnosin and Lysostaphin, Show Synergistic Anticancer Activity Against Gemcitabine-Resistant Cholangiocarcinoma Cell Lines","author":"K Kerdkumthong","year":"2023","journal-title":"Probiotics Antimicro"},{"issue":"16","key":"pone.0306060.ref018","doi-asserted-by":"crossref","first-page":"4475","DOI":"10.1002\/pmic.200500921","article-title":"Differential expression analysis of Escherichia coli proteins using a novel software for relative quantitation of LC\u2010MS\/MS data","volume":"6","author":"C Johansson","year":"2006","journal-title":"Proteomics"},{"issue":"5","key":"pone.0306060.ref019","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1002\/rcm.2898","article-title":"Evaluation of sample fractionation using micro\u2010scale liquid\u2010phase isoelectric focusing on mass spectrometric identification and quantitation of proteins in a SILAC experiment","volume":"21","author":"A Thorsell","year":"2007","journal-title":"Rapid Commun Spectrom"},{"issue":"22","key":"pone.0306060.ref020","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1093\/bioinformatics\/btr490","article-title":"RNA-Seq analysis in MeV","volume":"27","author":"EA Howe","year":"2011","journal-title":"Bioinformatics"},{"issue":"D1","key":"pone.0306060.ref021","doi-asserted-by":"crossref","first-page":"D419","DOI":"10.1093\/nar\/gky1038","article-title":"PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools","volume":"47","author":"H Mi","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"pone.0306060.ref022","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: a graphical gene-set enrichment tool for animals and plants","volume":"36","author":"SX Ge","year":"2020","journal-title":"Bioinformatics"},{"issue":"6","key":"pone.0306060.ref023","first-page":"408","article-title":"Second-line systemic treatment for advanced cholangiocarcinoma","volume":"5","author":"JE Rogers","year":"2014","journal-title":"J Gastrointest Oncol"},{"issue":"9935","key":"pone.0306060.ref024","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1016\/S0140-6736(13)61903-0","article-title":"Cholangiocarcinoma","volume":"383","author":"N Razumilava","year":"2014","journal-title":"The Lancet"},{"issue":"4","key":"pone.0306060.ref025","doi-asserted-by":"crossref","first-page":"927","DOI":"10.7150\/jca.27160","article-title":"5\u2019-Methylthioadenosine and Cancer: old molecules, new understanding","volume":"10","author":"Y Li","year":"2019","journal-title":"J Cancer"},{"issue":"19","key":"pone.0306060.ref026","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1016\/j.chroma.2010.01.025","article-title":"Quantification of intermediates of the methionine and polyamine metabolism by liquid chromatography\u2013tandem mass spectrometry in cultured tumor cells and liver biopsies","volume":"1217","author":"AP Stevens","year":"2010","journal-title":"J Chromatogr A"},{"issue":"8","key":"pone.0306060.ref027","doi-asserted-by":"crossref","first-page":"e1184802","DOI":"10.1080\/2162402X.2016.1184802","article-title":"Suppressive effects of tumor cell-derived 5\u2032-deoxy-5\u2032-methylthioadenosine on human T cells","volume":"5","author":"FC Henrich","year":"2016","journal-title":"Oncoimmunology"},{"issue":"6","key":"pone.0306060.ref028","first-page":"2297","article-title":"Correlation between growth inhibition and presence of 5\u2019-methylthioadenosine in cells treated with interferon","volume":"44","author":"F de Ferra","year":"1984","journal-title":"Cancer Res"},{"issue":"1","key":"pone.0306060.ref029","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/0006-291X(84)90932-X","article-title":"Effect of 5\u2019-methylthioadenosine on induction of murine erythroleukemia cell differentiation","volume":"124","author":"TD Shafman","year":"1984","journal-title":"Biochem Biophys Res Commun"},{"issue":"8","key":"pone.0306060.ref030","first-page":"3035","article-title":"Effect of 5\u2019\u2019-methylthioadenosine and its analogs on murine lymphoid cell proliferation","volume":"41","author":"RW Wolford","year":"1981","journal-title":"Cancer Res"},{"key":"pone.0306060.ref031","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2407-10-265","article-title":"Methylthioadenosine (MTA) inhibits melanoma cell proliferation and in vivo tumor growth","volume":"10","author":"P Andreu-P\u00e9rez","year":"2010","journal-title":"BMC cancer"},{"issue":"3","key":"pone.0306060.ref032","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1158\/1535-7163.MCT-11-0826","article-title":"Next Generation Sequencing of Prostate Cancer from a Patient Identifies a Deficiency of Methylthioadenosine Phosphorylase, an Exploitable Tumor TargetNGS-Guided Personalized Therapy for MTAP-Deficient PCa","volume":"11","author":"CC Collins","year":"2012","journal-title":"Mol Cancer Ther"},{"issue":"12","key":"pone.0306060.ref033","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.1073\/pnas.93.12.6203","article-title":"Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers","volume":"93","author":"T Nobori","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"issue":"15","key":"pone.0306060.ref034","doi-asserted-by":"crossref","first-page":"4386","DOI":"10.1158\/0008-5472.CAN-18-0814","article-title":"Specific targeting of MTAP-deleted tumors with a combination of 2\u2032-fluoroadenine and 5\u2032-methylthioadenosine","volume":"78","author":"B Tang","year":"2018","journal-title":"Cancer Res"},{"issue":"1","key":"pone.0306060.ref035","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/0008-8749(80)90052-0","article-title":"Inhibition of lymphocyte transformation by a naturally occurring metabolite: 5\u2019-methylthioadenosine","volume":"49","author":"AA Vandenbark","year":"1980","journal-title":"Cell Immunol"},{"key":"pone.0306060.ref036","article-title":"Cell morphology best predicts tumorigenicity and metastasis in vivo across multiple TNBC cell lines of different metastatic potential","author":"SJ Conner","year":"2023","journal-title":"BioRxiv"},{"issue":"6","key":"pone.0306060.ref037","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nrm3999","article-title":"Live to die another way: modes of programmed cell death and the signals emanating from dying cells","volume":"16","author":"Y Fuchs","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"2","key":"pone.0306060.ref038","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1006\/excr.1998.4000","article-title":"Induction of apoptosis in leukemia U937 cells by 5\u2019-deoxy-5\u2019-methylthioadenosine, a potent inhibitor of protein carboxylmethyltransferase","volume":"240","author":"SH Lee","year":"1998","journal-title":"Exp Cell Res"},{"issue":"1","key":"pone.0306060.ref039","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1124\/mol.108.054411","article-title":"S-Adenosylmethionine and methylthioadenosine inhibit cellular FLICE inhibitory protein expression and induce apoptosis in colon cancer cells","volume":"76","author":"TW Li","year":"2009","journal-title":"Mol Pharmacol"},{"issue":"1","key":"pone.0306060.ref040","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/hep.20274","article-title":"S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S)","volume":"40","author":"H Yang","year":"2004","journal-title":"Hepatol"},{"key":"pone.0306060.ref041","first-page":"1","article-title":"A Review on Caspases: Key Regulators of Biological Activities and Apoptosis","author":"G Sahoo","year":"2023","journal-title":"Mol Neurobiol"},{"issue":"2","key":"pone.0306060.ref042","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1096\/fj.201801417R","article-title":"Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis","volume":"33","author":"HA Kalpage","year":"2019","journal-title":"The FASEB J"},{"key":"pone.0306060.ref043","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1023\/A:1022945107762","article-title":"The mitochondrial membrane potential (\u0394\u03c8 m) in apoptosis; an update","volume":"8","author":"JD Ly","year":"2003","journal-title":"Apoptosis"},{"issue":"5","key":"pone.0306060.ref044","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/j.1365-2796.2010.02268.x","article-title":"Redox sensing: orthogonal control in cell cycle and apoptosis signalling","volume":"268","author":"DP Jones","year":"2010","journal-title":"J Intern Med"},{"issue":"1","key":"pone.0306060.ref045","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy","volume":"15","author":"PE Czabotar","year":"2014","journal-title":"Nat Rev Mol Cell biol"},{"issue":"4","key":"pone.0306060.ref046","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/1759-7714.12613","article-title":"ALK\u2010rearrangement in non\u2010small\u2010cell lung cancer (NSCLC)","volume":"9","author":"X Du","year":"2018","journal-title":"Thorac. Cancer"},{"issue":"2","key":"pone.0306060.ref047","doi-asserted-by":"crossref","first-page":"e31323","DOI":"10.1371\/journal.pone.0031323","article-title":"KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only","volume":"7","author":"Y Togashi","year":"2012","journal-title":"PloS one"},{"issue":"2","key":"pone.0306060.ref048","doi-asserted-by":"crossref","first-page":"183","DOI":"10.20892\/j.issn.2095-3941.2017.0017","article-title":"Rapid response of brain metastasis to crizotinib in a patient with KLC1-ALK fusion and MET gene amplification positive non-small cell lung cancer: a case report","volume":"14","author":"P Wang","year":"2017","journal-title":"Mol. Cancer Biol"},{"issue":"6","key":"pone.0306060.ref049","doi-asserted-by":"crossref","first-page":"a004630","DOI":"10.1101\/mcs.a004630","article-title":"Serial liquid biopsies for detection of treatment failure and profiling of resistance mechanisms in KLC1\u2013ALK-rearranged lung cancer","volume":"5","author":"S Dietz","year":"2019","journal-title":"Mol. Case Stud"},{"issue":"1","key":"pone.0306060.ref050","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3390\/cancers16010009","article-title":"KLC1-ROS1 Fusion Exerts Oncogenic Properties of Glioma Cells via Specific Activation of JAK-STAT Pathway","volume":"16","author":"T Fujii","year":"2023","journal-title":"Cancers"},{"key":"pone.0306060.ref051","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1007\/s10014-018-0330-3","article-title":"Identification of a novel KLC1\u2013ROS1 fusion in a case of pediatric low-grade localized glioma","volume":"36","author":"Y Nakano","year":"2019","journal-title":"Brain Tumor Pathol"},{"issue":"10","key":"pone.0306060.ref052","first-page":"2174","article-title":"14-3-3\u03b3-Mediated transport of plakoglobin to the cell border is required for the initiation of desmosome assembly in vitro and in vivo","volume":"127","author":"L Sehgal","year":"2014","journal-title":"J Cell Sci"},{"key":"pone.0306060.ref053","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ebiom.2019.06.009","article-title":"A role for kinesin-1 subunits KIF5B\/KLC1 in regulating epithelial mesenchymal plasticity in breast tumorigenesis","volume":"45","author":"A Moamer","year":"2019","journal-title":"EBioMedicine"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0306060","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T17:36:56Z","timestamp":1719423416000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0306060"}},"subtitle":[],"editor":[{"given":"Matias A","family":"Avila","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,6,26]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0306060","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,26]]}}}