{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T04:17:53Z","timestamp":1745381873431,"version":"3.40.4"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["2017-67015-26083"],"award-info":[{"award-number":["2017-67015-26083"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["1S10OD010786-01"],"award-info":[{"award-number":["1S10OD010786-01"]}]},{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture","doi-asserted-by":"publisher","award":["2032-51530-025-00D"],"award-info":[{"award-number":["2032-51530-025-00D"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Bovine respiratory syncytial virus (BRSV) infection is a part of the bovine respiratory disease complex. This is one of the most significant problems in both the dairy and beef production sector, inflicting severe economic damage to the industry. BRSV manifests clinically as a respiratory syndrome, affecting both upper and lower respiratory tract, including bronchiolitis with dyspnea and wheezing. It has been shown previously that these symptoms caused by IL-4\/IL-13 domination in the immune response are associated with an antibody isotype switch to IgE. Prostaglandin production, such as PGE<jats:sub>2<\/jats:sub> is another factor contributing to the pathogenesis of the disease. In this work we demonstrated the effects of ibuprofen and antiviral fusion protein inhibitor (FPI) separately and combined. We showed the synergistic effect of ibuprofen in combination with FPI on antiviral effects and suppression of PGE<jats:sub>2<\/jats:sub>, resulting in improved cytoplasmic toll-like receptor recognition and humoral immune responses mediated by antimicrobial peptide in lungs. We also demonstrated a Th1\/Th2 balance shift towards a Th2 response in lungs and mediastinal lymph nodes, favorable to IL-4\/IL-13 responses. This shift may explain the factors contributing to higher viral loads and the lack of histopathological improvement with ibuprofen administered without FPI. Additionally, we demonstrated that endocannabinoids may play a crucial role as natural regulators of the inflammation, adaptive immune response, and resolution of the inflammatory process.<\/jats:p>","DOI":"10.1371\/journal.pone.0321642","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T17:32:22Z","timestamp":1745343142000},"page":"e0321642","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune mechanisms affected by cyclooxygenase inhibition combined with antiviral treatment in calves infected with bovine respiratory syncytial virus"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3188-1595","authenticated-orcid":true,"given":"Maxim","family":"Lebedev","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Walsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9632-6571","authenticated-orcid":true,"given":"John W.","family":"Newman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria N.","family":"Mutua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather A.","family":"McEligot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco R.","family":"Carvallo Chaigneau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurel J.","family":"Gershwin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"issue":"3","key":"pone.0321642.ref001","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1017\/S1751731116001622","article-title":"Invited review: relationship between cattle transport, immunity and respiratory disease","volume":"11","author":"B Earley","year":"2017","journal-title":"Animal"},{"issue":"2","key":"pone.0321642.ref002","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1017\/S1466252314000176","article-title":"Review of BRD pathogenesis: the old and the new","volume":"15","author":"D Mosier","year":"2015","journal-title":"Anim Health Res Rev"},{"issue":"2","key":"pone.0321642.ref003","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1017\/S1466252314000255","article-title":"The monster we don\u2019t see: subclinical BRD in beef cattle","volume":"15","author":"D Griffin","year":"2014","journal-title":"Anim Health Res Rev"},{"issue":"8","key":"pone.0321642.ref004","doi-asserted-by":"crossref","first-page":"7288","DOI":"10.3168\/jds.2018-14773","article-title":"Management factors associated with bovine respiratory disease in preweaned calves on California dairies: The BRD 100 study","volume":"102","author":"GU Maier","year":"2019","journal-title":"J Dairy Sci"},{"issue":"1","key":"pone.0321642.ref005","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s12917-021-02935-5","article-title":"Review on bovine respiratory syncytial virus and bovine parainfluenza - usual suspects in bovine respiratory disease - a narrative review","volume":"17","author":"B Makoschey","year":"2021","journal-title":"BMC Vet Res"},{"issue":"1","key":"pone.0321642.ref006","article-title":"Immunology of bovine respiratory syncytial virus in calves","volume":"66","author":"G E","year":"2015","journal-title":"Mol Immunol[Internet]"},{"issue":"3","key":"pone.0321642.ref007","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1128\/JVI.00671-08","article-title":"Respiratory syncytial virus activates innate immunity through Toll-like receptor 2","volume":"83","author":"MR Murawski","year":"2009","journal-title":"J Virol"},{"issue":"6","key":"pone.0321642.ref008","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1128\/JVI.79.6.3350-3357.2005","article-title":"Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression","volume":"79","author":"BD Rudd","year":"2005","journal-title":"J Virol"},{"issue":"4","key":"pone.0321642.ref009","first-page":"2231","article-title":"Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation","volume":"185","author":"NW Lukacs","year":"2010","journal-title":"J Immunol Baltim Md"},{"issue":"2","key":"pone.0321642.ref010","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/imm.12075","article-title":"Differential chemokine and cytokine production by neonatal bovine \u03b3\u03b4 T-cell subsets in response to viral toll-like receptor agonists and in vivo respiratory syncytial virus infection","volume":"139","author":"JL McGill","year":"2013","journal-title":"Immunology"},{"issue":"3","key":"pone.0321642.ref011","doi-asserted-by":"crossref","first-page":"e33074","DOI":"10.1371\/journal.pone.0033074","article-title":"Differential expression of cytokines in response to respiratory syncytial virus infection of calves with high or low circulating 25-hydroxyvitamin D3","volume":"7","author":"RE Sacco","year":"2012","journal-title":"PLoS One"},{"issue":"2","key":"pone.0321642.ref012","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1051\/vetres:2006053","article-title":"Bovine respiratory syncytial virus infection","volume":"38","author":"JF Valarcher","year":"2007","journal-title":"Vet Res"},{"issue":"6","key":"pone.0321642.ref013","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1099\/vir.0.064931-0","article-title":"Recombinant bovine respiratory syncytial virus with deletion of the SH gene induces increased apoptosis and pro-inflammatory cytokines in vitro, and is attenuated and induces protective immunity in calves","volume":"95","author":"G Taylor","year":"2014","journal-title":"J Gen Virol"},{"issue":"3","key":"pone.0321642.ref014","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.cimid.2012.01.005","article-title":"Immunology of bovine respiratory syncytial virus infection of cattle","volume":"35","author":"LJ Gershwin","year":"2012","journal-title":"Comp Immunol Microbiol Infect Dis"},{"issue":"1","key":"pone.0321642.ref015","doi-asserted-by":"crossref","first-page":"134","DOI":"10.2460\/ajvr.72.1.134","article-title":"Assessment of IgE response and cytokine gene expression in pulmonary efferent lymph collected after ovalbumin inhalation during experimental infection of calves with bovine respiratory syncytial virus","volume":"72","author":"LJ Gershwin","year":"2011","journal-title":"Am J Vet Res"},{"issue":"3","key":"pone.0321642.ref016","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2460\/ajvr.2000.61.291","article-title":"Bovine respiratory syncytial virus-specific IgE is associated with interleukin-2 and -4, and interferon-gamma expression in pulmonary lymph of experimentally infected calves","volume":"61","author":"LJ Gershwin","year":"2000","journal-title":"Am J Vet Res"},{"issue":"4","key":"pone.0321642.ref017","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/0165-2427(89)90077-9","article-title":"Detection of IgE antibodies to bovine respiratory syncytial virus","volume":"20","author":"RS Stewart","year":"1989","journal-title":"Vet Immunol Immunopathol"},{"issue":"3","key":"pone.0321642.ref018","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2460\/ajvr.1989.50.03.349","article-title":"Role of IgE in the pathogenesis of bovine respiratory syncytial virus in sequential infections in vaccinated and nonvaccinated calves","volume":"50","author":"RS Stewart","year":"1989","journal-title":"Am J Vet Res"},{"issue":"1","key":"pone.0321642.ref019","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0147-9571(03)00036-5","article-title":"Cytotoxic T lymphocyte activity and cytokine expression in calves vaccinated with formalin-inactivated bovine respiratory syncytial virus prior to challenge","volume":"27","author":"AR Woolums","year":"2004","journal-title":"Comp Immunol, Microbiol Infect Dis"},{"issue":"8","key":"pone.0321642.ref020","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.2460\/ajvr.1989.50.08.1254","article-title":"Prostaglandin and thromboxane concentrations in plasma and lung lavage fluids during sequential infection of vaccinated and nonvaccinated calves with bovine respiratory syncytial virus","volume":"50","author":"LJ Gershwin","year":"1989","journal-title":"Am J Vet Res"},{"issue":"4","key":"pone.0321642.ref021","doi-asserted-by":"crossref","first-page":"e0152913","DOI":"10.1371\/journal.pone.0152913","article-title":"A Randomized Placebo Controlled Trial of Ibuprofen for Respiratory Syncytial Virus Infection in a Bovine Model","volume":"11","author":"P Walsh","year":"2016","journal-title":"PLoS One"},{"issue":"3","key":"pone.0321642.ref022","doi-asserted-by":"crossref","first-page":"e0230245","DOI":"10.1371\/journal.pone.0230245","article-title":"A randomized controlled trial of a combination of antiviral and nonsteroidal anti-inflammatory treatment in a bovine model of respiratory syncytial virus infection","volume":"15","author":"P Walsh","year":"2020","journal-title":"PLoS One"},{"issue":"6","key":"pone.0321642.ref023","doi-asserted-by":"crossref","first-page":"e0252455","DOI":"10.1371\/journal.pone.0252455","article-title":"A randomized controlled trial comparing non-steroidal anti-inflammatory and fusion protein inhibitors singly and in combination on the histopathology of bovine respiratory syncytial virus infection","volume":"16","author":"FRC Carvallo Chaigneau","year":"2021","journal-title":"PLoS One"},{"issue":"2","key":"pone.0321642.ref024","doi-asserted-by":"crossref","first-page":"e0246695","DOI":"10.1371\/journal.pone.0246695","article-title":"Analysis of lung transcriptome in calves infected with Bovine Respiratory Syncytial Virus and treated with antiviral and\/or cyclooxygenase inhibitor","volume":"16","author":"M Lebedev","year":"2021","journal-title":"PLoS One"},{"issue":"4","key":"pone.0321642.ref025","doi-asserted-by":"crossref","first-page":"473","DOI":"10.2460\/ajvr.1999.60.04.473","article-title":"Evaluation of severe disease induced by aerosol inoculation of calves with bovine respiratory syncytial virus","volume":"60","author":"AR Woolums","year":"1999","journal-title":"Am J Vet Res"},{"issue":"1","key":"pone.0321642.ref026","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"A Dobin","year":"2013 Jan 1","journal-title":"Bioinformatics"},{"issue":"7","key":"pone.0321642.ref027","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0321642.ref028","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1194\/jlr.M071738","article-title":"Sweat lipid mediator profiling: a noninvasive approach for cutaneous research","volume":"58","author":"K Agrawal","year":"2017","journal-title":"J Lipid Res"},{"key":"pone.0321642.ref029","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"P Langfelder","year":"2008","journal-title":"BMC Bioinformatics"},{"issue":"8","key":"pone.0321642.ref030","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"G Bindea","year":"2009","journal-title":"Bioinformatics"},{"issue":"1","key":"pone.0321642.ref031","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cvfa.2007.11.001","article-title":"Neonatal immune development in the calf and its impact on vaccine response","volume":"24","author":"CCL Chase","year":"2008","journal-title":"Vet Clin North Am Food Anim Pract"},{"issue":"1","key":"pone.0321642.ref032","doi-asserted-by":"crossref","first-page":"208","DOI":"10.4049\/jimmunol.1303398","article-title":"Bovine \u03b3\u03b4 T cells are a major regulatory T cell subset","volume":"193","author":"E Guzman","year":"2014","journal-title":"J Immunol Author Choice"},{"issue":"1","key":"pone.0321642.ref033","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/BF00394928","article-title":"Serum thromboxane generation by platelets in calves and adult cows","volume":"3","author":"SD Semrad","year":"1993","journal-title":"Comp Haematol Int"},{"issue":"13","key":"pone.0321642.ref034","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1084\/jem.20140137","article-title":"Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell-dendritic cell interactions","volume":"211","author":"F Moalli","year":"2014","journal-title":"J Exp Med"},{"issue":"9","key":"pone.0321642.ref035","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/ptr.4882","article-title":"Inhibition of prostaglandin D\u2082 production by trihydroxy fatty acids isolated from Ulmus davidiana var. japonica","volume":"27","author":"HG Choi","year":"2013","journal-title":"Phytother Res PTR"},{"issue":"12","key":"pone.0321642.ref036","doi-asserted-by":"crossref","first-page":"6871","DOI":"10.4049\/jimmunol.161.12.6871","article-title":"The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: a novel mechanism of regulation of IL-1 responsiveness","volume":"161","author":"D Lang","year":"1998","journal-title":"J Immunol"},{"issue":"1","key":"pone.0321642.ref037","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1046\/j.1365-2249.1998.00471.x","article-title":"The role of IL-13 in IgE synthesis by allergic asthma patients","volume":"111","author":"TCTM Van Der Pouw Kraan","year":"1998","journal-title":"Clin Exp Immunol"},{"issue":"7","key":"pone.0321642.ref038","doi-asserted-by":"crossref","first-page":"e0132627","DOI":"10.1371\/journal.pone.0132627","article-title":"Cytomegalovirus Infection Triggers the Secretion of the PPAR\u03b3 Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures","volume":"10","author":"K Leghmar","year":"2015","journal-title":"PLoS One"},{"issue":"4","key":"pone.0321642.ref039","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.plipres.2006.02.003","article-title":"Inflammation and immune regulation by 12\/15-lipoxygenases","volume":"45","author":"H K\u00fchn","year":"2006","journal-title":"Prog Lipid Res"},{"issue":"6","key":"pone.0321642.ref040","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1165\/rcmb.2017-0031OC","article-title":"Preferential Generation of 15-HETE-PE Induced by IL-13 Regulates Goblet Cell Differentiation in Human Airway Epithelial Cells","volume":"57","author":"J Zhao","year":"2017","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"2","key":"pone.0321642.ref041","first-page":"85","article-title":"Endocannabinoids and immune regulation","volume":"60","author":"R Pandey","year":"2009","journal-title":"Pharmacol Res Off J Ital Pharmacol Soc"},{"issue":"2","key":"pone.0321642.ref042","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1600-0773.1997.tb00291.x","article-title":"Ibuprofen inhibits the metabolism of the endogenous cannabimimetic agent anandamide","volume":"80","author":"CJ Fowler","year":"1997","journal-title":"Pharmacol Toxicol"},{"issue":"3","key":"pone.0321642.ref043","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1016\/S0006-291X(88)80428-5","article-title":"Neutrophil microsomes biosynthesize linoleate epoxide (9, 10-epoxy-12-octadecenoate), a biological active substance","volume":"152","author":"T Ozawa","year":"1988","journal-title":"Biochem Biophys Res Commun"},{"issue":"4","key":"pone.0321642.ref044","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/BF01428400","article-title":"Immunohistochemical dynamics of leukotoxin (9,10-epoxy-12-octadecenoic acid) in lungs of rats","volume":"107","author":"W Zhang","year":"1995","journal-title":"Int J Legal Med"},{"issue":"1","key":"pone.0321642.ref045","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/0006-291X(86)91227-1","article-title":"Neutrophils biosynthesize leukotoxin, 9, 10-epoxy-12-octadecenoate","volume":"137","author":"M Hayakawa","year":"1986","journal-title":"Biochem Biophys Res Commun"},{"issue":"2","key":"pone.0321642.ref046","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s12038-007-0028-x","article-title":"Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst","volume":"32","author":"DA Thompson","year":"2007","journal-title":"J Biosci"},{"issue":"6","key":"pone.0321642.ref047","doi-asserted-by":"crossref","first-page":"a022236","DOI":"10.1101\/cshperspect.a022236","article-title":"Regulation of the Immune Response by TGF-\u03b2: From Conception to Autoimmunity and Infection","volume":"9","author":"S Sanjabi","year":"2017","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"4","key":"pone.0321642.ref048","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.immuni.2019.03.021","article-title":"The IL-17 family of cytokines in health and disease","volume":"50","author":"MJ McGeachy","year":"2019","journal-title":"Immunity"},{"issue":"11","key":"pone.0321642.ref049","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1093\/intimm\/12.11.1499","article-title":"Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation","volume":"12","author":"R Umeshita-Suyama","year":"2000","journal-title":"Int Immunol"},{"issue":"14","key":"pone.0321642.ref050","doi-asserted-by":"crossref","first-page":"e141326","DOI":"10.1172\/jci.insight.141326","article-title":"STAT4 is expressed in neutrophils and promotes antimicrobial immunity","volume":"6","author":"P Mehrpouya-Bahrami","year":"2021","journal-title":"JCI Insight"},{"issue":"17","key":"pone.0321642.ref051","doi-asserted-by":"crossref","first-page":"9409","DOI":"10.1128\/JVI.00947-12","article-title":"STAT4 regulates antiviral gamma interferon responses and recurrent disease during herpes simplex virus 2 infection","volume":"86","author":"A Svensson","year":"2012","journal-title":"J Virol"},{"issue":"6","key":"pone.0321642.ref052","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.it.2014.04.002","article-title":"GATA3: a master of many trades in immune regulation","volume":"35","author":"YY Wan","year":"2014","journal-title":"Trends Immunol"},{"issue":"11","key":"pone.0321642.ref053","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.1172\/JCI57456","article-title":"GATA3 controls Foxp3\u207a regulatory T cell fate during inflammation in mice","volume":"121","author":"EA Wohlfert","year":"2011","journal-title":"J Clin Invest"},{"issue":"7","key":"pone.0321642.ref054","doi-asserted-by":"crossref","first-page":"e01888-21","DOI":"10.1128\/jvi.01888-21","article-title":"GATA3 inhibits viral infection by promoting microRNA-155 expression","volume":"96","author":"J Li","year":"2022","journal-title":"J Virol"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0321642","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T17:32:35Z","timestamp":1745343155000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0321642"}},"subtitle":[],"editor":[{"given":"Angel","family":"Abuelo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,22]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0321642","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,22]]}}}