{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T19:48:13Z","timestamp":1772480893774,"version":"3.50.1"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University","award":["CTG168013"],"award-info":[{"award-number":["CTG168013"]}]},{"name":"Thailand Science Research and Innovation Fund","award":["HEA_FF_68_026_3200_003"],"award-info":[{"award-number":["HEA_FF_68_026_3200_003"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"\n Transforming growth factor \u03b2 (TGF-\u03b2) is a pluripotent cytokine that plays a pivotal role in regulating bone remodeling. In this study, we investigated the skeletal phenotype of 24-week-old transgenic female mice expressing a constitutively active TGF-\u03b2 receptor type I (\n T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n ) under the control of inducible Mx1-Cre promoter. Poly(I:C) injection was used to induce expression of\n T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n to generate\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n mice. In\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n mice, serum calcium levels were increased, while parathyroid hormone (PTH) levels were decreased. Micro-computed tomography (\u03bcCT) analysis revealed a significant increase in cancellous and cortical bone volume in femurs and mandibles of\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n mice compared to wild type mice. Histomorphometric analysis confirmed that this enhanced bone volume was associated with an increased number of osteoblasts and a reduced number of osteoclasts. Constitutive\n T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n activation resulted in increased alkaline phosphatase and mineralization in primary cultures, while osteoclast cultures from\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n mice formed decreased TRAP positive osteoclasts compared to wild-type mice. Furthermore, qPCR analysis demonstrated upregulation of osteoblast differentiation markers, including\n Runx2<\/jats:italic>\n ,\n Sp7<\/jats:italic>\n ,\n Alpl<\/jats:italic>\n ,\n Col1a1,<\/jats:italic>\n and\n Ptch2<\/jats:italic>\n , while osteoclast-related genes such as\n Ctsk<\/jats:italic>\n and\n Acp5<\/jats:italic>\n were downregulated in both femoral and mandibular bone\n in vivo<\/jats:italic>\n . Similarly, osteoblast-related genes were increased in\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n osteoblasts, whereas osteoclast-related genes were decreased in\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n osteoclasts\n in vitro<\/jats:italic>\n .\n Mx1;T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n \n CA<\/jats:italic>\n <\/jats:sup>\n mice had increased microindentation. These results suggest that constitutive activation of TGF-\u03b2 signaling promotes bone formation by stimulating osteoblast number while suppressing osteoclast number. This study highlights the important role of TGF-\u03b2 in bone remodeling and homeostasis and may provide potential therapeutic targets for\n T<\/jats:italic>\n \u03b2\n RI<\/jats:italic>\n -associated bone diseases.\n <\/jats:p>","DOI":"10.1371\/journal.pone.0344279","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T18:40:26Z","timestamp":1772476826000},"page":"e0344279","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Constitutive activation of TGF-\u03b2 receptor type I promotes cortical and cancellous bone formation in adult mice"],"prefix":"10.1371","volume":"21","author":[{"given":"Tipthanan","family":"Chotipinit","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Parichart","family":"Toejing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chinnatam","family":"Phetkong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Somyoth","family":"Sridurongrit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5566-6403","authenticated-orcid":true,"given":"Asada","family":"Leelahavanichkul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5875-314X","authenticated-orcid":true,"given":"Julia F.","family":"Charles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-3039","authenticated-orcid":true,"given":"Sutada","family":"Lotinun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"issue":"6","key":"pone.0344279.ref001","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1210\/er.2004-0001","article-title":"Transforming growth factor-beta1 to the bone","volume":"26","author":"K Janssens","year":"2005","journal-title":"Endocr Rev"},{"issue":"4","key":"pone.0344279.ref002","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1055\/s-2001-15109","article-title":"TGFbeta1 and TGFbeta2 mRNA and protein expression in human bone samples","volume":"109","author":"S Hering","year":"2001","journal-title":"Exp Clin Endocrinol Diabetes"},{"issue":"2","key":"pone.0344279.ref003","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1083\/jcb.108.2.661","article-title":"Expression of transforming growth factor-beta 1 in specific cells and tissues of adult and neonatal mice","volume":"108","author":"NL Thompson","year":"1989","journal-title":"J Cell Biol"},{"issue":"2","key":"pone.0344279.ref004","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41422-023-00918-9","article-title":"The roles and regulatory mechanisms of TGF-\u03b2 and BMP signaling in bone and cartilage development, homeostasis and disease","volume":"34","author":"M Wu","year":"2024","journal-title":"Cell Res"},{"key":"pone.0344279.ref005","doi-asserted-by":"crossref","first-page":"16009","DOI":"10.1038\/boneres.2016.9","article-title":"TGF-\u03b2 and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease","volume":"4","author":"M Wu","year":"2016","journal-title":"Bone Res"},{"issue":"7","key":"pone.0344279.ref006","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1002\/jbmr.357","article-title":"Regulation of RANKL-induced osteoclastogenesis by TGF-\u03b2 through molecular interaction between Smad3 and Traf6","volume":"26","author":"T Yasui","year":"2011","journal-title":"J Bone Miner Res"},{"issue":"7","key":"pone.0344279.ref007","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nm.1979","article-title":"TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation","volume":"15","author":"Y Tang","year":"2009","journal-title":"Nat Med"},{"issue":"2","key":"pone.0344279.ref008","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.ydbio.2009.06.002","article-title":"Critical roles of the TGF-beta type I receptor ALK5 in perichondrial formation and function, cartilage integrity, and osteoblast differentiation during growth plate development","volume":"332","author":"T Matsunobu","year":"2009","journal-title":"Dev Biol"},{"issue":"2","key":"pone.0344279.ref009","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ydbio.2007.07.040","article-title":"Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints","volume":"310","author":"H-S Seo","year":"2007","journal-title":"Dev Biol"},{"issue":"2","key":"pone.0344279.ref010","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.ydbio.2009.08.015","article-title":"Tgfbr2 is required for development of the skull vault","volume":"334","author":"H-S Seo","year":"2009","journal-title":"Dev Biol"},{"issue":"9","key":"pone.0344279.ref011","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/dvg.20653","article-title":"A rapid strategy to detect the recombined allele in LSL-T\u03b2RICA transgenic mice","volume":"48","author":"DF Vincent","year":"2010","journal-title":"Genesis"},{"issue":"13","key":"pone.0344279.ref012","doi-asserted-by":"crossref","first-page":"10797","DOI":"10.3390\/ijms241310797","article-title":"Accelerated bone loss in transgenic mice expressing constitutively active TGF-\u03b2 receptor type I","volume":"24","author":"P Toejing","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"10","key":"pone.0344279.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0187030","article-title":"Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice","volume":"12","author":"LJ Brylka","year":"2017","journal-title":"PLoS One"},{"issue":"1","key":"pone.0344279.ref014","doi-asserted-by":"crossref","first-page":"46","DOI":"10.5735\/086.047.0105","article-title":"Measurement error in morphometric studies: Comparison between manual and computerized methods","volume":"47","author":"F Mu\u00f1oz-Mu\u00f1oz","year":"2010","journal-title":"Annales Zoologici Fennici"},{"issue":"7","key":"pone.0344279.ref015","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"ML Bouxsein","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"1","key":"pone.0344279.ref016","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee","volume":"28","author":"DW Dempster","year":"2013","journal-title":"J Bone Miner Res"},{"issue":"2","key":"pone.0344279.ref017","doi-asserted-by":"crossref","first-page":"100452","DOI":"10.1016\/j.xpro.2021.100452","article-title":"Primary mouse osteoblast and osteoclast culturing and analysis","volume":"2","author":"C Chevalier","year":"2021","journal-title":"STAR Protoc"},{"issue":"5229","key":"pone.0344279.ref018","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.7660125","article-title":"Inducible gene targeting in mice","volume":"269","author":"R K\u00fchn","year":"1995","journal-title":"Science"},{"issue":"11","key":"pone.0344279.ref019","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1172\/JCI35711","article-title":"NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism","volume":"118","author":"AO Aliprantis","year":"2008","journal-title":"J Clin Invest"},{"issue":"11","key":"pone.0344279.ref020","doi-asserted-by":"crossref","first-page":"5829","DOI":"10.3390\/ijms25115829","article-title":"Differential gene expression involved in bone turnover of mice expressing constitutively active TGF\u03b2 receptor type I","volume":"25","author":"O Myint","year":"2024","journal-title":"Int J Mol Sci"},{"key":"pone.0344279.ref021","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.coph.2015.03.005","article-title":"Parathyroid hormone: Anabolic and catabolic actions on the skeleton","volume":"22","author":"BC Silva","year":"2015","journal-title":"Curr Opin Pharmacol"},{"issue":"3","key":"pone.0344279.ref022","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/ncb0310-205","article-title":"PTH battles TGF-beta in bone","volume":"12","author":"A Atfi","year":"2010","journal-title":"Nat Cell Biol"},{"issue":"1","key":"pone.0344279.ref023","doi-asserted-by":"crossref","first-page":"9925","DOI":"10.1038\/s41598-017-09793-y","article-title":"Transforming growth factor beta is regulated by a glucocorticoid-dependent mechanism in denervation mouse bone","volume":"7","author":"Y Li","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0344279.ref024","doi-asserted-by":"crossref","first-page":"4982","DOI":"10.1038\/s41598-017-05226-y","article-title":"The production of fibroblast growth factor 23 is controlled by TGF-\u03b22","volume":"7","author":"M Feger","year":"2017","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0344279.ref025","first-page":"229","article-title":"FGF23 promotes renal calcium reabsorption through the TRPV5 channel","volume":"33","author":"O Andrukhova","year":"2014","journal-title":"EMBO J"},{"issue":"1","key":"pone.0344279.ref026","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13287-024-03761-w","article-title":"TGF-\u03b2 signaling regulates differentiation of MSCs in bone metabolism: Disputes among viewpoints","volume":"15","author":"E Wei","year":"2024","journal-title":"Stem Cell Res Ther"},{"key":"pone.0344279.ref027","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/B978-0-12-364935-5.50009-2","article-title":"Pathology of recombinant human transforming growth factor-beta 1 in rats and rabbits","author":"TG Terrell","year":"1993","journal-title":"Int Rev Exp Pathol"},{"issue":"2","key":"pone.0344279.ref028","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1111\/j.1601-0825.1995.tb00166.x","article-title":"Transforming growth factor-beta 1 coated beta-tricalcium phosphate pellets stimulate healing of experimental bone defects of rat calvariae","volume":"1","author":"K Okuda","year":"1995","journal-title":"Oral Dis"},{"key":"pone.0344279.ref029","doi-asserted-by":"crossref","first-page":"721775","DOI":"10.3389\/fphys.2021.721775","article-title":"TGF-Beta Receptor II Is critical for osteogenic progenitor cell proliferation and differentiation during postnatal alveolar bone formation","volume":"12","author":"C Xu","year":"2021","journal-title":"Front Physiol"},{"issue":"11","key":"pone.0344279.ref030","article-title":"TGF-\u03b2\/Smad2 signalling regulates enchondral bone formation of Gli1+ periosteal cells during fracture healing","volume":"53","author":"C Xia","year":"2020","journal-title":"Cell Prolif"},{"issue":"13","key":"pone.0344279.ref031","doi-asserted-by":"crossref","first-page":"6651","DOI":"10.3390\/ijms22136651","article-title":"Osteoblast differentiation and signaling: Established concepts and emerging topics","volume":"22","author":"M Ponzetti","year":"2021","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0344279.ref032","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/jcb.240550312","article-title":"Role of active and latent transforming growth factor beta in bone formation","volume":"55","author":"LF Bonewald","year":"1994","journal-title":"J Cell Biochem"},{"issue":"47","key":"pone.0344279.ref033","doi-asserted-by":"crossref","first-page":"7156","DOI":"10.1038\/sj.onc.1205937","article-title":"Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein","volume":"21","author":"K-S Lee","year":"2002","journal-title":"Oncogene"},{"key":"pone.0344279.ref034","article-title":"TGF-beta1 release from biodegradable polymer microparticles: Its effects on marrow stromal osteoblast function","author":"L Lu","year":"2001","journal-title":"J Bone Joint Surg Am"},{"issue":"5","key":"pone.0344279.ref035","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/cbf.3812","article-title":"Inhibition of TGF-\u03b2 type I receptor by SB505124 down-regulates osteoblast differentiation and mineralization of human mesenchymal stem cells","volume":"41","author":"N Almuraikhi","year":"2023","journal-title":"Cell Biochem Funct"},{"issue":"2","key":"pone.0344279.ref036","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/ijos.2015.14","article-title":"The Hedgehog signalling pathway in bone formation","volume":"7","author":"J Yang","year":"2015","journal-title":"Int J Oral Sci"},{"issue":"10","key":"pone.0344279.ref037","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/dvg.20768","article-title":"Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling","volume":"49","author":"K Lenton","year":"2011","journal-title":"Genesis"},{"issue":"6","key":"pone.0344279.ref038","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.bone.2009.08.009","article-title":"Sonic hedgehog alleviates the inhibitory effects of high glucose on the osteoblastic differentiation of bone marrow stromal cells","volume":"45","author":"C-C Guan","year":"2009","journal-title":"Bone"},{"issue":"1","key":"pone.0344279.ref039","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbrc.2015.09.139","article-title":"Expression pattern of sonic hedgehog signaling and calcitonin gene-related peptide in the socket healing process after tooth extraction","volume":"467","author":"P Pang","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"pone.0344279.ref040","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1089\/scd.2004.13.536","article-title":"Molecular mechanisms behind the dose-dependent differential activation of MAPK pathways induced by transforming growth factor-beta1 in hematopoietic cells","volume":"13","author":"VP Kale","year":"2004","journal-title":"Stem Cells Dev"},{"issue":"1","key":"pone.0344279.ref041","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/jcp.20036","article-title":"Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-beta regulation of osteoclast differentiation","volume":"200","author":"M Karst","year":"2004","journal-title":"J Cell Physiol"},{"issue":"9","key":"pone.0344279.ref042","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.3390\/cells9092073","article-title":"Osteoblast-Osteoclast Communication and Bone Homeostasis","volume":"9","author":"J-M Kim","year":"2020","journal-title":"Cells"},{"key":"pone.0344279.ref043","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.imlet.2018.12.003","article-title":"A dual role of TGF-\u03b2 in human osteoclast differentiation mediated by Smad1 versus Smad3 signaling","volume":"206","author":"B Lee","year":"2019","journal-title":"Immunol Lett"},{"issue":"5","key":"pone.0344279.ref044","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.4049\/jimmunol.0804314","article-title":"GM-CSF regulates fusion of mononuclear osteoclasts into bone-resorbing osteoclasts by activating the Ras\/ERK pathway","volume":"183","author":"MS Lee","year":"2009","journal-title":"J Immunol"},{"issue":"1","key":"pone.0344279.ref045","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1136\/ard.2008.104786","article-title":"Interleukin-1 is essential for systemic inflammatory bone loss","volume":"69","author":"K Polzer","year":"2010","journal-title":"Ann Rheum Dis"},{"issue":"9","key":"pone.0344279.ref046","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1002\/art.24781","article-title":"Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo","volume":"60","author":"R Axmann","year":"2009","journal-title":"Arthritis Rheum"},{"issue":"10","key":"pone.0344279.ref047","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1002\/eji.200838192","article-title":"IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells","volume":"38","author":"L Chen","year":"2008","journal-title":"Eur J Immunol"},{"key":"pone.0344279.ref048","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.bone.2018.01.027","article-title":"Efficacy of anti-IL-23 monotherapy versus combination therapy with anti-IL-17 in estrogen deficiency induced bone loss conditions","volume":"110","author":"P Shukla","year":"2018","journal-title":"Bone"},{"key":"pone.0344279.ref049","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1471-2121-8-4","article-title":"Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus","volume":"8","author":"KE Evans","year":"2007","journal-title":"BMC Cell Biol"},{"issue":"6","key":"pone.0344279.ref050","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1177\/154405910708600614","article-title":"IL-10 gene transfer attenuates P. gingivalis-induced inflammation","volume":"86","author":"Y Houri-Haddad","year":"2007","journal-title":"J Dent Res"},{"issue":"2","key":"pone.0344279.ref051","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1002\/art.27200","article-title":"Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling","volume":"62","author":"GD Kalliolias","year":"2010","journal-title":"Arthritis Rheum"},{"issue":"2","key":"pone.0344279.ref052","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1182\/blood-2007-03-082941","article-title":"The ubiquitin-mediated degradation of Jak1 modulates osteoclastogenesis by limiting interferon-beta-induced inhibitory signaling","volume":"111","author":"Y Lee","year":"2008","journal-title":"Blood"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0344279","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T18:40:34Z","timestamp":1772476834000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0344279"}},"subtitle":[],"editor":[{"given":"Khalid Said","family":"Mohammad","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,2]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0344279","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,2]]}}}