{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T09:39:44Z","timestamp":1789205984360,"version":"build-2803163510"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015179","name":"Transplantation Society","doi-asserted-by":"publisher","award":["TTS Grant 2022"],"award-info":[{"award-number":["TTS Grant 2022"]}],"id":[{"id":"10.13039\/100015179","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008061","name":"Fundaci\u00f3n Mutua Madrile\u00f1a","doi-asserted-by":"publisher","award":["MUTUA-2019"],"award-info":[{"award-number":["MUTUA-2019"]}],"id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["FIS PI21\/01332"],"award-info":[{"award-number":["FIS PI21\/01332"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Intestinal transplantation (ITx) represents the only curative option for patients with irreversible intestinal failure. Nevertheless, its rejection rate surpasses that of other solid organ transplants due to the heightened immunological load of the gut. Regulatory T-cells (Tregs) are key players in the induction and maintenance of peripheral tolerance, suggesting their potential involvement in modulating host\n                      <jats:italic>vs<\/jats:italic>\n                      . graft responses after ITx. Thus, we investigated the association of Tregs with allograft outcomes in pediatric patients and in an experimental model of small bowel transplantation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Treg frequency in human samples was analyzed by Flow cytometry (CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD25\n                      <jats:sup>high<\/jats:sup>\n                      CD127\n                      <jats:sup>-<\/jats:sup>\n                      , blood samples) and immunohistochemistry (FoxP3, graft samples). Experimental allogenic-heterotopic small bowel transplantation was performed in rats and animals divided into 3 groups: non-immunosuppressant treatment, rapamycin (2 mg\/kg), and tacrolimus (0.6 mg\/kg) treatment. Acute cellular rejection (ACR) was diagnosed based on clinical and histological findings, graft gene expression of pro- and anti-inflammatory mediators assessed by RT-qPCR, serum IL-6 and IL-10 levels by Luminex, and Treg frequency analyzed by flow cytometry (CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD25\n                      <jats:sup>high<\/jats:sup>\n                      FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Blood samples from patients undergoing ACR exhibited a significant reduction in the Treg number compared to those with normo-functional grafts. Similarly, a diminished number of FoxP3\n                      <jats:sup>+<\/jats:sup>\n                      cells was observed in mucosa samples with ACR. In the experimental model, rapamycin-treated animals displayed clinical and histological findings resembling those not receiving immunosuppression treatment. Notably, ACR correlated with a high CD8\/CD4 ratio, loss of T-cell chimerism, mRNA upregulation of pro-inflammatory genes and diminished graft Treg frequency. In contrast, tacrolimus treatment prevented ACR and facilitate blood and graft Treg expansion. Remarkably, recipients who achieved Treg expansion within the graft remained free of ACR even after discontinuation of the immunosuppressant treatment and this phenomenon was associated with increased levels of serum IL-10.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our clinical and experimental findings underscore the association between Treg frequency and graft rejection after ITx, advocating for strategies that promote their expansion within the gut mucosa to enhance long-term outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0307534","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T13:51:18Z","timestamp":1737726678000},"page":"e0307534","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Low regulatory T-cells frequency is associated with graft rejection after small bowel transplantation: Clinical and experimental evidence"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9020-2225","authenticated-orcid":true,"given":"Rodrigo","family":"Papa-Gobbi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Stringa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Virginia","family":"Gentilini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Ivanoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Machuca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nidia Monserrat","family":"Arreola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Serradilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Estefan\u00eda-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Talayero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Velayos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"S\u00e1nchez\u2014Zapardiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Gondolesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane","family":"Andr\u00e9s-Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Rumbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Hern\u00e1ndez-Oliveros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"pone.0307534.ref001","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/ajt.12979","article-title":"Intestinal transplant registry report: Global activity and trends","volume":"15","author":"D Grant","year":"2015","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref002","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.suc.2018.09.008","article-title":"Small Bowel Transplantation.","volume":"99","author":"S Kesseli","year":"2019","journal-title":"Surg Clin North Am"},{"key":"pone.0307534.ref003","first-page":"63","article-title":"Intestinal transplant. Review and description of its evolution in Latin America.","volume":"39","author":"GE Gondolesi","year":"2009","journal-title":"Acta Gastroenterol Latinoam"},{"key":"pone.0307534.ref004","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/MOG.0000000000000358","article-title":"Intestinal transplantation: A review","volume":"33","author":"L Loo","year":"2017","journal-title":"Curr. Opin. Gastroenterol"},{"key":"pone.0307534.ref005","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.00043","article-title":"Past, present, and future of regulatory T cell therapy in transplantation and autoimmunity","volume":"10","author":"M Romano","year":"2019","journal-title":"Front. Immunol"},{"key":"pone.0307534.ref006","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00555","article-title":"Regulatory T cell-derived exosomes: Possible therapeutic and diagnostic tools in transplantation.","author":"A Agarwal","year":"2014","journal-title":"Front. Immunol"},{"key":"pone.0307534.ref007","article-title":"Regulatory T cell-derived extracellular vesicles modify dendritic cell function","volume":"8","author":"SL Tung","year":"2018","journal-title":"Sci Rep"},{"key":"pone.0307534.ref008","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.immuni.2009.08.011","article-title":"Regulatory T Cells Reinforce Intestinal Homeostasis","volume":"31","author":"MJ Barnes","year":"2009","journal-title":"Immunity"},{"key":"pone.0307534.ref009","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nri.2017.75","article-title":"The regulation of immune tolerance by FOXP3","volume":"17","author":"L Lu","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"pone.0307534.ref010","article-title":"Early expansion of donor-specific Tregs in tolerant kidney transplant recipients.","author":"TM Savage","year":"2018","journal-title":"JCI insight"},{"key":"pone.0307534.ref011","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1111\/j.1600-6143.2004.00611.x","article-title":"Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation","volume":"4","author":"Y Li","year":"2004","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref012","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1016\/S0140-6736(20)30167-7","article-title":"Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1\/2A trials","volume":"395","author":"B Sawitzki","year":"2020","journal-title":"Lancet"},{"key":"pone.0307534.ref013","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.bj.2022.01.005","article-title":"Cell therapy in vascularized composite allotransplantation","volume":"45","author":"MR Anggelia","year":"2022","journal-title":"Biomed J"},{"key":"pone.0307534.ref014","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1111\/ajt.13815","article-title":"The Leuven immunomodulatory protocol promotes T-regulatory cells and substantially prolongs survival after first intestinal transplantation","volume":"16","author":"LJ Ceulemans","year":"2016","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref015","doi-asserted-by":"crossref","first-page":"3205","DOI":"10.1016\/j.transproceed.2006.10.093","article-title":"The Role of Foxp3+ Regulatory T Cells in Liver Transplant Tolerance","volume":"38","author":"W Li","year":"2006","journal-title":"Transplant Proc"},{"key":"pone.0307534.ref016","doi-asserted-by":"crossref","first-page":"e693","DOI":"10.1097\/TXD.0000000000001152","article-title":"The Presence of a Marked Imbalance Between Regulatory T Cells and Effector T Cells Reveals That Tolerance Mechanisms Could Be Compromised in Heart Transplant Children.","volume":"7","author":"E Bernaldo-de-Quir\u00f3s","year":"2021","journal-title":"Transplant Direct"},{"key":"pone.0307534.ref017","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1097\/TP.0000000000001379","article-title":"Impact of Immune-Modulatory Drugs on Regulatory T Cell","volume":"100","author":"A Furukawa","year":"2016","journal-title":"Transplantation"},{"key":"pone.0307534.ref018","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/cyto.b.21728","article-title":"Extended immunophenotyping reference values in a healthy pediatric population.","volume":"96","author":"M Garcia-Prat","year":"2019","journal-title":"Cytom Part B\u2014Clin Cytom"},{"key":"pone.0307534.ref019","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2022.1074577","article-title":"Antibody-removal therapies for de novo DSA in pediatric intestinal recipients: Why, when, and how? A single-center experience.","volume":"10","author":"M Lasa-L\u00e1zaro","year":"2023","journal-title":"Front Pediatr"},{"key":"pone.0307534.ref020","doi-asserted-by":"crossref","first-page":"e220","DOI":"10.1097\/TXD.0000000000000718","article-title":"Gut Permeability and Glucose Absorption Are Affected at Early Stages of Graft Rejection in a Small Bowel Transplant Rat Model.","volume":"3","author":"P Stringa","year":"2017","journal-title":"Transplant Direct"},{"key":"pone.0307534.ref021","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1111\/tri.13672","article-title":"Donor\u2019s graft ex vivo T-cell depletion with fludarabine reduces graft-versus-host disease signs and improves survival after intestinal transplantation\u2013an experimental study","volume":"33","author":"M Vela","year":"2020","journal-title":"Transpl Int"},{"key":"pone.0307534.ref022","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/ti.2023.10803","article-title":"Experimental Assessment of Intestinal Damage in Controlled Donation After Circulatory Death for Visceral Transplantation.","volume":"36","author":"P Stringa","year":"2023","journal-title":"Transpl Int"},{"key":"pone.0307534.ref023","doi-asserted-by":"crossref","DOI":"10.3389\/ti.2023.11518","article-title":"Preclinical Study of DCD and Normothermic Perfusion for Visceral Transplantation.","volume":"36","author":"J Serradilla","year":"2023","journal-title":"Transpl Int"},{"key":"pone.0307534.ref024","article-title":"Spatiotemporal regulation of galectin-1-induced T-cell death in lamina propria from Crohn\u2019s disease and ulcerative colitis patients","author":"R Papa-Gobbi","year":"2021","journal-title":"Apoptosis"},{"key":"pone.0307534.ref025","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1097\/01.TP.0000062840.49159.2F","article-title":"A schema for histologic grading of small intestine allograft acute rejection. In: Transplantation","author":"T Wu","year":"2003","journal-title":"Transplantation"},{"key":"pone.0307534.ref026","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2-\u0394\u0394CT method.","volume":"25","author":"KJ Livak","year":"2001","journal-title":"Methods"},{"key":"pone.0307534.ref027","doi-asserted-by":"crossref","DOI":"10.1002\/biof.1252","article-title":"A galectin-specific signature in the gut delineates Crohn\u2019s disease and ulcerative colitis from other human inflammatory intestinal disorders","volume":"42","author":"R Papa Gobbi","year":"2016","journal-title":"BioFactors"},{"key":"pone.0307534.ref028","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.amjsurg.2006.09.032","article-title":"Increased iNOS-expressing macrophage in long-term surviving rat small-bowel grafts","volume":"194","author":"X Li","year":"2007","journal-title":"Am J Surg"},{"key":"pone.0307534.ref029","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.trim.2011.07.005","article-title":"Effects of immunosuppressive therapy after experimental small bowel transplantation in rats","volume":"25","author":"T Pech","year":"2011","journal-title":"Transpl Immunol"},{"key":"pone.0307534.ref030","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.stem.2018.11.007","article-title":"Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool","volume":"24","author":"J Fu","year":"2019","journal-title":"Cell Stem Cell"},{"key":"pone.0307534.ref031","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1111\/ajt.13325","article-title":"Macrochimerism in Intestinal Transplantation: Association with Lower Rejection Rates and Multivisceral Transplants, Without GVHD.","volume":"15","author":"J Zuber","year":"2015","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref032","article-title":"Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation","volume":"131","author":"J Fu","year":"2021","journal-title":"J Clin Invest"},{"key":"pone.0307534.ref033","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/ajt.13435","article-title":"Innate lymphoid cells groups 1 and 3 in the epithelial compartment of functional human intestinal allografts.","volume":"16","author":"P Talayero","year":"2016","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref034","doi-asserted-by":"crossref","DOI":"10.1002\/cti2.1099","article-title":"Regulatory T cells in solid organ transplantation","volume":"9","author":"M Atif","year":"2020","journal-title":"Clin. Transl. Immunol"},{"key":"pone.0307534.ref035","article-title":"The Next Frontier of Regulatory T Cells: Promising Immunotherapy for Autoimmune Diseases and Organ Transplantations","volume":"11","author":"V. Terry L","year":"2020","journal-title":"Front. Immunol"},{"key":"pone.0307534.ref036","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2022\/6255339","article-title":"Mammalian Target of Rapamycin Inhibitors and Wound Healing Complications in Kidney Transplantation: Old Myths and New Realities.","volume":"2022","author":"MA Mabood Khalil","year":"2022","journal-title":"J Transplant"},{"key":"pone.0307534.ref037","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1097\/MOT.0b013e32835ef1eb","article-title":"Damink SWMO. New insights in intestinal ischemia-reperfusion injury: Implications for intestinal transplantation","volume":"18","author":"K Lenaerts","year":"2013","journal-title":"Curr. Opin. Organ Transplant"},{"key":"pone.0307534.ref038","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1111\/tri.13959","article-title":"Delayed introduction of sirolimus in paediatric intestinal transplant recipients: indications and long-term benefits.","volume":"34","author":"AM Andres","year":"2021","journal-title":"Transpl Int"},{"key":"pone.0307534.ref039","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.trim.2018.09.003","article-title":"Characterization of T cell immunophenotypes in intestinal transplantation: A pilot study","volume":"51","author":"MAR Guerra","year":"2018","journal-title":"Transpl Immunol"},{"key":"pone.0307534.ref040","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1111\/ctr.12464","article-title":"Immunosuppressive therapies after intestinal transplant modulate the expression of Th1 signature genes during acute cellular rejection. Implications in the search for rejection biomarkers","volume":"28","author":"A Zambernardi","year":"2014","journal-title":"Clin Transplant"},{"key":"pone.0307534.ref041","first-page":"S467","article-title":"CD4 + and CD8 + T cell subset distribution in the blood of small-bowel-grafted rats: modification during graft-versus-host disease","volume":"11","author":"A Marni","year":"1998","journal-title":"Transpl Int"},{"key":"pone.0307534.ref042","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1097\/TP.0000000000000491","article-title":"Role of innate and acquired immune mechanisms in clinical intestinal transplant rejection","volume":"99","author":"JM Mathew","year":"2015","journal-title":"Transplantation"},{"key":"pone.0307534.ref043","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1111\/ajt.12934","article-title":"Superiority of rapamycin over tacrolimus in preserving nonhuman primate treg half-life and phenotype after adoptive transfer.","volume":"14","author":"K Singh","year":"2014","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2020.00643","article-title":"Myeloid-Derived Suppressor Cells in Kidney Transplant Recipients and the Effect of Maintenance Immunotherapy.","volume":"11","author":"M Iglesias-Escudero","year":"2020","journal-title":"Front Immunol"},{"key":"pone.0307534.ref045","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1097\/01.TP.0000153505.73700.32","article-title":"Inhibitory and stimulatory effects of cyclosporine A on the development of regulatory T cells in vivo. In: Transplantation","author":"M Kawai","year":"2005","journal-title":"Transplantation"},{"key":"pone.0307534.ref046","doi-asserted-by":"crossref","first-page":"E1512","DOI":"10.1097\/TXD.0000000000001512","article-title":"The First Collective Examination of Immunosuppressive Practices Among American Intestinal Transplant Centers.","volume":"9","author":"J Weiner","year":"2023","journal-title":"Transplant Direct"},{"key":"pone.0307534.ref047","doi-asserted-by":"crossref","first-page":"G599","DOI":"10.1152\/ajpgi.00063.2004","article-title":"IL-10 modulates intestinal damage and epithelial cell apoptosis in T cell-mediated enteropathy","volume":"287","author":"P Zhou","year":"2004","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"pone.0307534.ref048","article-title":"IL-10 Modulates Th17 Pathogenicity during Autoimmune Diseases.","volume":"7","author":"B. Guo","year":"2016","journal-title":"J Clin Cell Immunol"},{"key":"pone.0307534.ref049","first-page":"1","article-title":"Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab","author":"A Kroemer","year":"2020","journal-title":"Am J Transplant"},{"key":"pone.0307534.ref050","article-title":"IL-34 Actions on FOXP3 + Tregs and CD14 + Monocytes Control Human Graft Rejection","volume":"11","author":"S B\u00e9zie","year":"2020","journal-title":"nt Immunol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0307534","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T13:51:36Z","timestamp":1737726696000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0307534"}},"subtitle":[],"editor":[{"given":"Justyna","family":"Go\u0142\u0119biewska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0307534","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]}}}