{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T23:55:30Z","timestamp":1776210930788,"version":"3.50.1"},"reference-count":54,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T00:00:00Z","timestamp":1698969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EPIGEN project research","award":["CPER FEDER 2019221-0022768"],"award-info":[{"award-number":["CPER FEDER 2019221-0022768"]}]},{"name":"Regional Council of La R\u00e9union","award":["CPER FEDER 2019221-0022768"],"award-info":[{"award-number":["CPER FEDER 2019221-0022768"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Infection by arthritogenic alphaviruses (aavs) can lead to reactive arthritis, which is characterized by inflammation and persistence of the virus; however, its mechanisms remain ill-characterized. Intriguingly, it has been shown that viral persistence still takes place in spite of robust innate and adaptive immune responses, characterized notably by the infiltration of macrophages (sources of TNF-alpha) as well as T\/NK cells (sources of IFN-gamma) in the infected joint. Aavs are known to target mesenchymal stem cells (MSCs) in the synovium, and we herein tested the hypothesis that the infection of MSCs may promote the expression of immunoregulators to skew the anti-viral cellular immune responses. We compared the regulated expression via human synovial MSCs of pro-inflammatory mediators (e.g., IL-1\u03b2, IL6, CCL2, miR-221-3p) to that of immunoregulators (e.g., IDO, TSG6, GAS6, miR146a-5p). We used human synovial tissue-derived MSCs which were infected with O\u2019Nyong-Nyong alphavirus (ONNV, class II aav) alone, or combined with recombinant human TNF-\u03b1 or IFN-\u03b3, to mimic the clinical settings. We confirmed via qPCR and immunofluorescence that ONNV infected human synovial tissue-derived MSCs. Interestingly, ONNV alone did not regulate the expression of pro-inflammatory mediators. In contrast, IDO, TSG6, and GAS6 mRNA expression were increased in response to ONNV infection alone, but particularly when combined with both recombinant cytokines. ONNV infection equally decreased miR-146a-5p and miR-221-3p in the untreated cells and abrogated the stimulatory activity of the recombinant TNF-\u03b1 but not the IFN-gamma. Our study argues for a major immunoregulatory phenotype of MSCs infected with ONNV which may favor virus persistence in the inflamed joint.<\/jats:p>","DOI":"10.3390\/ijms242115932","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T02:41:56Z","timestamp":1698979316000},"page":"15932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Human Synovial Mesenchymal Stem Cells Expressed Immunoregulatory Factors IDO and TSG6 in a Context of Arthritis Mediated by Alphaviruses"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0690-5797","authenticated-orcid":false,"given":"Melissa","family":"Payet","sequence":"first","affiliation":[{"name":"Research Unit \u2018Etudes Pharmaco-Immunologiques\u2019 UR EPI, Universit\u00e9 de la R\u00e9union, 97400 Saint-Denis, La R\u00e9union, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4335-9016","authenticated-orcid":false,"given":"Axelle","family":"Septembre-Malaterre","sequence":"additional","affiliation":[{"name":"Research Unit \u2018Etudes Pharmaco-Immunologiques\u2019 UR EPI, Universit\u00e9 de la R\u00e9union, 97400 Saint-Denis, La R\u00e9union, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-8063","authenticated-orcid":false,"given":"Philippe","family":"Gasque","sequence":"additional","affiliation":[{"name":"Research Unit \u2018Etudes Pharmaco-Immunologiques\u2019 UR EPI, Universit\u00e9 de la R\u00e9union, 97400 Saint-Denis, La R\u00e9union, France"},{"name":"Immunology Laboratory (LICE-OI), CHU Bellepierre, Reunion University Hospital, 97400 Saint-Denis, La R\u00e9union, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Guillot","sequence":"additional","affiliation":[{"name":"Research Unit \u2018Etudes Pharmaco-Immunologiques\u2019 UR EPI, Universit\u00e9 de la R\u00e9union, 97400 Saint-Denis, La R\u00e9union, France"},{"name":"Rheumatology Clinical Department, CHU Bellepierre, Reunion University Hospital, 97400 Saint-Denis, La R\u00e9union, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mostafavi, H., Abeyratne, E., Zaid, A., and Taylor, A. (2019). Arthritogenic Alphavirus-Induced Immunopathology and Targeting Host Inflammation as a Therapeutic Strategy for Alphaviral Disease. Viruses, 11.","DOI":"10.3390\/v11030290"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41572-023-00429-2","article-title":"Chikungunya Fever","volume":"9","author":"Bartholomeeusen","year":"2023","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/BOR.0b013e328303220b","article-title":"Alphaviruses: An Emerging Cause of Arthritis?","volume":"20","author":"Toivanen","year":"2008","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1097\/01.bor.0000130537.76808.26","article-title":"Clinical and Pathologic Aspects of Arthritis Due to Ross River Virus and Other Alphaviruses","volume":"16","author":"Suhrbier","year":"2004","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nrrheum.2012.64","article-title":"Arthritogenic Alphaviruses\u2014An Overview","volume":"8","author":"Suhrbier","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/nri888","article-title":"Viruses and Interferon: A Fight for Supremacy","volume":"2","author":"Katze","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Couderc, T., Chretien, F., Schilte, C., Disson, O., Brigitte, M., Guivel-Benhassine, F., Touret, Y., Barau, G., Cayet, N., and Schuffenecker, I. (2008). A Mouse Model for Chikungunya: Young Age and Inefficient Type-I Interferon Signaling Are Risk Factors for Severe Disease. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.0040029"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8021","DOI":"10.1128\/JVI.02603-09","article-title":"Chikungunya Virus Arthritis in Adult Wild-Type Mice","volume":"84","author":"Gardner","year":"2010","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1056\/NEJMc1505501","article-title":"Chikungunya Virus Infections","volume":"373","author":"Simon","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5903","DOI":"10.4049\/jimmunol.0904181","article-title":"Active Infection of Human Blood Monocytes by Chikungunya Virus Triggers an Innate Immune Response","volume":"184","author":"Her","year":"2010","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000025023","article-title":"An Arthrogenic Alphavirus Induces Monocyte Chemoattractant Protein-1 and Interleukin-8","volume":"43","author":"Mateo","year":"2000","journal-title":"Intervirology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/infdis\/jiq042","article-title":"Persistent Arthralgia Induced by Chikungunya Virus Infection Is Associated with Interleukin-6 and Granulocyte Macrophage Colony-Stimulating Factor","volume":"203","author":"Chow","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kelvin, A.A., Banner, D., Silvi, G., Moro, M.L., Spataro, N., Gaibani, P., Cavrini, F., Pierro, A., Rossini, G., and Cameron, M.J. (2011). Inflammatory Cytokine Expression Is Associated with Chikungunya Virus Resolution and Symptom Severity. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001279"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.tim.2014.09.005","article-title":"Arthritogenic Alphaviruses: New Insights into Arthritis and Bone Pathology","volume":"23","author":"Chen","year":"2014","journal-title":"Trends Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/j.micinf.2009.10.001","article-title":"Chikungunya Virus Takes Centre Stage in Virally Induced Arthritis: Possible Cellular and Molecular Mechanisms to Pathogenesis","volume":"11","author":"Das","year":"2009","journal-title":"Microbes Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1002\/art.30112","article-title":"Disease Exacerbation by Etanercept in a Mouse Model of Alphaviral Arthritis and Myositis","volume":"63","author":"Zaid","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10877","DOI":"10.1128\/JVI.00949-10","article-title":"Chikungunya Virus Nonstructural Protein 2 Inhibits Type I\/II Interferon-Stimulated JAK-STAT Signaling","volume":"84","author":"Fros","year":"2010","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/1743-422X-9-213","article-title":"Deciphering the Differential Response of Two Human Fibroblast Cell Lines Following Chikungunya Virus Infection","volume":"9","author":"Denizot","year":"2012","journal-title":"Virol. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1186\/1743-422X-8-432","article-title":"Chikungunya Triggers an Autophagic Process Which Promotes Viral Replication","volume":"8","author":"Gay","year":"2011","journal-title":"Virol. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1080\/22221751.2021.2000891","article-title":"Single-Cell Analysis of Arthritogenic Alphavirus-Infected Human Synovial Fibroblasts Links Low Abundance of Viral RNA to Induction of Innate Immunity and Arthralgia-Associated Gene Expression","volume":"10","author":"Pott","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/s41586-018-0121-3","article-title":"Mxra8 Is a Receptor for Multiple Arthritogenic Alphaviruses","volume":"557","author":"Zhang","year":"2018","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ba\u010denkov\u00e1, D., Trebu\u0148ov\u00e1, M., Morochovi\u010d, R., Dosedla, E., Findrik Balogov\u00e1, A., Ga\u0161parov\u00e1, P., and \u017div\u010d\u00e1k, J. (2022). Interaction between Mesenchymal Stem Cells and the Immune System in Rheumatoid Arthritis. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080941"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1242\/jcs.00407","article-title":"TSG-6: A Multifunctional Protein Associated with Inflammation","volume":"116","author":"Milner","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.it.2012.10.001","article-title":"Indoleamine 2,3 Dioxygenase and Metabolic Control of Immune Responses","volume":"34","author":"Munn","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1038\/s41418-017-0006-2","article-title":"Kynurenic Acid, an IDO Metabolite, Controls TSG-6-Mediated Immunosuppression of Human Mesenchymal Stem Cells","volume":"25","author":"Wang","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E8151","DOI":"10.1073\/pnas.1614935113","article-title":"TNF\u03b1-Stimulated Gene-6 (TSG6) Activates Macrophage Phenotype Transition to Prevent Inflammatory Lung Injury","volume":"113","author":"Mittal","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12627","DOI":"10.1074\/jbc.M116.720953","article-title":"The Anti-Inflammatory Protein TSG-6 Regulates Chemokine Function by Inhibiting Chemokine\/Glycosaminoglycan Interactions","volume":"291","author":"Dyer","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16766","DOI":"10.1073\/pnas.1416121111","article-title":"TSG-6 as a Biomarker to Predict Efficacy of Human Mesenchymal Stem\/Progenitor Cells (hMSCs) in Modulating Sterile Inflammation in Vivo","volume":"111","author":"Lee","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1182\/blood-2013-09-528752","article-title":"TAM Receptors, Gas6, and Protein S: Roles in Inflammation and Hemostasis","volume":"123","year":"2014","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.4049\/jimmunol.162.6.3498","article-title":"A Novel Receptor Tyrosine Kinase, Mer, Inhibits TNF-Alpha Production and Lipopolysaccharide-Induced Endotoxic Shock","volume":"162","author":"Camenisch","year":"1999","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.cell.2007.10.034","article-title":"TAM Receptors Are Pleiotropic Inhibitors of the Innate Immune Response","volume":"131","author":"Rothlin","year":"2007","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/art.37786","article-title":"Therapeutic Efficacy of Tyro3, Axl, and MerTK Agonists in Collagen-Induced Arthritis","volume":"65","author":"Vermeij","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Payet, M., Dargai, F., Gasque, P., and Guillot, X. (2021). Epigenetic Regulation (Including Micro-RNAs, DNA Methylation and Histone Modifications) of Rheumatoid Arthritis: A Systematic Review. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212170"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/nm.2815","article-title":"The microRNA miR-23b Suppresses IL-17-Associated Autoimmune Inflammation by Targeting TAB2, TAB3 and IKK-\u03b1","volume":"18","author":"Zhu","year":"2012","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.3892\/mmr.2015.3642","article-title":"Downregulation of microRNA-221 Decreases Migration and Invasion in Fibroblast-like Synoviocytes in Rheumatoid Arthritis","volume":"12","author":"Yang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.3389\/fimmu.2019.03087","article-title":"miR-221-3p Drives the Shift of M2-Macrophages to a Pro-Inflammatory Function by Suppressing JAK3\/STAT3 Activation","volume":"10","author":"Quero","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5246","DOI":"10.4049\/jimmunol.179.8.5246","article-title":"Induction of Indoleamine 2,3-Dioxygenase in Vascular Smooth Muscle Cells by Interferon-Gamma Contributes to Medial Immunoprivilege","volume":"179","author":"Cuffy","year":"2007","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.stem.2013.09.006","article-title":"Mesenchymal Stromal Cells: Sensors and Switchers of Inflammation","volume":"13","author":"Bernardo","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/icb.2012.56","article-title":"Mechanisms of Mesenchymal Stromal Cell Immunomodulation","volume":"91","author":"English","year":"2013","journal-title":"Immunol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.stem.2007.11.014","article-title":"Mesenchymal Stem Cell-Mediated Immunosuppression Occurs via Concerted Action of Chemokines and Nitric Oxide","volume":"2","author":"Ren","year":"2008","journal-title":"Cell Stem Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1002\/stem.118","article-title":"Species Variation in the Mechanisms of Mesenchymal Stem Cell-Mediated Immunosuppression","volume":"27","author":"Ren","year":"2009","journal-title":"Stem Cells"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1182\/blood-2006-11-056010","article-title":"Noncanonical NF-kappaB Signaling in Dendritic Cells Is Required for Indoleamine 2,3-Dioxygenase (IDO) Induction and Immune Regulation","volume":"110","author":"Tas","year":"2007","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1186\/s13287-022-03075-9","article-title":"Exosome from Indoleamine 2,3-Dioxygenase-Overexpressing Bone Marrow Mesenchymal Stem Cells Accelerates Repair Process of Ischemia\/Reperfusion-Induced Acute Kidney Injury by Regulating Macrophages Polarization","volume":"13","author":"Xie","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101617","DOI":"10.1016\/j.molmet.2022.101617","article-title":"Indoleamine 2,3-Dioxygenase Mediates the Therapeutic Effects of Adipose-Derived Stromal\/Stem Cells in Experimental Periodontitis by Modulating Macrophages through the Kynurenine-AhR-NRF2 Pathway","volume":"66","author":"Li","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"41","DOI":"10.4137\/IJTR.S26862","article-title":"Tryptophan Catabolism in Chronic Viral Infections: Handling Uninvited Guests","volume":"8","author":"Mehraj","year":"2015","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5914","DOI":"10.4049\/jimmunol.0900255","article-title":"Persistent Chronic Inflammation and Infection by Chikungunya Arthritogenic Alphavirus in Spite of a Robust Host Immune Response","volume":"184","author":"Hoarau","year":"2010","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1083\/jcb.116.2.545","article-title":"A Novel Secretory Tumor Necrosis Factor-Inducible Protein (TSG-6) Is a Member of the Family of Hyaluronate Binding Proteins, Closely Related to the Adhesion Receptor CD44","volume":"116","author":"Lee","year":"1992","journal-title":"J. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6593","DOI":"10.4049\/jimmunol.151.11.6593","article-title":"TSG-6: A TNF-, IL-1-, and LPS-Inducible Secreted Glycoprotein Associated with Arthritis","volume":"151","author":"Wisniewski","year":"1993","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1053\/joca.2000.0348","article-title":"Up-Regulation and Differential Expression of the Hyaluronan-Binding Protein TSG-6 in Cartilage and Synovium in Rheumatoid Arthritis and Osteoarthritis","volume":"9","author":"Bayliss","year":"2001","journal-title":"Osteoarthr. Cartil."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1002\/art.10503","article-title":"Reduced Susceptibility to Collagen-Induced Arthritis in DBA\/1J Mice Expressing the TSG-6 Transgene","volume":"46","author":"Mindrescu","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0002-9440(10)63018-0","article-title":"Anti-Inflammatory and Chondroprotective Effect of TSG-6 (Tumor Necrosis Factor-\u03b1-Stimulated Gene-6) in Murine Models of Experimental Arthritis","volume":"159","author":"Kamath","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"23944","DOI":"10.18632\/oncotarget.24050","article-title":"MicroRNA-146a Suppresses Rheumatoid Arthritis Fibroblast-like Synoviocytes Proliferation and Inflammatory Responses by Inhibiting the TLR4\/NF-kB Signaling","volume":"9","author":"Liu","year":"2018","journal-title":"Oncotarget"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Selvamani, S.P., Mishra, R., and Singh, S.K. (2014). Chikungunya Virus Exploits miR-146a to Regulate NF-\u03baB Pathway in Human Synovial Fibroblasts. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0103624"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1002\/art.23386","article-title":"Altered Expression of MicroRNA in Synovial Fibroblasts and Synovial Tissue in Rheumatoid Arthritis","volume":"58","author":"Stanczyk","year":"2008","journal-title":"Arthritis Rheum."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15932\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:16:25Z","timestamp":1760130985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/21\/15932"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,3]]},"references-count":54,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242115932"],"URL":"https:\/\/doi.org\/10.3390\/ijms242115932","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,3]]}}}