{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:53:16Z","timestamp":1790124796460,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bavarian Innovation Fund","award":["MAIN457_FVJE024"],"award-info":[{"award-number":["MAIN457_FVJE024"]}]},{"name":"Novartis Pharma","award":["MAIN457_FVJE024"],"award-info":[{"award-number":["MAIN457_FVJE024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Considering the high plasticity of FoxP3+ regulatory T (Treg) cells and Interleukin (IL)-17-producing Th17 cells, we hypothesized that a Th17 inflammatory milieu may impair the functional properties of Treg cells in chronic inflammatory arthritides. Therefore, a cross-sectional explorative analysis was set up in patients with psoriatic arthritis (PsoA), rheumatoid arthritis, or spondyloarthritis to investigate the features of Th17 and Treg cells. T cell subpopulation counts, FOXP3 mRNA expression, CpG methylation of the FOXP3 gene, and the suppressive capacity of isolated Treg cells were determined. Ex vivo analysis of PsoA-derived peripheral blood lymphocytes showed a Th17-mediated inflammation. It was accompanied by demethylation of the FOXP3 promotor and Treg-specific demethylated region (TSDR) in Treg cells which, however, resulted neither in elevated FOXP3 mRNA expression nor in increased suppressive Treg cell capacity. To clarify this conundrum, in vitro stimulation of isolated Treg cells with Th17-inducing cytokines (IL-1\u03b2, IL-6, IL-23, TGF\u03b2), recombinant IL-17, or the anti-IL-17A antibody secukinumab was performed, demonstrating that cell culture conditions polarizing towards Th17, but not IL-17 itself, impair the suppressive function of Treg cells, accompanied by diminished FOXP3 mRNA expression due to hypermethylation of the FOXP3 promotor and TSDR. This potential causal relationship between Th17 inflammation and impaired Treg cell function requires attention regarding the development of immunomodulatory therapies.<\/jats:p>","DOI":"10.3390\/ijms26157339","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T16:16:10Z","timestamp":1753805770000},"page":"7339","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Influence of a Th17-Inducing Cytokine Milieu on Phenotypical and Functional Properties of Regulatory T Cells in Chronic Inflammatory Arthritis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3004-4067","authenticated-orcid":false,"given":"Tobias","family":"Schwarz","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Almanzar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Wulfheide","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Woidich","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2064-6728","authenticated-orcid":false,"given":"Marie-Therese","family":"Holzer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5970-982X","authenticated-orcid":false,"given":"Timotheos","family":"Christoforou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Karle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Radtke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Brauneiser","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0737-0763","authenticated-orcid":false,"given":"Thomas","family":"Haaf","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Wuerzburg, 97074 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-8104","authenticated-orcid":false,"given":"Ramya","family":"Potabattula","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Wuerzburg, 97074 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Ortega","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Molecular Psychiatry, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus-Peter","family":"Lesch","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Division of Molecular Psychiatry, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6600-3691","authenticated-orcid":false,"given":"Arne","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Rheumatology\/Clinical Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Benoit","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6421-9699","authenticated-orcid":false,"given":"Astrid","family":"Schmieder","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7095-9848","authenticated-orcid":false,"given":"Matthias","family":"Goebeler","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Schmalzing","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Rheumatology\/Clinical Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8028-8099","authenticated-orcid":false,"given":"Martin","family":"Feuchtenberger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Rheumatology\/Clinical Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"},{"name":"Department of Rheumatology, Med|Bayern Ost Medizinische Versorgungszentren Burghausen-Altoetting GmbH, 84489 Burghausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Prelog","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pediatric Rheumatology\/Special Immunology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/nri3707","article-title":"The IL-23\u2013IL-17 Immune Axis: From Mechanisms to Therapeutic Testing","volume":"14","author":"Gaffen","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/ni1254","article-title":"Interleukin 17\u2013Producing CD4+ Effector T Cells Develop via a Lineage Distinct from the T Helper Type 1 and 2 Lineages","volume":"6","author":"Harrington","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/ni1261","article-title":"A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17","volume":"6","author":"Park","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_4","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":"Lu","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Rodolfi, S., Davidson, C., and Vecellio, M. (2024). Regulatory T Cells in Spondyloarthropathies: Genetic Evidence, Functional Role, and Therapeutic Possibilities. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1303640"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R136","DOI":"10.1186\/ar4317","article-title":"Th17 and Th22 Cells in Psoriatic Arthritis and Psoriasis","volume":"15","author":"Benham","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kim, J., Moreno, A., and Krueger, J.G. (2022). The Imbalance between Type 17 T-Cells and Regulatory Immune Cell Subsets in Psoriasis Vulgaris. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1005115"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1084\/jem.20071397","article-title":"Preferential Recruitment of CCR6-Expressing Th17 Cells to Inflamed Joints via CCL20 in Rheumatoid Arthritis and Its Animal Model","volume":"204","author":"Hirota","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1084\/jem.20062259","article-title":"T Cell Self-Reactivity Forms a Cytokine Milieu for Spontaneous Development of IL-17+ Th Cells That Cause Autoimmune Arthritis","volume":"204","author":"Hirota","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1172\/JCI5703","article-title":"IL-17 in Synovial Fluids from Patients with Rheumatoid Arthritis Is a Potent Stimulator of Osteoclastogenesis","volume":"103","author":"Kotake","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhang, J., Liu, H., Chen, Y., Liu, H., Zhang, S., Yin, G., and Xie, Q. (2024). Augmenting Regulatory T Cells: New Therapeutic Strategy for Rheumatoid Arthritis. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1312919"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jiang, Q., Yang, G., Liu, Q., Wang, S., and Cui, D. (2021). Function and Role of Regulatory T Cells in Rheumatoid Arthritis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.626193"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3837","DOI":"10.1007\/s10067-022-06315-8","article-title":"Imbalance of Th17, Treg, and Helper Innate Lymphoid Cell in the Peripheral Blood of Patients with Rheumatoid Arthritis","volume":"41","author":"Wang","year":"2022","journal-title":"Clin. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1007\/s10753-016-0470-8","article-title":"Foxp3, Regulatory T Cell, and Autoimmune Diseases","volume":"40","author":"Tao","year":"2017","journal-title":"Inflammation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9358","DOI":"10.1074\/jbc.C600321200","article-title":"STAT3 Regulates Cytokine-Mediated Generation of Inflammatory Helper T Cells","volume":"282","author":"Yang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The Orphan Nuclear Receptor ROR\u03b3t Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1084\/jem.20041257","article-title":"IL-23 Drives a Pathogenic T Cell Population That Induces Autoimmune Inflammation","volume":"201","author":"Langrish","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.immuni.2009.02.007","article-title":"Critical Regulation of Early Th17 Cell Differentiation by Interleukin-1 Signaling","volume":"30","author":"Chung","year":"2009","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/ni.1993","article-title":"Fate Mapping of IL-17-Producing T Cells in Inflammatory Responses","volume":"12","author":"Hirota","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1007\/s00011-023-01808-x","article-title":"Treg Plasticity and Human Diseases","volume":"72","author":"Zhang","year":"2023","journal-title":"Inflamm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1189\/jlb.1RU0114-010RR","article-title":"IL-17+Foxp3+ T Cells: An Intermediate Differentiation Stage between Th17 Cells and Regulatory T Cells","volume":"96","author":"Du","year":"2014","journal-title":"J. Leukoc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nm.3432","article-title":"Pathogenic Conversion of Foxp3+ T Cells into TH17 Cells in Autoimmune Arthritis","volume":"20","author":"Komatsu","year":"2014","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1159\/000450949","article-title":"Disease Manifestation and Inflammatory Activity as Modulators of Th17\/Treg Balance and RORC\/FoxP3 Methylation in Systemic Sclerosis","volume":"171","author":"Almanzar","year":"2016","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12969-022-00680-z","article-title":"Mitigated Suppressive Function of Regulatory T Cells (Treg) upon Th17-Inducing Cytokines in Oligo- and Polyarticular Juvenile Idiopathic Arthritis (JIA) Patients","volume":"20","author":"Holzer","year":"2022","journal-title":"Pediatr. Rheumatol. Online J."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Schreiber, L., Pietzsch, B., Floess, S., Farah, C., J\u00e4nsch, L., Schmitz, I., and Huehn, J. (2014). The Treg-Specific Demethylated Region Stabilizes Foxp3 Expression Independently of NF-\u03baB Signaling. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088318"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3180","DOI":"10.4049\/jimmunol.1203473","article-title":"Active Demethylation of the Foxp3 Locus Leads to the Generation of Stable Regulatory T Cells within the Thymus","volume":"190","author":"Toker","year":"2013","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/nri2474","article-title":"Epigenetic Control of FOXP3 Expression: The Key to a Stable Regulatory T-Cell Lineage?","volume":"9","author":"Huehn","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ellmeier, W., and Taniuchi, I. (2014). Transcriptional Control of Regulatory T Cells. Transcriptional Control of Lineage Differentiation in Immune Cells, Springer International Publishing.","DOI":"10.1007\/978-3-319-07395-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.smim.2015.02.002","article-title":"Epigenetic and Transcriptional Control of Foxp3+ Regulatory T Cells","volume":"27","author":"Huehn","year":"2015","journal-title":"Semin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/eji.201747244","article-title":"Short-Term Cytokine Stimulation Reveals Regulatory T Cells with down-Regulated Foxp3 Expression in Human Peripheral Blood","volume":"48","author":"Tabares","year":"2018","journal-title":"Eur. J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.4049\/jimmunol.1003224","article-title":"CD4+FOXP3+ T Regulatory Cells in Human Autoimmunity: More than a Numbers Game","volume":"187","author":"Long","year":"2011","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.clim.2017.05.013","article-title":"Increased Proportions of Functionally Impaired Regulatory T Cell Subsets in Systemic Sclerosis","volume":"184","author":"Ugor","year":"2017","journal-title":"Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R93","DOI":"10.1186\/ar3817","article-title":"Synovial Cytokine Expression in Psoriatic Arthritis and Associations with Lymphoid Neogenesis and Clinical Features","volume":"14","author":"Celis","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100094","DOI":"10.1016\/j.xjidi.2021.100094","article-title":"Transcriptomic Profiling of Plaque Psoriasis and Cutaneous T-Cell Subsets during Treatment with Secukinumab","volume":"2","author":"Liu","year":"2021","journal-title":"JID Innov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1182\/blood-2009-05-219584","article-title":"Epigenetic Mechanisms of Regulation of Foxp3 Expression","volume":"114","author":"Lal","year":"2009","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.4049\/jimmunol.182.1.259","article-title":"Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation","volume":"182","author":"Lal","year":"2009","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Herppich, S., Toker, A., Pietzsch, B., Kitagawa, Y., Ohkura, N., Miyao, T., Floess, S., Hori, S., Sakaguchi, S., and Huehn, J. (2019). Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02382"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1084\/jem.20040165","article-title":"Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNF\u03b1 Therapy","volume":"200","author":"Ehrenstein","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Johnson, B., Cheng, L., Koenitzer, J., Catlett, I.M., and Schafer, P. (2024). Nonclinical Evaluations of Deucravacitinib and Janus Kinase Inhibitors in Homeostatic and Inflammatory Pathways. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1437512"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molimm.2020.08.002","article-title":"Decipher Manifestations and Treg\/Th17 Imbalance in Multi-Staging Rheumatoid Arthritis and Correlation with TSDR\/RORC Methylation","volume":"127","author":"Huang","year":"2020","journal-title":"Mol. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/art.39031","article-title":"Methotrexate Restores Regulatory T Cell Function through Demethylation of the FoxP3 Upstream Enhancer in Patients with Rheumatoid Arthritis","volume":"67","author":"Cribbs","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/intimm\/dxm014","article-title":"Activation-Induced FOXP3 in Human T Effector Cells Does Not Suppress Proliferation or Cytokine Production","volume":"19","author":"Allan","year":"2007","journal-title":"Int. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Potabattula, R., Dittrich, M., Schorsch, M., Hahn, T., Haaf, T., and El Hajj, N. (2019). Male Obesity Effects on Sperm and Next-Generation Cord Blood DNA Methylation. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0218615"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1093\/biomet\/93.3.491","article-title":"Adaptive Linear Step-up Procedures That Control the False Discovery Rate","volume":"93","author":"Benjamini","year":"2006","journal-title":"Biometrika"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7339\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:18:22Z","timestamp":1760033902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7339"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":44,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157339"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157339","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,29]]}}}