{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T10:13:08Z","timestamp":1766139188808,"version":"3.41.2"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To explore the gut microbiota and proteomic characteristics of hypothyroidism in the first half of pregnancy (referred to as hypothyroidism in the first half of pregnancy) and its association with Th (T helper cells, Th)1\/Th2 balance using metagenomics combined with proteomics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Stool and blood samples were collected from 20 hypothyroid (hypothyroidism group) and normal pregnant women (normal group) in the first half of pregnancy. Flora and proteomic characteristics were analyzed using metagenomics sequencing and 4D-DIA proteomics. Th1 and Th2 cells were quantified, and cytokine levels were measured using cellular micro-bead arra. The enzyme-linked immunosorbent test (ELISA) was utilized to assess differential proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>(1) Metagenomic sequencing revealed distinct microbial profiles: The \u03b2-diversity of gut microbiota was diminished in the hypothyroidism group (p &amp;lt; 0.05). LEfSe analysis identified <jats:italic>Phocaeicola vulgatus<\/jats:italic> and <jats:italic>Bacteroides fragilis<\/jats:italic> enriched in the hypothyroidism group (p&amp;lt;0.05), and Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis showed significant enrichment in pathways related to peptidoglycan biosynthesis and glycerol ester metabolism.(2) Proteomic analysis demonstrated downregulation of Diacylglycerol Kinase Kappa (DGKK) and P05109|S10A8(S10A8) proteins in the hypothyroidism group, with marked enrichment in the KEGG pathways for vascular smooth muscle contraction and phosphatidylinositol signaling. (3) ELISA validation confirmed that the proteins DGKK and S10A8 were downregulated in pregnant women in the hypothyroidism group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Increased <jats:italic>P. vulgatus<\/jats:italic> and <jats:italic>B. fragilis<\/jats:italic>, decreased DGKK and S10A8 proteins, and a left shift in the Th1\/Th2 balance in patients with hypothyroidism in the first half of pregnancy may be associated with the development of the disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1500866","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T10:55:33Z","timestamp":1747306533000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["An exploratory study on the metagenomic and proteomic characterization of hypothyroidism in the first half of pregnancy and correlation with Th1\/Th2 balance"],"prefix":"10.3389","volume":"16","author":[{"given":"Chenchen","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zongzong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yixin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengkun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn311282-20220416-00234","article-title":"Guidelines for prevention and management of thyroid diseases during pregnancy and perinatal period","volume":"38","year":"2022","journal-title":"Chin J Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00604-z","article-title":"Assessment and treatment of thyroid disorders in pregnancy and the postpartum period","volume":"18","author":"Lee","year":"2022","journal-title":"Nat Rev Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e","DOI":"10.61622\/rbgo\/2024rbgo72","article-title":"Biochemical markers for prediction of the first half pregnancy losses: a review","volume":"46","author":"Kuspanova","year":"2024","journal-title":"Rev Bras Ginecol Obstet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1600266","article-title":"The Human Intestinal Microbiome in Health and Disease","volume":"375","author":"Lynch","year":"2016","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.035","article-title":"The impact of the gut microbiota on human health: an integrative view","volume":"148","author":"Clemente","year":"2012","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1136\/annrheumdis-2021-eular.2783","article-title":"Pos0396 the level of peripheral regulatory t cells is associated with the changes of intestinal microbiota in patients with rheumatoid arthritis ann rheum dis","volume":"2","author":"Wu","year":"2021","journal-title":"Ann Rheum Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.943408","article-title":"The relationships between the gut microbiota and its metabolites with thyroid diseases","volume":"13","author":"Jiang","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1152\/ajpendo.00234.2020","article-title":"Oral and intestinal microbial features in pregnant women with hypothyroidism and their correlations with pregnancy outcomes","volume":"11","author":"Wang","year":"2020","journal-title":"Am J Physiol-Endoc M"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.792536","article-title":"Plasma Lipid Profile and Intestinal Microflora in Pregnancy Women With Hypothyroidism and Their Correlation With Pregnancy Outcomes","volume":"12","author":"Cai","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1159238","article-title":"Correlation between the intestinal microflora and peripheral blood Th1\/Th2 balance in hypothyroidism during the first half of pregnancy","volume":"13","author":"Wu","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1177\/1933719108329095","article-title":"Inflammation and pregnancy","volume":"1","author":"Challis","year":"2009","journal-title":"Reprod Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00015","article-title":"Cytokine Targeting by miRNAs in Autoimmune Diseases","volume":"10","author":"Salvi","year":"2019","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218011","article-title":"CD4 T Helper Cell Subsets and Related Human Immunological Disorders","volume":"21","author":"Zhu","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B14","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/bs.pmbts.2020.03.007","article-title":"Relationship between T cells and microbiota in health and disease","volume":"171","author":"Kageyama","year":"2020","journal-title":"Prog Mol Biol Transl Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.clim.2003.11.017","article-title":"Cytometric bead array: a multiplexed assay platform with applications in various areas of biology","volume":"2","author":"Morgan","year":"2004","journal-title":"Clin Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1111\/ijlh.13315","article-title":"Evaluation of the BD Stem Cell Enumeration Kit on the BD FACSCanto II flow cytometer using bd facscanto clinical and bd facsdiva software","volume":"1","author":"Rimac","year":"2021","journal-title":"Int J Lab Hematol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat Methods"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv033","article-title":"MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph","volume":"31","author":"Li","year":"2015","journal-title":"Bioinformatics"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0140821","DOI":"10.1128\/msystems.01408-21","article-title":"Using AnnoTree to Get More Assignments, Faster, in DIAMOND+MEGAN Microbiome Analysis","volume":"7","author":"Gautam","year":"2022","journal-title":"mSystems"},{"key":"B20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1186\/s12859-020-03591-6","article-title":"CDSnake: Snakemake pipeline for retrieval of annotated OTUs from paired-end reads using CD-HIT utilities","volume":"21","author":"Kondratenko","year":"2020","journal-title":"BMC Bioinf"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e0289693","DOI":"10.1371\/journal.pone.0289693","article-title":"Portable BLAST-like algorithm library and its implementations for command line, Python and R","volume":"18","author":"Schmid","year":"2023","journal-title":"PLoS One"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1155\/2024\/7709277","article-title":"What Are the Reliable Plasma Biomarkers for Mild Cognitive Impairment? A Clinical 4D Proteomics Study and Validation","volume":"2024","author":"Hou","year":"2024","journal-title":"Mediat Inflamm"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00909-14","article-title":"Preferential packing of acidic glycosidases and proteases into Bacteroides outer membrane vesicles","volume":"5","author":"Elhenawy","year":"2014","journal-title":"mBio"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.970725","article-title":"Bacteroides fragilis outer membrane vesicles preferentially activate innate immune receptors compared to their parent bacteria","volume":"13","author":"Gilmore","year":"2022","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/iai.32.1.225-231.1981","article-title":"Production of experimental ulcerative colitis in gnotobiotic guinea pigs with simplified microflora","volume":"32","author":"Onderdonk","year":"1981","journal-title":"Infect Immun"},{"key":"B26","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41564-021-01050-3","article-title":"Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity","volume":"1","author":"Mills","year":"2022","journal-title":"Nat Microbiol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/s41575-019-0209-8","article-title":"Gut microbiota in colorectal cancer: mechanisms of action and clinical applications","volume":"16","author":"Wong","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/nu14091893","article-title":"Intestinal Barrier Permeability in Allergic Diseases","volume":"14","author":"Niewiem","year":"2022","journal-title":"Nutrients"},{"key":"B29","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1089\/thy.2022.0491","article-title":"A Comprehensive Review of Thyroid Hormone Metabolism in the Gut and Its Clinical Implications","volume":"33","author":"Fenneman","year":"2023","journal-title":"Thyroid"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1042\/CS20200475","article-title":"Gut dysbiosis is associated with primary hypothyroidism with interaction on gut-thyroid axis","volume":"134","author":"Su","year":"2020","journal-title":"Clin Sci (Lond)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.469080","article-title":"Discovery of \u03b2-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase involved in the metabolism of N-glycans","volume":"288","author":"Nihira","year":"2013","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1039\/c6ob00320f","article-title":"Insights into the catalytic mechanism of N-acetylglucosaminidase glycoside hydrolase from Bacillus subtilis: a QM\/MM study","volume":"14","author":"Su","year":"2016","journal-title":"Org Biomol Chem"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.00498","article-title":"Outer Membrane Vesicles From Probiotic and Commensal Escherichia coli Activate NOD1-Mediated Immune Responses in Intestinal Epithelial Cells","volume":"9","author":"Ca\u00f1as","year":"2018","journal-title":"Front Microbiol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3892\/etm.2022.11750","article-title":"Promotion of IL\u221217\/NF\u2212\u03baB signaling in autoimmune thyroid diseases","volume":"25","author":"Lu","year":"2023","journal-title":"Exp Ther Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s11739-023-03374-w","article-title":"Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review","volume":"19","author":"Di Vincenzo","year":"2024","journal-title":"Intern Emerg Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1039\/d3fo03386d","article-title":"Highland barley \u03b2-glucan supplementation attenuated hepatic lipid accumulation in Western diet-induced non-alcoholic fatty liver disease mice by modulating gut microbiota","volume":"15","author":"Liu","year":"2024","journal-title":"Food Funct"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1210\/er.2008-0007","article-title":"Glycerolipid metabolism and signaling in health and disease","volume":"29","author":"Prentki","year":"2008","journal-title":"Endocr Rev"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1113\/JP282302","article-title":"Hydrogen peroxide and phosphoinositide metabolites synergistically regulate a cation current to influence neuroendocrine cell bursting","volume":"599","author":"Chauhan-Puri","year":"2021","journal-title":"J Physiol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(89)90323-8","article-title":"The de novo synthesis of molecular species of phosphatidylinositol from endogenously labeled CDP diacylglycerol in alveolar macrophage microsomes","volume":"268","author":"Nakagawa","year":"1989","journal-title":"Arch Biochem Biophys"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-3469","article-title":"The expression of dual oxidase, thyroid peroxidase, and caveolin-1 differs according to the type of immune response (TH1\/TH2) involved in thyroid autoimmune disorders","volume":"99","author":"Marique","year":"2014","journal-title":"J Clin Endocr Metab"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24043393","article-title":"Selenium, Iodine and Iron-Essential Trace Elements for Thyroid Hormone Synthesis and Metabolism","volume":"24","author":"K\u00f6hrle","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B42","doi-asserted-by":"publisher","first-page":"e40277","DOI":"10.1371\/journal.pone.0040277","article-title":"Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation","volume":"7","author":"Berthier","year":"2012","journal-title":"PLoS One"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2377fje","article-title":"The arachidonic acid-binding protein S100A8\/A9 promotes NADPH oxidase activation by interaction with p67phox and Rac-2","volume":"19","author":"Kerkhoff","year":"2005","journal-title":"FASEB J"},{"key":"B44","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1152\/ajpendo.00365.2023","article-title":"NADPH oxidase 4-derived hydrogen peroxide counterbalances testosterone-induced endothelial dysfunction and migration","volume":"6","author":"Alves","year":"2024","journal-title":"Am J Physiol-Endoc M"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2019.02.003","article-title":"Thyroid peroxidase as a dual active site enzyme: Focus on biosynthesis, hormonogenesis and thyroid disorders of autoimmunity and cancer","volume":"160","author":"Godlewska","year":"2019","journal-title":"Biochimie"},{"key":"B46","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s11658-023-00435-y","article-title":"Extracellular vesicles derived from CD4+ T cells carry DGKK to promote sepsis-induced lung injury by regulating oxidative stress and inflammation","volume":"2","author":"Tu","year":"2023","journal-title":"Cell Mol Biol Lett"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0366","article-title":"A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates\/Ca2+ cascade mediates TSH action on thyroid hormone synthesis","volume":"92","author":"Grasberger","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-018-9477-9","article-title":"Myo-inositol in autoimmune thyroiditis, and hypothyroidism","volume":"19","author":"Fallahi","year":"2018","journal-title":"Rev Endocr Metab Dis"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfae069.190","article-title":"1610 FGF23-mediated hypertension via augmented calcium entry in vascular smooth muscle cells","volume":"39","author":"Mu\u00f1oz-Casta\u00f1eda","year":"2024","journal-title":"Nephrol Dial Transpl"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2024.149961","article-title":"Nardilysin in vascular smooth muscle cells controls blood pressure via the regulation of calcium dynamics","author":"Batbaatar","year":"2024","journal-title":"Biochem Bioph Res Co"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1509-z","article-title":"Canonical transient receptor potential channel 2 (TRPC2): old name-new games. Importance in regulating of rat thyroid cell physiology","volume":"466","author":"T\u00f6rnquist","year":"2014","journal-title":"Pflugers Arch"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2018.5825","article-title":"Immunological changes of T helper cells in flow cytometer-sorted CD4+ T cells from patients with Hashimoto\u2019s thyroiditis","volume":"15","author":"Guo","year":"2018","journal-title":"Exp Ther Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2023.101773","article-title":"Chemokines in thyroid autoimmunity","volume":"37","author":"Ferrari","year":"2023","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-08-0092","article-title":"Differential expression of Fas system apoptotic molecules in peripheral lymphocytes from patients with Graves\u2019 disease and Hashimoto\u2019s thyroiditis","volume":"158","author":"Fountoulakis","year":"2008","journal-title":"Eur J Endocrinol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.10.016","article-title":"Autoimmune thyroid disorders","volume":"14","author":"Antonelli","year":"2015","journal-title":"Autoimmun Rev"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2019.101367","article-title":"Hashimotos\u2019 thyroiditis: Epidemiology, pathogenesis, clinic and therapy","volume":"33","author":"Ragusa","year":"2019","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.107183","article-title":"Bacteroides thetaiotaomicron relieves colon inflammation by activating aryl hydrocarbon receptor and modulating CD4+T cell homeostasis","volume":"90","author":"Li","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e21798","DOI":"10.1096\/fj.202101013","article-title":"S100A8 may govern hyper-inflammation in severe COVID-19","volume":"35","author":"Deguchi","year":"2021","journal-title":"FASEB J"},{"key":"B59","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.celrep.2023.113006","article-title":"S100A8\/A9-alarmin promotes local myeloid-derived suppressor cell activation restricting severe autoimmune arthritis","volume":"7","author":"von Wulffen","year":"2023","journal-title":"Cell Rep"},{"key":"B60","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/cbin.11955","article-title":"Dominant immune cells in pregnancy and pregnancy complications: T helper cells (TH1\/TH2, TH17\/Treg cells), NK cells, MDSCs, and the immune checkpoints","volume":"2","author":"Esparvarinha","year":"2023","journal-title":"Cell Biol Int"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05631-4","article-title":"Fc\u03b3RIIIA activation-mediated up-regulation of glycolysis alters MDSCs modulation in CD4+ T cell subsets of Sj\u00f6gren syndrome","volume":"1","author":"Qi","year":"2023","journal-title":"Cell Death Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1500866\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T10:55:35Z","timestamp":1747306535000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1500866\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":61,"alternative-id":["10.3389\/fimmu.2025.1500866"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1500866","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,5,15]]},"article-number":"1500866"}}