{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T18:59:19Z","timestamp":1785265159131,"version":"3.55.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,3,1]],"date-time":"2019-03-01T00:00:00Z","timestamp":1551398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Although the expansion of myeloid-derived suppressor cells (MDSCs) has been reported in autoimmune disorders, it is largely unclear how MDSCs contribute to the development of primary Sj\u00f6gren syndrome (pSS). In this study, we found significantly increased MDSCs with gradually diminished suppressive capacity during disease development in mice with experimental Sj\u00f6gren syndrome (ESS). The ligand for glucocorticoid-induced TNFR family\u2013related protein (GITRL) was increased along ESS progression, whereas the increased GITRL was found to attenuate the immunosuppressive function of MDSCs. Moreover, blocking GITR signal in MDSCs significantly restored their immunosuppressive function and alleviated ESS progression in mice. In pSS patients, expanded MDSCs were found to express low levels of arginase. Significantly increased serum GITRL levels were closely correlated with patients with higher Sj\u00f6gren syndrome disease activity index. Furthermore, treatment with recombinant GITRL markedly reduced the immunosuppressive function of human MDSCs. Together, our studies have demonstrated a critical role of GITRL in modulating the suppressive function of MDSCs, which may facilitate the validation of GITRL as a therapeutic target for the treatment of pSS.<\/jats:p>","DOI":"10.4049\/jimmunol.1801051","type":"journal-article","created":{"date-parts":[[2019,2,13]],"date-time":"2019-02-13T20:45:52Z","timestamp":1550090752000},"page":"1693-1703","source":"Crossref","is-referenced-by-count":54,"title":["Increased GITRL Impairs the Function of Myeloid-Derived Suppressor Cells and Exacerbates Primary Sj\u00f6gren Syndrome"],"prefix":"10.1093","volume":"202","author":[{"given":"Jie","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Affiliated People\u2019s Hospital, Jiangsu University , Zhenjiang 212002 ,","place":["China"]},{"name":"Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University , Zhenjiang 212013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Rui","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University , Zhenjiang 212001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Hong","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University , Zhenjiang 212013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong , Hong Kong 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4540-452X","authenticated-orcid":false,"given":"Fan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong , Hong Kong 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong , Hong Kong 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ma","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University , Zhenjiang 212013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongye","family":"Guo","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University , Zhenjiang 212013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxi","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University , Zhenjiang 212013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kongyang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Second Clinical Medical College of Jinan University, Shenzhen People\u2019s Hospital , Shenzhen 518020 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Peking Union Medical College Hospital , Beijing 100730 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongzhou","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Second Clinical Medical College of Jinan University, Shenzhen People\u2019s Hospital , Shenzhen 518020 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Peking Union Medical College Hospital , Beijing 100730 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-0967","authenticated-orcid":false,"given":"Liwei","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shenzhen Institute of Research and Innovation, The University of Hong Kong , Hong Kong 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6584-1183","authenticated-orcid":false,"given":"Shengjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Affiliated People\u2019s Hospital, Jiangsu University , Zhenjiang 212002 ,","place":["China"]},{"name":"Jiangsu Key Laboratory of Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University , Zhenjiang 212013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,15]]},"reference":[{"key":"2025030417561217100_r1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S0140-6736(05)66990-5","article-title":"Sj\u00f6gren\u2019s syndrome","volume":"366","author":"Fox","year":"2005","journal-title":"Lancet"},{"key":"2025030417561217100_r2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nrrheum.2013.110","article-title":"Advances in understanding the pathogenesis of primary Sj\u00f6gren\u2019s syndrome","volume":"9","author":"Nocturne","year":"2013","journal-title":"Nat. Rev. Rheumatol."},{"key":"2025030417561217100_r3","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.autrev.2018.05.005","article-title":"Clinical and immunological parameters of Sj\u00f6gren\u2019s syndrome","volume":"17","author":"Psianou","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"2025030417561217100_r4","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.jaut.2012.05.019","article-title":"The T cell in Sjogren\u2019s syndrome: force majeure, not spectateur","volume":"39","author":"Singh","year":"2012","journal-title":"J. Autoimmun."},{"key":"2025030417561217100_r5","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.jaut.2012.05.014","article-title":"B cells in Sj\u00f6gren\u2019s syndrome: From pathophysiology to diagnosis and treatment","volume":"39","author":"Cornec","year":"2012","journal-title":"J. Autoimmun."},{"key":"2025030417561217100_r6","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.4049\/jimmunol.181.4.2898","article-title":"Identification of IL-18 and Th17 cells in salivary glands of patients with Sj\u00f6gren\u2019s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18","volume":"181","author":"Sakai","year":"2008","journal-title":"J. Immunol."},{"key":"2025030417561217100_r7","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1002\/art.23214","article-title":"Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sj\u00f6gren\u2019s syndrome: Findings in humans and mice","volume":"58","author":"Nguyen","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2025030417561217100_r8","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1136\/annrheumdis-2013-204584","article-title":"Th17 cells play a critical role in the development of experimental Sj\u00f6gren\u2019s syndrome","volume":"74","author":"Lin","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"2025030417561217100_r9","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/cmi.2017.8","article-title":"Proteasome inhibition suppresses Th17 cell generation and ameliorates autoimmune development in experimental Sj\u00f6gren\u2019s syndrome","volume":"14","author":"Xiao","year":"2017","journal-title":"Cell. Mol. Immunol."},{"key":"2025030417561217100_r10","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417561217100_r11","doi-asserted-by":"crossref","first-page":"7503","DOI":"10.1158\/0008-5472.CAN-09-2152","article-title":"Regulatory myeloid suppressor cells in health and disease","volume":"69","author":"Nagaraj","year":"2009","journal-title":"Cancer Res."},{"key":"2025030417561217100_r12","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3389\/fimmu.2018.00473","article-title":"Long non-coding RNA HOXA transcript antisense RNA myeloid-specific 1-HOXA1 axis downregulates the immunosuppressive activity of myeloid-derived suppressor cells in lung cancer","volume":"9","author":"Tian","year":"2018","journal-title":"Front. Immunol."},{"key":"2025030417561217100_r13","doi-asserted-by":"crossref","first-page":"5828","DOI":"10.4049\/jimmunol.0903636","article-title":"Myeloid-derived suppressor cells prevent type 1 diabetes in murine models","volume":"185","author":"Yin","year":"2010","journal-title":"J. Immunol."},{"key":"2025030417561217100_r14","doi-asserted-by":"crossref","first-page":"5228","DOI":"10.4049\/jimmunol.179.8.5228","article-title":"CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis","volume":"179","author":"Zhu","year":"2007","journal-title":"J. Immunol."},{"key":"2025030417561217100_r15","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.4049\/jimmunol.1101816","article-title":"Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. [Published erratum appears in 2014 J. Immunol. 192: 1334.]","volume":"188","author":"Ioannou","year":"2012","journal-title":"J. Immunol."},{"key":"2025030417561217100_r16","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.4049\/jimmunol.1200086","article-title":"Mouse CD11b+Gr-1+ myeloid cells can promote Th17 cell differentiation and experimental autoimmune encephalomyelitis","volume":"189","author":"Yi","year":"2012","journal-title":"J. Immunol."},{"key":"2025030417561217100_r17","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.4049\/jimmunol.1203535","article-title":"Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis","volume":"191","author":"Fujii","year":"2013","journal-title":"J. Immunol."},{"key":"2025030417561217100_r18","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1136\/annrheumdis-2014-205508","article-title":"Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis","volume":"75","author":"Guo","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"2025030417561217100_r19","doi-asserted-by":"crossref","first-page":"331ra40","DOI":"10.1126\/scitranslmed.aae0482","article-title":"Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus","volume":"8","author":"Wu","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"2025030417561217100_r20","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/art.39441","article-title":"Elimination of granulocytic myeloid-derived suppressor cells in lupus-prone mice linked to reactive oxygen species-dependent extracellular trap formation","volume":"68","author":"Vlachou","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"2025030417561217100_r21","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1042\/CS20160311","article-title":"Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs","volume":"130","author":"Ji","year":"2016","journal-title":"Clin. Sci. (Lond.)"},{"key":"2025030417561217100_r22","doi-asserted-by":"crossref","first-page":"7306","DOI":"10.4049\/jimmunol.172.12.7306","article-title":"Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells","volume":"172","author":"Kanamaru","year":"2004","journal-title":"J. Immunol."},{"key":"2025030417561217100_r23","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/sj.gene.6364026","article-title":"Cloning and characterization of GITR ligand","volume":"4","author":"Kim","year":"2003","journal-title":"Genes Immun."},{"key":"2025030417561217100_r24","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1615\/CritRevImmunol.v30.i6.40","article-title":"Role of the glucocorticoid-induced TNFR-related protein (GITR)-GITR ligand pathway in innate and adaptive immunity","volume":"30","author":"Azuma","year":"2010","journal-title":"Crit. Rev. Immunol."},{"key":"2025030417561217100_r25","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1073\/pnas.0710529105","article-title":"Evolution of GITRL immune function: Murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily","volume":"105","author":"Chattopadhyay","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417561217100_r26","doi-asserted-by":"crossref","first-page":"19452","DOI":"10.1073\/pnas.0709264104","article-title":"Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: Implications for function","volume":"104","author":"Chattopadhyay","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417561217100_r27","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nri1867","article-title":"The GITR-GITRL interaction: Co-stimulation or contrasuppression of regulatory activity?","volume":"6","author":"Shevach","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417561217100_r28","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1096\/fj.04-3556com","article-title":"Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis","volume":"19","author":"Cuzzocrea","year":"2005","journal-title":"FASEB J."},{"key":"2025030417561217100_r29","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.ajpath.2011.11.018","article-title":"Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells","volume":"180","author":"Wang","year":"2012","journal-title":"Am. J. Pathol."},{"key":"2025030417561217100_r30","doi-asserted-by":"crossref","first-page":"4686","DOI":"10.4049\/jimmunol.172.8.4686","article-title":"Cutting edge: Ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis","volume":"172","author":"Kohm","year":"2004","journal-title":"J. Immunol."},{"key":"2025030417561217100_r31","doi-asserted-by":"crossref","first-page":"e7848","DOI":"10.1371\/journal.pone.0007848","article-title":"Key role of the GITR\/GITRLigand pathway in the development of murine autoimmune diabetes: A potential therapeutic target","volume":"4","author":"You","year":"2009","journal-title":"PLoS One"},{"key":"2025030417561217100_r32","doi-asserted-by":"crossref","first-page":"340751","DOI":"10.1155\/2013\/340751","article-title":"Correlation of increased blood levels of GITR and GITRL with disease severity in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"2013","author":"Gan","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"2025030417561217100_r33","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3109\/08916934.2012.757307","article-title":"Sj\u00f6gren\u2019s syndrome-like autoimmune sialadenitis in MRL-Faslpr mice is associated with expression of glucocorticoid-induced TNF receptor-related protein (GITR) ligand and 4-1BB ligand","volume":"46","author":"Saito","year":"2013","journal-title":"Autoimmunity"},{"key":"2025030417561217100_r34","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.4049\/jimmunol.1500209","article-title":"MicroRNA-9 regulates the differentiation and function of myeloid-derived suppressor cells via targeting Runx1","volume":"195","author":"Tian","year":"2015","journal-title":"J. Immunol."},{"key":"2025030417561217100_r35","doi-asserted-by":"crossref","first-page":"15059","DOI":"10.1073\/pnas.2334901100","article-title":"Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells","volume":"100","author":"Tone","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417561217100_r36","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/cmi.2015.82","article-title":"Olfactory ecto-mesenchymal stem cells possess immunoregulatory function and suppress autoimmune arthritis","volume":"13","author":"Rui","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"2025030417561217100_r37","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1002\/eji.201242841","article-title":"\u03b2-Glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid-derived suppressor cells","volume":"43","author":"Tian","year":"2013","journal-title":"Eur. J. Immunol."},{"key":"2025030417561217100_r38","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.4049\/jimmunol.1400857","article-title":"Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis","volume":"193","author":"Li","year":"2014","journal-title":"J. Immunol."},{"key":"2025030417561217100_r39","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.4049\/jimmunol.1700617","article-title":"Myeloid-derived suppressor cells mediate inflammation resolution in humans and mice with autoimmune uveoretinitis","volume":"200","author":"Jeong","year":"2018","journal-title":"J. Immunol."},{"key":"2025030417561217100_r40","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.molimm.2018.07.016","article-title":"Myeloid-derived suppressor cells exacerbate Sj\u00f6gren\u2019s syndrome by inhibiting Th2 immune responses","volume":"101","author":"Qi","year":"2018","journal-title":"Mol. Immunol."},{"key":"2025030417561217100_r41","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.intimp.2011.01.026","article-title":"MDSC in autoimmunity","volume":"11","author":"Cripps","year":"2011","journal-title":"Int. Immunopharmacol."},{"key":"2025030417561217100_r42","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.bbadis.2015.10.015","article-title":"Myeloid derived suppressor cells in inflammatory conditions of the central nervous system","volume":"1862","author":"Melero-Jerez","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"2025030417561217100_r43","doi-asserted-by":"crossref","first-page":"2969","DOI":"10.1002\/eji.201040895","article-title":"The biology of myeloid-derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity","volume":"40","author":"Youn","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025030417561217100_r44","doi-asserted-by":"crossref","first-page":"4410","DOI":"10.4049\/jimmunol.172.7.4410","article-title":"Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response","volume":"172","author":"Sunderk\u00f6tter","year":"2004","journal-title":"J. Immunol."},{"key":"2025030417561217100_r45","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/eji.200324804","article-title":"GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations","volume":"34","author":"Ronchetti","year":"2004","journal-title":"Eur. J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/202\/6\/1693\/61419898\/ji1801051.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/202\/6\/1693\/61419898\/ji1801051.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T19:48:46Z","timestamp":1741117726000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/202\/6\/1693\/7952391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,3,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1801051","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,3]]},"published":{"date-parts":[[2019,3]]}}}