{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:06:03Z","timestamp":1790280363612,"version":"4.1.0"},"reference-count":64,"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":[{"name":"NSERC Discovery Grant","award":["RSP2024R357"],"award-info":[{"award-number":["RSP2024R357"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The cytotoxic T-lymphocyte antigen-4 (CTLA4) is essential in controlling T cell activity within the immune system. Thus, uncovering the molecular dynamics of single nucleotide polymorphisms (SNPs) within the <jats:italic>CTLA4<\/jats:italic> gene is critical. We identified the non-synonymous SNPs (nsSNPs), examined their impact on protein stability, and identified the protein sequences associated with them in the human <jats:italic>CTLA4<\/jats:italic> gene. There were 3134 SNPs (rsIDs) in our study. Out of these, 186 missense variants (5.93%), 1491 intron variants (47.57%), and 91 synonymous variants (2.90%), while the remaining SNPs were unspecified. We utilized SIFT, PolyPhen-2, PROVEAN, and SNAP for identifying deleterious nsSNPs, and SNPs&amp;GO, PhD SNP, and PANTHER for verifying risk nsSNPs in the <jats:italic>CTLA4<\/jats:italic> gene. Following SIFT analysis, six nsSNPs were identified as deleterious and reporting second and third nsSNPs as probably damaging and one as benign, respectively. From upstream analysis, rs138279736, rs201778935, rs369567630, and rs376038796 were found to be deleterious, probably damaging, and disease associated. ConSurf predicted conservation scores for four nsSNPs, and Project Hope suggested that all mutations could disrupt protein interactions. Furthermore, mCSM and DynaMut2 analyses indicated a decrease in \u0394\u0394G stability for the mutants. GeneMANIA and STRING networks highlighted correlations with <jats:italic>CD86<\/jats:italic> and <jats:italic>CD80<\/jats:italic> genes. Finally, MD simulation revealed consistent fluctuation in RMSD and RMSF, consequently Rg, hydrogen bonds, and PCA in the mutant proteins compared with wild-type, which might alter the functional and structural stability of CTLA4 protein. The current comprehensive study shows how various nsSNPs in the <jats:italic>CTLA4<\/jats:italic> gene can modify the structural and functional characteristics of the protein, potentially influencing the pathogenesis of diseases in humans. Further, experimental studies are needed to analyze the effect of these nsSNPs on the susceptibility of pathological phenotype populations.<\/jats:p>","DOI":"10.1371\/journal.pone.0316465","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T19:15:04Z","timestamp":1737746104000},"page":"e0316465","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigating the functional and structural effect of non-synonymous single nucleotide polymorphisms in the cytotoxic T-lymphocyte antigen-4 gene: An in-silico study"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0266-4711","authenticated-orcid":true,"given":"Md. 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Available: https:\/\/pubmed.ncbi.nlm.nih.gov\/8666782\/"},{"key":"pone.0316465.ref003","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.4049\/jimmunol.156.11.4154","article-title":"Regulation of CTLA-4 expression during T cell activation","volume":"156","author":"D Perkins","year":"1996","journal-title":"The Journal of Immunology"},{"key":"pone.0316465.ref004","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/1074-7613(95)90161-2","article-title":"CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-xL","volume":"3","author":"LH Boise","year":"1995","journal-title":"Immunity"},{"key":"pone.0316465.ref005","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1006\/geno.1999.5930","article-title":"Complete Sequence Determination of the Mouse and Human CTLA4 Gene Loci: Cross-Species DNA Sequence Similarity beyond Exon Borders","volume":"60","author":"V Ling","year":"1999","journal-title":"Genomics"},{"key":"pone.0316465.ref006","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.4049\/jimmunol.151.7.3489","article-title":"Characterization of CTLA-4 structure and expression on human T cells","volume":"151","author":"T Lindsten","year":"1993","journal-title":"The Journal of Immunology"},{"key":"pone.0316465.ref007","first-page":"2740","article-title":"CTLA-4 gene polymorphism in Japanese patients with rheumatoid arthritis","volume":"27","author":"T Yanagawa","year":"2000","journal-title":"J Rheumatol"},{"key":"pone.0316465.ref008","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/sj.gene.6363933","article-title":"Association of the CTLA4 promoter region (-1661G allele) with type 1 diabetes in the South Moroccan population.","volume":"4","author":"L Bouqbis","year":"2003","journal-title":"Genes Immun"},{"key":"pone.0316465.ref009","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/1471-2407-7-173","article-title":"Association of CTLA-4 gene polymorphisms with sporadic breast cancer in Chinese Han population","volume":"7","author":"L Wang","year":"2007","journal-title":"BMC Cancer"},{"key":"pone.0316465.ref010","first-page":"2017","article-title":"CTLA-4 polymorphisms associate with breast cancer susceptibility in Asians: A meta-analysis.","author":"Z Dai","year":"2017","journal-title":"PeerJ"},{"key":"pone.0316465.ref011","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1111\/j.1440-1746.2007.04862.x","article-title":"CTLA-4 gene promoter and exon 1 polymorphisms in Iranian patients with gastric and colorectal cancers","volume":"22","author":"A Hadinia","year":"2007","journal-title":"J Gastroenterol Hepatol"},{"key":"pone.0316465.ref012","doi-asserted-by":"crossref","first-page":"1198365","DOI":"10.3389\/fimmu.2023.1198365","article-title":"Current understanding of CTLA-4: from mechanism to autoimmune diseases.","volume":"14","author":"MM Hossen","year":"2023","journal-title":"Front Immunol"},{"key":"pone.0316465.ref013","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1530\/eje.0.1480013","article-title":"Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves\u2019 ophthalmopathy in European and Japanese populations.","volume":"148","author":"T Bednarczuk","year":"2003","journal-title":"Eur J Endocrinol"},{"key":"pone.0316465.ref014","article-title":"REVIEW CTLA-4 and its role in autoimmune thyroid disease","author":"DA Chistiakov","year":"2003","journal-title":"J Mol Endocrinol"},{"key":"pone.0316465.ref015","doi-asserted-by":"crossref","first-page":"843","DOI":"10.2337\/diacare.26.3.843","article-title":"Association of the CTLA-4 Gene 49 A\/G Polymorphism With Type 1 Diabetes and Autoimmune Thyroid Disease in Japanese Children","volume":"26","author":"M Mochizuki","year":"2003","journal-title":"Diabetes Care"},{"key":"pone.0316465.ref016","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1080\/08916934.2018.1516759","article-title":"Increased circulating follicular regulatory T cells in Hashimoto\u2019s thyroiditis","volume":"51","author":"J Zhao","year":"2018","journal-title":"Autoimmunity"},{"key":"pone.0316465.ref017","doi-asserted-by":"crossref","first-page":"598076","DOI":"10.3389\/fmed.2021.598076","article-title":"The Association Between CTLA-4, CD80\/86, and CD28 Gene Polymorphisms and Rheumatoid Arthritis: An Original Study and Meta-Analysis.","volume":"8","author":"W Liu","year":"2021","journal-title":"Front Med (Lausanne)."},{"key":"pone.0316465.ref018","doi-asserted-by":"crossref","unstructured":"Liu J, Zhang HX. CTLA-4 Polymorphisms and Systemic Lupus Erythematosus: A Comprehensive Meta-Analysis. https:\/\/home.liebertpub.com\/gtmb. 2013;17: 226\u2013231. doi: 10.1089\/GTMB.2012.0302","DOI":"10.1089\/gtmb.2012.0302"},{"key":"pone.0316465.ref019","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1159\/000490025","article-title":"Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy","volume":"47","author":"Y Zhao","year":"2018","journal-title":"Cell Physiol Biochem"},{"key":"pone.0316465.ref020","doi-asserted-by":"crossref","first-page":"E19433","DOI":"10.1097\/MD.0000000000019433","article-title":"CTLA-4 rs5742909 polymorphism and cervical cancer risk: A meta-analysis","volume":"99","author":"SW Hu","year":"2020","journal-title":"Medicine"},{"key":"pone.0316465.ref021","doi-asserted-by":"crossref","first-page":"630","DOI":"10.3748\/wjg.v12.i4.630","article-title":"Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to chronic hepatitis B","volume":"12","author":"AH Mohammad Alizadeh","year":"2006","journal-title":"World J Gastroenterol"},{"key":"pone.0316465.ref022","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00251-015-0840-7","article-title":"A CT60G>A polymorphism in the CTLA-4 gene of the recipient may confer susceptibility to acute graft versus host disease after allogeneic hematopoietic stem cell transplantation","volume":"67","author":"L Karabon","year":"2015","journal-title":"Immunogenetics"},{"key":"pone.0316465.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12864-019-5533-4","article-title":"A high-throughput SNP discovery strategy for RNA-seq data","volume":"20","author":"Y Zhao","year":"2019","journal-title":"BMC Genomics"},{"key":"pone.0316465.ref024","first-page":"2022","article-title":"Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene.","author":"MNI Bappy","year":"2022","journal-title":"Genet Res (Camb)."},{"key":"pone.0316465.ref025","first-page":"1","article-title":"In silico functional, structural and pathogenicity analysis of missense single nucleotide polymorphisms in human MCM6 gene","volume":"14","author":"MM Kamal","year":"2024","journal-title":"Scientific Reports 2024 14:1."},{"key":"pone.0316465.ref026","first-page":"2012","article-title":"Analyzing effects of naturally occurring missense mutations.","author":"Z Zhang","year":"2012","journal-title":"Comput Math Methods Med."},{"key":"pone.0316465.ref027","doi-asserted-by":"crossref","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT web server: predicting effects of amino acid substitutions on proteins","volume":"40","author":"NL Sim","year":"2012","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0316465.ref028","first-page":"20.1","article-title":"Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2","volume":"76","author":"I Adzhubei","year":"2013","journal-title":"Curr Protoc Hum Genet"},{"key":"pone.0316465.ref029","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Y Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"pone.0316465.ref030","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1093\/nar\/gkm238","article-title":"SNAP: predict effect of non-synonymous polymorphisms on function","volume":"35","author":"Y Bromberg","year":"2007","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pone.0316465.ref031","first-page":"1","article-title":"WS-SNPs&GO: a web server for predicting the deleterious effect of human protein variants using functional annotation","volume":"14","author":"E Capriotti","year":"2013","journal-title":"BMC Genomics"},{"key":"pone.0316465.ref032","doi-asserted-by":"crossref","first-page":"W306","DOI":"10.1093\/nar\/gki375","article-title":"I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure","volume":"33","author":"E Capriotti","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"pone.0316465.ref033","doi-asserted-by":"crossref","first-page":"W215","DOI":"10.1093\/nar\/gkr363","article-title":"SDM\u2014a server for predicting effects of mutations on protein stability and malfunction","volume":"39","author":"CL Worth","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"pone.0316465.ref034","doi-asserted-by":"crossref","first-page":"W529","DOI":"10.1093\/nar\/gkq399","article-title":"ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids","volume":"38","author":"H Ashkenazy","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"pone.0316465.ref035","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-11-548","article-title":"Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces","volume":"11","author":"H Venselaar","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"pone.0316465.ref036","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/bioinformatics\/btt691","article-title":"mCSM: predicting the effects of mutations in proteins using graph-based signatures","volume":"30","author":"DEV Pires","year":"2014","journal-title":"Bioinformatics"},{"key":"pone.0316465.ref037","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/pro.3942","article-title":"DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations","volume":"30","author":"CH Rodrigues","year":"2021","journal-title":"Protein Science"},{"key":"pone.0316465.ref038","doi-asserted-by":"crossref","first-page":"W115","DOI":"10.1093\/nar\/gkt533","article-title":"GeneMANIA Prediction Server 2013 Update","volume":"41","author":"K Zuberi","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"pone.0316465.ref039","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"D Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pone.0316465.ref040","doi-asserted-by":"crossref","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs","volume":"47","author":"Y Liao","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pone.0316465.ref041","doi-asserted-by":"crossref","first-page":"28773","DOI":"10.1039\/D3RA03923D","article-title":"Natural defense against multi-drug resistant Pseudomonas aeruginosa: Cassia occidentalis L. in vitro and in silico antibacterial activity","volume":"13","author":"RR Imon","year":"2023","journal-title":"RSC Adv"},{"key":"pone.0316465.ref042","doi-asserted-by":"crossref","first-page":"9954","DOI":"10.1021\/jp003020w","article-title":"Structure and Dynamics of the TIP3P, SPC, and SPC\/E Water Models at 298 K","volume":"105","author":"P Mark","year":"2001","journal-title":"Journal of Physical Chemistry A"},{"key":"pone.0316465.ref043","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1021\/acs.jctc.8b01026","article-title":"OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules.","volume":"15","author":"K Roos","year":"2019","journal-title":"J Chem Theory Comput."},{"key":"pone.0316465.ref044","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1103\/PhysRevLett.80.2733","article-title":"Vibrational Dynamics of Folded Proteins: Significance of Slow and Fast Motions in Relation to Function and Stability","volume":"80","author":"I Bahar","year":"1998","journal-title":"Phys Rev Lett"},{"key":"pone.0316465.ref045","first-page":"271","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume":"322","author":"K Wing","year":"2008","journal-title":"Science (1979)."},{"key":"pone.0316465.ref046","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1182\/blood-2017-06-741033","article-title":"CTLA-4: a moving target in immunotherapy","volume":"131","author":"B Rowshanravan","year":"2018","journal-title":"Blood"},{"key":"pone.0316465.ref047","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4\u2013insufficient subjects","volume":"142","author":"C Schwab","year":"2018","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"pone.0316465.ref048","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.1016\/j.jmb.2013.07.014","article-title":"Molecular mechanisms of disease-causing missense mutations","volume":"425","author":"S Stefl","year":"2013","journal-title":"J Mol Biol"},{"key":"pone.0316465.ref049","first-page":"10","article-title":"Prediction and assessment of deleterious and disease causing nonsynonymous single nucleotide polymorphisms (nsSNPs) in human FOXP4 gene: An in-silico study.","author":"MM Kamal","year":"2024","journal-title":"Heliyon"},{"key":"pone.0316465.ref050","first-page":"1","article-title":"In Silico Functional and Structural Analysis of Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in Human Paired Box 4 Gene.","author":"MM Kamal","year":"2023","journal-title":"Biochem Genet"},{"key":"pone.0316465.ref051","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1002\/humu.21242","article-title":"Performance of protein stability predictors","volume":"31","author":"S Khan","year":"2010","journal-title":"Hum Mutat"},{"key":"pone.0316465.ref052","first-page":"5","article-title":"Real-time visualization and exploration of protein empty space with varying parameters","author":"O Strnad","year":"2013","journal-title":"Int J Adv Life Sci"},{"key":"pone.0316465.ref053","first-page":"1","article-title":"Introduction to Costimulation and Costimulatory Molecules.","author":"MA Mir","year":"2015","journal-title":"Developing Costimulatory Molecules for Immunotherapy of Diseases."},{"key":"pone.0316465.ref054","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/B978-0-12-802585-7.00002-9","volume-title":"Developing Costimulatory Molecules for Immunotherapy of Diseases","author":"MA Mir","year":"2015"},{"key":"pone.0316465.ref055","doi-asserted-by":"crossref","first-page":"e0268826","DOI":"10.1371\/journal.pone.0268826","article-title":"In silico functional and pathway analysis of risk genes and SNPs for type 2 diabetes in Asian population","volume":"17","author":"MN Islam","year":"2022","journal-title":"PLoS One"},{"key":"pone.0316465.ref056","doi-asserted-by":"crossref","DOI":"10.1039\/D1RA06842C","article-title":"GC-MS analysis of phytoconstituents from Ruellia prostrata and Senna tora and identification of potential anti-viral activity against SARS-CoV-2 \u2020.","author":"R Alam","year":"2021"},{"key":"pone.0316465.ref057","first-page":"98","article-title":"Association of CTLA-4 tagging polymorphisms and haplotypes with hepatocellular carcinoma risk: A case-control study.","author":"J Yang","year":"2019","journal-title":"Medicine"},{"key":"pone.0316465.ref058","doi-asserted-by":"crossref","first-page":"372","DOI":"10.4103\/1110-2098.141711","article-title":"Cytotoxic T-lymphocyte antigen-4 gene polymorphisms in hepatocellular carcinoma patients in Egypt.","volume":"27","author":"HH El-Said","year":"2014","journal-title":"Menoufia Medical Journal"},{"key":"pone.0316465.ref059","first-page":"22","article-title":"Association of CTLA-4 and IL-4 polymorphisms in viral induced liver cancer","author":"M Shabbir","year":"2022","journal-title":"BMC Cancer"},{"key":"pone.0316465.ref060","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1515\/med-2016-0052","article-title":"Correlation between CTLA-4 gene rs221775A>G single nucleotide polymorphism and multiple sclerosis susceptibility. A meta-analysis.","volume":"11","author":"X Haibing","year":"2016","journal-title":"Open Medicine (Poland)."},{"key":"pone.0316465.ref061","doi-asserted-by":"crossref","first-page":"162","DOI":"10.14740\/wjon1046w","article-title":"CTLA-4 Genetic Variants (rs11571317 and rs3087243): Role in Susceptibility and Progression of Breast Cancer.","volume":"8","author":"M Goske","year":"2017","journal-title":"World J Oncol"},{"key":"pone.0316465.ref062","doi-asserted-by":"crossref","first-page":"110614","DOI":"10.18632\/oncotarget.22702","article-title":"Association between rs3087243 and rs231775 polymorphism within the cytotoxic T-lymphocyte antigen 4 gene and Graves\u2019 disease: a case\/control study combined with meta-analyses","volume":"8","author":"Y Tu","year":"2017","journal-title":"Oncotarget"},{"key":"pone.0316465.ref063","first-page":"1","article-title":"Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene","volume":"12","author":"M Irfan","year":"2022","journal-title":"Scientific Reports 2022 12:1."},{"key":"pone.0316465.ref064","first-page":"132","article-title":"Association of the CTLA4 promoter region (\u22121661G allele) with type 1 diabetes in the South Moroccan population.","volume":"4","author":"L Bouqbis","year":"2003","journal-title":"Genes & Immunity 2003 4:2."}],"updated-by":[{"DOI":"10.1371\/journal.pone.0320345","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T00:00:00Z","timestamp":1741564800000}}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316465","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T19:15:23Z","timestamp":1737746123000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0316465"}},"subtitle":[],"editor":[{"given":"Rajesh Kumar","family":"Pathak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0316465","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]}}}