{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:55:20Z","timestamp":1753890920683,"version":"3.41.2"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"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. Genet."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> At a false discovery rate of &amp;lt;0.01, we identified 11 low-frequency AMD variants (minor allele frequency &amp;lt;0.05). Two of those variants were present in the complement <jats:italic>C4A<\/jats:italic> gene, including the replacement of the residues that contribute to the Rodgers-1\/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 (<jats:italic>p<\/jats:italic> = 3.2 \u00d7 10<jats:sup>\u22125<\/jats:sup>) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, <jats:italic>p<\/jats:italic> = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including <jats:italic>C4A<\/jats:italic>, which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD.<\/jats:p>","DOI":"10.3389\/fgene.2023.1274743","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T04:41:06Z","timestamp":1706503266000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration"],"prefix":"10.3389","volume":"14","author":[{"given":"Johanna M.","family":"Seddon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dikha","family":"De","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Casazza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun-Yun","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Punzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Daly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danlei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha L.","family":"Coss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John P.","family":"Atkinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chack-Yung","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. methods"},{"key":"B2","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/s0002-9394(02)01624-0","article-title":"A role for local inflammation in the formation of drusen in the aging eye","volume":"134","author":"Anderson","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1097\/APO.0000000000000570","article-title":"The role of inflammation in age-related macular degeneration: updates and possible therapeutic approaches","volume":"12","author":"Arrigo","year":"2023","journal-title":"Asia-Pacific J. Ophthalmol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/BF00364869","article-title":"Polymorphism of human complement component C4","volume":"21","author":"Belt","year":"1985","journal-title":"Immunogenetics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.clinbiochem.2015.05.024","article-title":"Detection of alloantibody-mediated complement activation: a diagnostic advance in monitoring kidney transplant rejection?","volume":"49","author":"Bohmig","year":"2016","journal-title":"Clin. Biochem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/307237a0","article-title":"A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B","volume":"307","author":"Carroll","year":"1984","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"6868","DOI":"10.1073\/pnas.87.17.6868","article-title":"Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A","volume":"87","author":"Carroll","year":"1990","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/0167-5699(84)90223-8","article-title":"The 20 faces of the fourth component of complement","volume":"5","author":"Chan","year":"1984","journal-title":"Immunol. Today"},{"key":"B9","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1189\/jlb.3RI0615-239R","article-title":"Parainflammation, chronic inflammation, and age\u2010related macular degeneration","volume":"98","author":"Chen","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"13094","DOI":"10.1073\/pnas.2000339117","article-title":"Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies","volume":"117","author":"Cheng","year":"2020","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"Unit 13.8","DOI":"10.1002\/0471142735.im1308s68","article-title":"Human complement components C4A and C4B genetic diversities: complex genotypes and phenotypes","author":"Chung","year":"2005","journal-title":"Curr. Protoc. Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"Cingolani","year":"2012","journal-title":"Fly"},{"key":"B13","doi-asserted-by":"publisher","first-page":"102979","DOI":"10.1016\/j.jaut.2022.102979","article-title":"The complement system and human autoimmune diseases","volume":"137","author":"Coss","year":"2023","journal-title":"J. Autoimmun."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1093\/nar\/23.12.2120","article-title":"Human helicase gene SKI2W in the HLA class III region exhibits striking structural similarities to the yeast antiviral gene SKI2 and to the human gene KIAA0052: emergence of a new gene family","volume":"23","author":"Dangel","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/379177a0","article-title":"The reaction mechanism of the internal thioester in the human complement component C4","volume":"379","author":"Dodds","year":"1996","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/ejhg.2008.140","article-title":"Variation near complement factor I is associated with risk of advanced AMD","volume":"17","author":"Fagerness","year":"2009","journal-title":"Eur. J. Hum. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1001\/jamaophthalmol.2015.0814","article-title":"Phenotypic characterization of complement factor H R1210C rare genetic variant in age-related macular degeneration","volume":"133","author":"Ferrara","year":"2015","journal-title":"JAMA Ophthalmol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1034\/j.1600-6143.2003.00171.x","article-title":"Complement C4d in graft capillaries - the missing link in the recognition of humoral alloreactivity","volume":"3","author":"Feucht","year":"2003","journal-title":"Am. J. Transplant."},{"key":"B19","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1111\/j.1365-2249.1991.tb02954.x","article-title":"Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection","volume":"86","author":"Feucht","year":"1991","journal-title":"Clin. Exp. Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/ng.2578","article-title":"Seven new loci associated with age-related macular degeneration","volume":"45","author":"Fritsche","year":"2013","journal-title":"Nat. Genet."},{"key":"B21","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/ng.3448","article-title":"A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants","volume":"48","author":"Fritsche","year":"2016","journal-title":"Nat. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/j.1399-0039.1976.tb00578.x","article-title":"Rga (Rodgers) and the HLA region: linkage and associations","volume":"8","author":"Giles","year":"1976","journal-title":"Tissue Antigens"},{"key":"B23","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1007\/BF00364431","article-title":"Antigenic determinants expressed by human C4 allotypes; a study of 325 families provides evidence for the structural antigenic model","volume":"27","author":"Giles","year":"1988","journal-title":"Immunogenetics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1002\/sctm.19-0321","article-title":"Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions","volume":"9","author":"Gong","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s12974-016-0548-0","article-title":"Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)","volume":"13","author":"Grassmann","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2447","DOI":"10.1534\/g3.118.200925","article-title":"GRAF-pop: a fast distance-based method to infer subject ancestry from multiple genotype datasets without principal components analysis","volume":"9","author":"Jin","year":"2019","journal-title":"G3 Genes, Genomes, Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"7348","DOI":"10.1038\/s41598-018-25557-8","article-title":"Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy","volume":"8","author":"Katschke","year":"2018","journal-title":"Sci. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1126\/science.1109557","article-title":"Complement factor H polymorphism in age-related macular degeneration","volume":"308","author":"Klein","year":"2005","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","first-page":"6628","DOI":"10.1167\/iovs.12-9587","article-title":"Activation of the alternative complement pathway in vitreous is controlled by genetics in age-related macular degeneration","volume":"53","author":"Loyet","year":"2012","journal-title":"Investigative Ophthalmol. Vis. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1038\/ng1873","article-title":"Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration","volume":"38","author":"Maller","year":"2006","journal-title":"Nat. Genet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1038\/ng2131","article-title":"Variation in complement factor 3 is associated with risk of age-related macular degeneration","volume":"39","author":"Maller","year":"2007","journal-title":"Nat. Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1159\/000019079","article-title":"Reference typing report for complement component C4","volume":"15","author":"Mauff","year":"1998","journal-title":"Exp. Clin. Immunogenetics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"7395","DOI":"10.1073\/pnas.0912019107","article-title":"Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC)","volume":"107","author":"Neale","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0207677","DOI":"10.1371\/journal.pone.0207677","article-title":"The impact of a fine-scale population stratification on rare variant association test results","volume":"13","author":"Persyn","year":"2018","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1038\/ng.976","article-title":"A rare penetrant mutation in CFH confers high risk of age-related macular degeneration","volume":"43","author":"Raychaudhuri","year":"2011","journal-title":"Nat. Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1159\/000463175","article-title":"Monoclonal antipeptide antibodies against amino acid residues 1101-1106 of human C4 distinguish C4A from C4B","volume":"8","author":"Reilly","year":"","journal-title":"Complement Inflamm."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3018","DOI":"10.4049\/jimmunol.147.9.3018","article-title":"Amino acid residues 1101-1105 of the isotypic region of human C4B is important to the covalent binding activity of complement component C4","volume":"147","author":"Reilly","year":"","journal-title":"J. Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1001\/jamaophthalmol.2022.4401","article-title":"Prevalence of age-related macular degeneration in the US in 2019","volume":"140","author":"Rein","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic acids Res."},{"key":"B41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-319-21416-0_1","article-title":"An introduction to meta-analysis in R","volume-title":"Meta-analysis with R","author":"Schwarzer","year":"2015"},{"key":"B42","doi-asserted-by":"publisher","first-page":"6513","DOI":"10.1167\/iovs.17-23544","article-title":"Macular degeneration epidemiology: nature-Nurture, lifestyle factors, genetic risk, and gene-environment interactions\u2013the Weisenfeld Award Lecture","volume":"58","author":"Seddon","year":"2017","journal-title":"Investigative Ophthalmol. Vis. Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e87047","DOI":"10.1371\/journal.pone.0087047","article-title":"Three new genetic loci (R1210C in CFH, variants in COL8A1 and RAD51B) are independently related to progression to advanced macular degeneration","volume":"9","author":"Seddon","year":"2014","journal-title":"PLoS One"},{"key":"B44","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.ajo.2018.10.022","article-title":"Validated prediction models for macular degeneration progression and predictors of visual acuity loss identify high-risk individuals","volume":"198","author":"Seddon","year":"2019","journal-title":"Am. J. Ophthalmol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"100265","DOI":"10.1016\/j.xops.2022.100265","article-title":"Rare dysfunctional complement factor I genetic variants and progression to advanced age-related macular degeneration","volume":"3","author":"Seddon","year":"2023","journal-title":"Ophthalmol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.ophtha.2005.11.001","article-title":"Evaluation of the clinical age-related maculopathy staging system","volume":"113","author":"Seddon","year":"2006","journal-title":"Ophthalmology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1167\/iovs.61.14.32","article-title":"Rare and common genetic variants, smoking, and body mass index: progression and earlier age of developing advanced age-related macular degeneration","volume":"61","author":"Seddon","year":"2020","journal-title":"Investigative Ophthalmol. Vis. Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1038\/ng.2741","article-title":"Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration","volume":"45","author":"Seddon","year":"2013","journal-title":"Nat. Genet."},{"key":"B49","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/s41588-021-00885-0","article-title":"Advancing human genetics research and drug discovery through exome sequencing of the UK Biobank","volume":"53","author":"Szustakowski","year":"2021","journal-title":"Nat. Genet."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1016\/s0022-2836(02)00854-9","article-title":"X-ray crystal structure of the C4d fragment of human complement component C4","volume":"322","author":"Van Den Elsen","year":"2002","journal-title":"J. Mol. Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.ajhg.2011.05.029","article-title":"Rare-variant association testing for sequencing data with the sequence kernel association test","volume":"89","author":"Wu","year":"2011","journal-title":"Am. J. Hum. Genet."},{"key":"B52","doi-asserted-by":"publisher","first-page":"3012","DOI":"10.4049\/jimmunol.179.5.3012","article-title":"Sensitive and specific real-time polymerase chain reaction assays to accurately determine copy number variations (CNVs) of human complement C4A, C4B, C4-long, C4-short, and RCCX modules: elucidation of C4 CNVs in 50 consanguineous subjects with defined HLA genotypes","volume":"179","author":"Wu","year":"2007","journal-title":"J. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1086\/518257","article-title":"Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans","volume":"80","author":"Yang","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"B54","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1006\/geno.1998.5499","article-title":"Four ubiquitously expressed genes, RD (D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1 (D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA","volume":"53","author":"Yang","year":"1998","journal-title":"Genomics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.4049\/jimmunol.146.3.1057","article-title":"The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene","volume":"146","author":"Yu","year":"1991","journal-title":"J. Immunol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1002\/j.1460-2075.1986.tb04582.x","article-title":"Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity","volume":"5","author":"Yu","year":"1986","journal-title":"EMBO J."},{"key":"B57","first-page":"117","article-title":"Molecular genetic analyses of human complement components C4A and C4B","volume-title":"Manual of clinical laboratory immunology","author":"Yu","year":"2002"},{"key":"B58","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/BF00364425","article-title":"A structural model for the location of the Rodgers and the Chido antigenic determinants and their correlation with the human complement component C4A\/C4B isotypes","volume":"27","author":"Yu","year":"1988","journal-title":"Immunogenetics"},{"key":"B59","doi-asserted-by":"publisher","first-page":"5283","DOI":"10.1093\/hmg\/ddu226","article-title":"Whole-exome sequencing identifies rare, functional CFH variants in families with macular degeneration","volume":"23","author":"Yu","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"B60","doi-asserted-by":"publisher","first-page":"5276","DOI":"10.1093\/hmg\/ddw336","article-title":"Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration","volume":"25","author":"Yu","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/ng.2758","article-title":"Identification of a rare coding variant in complement 3 associated with age-related macular degeneration","volume":"45","author":"Zhan","year":"2013","journal-title":"Nat. Genet."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.3390\/cells8091008","article-title":"An RNA metabolism and surveillance quartet in the major histocompatibility complex","volume":"8","author":"Zhou","year":"2019","journal-title":"Cells"},{"key":"B63","doi-asserted-by":"publisher","first-page":"739430","DOI":"10.3389\/fimmu.2021.739430","article-title":"Human complement C4B allotypes and deficiencies in selected cases with autoimmune diseases","volume":"12","author":"Zhou","year":"2021","journal-title":"Front. Immunol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1274743\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T04:41:12Z","timestamp":1706503272000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2023.1274743\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,29]]},"references-count":63,"alternative-id":["10.3389\/fgene.2023.1274743"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2023.1274743","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2024,1,29]]},"article-number":"1274743"}}