{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T06:15:49Z","timestamp":1783577749440,"version":"3.55.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"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. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) is crucial for the canonical wingless signaling pathway and the clearance of LDL from the bloodstream. Genetic variants in the\n                    <jats:italic>LRP6<\/jats:italic>\n                    gene have been conclusively associated with cardiovascular diseases (CVDs) and metabolic syndrome. However, the structural, cellular, and functional implications of these variations have not been fully elucidated. In this study, we examined the subcellular localization, stability, and degradation of 10 LRP6 missense variants (K82N, R360H, Y418H, N433S, R473Q, S488Y, R611C, P1066T, P1206H, and I1264V) previously reported to be associated with various CVD conditions. We assessed the effect of these missense variants on LRP6 subcellular localization by overexpressing them in HeLa and human embryonic kidney (HEK293T) mammalian cell lines. Molecular dynamic (MD) simulation was performed on two variants to evaluate their stability. In addition, the stability of all the variants was evaluated experimentally by measuring their half-lives and comparing them to the wild-type (WT) protein, using cycloheximide chase assays and inhibitor treatments. Our findings suggest that approximately 45% of the wild-type LRP6 protein achieves its mature form within 24\u201348\u00a0h of overexpression, indicating its modest trafficking through the endoplasmic reticulum (ER), maturation, and transport to the plasma membrane. On the other hand, CVD-associated LRP6 variants Y418H, N433S, R473Q, and P1206H exhibited significantly lower maturation levels and, in some cases, were semi-quantitatively present in the immature form, suggesting retention within the ER and failure to pass the highly stringent ER quality control systems. The\n                    <jats:italic>in silico<\/jats:italic>\n                    stability assessment revealed that all 10 LRP6 missense variants are predicted to have a negative impact on protein stability. Interestingly, MD simulation elaborated that one fully ER-retained variant, P1066T, has altered structural interactions of the protein, affecting its folding. ER retention of some CVD-associated LRP6 variants could contribute to diseases via the reduction in LRP6 plasma membrane localization and consequently loss or reduction of LRP6 function, potentially leading to dysregulated signaling efficiency. This study contributes to improving our understanding of the cellular behavior of several LRP6 missense variants causing CVD conditions and has potential applications in diagnosis and the development of new therapies for their associated conditions.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1828772","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:36:40Z","timestamp":1783575400000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of the cellular impact of missense variants in low-density lipoprotein receptor-related protein 6 (LRP6) associated with cardiovascular diseases in HeLa and HEK293T cell lines"],"prefix":"10.3389","volume":"14","author":[{"given":"Anjana","family":"Raj","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al-Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda I.","family":"Samha","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al-Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Badawi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al-Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"John","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al-Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alia","family":"Almehrezi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al-Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A.","family":"Ghattas","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Al Ain University","place":["Abu Dhabi, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassam R.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University","place":["Al-Ain, United Arab Emirates"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1097\/MOL.0000000000000276","article-title":"Metabolic syndrome: genetic insights into disease pathogenesis","volume":"27","author":"Abou Ziki","year":"2016","journal-title":"Curr. Opin. Lipidol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.bbrc.2010.05.045","article-title":"A novel statin-mediated \u201cprenylation block-and-release\u201d assay provides insight into the membrane targeting mechanisms of small GTPases","volume":"397","author":"Ali","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B3","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1002\/mgg3.7","article-title":"Challenges of diagnostic exome sequencing in an inbred founder population","volume":"1","author":"Azmanov","year":"2013","journal-title":"Mol. Genet. Genomic Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1111\/tra.12902","article-title":"Genetic disruption of mammalian endoplasmic reticulum\u2010associated protein degradation: human phenotypes and animal and cellular disease models","volume":"24","author":"Badawi","year":"2023","journal-title":"Traffic"},{"key":"B5","doi-asserted-by":"publisher","first-page":"147084","DOI":"10.1016\/j.gene.2022.147084","article-title":"LDLR missense variants disturb structural conformation and LDLR activity in T-lymphocytes of Familial hypercholesterolemia patients","volume":"853","author":"Barbosa","year":"2023","journal-title":"Gene"},{"key":"B6","doi-asserted-by":"publisher","first-page":"9172","DOI":"10.1074\/jbc.M109.092130","article-title":"Reconstitution of a Frizzled8\u00b7Wnt3a\u00b7LRP6 signaling complex reveals multiple wnt and Dkk1 binding sites on LRP6","volume":"285","author":"Bourhis","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1006\/bbrc.1998.9061","article-title":"Isolation and characterization ofLRP6,a novel member of the low density Lipoprotein receptor gene family","volume":"248","author":"Brown","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1186\/s12967-018-1737-7","article-title":"Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease","volume":"16","author":"Cao","year":"2018","journal-title":"J. Transl. Med."},{"key":"B9","volume-title":"AMBER 18","author":"Case","year":"2018"},{"key":"B10","first-page":"22","article-title":"Preparation of calcium competent Escherichia coli and heat-shock transformation","volume":"1","author":"Chang","year":"2017"},{"key":"B11","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1016\/j.devcel.2011.09.007","article-title":"Structural and functional studies of LRP6 ectodomain reveal a platform for wnt signaling","volume":"21","author":"Chen","year":"2011","journal-title":"Dev. Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1038\/nsmb.2139","article-title":"Crystal structures of the extracellular domain of LRP6 and its complex with DKK1","volume":"18","author":"Cheng","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: an N \u22c5log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"B14","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/j.pop.2005.09.009","article-title":"Traditional and emerging risk factors for cardiovascular disease","volume":"32","author":"Eaton","year":"2005","journal-title":"Prim. Care Clin. Off. Pract."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1038\/s41598-020-58734-9","article-title":"Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR","volume":"10","author":"Galicia-Garcia","year":"2020","journal-title":"Sci. Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1111\/cge.13088","article-title":"Protein misfolding diseases: prospects of pharmacological treatment","volume":"93","author":"G\u00e1mez","year":"2018","journal-title":"Clin. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1097\/MOL.0000000000000445","article-title":"Wnt signaling in cardiovascular disease: opportunities and challenges","volume":"28","author":"Gay","year":"2017","journal-title":"Curr. Opin. Lipidol."},{"key":"B18","first-page":"19","article-title":"Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis","volume":"85","author":"Go","year":"2012","journal-title":"Yale J. Biol. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.cmet.2013.11.023","article-title":"The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue","volume":"19","author":"Go","year":"2014","journal-title":"Cell Metab."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.3390\/ijms17071173","article-title":"Mutant LRP6 impairs endothelial cell functions associated with familial normolipidemic coronary artery disease","volume":"17","author":"Guo","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B21","first-page":"183","article-title":"Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome","volume":"1","author":"Hadi","year":"2005","journal-title":"Vasc. Health Risk Manag."},{"key":"B22","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1242\/dmm.001180","article-title":"A comprehensive definition for metabolic syndrome","volume":"2","author":"Huang","year":"2009","journal-title":"Dis. Model Mech."},{"key":"B23","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1161\/CIRCRESAHA.116.303356","article-title":"Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress","volume":"116","author":"Ikeda","year":"2015","journal-title":"Circ. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/0005-2795(75)90043-4","article-title":"The oxygen affinity of haemoglobin tak, a variant with an elongated \u03b2 chain","volume":"412","author":"Imai","year":"1975","journal-title":"Biochim. Biophys. Acta BBA - Protein Struct."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1412236","DOI":"10.3389\/fcell.2024.1412236","article-title":"Cellular and functional evaluation of LDLR missense variants reported in hypercholesterolemic patients demonstrates their hypomorphic impacts on trafficking and LDL internalization","volume":"12","author":"Jawabri","year":"2024","journal-title":"Front. Cell Dev. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"264","DOI":"10.3389\/fcell.2020.00264","article-title":"Canonical WNT\/\u03b2-Catenin signaling activated by WNT9b and RSPO2 cooperation regulates facial morphogenesis in mice","volume":"8","author":"Jin","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1007\/s00439-020-02124-8","article-title":"Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities","volume":"139","author":"Kang","year":"2020","journal-title":"Hum. Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1016\/j.cell.2012.03.001","article-title":"Genetics of human cardiovascular disease","volume":"148","author":"Kathiresan","year":"2012","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1073\/pnas.1019443108","article-title":"Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation","volume":"108","author":"Keramati","year":"2011","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1161\/CIRCULATIONAHA.118.035658","article-title":"Whole-Genome sequencing to characterize monogenic and polygenic contributions in patients hospitalized with early-onset myocardial infarction","volume":"139","author":"Khera","year":"2019","journal-title":"Circulation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2871","DOI":"10.1016\/j.bbamcr.2014.08.013","article-title":"Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome","volume":"1843","author":"Kizhakkedath","year":"2014","journal-title":"Biochim. Biophys. Acta BBA - Mol. Cell Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1038\/s41598-017-19053-8","article-title":"Degradation routes of trafficking-defective VLDLR mutants associated with dysequilibrium syndrome","volume":"8","author":"Kizhakkedath","year":"2018","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1002\/2211-5463.12740","article-title":"Endoplasmic reticulum quality control of LDLR variants associated with familial hypercholesterolemia","volume":"9","author":"Kizhakkedath","year":"2019","journal-title":"FEBS Open Bio"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1016\/j.cjca.2019.06.030","article-title":"Therapeutic targeting of LRP6 in cardiovascular diseases: challenging but not wnt-possible","volume":"35","author":"Labb\u00e9","year":"2019","journal-title":"Can. J. Cardiol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1194\/jlr.M300482-JLR200","article-title":"Degradation of the LDL receptor class 2 mutants is mediated by a proteasome-dependent pathway","volume":"45","author":"Li","year":"2004","journal-title":"J. Lipid Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1280","DOI":"10.1161\/CIRCRESAHA.108.183863","article-title":"Mutation in EGFP domain of LDL receptor-related protein 6 impairs cellular LDL clearance","volume":"103","author":"Liu","year":"2008","journal-title":"Circ. Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1126\/science.1136370","article-title":"LRP6 mutation in a family with early coronary disease and metabolic risk factors","volume":"315","author":"Mani","year":"2007","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.ajhg.2015.08.014","article-title":"Loss-of-Function mutations in the WNT Co-receptor LRP6 cause autosomal-dominant oligodontia","volume":"97","author":"Massink","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1093\/cvr\/cvz338","article-title":"Lipoprotein receptor signalling in atherosclerosis","volume":"116","author":"Mineo","year":"2020","journal-title":"Cardiovasc Res."},{"key":"B40","article-title":"MOE (2020) manual version 2020.01","year":"2020","journal-title":"Chem. Comput. Group"},{"key":"B41","year":"2020"},{"key":"B42","article-title":"Cardiovascular disease","volume-title":"Statpearls","author":"Olvera Lopez","year":"2026"},{"key":"B43","doi-asserted-by":"publisher","first-page":"570355","DOI":"10.3389\/fgene.2020.570355","article-title":"Proteostasis regulation in the endoplasmic reticulum: an emerging theme in the molecular pathology and therapeutic management of familial hypercholesterolemia","volume":"11","author":"Oommen","year":"2020","journal-title":"Front. Genet."},{"key":"B44","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/35035124","article-title":"An LDL-receptor-related protein mediates Wnt signalling in mice","volume":"407","author":"Pinson","year":"2000","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1007\/s00109-010-0663-9","article-title":"Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease","volume":"88","author":"Ren","year":"2010","journal-title":"J. Mol. Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/jbiol186","article-title":"What are pharmacological chaperones and why are they interesting?","volume":"8","author":"Ringe","year":"2009","journal-title":"J. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.tcb.2003.11.001","article-title":"A trip to the ER: coping with stress","volume":"14","author":"Rutkowski","year":"2004","journal-title":"Trends Cell Biol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.bbrc.2009.06.033","article-title":"Wnt3a regulates proliferation and migration of HUVEC via canonical and non-canonical wnt signaling pathways","volume":"386","author":"Samarzija","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1021\/ct700119m","article-title":"Clustering molecular dynamics trajectories: 1. Characterizing the performance of different clustering algorithms","volume":"3","author":"Shao","year":"2007","journal-title":"J. Chem. Theory Comput."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1002\/humu.22360","article-title":"Rare nonconservative LRP6 mutations are associated with Metabolic syndrome","volume":"34","author":"Singh","year":"2013","journal-title":"Hum. Mutat."},{"key":"B51","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1074\/jbc.M507071200","article-title":"Retention of mutant low density lipoprotein receptor in Endoplasmic Reticulum (ER) leads to ER stress","volume":"281","author":"S\u00f8rensen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B52","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1016\/j.celrep.2015.09.028","article-title":"Impaired LRP6-TCF7L2 activity enhances smooth muscle cell plasticity and causes coronary artery disease","volume":"13","author":"Srivastava","year":"2015","journal-title":"Cell Rep."},{"key":"B53","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s12944-023-01835-x","article-title":"GRP78\/BiP alleviates oxLDL-induced hepatotoxicity in familial hypercholesterolemia caused by missense variants of LDLR in a HepG2 cellular model","volume":"22","author":"Varghese","year":"2023","journal-title":"Lipids Health Dis."},{"key":"B54","doi-asserted-by":"publisher","first-page":"613","DOI":"10.18632\/genesandcancer.146","article-title":"Extracellular LDLR repeats modulate Wnt signaling activity by promoting LRP6 receptor endocytosis mediated by the Itch E3 ubiquitin ligase","volume":"8","author":"Vijayakumar","year":"2017","journal-title":"Genes Cancer"},{"key":"B55","doi-asserted-by":"publisher","first-page":"43454","DOI":"10.1074\/jbc.M111.274332","article-title":"Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases","volume":"286","author":"Wang","year":"2011","journal-title":"J. Biol. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/s00441-019-03126-3","article-title":"Cardiac-specific LRP6 knockout induces lipid accumulation through Drp1\/CPT1b pathway in adult mice","volume":"380","author":"Wang","year":"2020","journal-title":"Cell Tissue Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"688241","DOI":"10.3389\/fgene.2021.688241","article-title":"Investigation of a novel LRP6 variant causing autosomal-dominant tooth agenesis","volume":"12","author":"xia","year":"2021","journal-title":"Front. Genet."},{"key":"B58","doi-asserted-by":"publisher","first-page":"e84345","DOI":"10.1371\/journal.pone.0084345","article-title":"Functional analysis LRP6 novel mutations in patients with coronary artery disease","volume":"9","author":"Xu","year":"2014","journal-title":"PLoS ONE"},{"key":"B59","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.devcel.2008.04.015","article-title":"Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of \u03b2-Catenin signaling","volume":"15","author":"Yamamoto","year":"2008","journal-title":"Dev. Cell"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1074\/jbc.M111.295287","article-title":"LRP6 protein regulates Low Density Lipoprotein (LDL) receptor-mediated LDL uptake","volume":"287","author":"Ye","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1016\/j.ymthe.2017.03.027","article-title":"Cardiovascular gene therapy: past, present, and future","volume":"25","author":"Yl\u00e4-Herttuala","year":"2017","journal-title":"Mol. Ther."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1828772\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:36:42Z","timestamp":1783575402000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2026.1828772\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":61,"alternative-id":["10.3389\/fcell.2026.1828772"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2026.1828772","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"article-number":"1828772"}}