{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T11:16:32Z","timestamp":1760267792001,"version":"3.41.2"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T00:00:00Z","timestamp":1642550400000},"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>Spinal Muscular Atrophy (SMA) is a heterogeneous group of neuromuscular diseases characterized by degeneration of anterior horn cells of the spinal cord, leading to muscular atrophy and weakness. Although the major cause of SMA is autosomal recessive exon deletions or loss-of-function mutations of <jats:italic>survival motor neuron 1<\/jats:italic> (<jats:italic>SMN1<\/jats:italic>) gene, next generation sequencing technologies are increasing the genetic heterogeneity of SMA. SMA type 4 (SMA4) is an adult onset, less severe form of SMA for which genetic and pathogenic causes remain elusive.Whole exome sequencing in a 30-year-old brother and sister with SMA4 identified a compound heterozygous mutation (p. G492R\/p. F610C) in calpain-1 (<jats:italic>CAPN1<\/jats:italic>)<jats:italic>.<\/jats:italic> Mutations in <jats:italic>CAPN1<\/jats:italic> have been previously associated with cerebellar ataxia and hereditary spastic paraplegia. Using skin fibroblasts from a patient bearing the p. G492R\/p. F610C mutation, we demonstrate reduced levels of <jats:italic>CAPN1<\/jats:italic> protein and protease activity. Functional characterization of the SMA4 fibroblasts revealed no changes in SMN protein levels and subcellular distribution. Additional cellular pathways associated with SMA remain unaffected in the patient fibroblasts, highlighting the tissue specificity of <jats:italic>CAPN1<\/jats:italic> dysfunction in SMA4 pathophysiology. This study provides genetic and functional evidence of <jats:italic>CAPN1<\/jats:italic> as a novel gene for the SMA4 phenotype and expands the phenotype of <jats:italic>CAPN1<\/jats:italic> mutation disorders.<\/jats:p>","DOI":"10.3389\/fgene.2021.801253","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T05:49:26Z","timestamp":1642571366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A Compound Heterozygous Mutation in Calpain 1 Identifies a New Genetic Cause for Spinal Muscular Atrophy Type 4 (SMA4)"],"prefix":"10.3389","volume":"12","author":[{"given":"G.","family":"Perez-Siles","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Ellis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Ashe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B.","family":"Grosz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Vucic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. C.","family":"Kiernan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K. A.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. W.","family":"Reddel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. L.","family":"Kennerson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,19]]},"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":"821","DOI":"10.1007\/s12035-013-8399-5","article-title":"Spinal Muscular Atrophy and the Antiapoptotic Role of Survival of Motor Neuron (SMN) Protein","volume":"47","author":"Anderton","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1007\/s12035-012-8245-1","article-title":"Primary Skin Fibroblasts as a Model of Parkinson's Disease","volume":"46","author":"Auburger","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/382638a0","article-title":"Functional Interaction of \u03b2-catenin with the Transcription Factor LEF-1","volume":"382","author":"Behrens","year":"1996","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1177\/1073858416649178","article-title":"Calpains: Master Regulators of Synaptic Plasticity","volume":"23","author":"Briz","year":"2017","journal-title":"Neuroscientist"},{"key":"B6","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/344540a0","article-title":"Genetic Mapping of Chronic Childhood-Onset Spinal Muscular Atrophy to Chromosome 5q1 1.2-13.3","volume":"344","author":"Brzustowicz","year":"1990","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1042\/bj20120921","article-title":"Structure-function Relationships in Calpains","volume":"447","author":"Campbell","year":"2012","journal-title":"Biochem. J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1016\/j.neuint.2004.04.005","article-title":"Degradation of Survival Motor Neuron (SMN) Protein Is Mediated via the Ubiquitin\/proteasome Pathway","volume":"45","author":"Chang","year":"2004","journal-title":"Neurochem. Int."},{"key":"B9","doi-asserted-by":"publisher","first-page":"100346","DOI":"10.1016\/j.xcrm.2021.100346","article-title":"Spinal Muscular Atrophy: From Approved Therapies to Future Therapeutic Targets for Personalized Medicine","volume":"2","author":"Chaytow","year":"2021","journal-title":"Cel Rep. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"eabf0891","DOI":"10.1126\/scitranslmed.abf0891","article-title":"Exercise Triggers CAPN1-Mediated AIF Truncation, Inducing Myocyte Cell Death in Arrhythmogenic Cardiomyopathy","volume":"13","author":"Chelko","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e46688","DOI":"10.1371\/journal.pone.0046688","article-title":"Predicting the Functional Effect of Amino Acid Substitutions and Indels","volume":"7","author":"Choi","year":"2012","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1006\/nbdi.1996.0010","article-title":"The Neurobiology of Childhood Spinal Muscular Atrophy","volume":"3","author":"Crawford","year":"1996","journal-title":"Neurobiol. Dis."},{"key":"B13","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/1750-1172-6-71","article-title":"Spinal Muscular Atrophy","volume":"6","author":"D'Amico","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e1001025","DOI":"10.1371\/journal.pcbi.1001025","article-title":"Identifying a High Fraction of the Human Genome to Be under Selective Constraint Using GERP++","volume":"6","author":"Davydov","year":"2010","journal-title":"Plos Comput. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41419-020-2688-5","article-title":"Calpain System Is Altered in Survival Motor Neuron-Reduced Cells from In Vitro and In Vivo Spinal Muscular Atrophy Models","volume":"11","author":"de la Fuente","year":"2020","journal-title":"Cell Death Dis"},{"key":"B16","doi-asserted-by":"publisher","first-page":"4414","DOI":"10.1007\/s12035-018-1379-z","article-title":"Calpain Inhibition Increases SMN Protein in Spinal Cord Motoneurons and Ameliorates the Spinal Muscular Atrophy Phenotype in Mice","volume":"56","author":"de la Fuente","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1007\/s00439-016-1720-4","article-title":"A 1.35 Mb DNA Fragment is Inserted into the DHMN1 Locus on Chromosome 7q34-q36.2","volume":"135","author":"Drew","year":"2016","journal-title":"Hum. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1007\/s13311-014-0314-x","article-title":"The Genetics of Spinal Muscular Atrophy: Progress and Challenges","volume":"12","author":"Farrar","year":"2015","journal-title":"Neurotherapeutics"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e15769","DOI":"10.1371\/journal.pone.0015769","article-title":"Molecular Determinants of Survival Motor Neuron (SMN) Protein Cleavage by the Calcium-Activated Protease, Calpain","volume":"5","author":"Fuentes","year":"2010","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1016\/j.ajhg.2016.04.002","article-title":"Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia","volume":"98","author":"Gan-Or","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e686","DOI":"10.1038\/cddis.2013.209","article-title":"Survival Motor Neuron Protein Reduction Deregulates Autophagy in Spinal Cord Motoneurons In Vitro","volume":"4","author":"Garcera","year":"2013","journal-title":"Cel Death Dis"},{"key":"B21","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/nature07451","article-title":"Calcium-bound Structure of Calpain and its Mechanism of Inhibition by Calpastatin","volume":"456","author":"Hanna","year":"2008","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","first-page":"5305","DOI":"10.1038\/s41467-021-25651-y","article-title":"Small-molecule Suppression of Calpastatin Degradation Reduces Neuropathology in Models of Huntington's Disease","volume":"12","author":"Hu","year":"2021","journal-title":"Nat. Commun."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4785","DOI":"10.1007\/s00018-021-03819-5","article-title":"Revisiting the Role of Mitochondria in Spinal Muscular Atrophy","volume":"78","author":"James","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1136\/jnnp-2018-318834","article-title":"Challenges in Modelling the Charcot-Marie-Tooth Neuropathies for Therapy Development","volume":"90","author":"Juneja","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B25","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The Mutational Constraint Spectrum Quantified from Variation in 141,456 Humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1002\/acn3.51169","article-title":"Novel CAPN1 Mutations Extend the Phenotypic Heterogeneity in Combined Spastic Paraplegia and Ataxia","volume":"7","author":"Lai","year":"2020","journal-title":"Ann. Clin. Transl Neurol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and Characterization of a Spinal Muscular Atrophy-Determining Gene","volume":"80","author":"Lefebvre","year":"1995","journal-title":"Cell"},{"key":"B28","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/ng0797-265","article-title":"Correlation between Severity and SMN Protein Level in Spinal Muscular Atrophy","volume":"16","author":"Lefebvre","year":"1997","journal-title":"Nat. Genet."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/s0092-8674(00)80367-0","article-title":"The Spinal Muscular Atrophy Disease Gene Product, SMN, and its Associated Protein SIP1 Are in a Complex with Spliceosomal snRNP Proteins","volume":"90","author":"Liu","year":"1997","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6307","DOI":"10.1073\/pnas.96.11.6307","article-title":"A Single Nucleotide in the SMN Gene Regulates Splicing and Is Responsible for Spinal Muscular Atrophy","volume":"96","author":"Lorson","year":"1999","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e149446","DOI":"10.1172\/jci.insight.149446","article-title":"Combining Multiomics and Drug Perturbation Profiles to Identify Muscle-specific Treatments for Spinal Muscular Atrophy","volume":"6","author":"Meijboom","year":"2021","journal-title":"JCI Insight"},{"key":"B32","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/s10048-020-00633-2","article-title":"Increasing Involvement of CAPN1 Variants in Spastic Ataxias and Phenotype-Genotype Correlations","volume":"22","author":"M\u00e9reaux","year":"2021","journal-title":"Neurogenetics"},{"key":"B33","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/j.tins.2021.07.003","article-title":"The Calcium-dependent Protease Calpain in Neuronal Remodeling and Neurodegeneration","volume":"44","author":"Metwally","year":"2021","journal-title":"Trends Neurosciences"},{"key":"B34","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/s0092-8674(00)80112-9","article-title":"XTcf-3 Transcription Factor Mediates \u03b2-Catenin-Induced Axis Formation in Xenopus Embryos","volume":"86","author":"Molenaar","year":"1996","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1093\/hmg\/8.7.1177","article-title":"A Single Nucleotide Difference that Alters Splicing Patterns Distinguishes the SMA Gene SMN1 from the Copy Gene SMN2","volume":"8","author":"Monani","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"B36","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1042\/bj3190683","article-title":"Non-erythroid Alpha-Spectrin Breakdown by Calpain and Interleukin 1 Beta-converting-enzyme-like Protease(s) in Apoptotic Cells: Contributory Roles of Both Protease Families in Neuronal Apoptosis","volume":"319","author":"Nath","year":"1996","journal-title":"Biochem. J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"db150963","DOI":"10.2337\/db15-0963","article-title":"Mitochondrial Calpain-1 Disrupts ATP Synthase and Induces Superoxide Generation in Type-1 Diabetic Hearts: a Novel Mechanism Contributing to Diabetic Cardiomyopathy","volume":"65","author":"Ni","year":"2016","journal-title":"Diabetes"},{"key":"B59","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.expneurol.2016.06.032","article-title":"Autophagy Modulators Regulate Survival Motor Neuron Protein Stability in Motoneurons","volume":"283","author":"Periyakaruppiah","year":"2016","journal-title":"Exp. Neurol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.1038\/s41419-017-0086-4","article-title":"Inhibition of Autophagy Delays Motoneuron Degeneration and Extends Lifespan in a Mouse Model of Spinal Muscular Atrophy","volume":"8","author":"Piras","year":"2017","journal-title":"Cel Death Dis"},{"key":"B39","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1101\/gr.097857.109","article-title":"Detection of Nonneutral Substitution Rates on Mammalian Phylogenies","volume":"20","author":"Pollard","year":"2010","journal-title":"Genome Res."},{"key":"B40","article-title":"Spinal Muscular Atrophy","volume-title":"GeneReviews((R)) [Internet]","author":"Prior","year":"1993"},{"key":"B41","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1111\/jnc.13536","article-title":"Calpastatin Inhibits Motor Neuron Death and Increases Survival of hSOD1G93A Mice","volume":"137","author":"Rao","year":"2016","journal-title":"J. Neurochem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"9222","DOI":"10.1523\/JNEUROSCI.1132-14.2014","article-title":"Specific Calpain Inhibition by Calpastatin Prevents Tauopathy and Neurodegeneration and Restores normal Lifespan in Tau P301L Mice","volume":"34","author":"Rao","year":"2014","journal-title":"J. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"R232","DOI":"10.1186\/gb-2007-8-11-r232","article-title":"Determinants of Protein Function Revealed by Combinatorial Entropy Optimization","volume":"8","author":"Reva","year":"2007","journal-title":"Genome Biol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B44","doi-asserted-by":"publisher","first-page":"105366","DOI":"10.1016\/j.nbd.2021.105366","article-title":"Intracellular Pathways Involved in Cell Survival Are Deregulated in Mouse and Human Spinal Muscular Atrophy Motoneurons","volume":"155","author":"Sansa","year":"","journal-title":"Neurobiol. Dis."},{"key":"B45","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s40478-021-01223-5","article-title":"Spinal Muscular Atrophy Autophagy Profile Is Tissue-dependent: Differential Regulation between Muscle and Motoneurons","volume":"9","author":"Sansa","year":"","journal-title":"Acta Neuropathol. Commun."},{"key":"B46","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation Prediction for the Deep-Sequencing Age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1074\/mcp.M115.053413","article-title":"Predictions of Cleavability of Calpain Proteolysis by Quantitative Structure-Activity Relationship Analysis Using Newly Determined Cleavage Sites and Catalytic Efficiencies of an Oligopeptide Array","volume":"15","author":"Shinkai-Ouchi","year":"2016","journal-title":"Mol. Cell Proteomics"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1101\/gr.3715005","article-title":"Evolutionarily Conserved Elements in Vertebrate, Insect, Worm, and Yeast Genomes","volume":"15","author":"Siepel","year":"2005","journal-title":"Genome Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"W452","DOI":"10.1093\/nar\/gks539","article-title":"SIFT Web Server: Predicting Effects of Amino Acid Substitutions on Proteins","volume":"40","author":"Sim","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/nrg2361","article-title":"Linkage Disequilibrium - Understanding the Evolutionary Past and Mapping the Medical Future","volume":"9","author":"Slatkin","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"B51","doi-asserted-by":"publisher","first-page":"263310552091430","DOI":"10.1177\/2633105520914301","article-title":"Molecular Crosstalk between Non-SMN-related and SMN-Related Spinal Muscular Atrophy","volume":"15","author":"\u0160olti\u0107","year":"2020","journal-title":"J. Exp. Neurosci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"3399","DOI":"10.1093\/hmg\/ddn234","article-title":"SMN Complex Localizes to the Sarcomeric Z-Disc and Is a Proteolytic Target of Calpain","volume":"17","author":"Walker","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"B53","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.celrep.2016.05.044","article-title":"Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans","volume":"16","author":"Wang","year":"2016","journal-title":"Cel Rep."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e201800268","DOI":"10.26508\/lsa.201800268","article-title":"Drug Screening with Human SMN2 Reporter Identifies SMN Protein Stabilizers to Correct SMA Pathology","volume":"2","author":"Wang","year":"2019","journal-title":"Life Sci. Alliance"},{"key":"B55","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1002\/(sici)1098-1004(200003)15:3<228:aid-humu3>3.0.co;2-9","article-title":"An Update of the Mutation Spectrum of the Survival Motor Neuron Gene (SMN1) in Autosomal Recessive Spinal Muscular Atrophy (SMA)","volume":"15","author":"Wirth","year":"2000","journal-title":"Hum. Mutat."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1172\/JCI71318","article-title":"Dysregulation of Ubiquitin Homeostasis and \u03b2-catenin Signaling Promote Spinal Muscular Atrophy","volume":"124","author":"Wishart","year":"2014","journal-title":"J. Clin. Invest."},{"key":"B57","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1146\/annurev.cellbio.13.1.119","article-title":"Molecular and Functional Analysis of Cadherin-Based Adherens Junctions","volume":"13","author":"Yap","year":"1997","journal-title":"Annu. Rev. Cel Dev. Biol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.801253\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T10:43:56Z","timestamp":1644835436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.801253\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,19]]},"references-count":60,"alternative-id":["10.3389\/fgene.2021.801253"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.801253","relation":{},"ISSN":["1664-8021"],"issn-type":[{"type":"electronic","value":"1664-8021"}],"subject":[],"published":{"date-parts":[[2022,1,19]]},"article-number":"801253"}}