{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:40:54Z","timestamp":1787902854204,"version":"build-2784847793"},"reference-count":48,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Central Universities of Central South University","award":["2021zzts0087"],"award-info":[{"award-number":["2021zzts0087"]}]},{"name":"the Central Universities of Central South University","award":["82101957"],"award-info":[{"award-number":["82101957"]}]},{"name":"the Central Universities of Central South University","award":["81902150"],"award-info":[{"award-number":["81902150"]}]},{"name":"the Central Universities of Central South University","award":["2020TQ0362"],"award-info":[{"award-number":["2020TQ0362"]}]},{"name":"the Central Universities of Central South University","award":["2021JJ40806"],"award-info":[{"award-number":["2021JJ40806"]}]},{"name":"the National Natural Science Foundation of China","award":["2021zzts0087"],"award-info":[{"award-number":["2021zzts0087"]}]},{"name":"the National Natural Science Foundation of China","award":["82101957"],"award-info":[{"award-number":["82101957"]}]},{"name":"the National Natural Science Foundation of China","award":["81902150"],"award-info":[{"award-number":["81902150"]}]},{"name":"the National Natural Science Foundation of China","award":["2020TQ0362"],"award-info":[{"award-number":["2020TQ0362"]}]},{"name":"the National Natural Science Foundation of China","award":["2021JJ40806"],"award-info":[{"award-number":["2021JJ40806"]}]},{"DOI":"10.13039\/501100002858","name":"the China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021zzts0087"],"award-info":[{"award-number":["2021zzts0087"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"the China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["82101957"],"award-info":[{"award-number":["82101957"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"the China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["81902150"],"award-info":[{"award-number":["81902150"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"the China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2020TQ0362"],"award-info":[{"award-number":["2020TQ0362"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"the China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021JJ40806"],"award-info":[{"award-number":["2021JJ40806"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Natural Science Foundation of Hunan Province","award":["2021zzts0087"],"award-info":[{"award-number":["2021zzts0087"]}]},{"name":"the Natural Science Foundation of Hunan Province","award":["82101957"],"award-info":[{"award-number":["82101957"]}]},{"name":"the Natural Science Foundation of Hunan Province","award":["81902150"],"award-info":[{"award-number":["81902150"]}]},{"name":"the Natural Science Foundation of Hunan Province","award":["2020TQ0362"],"award-info":[{"award-number":["2020TQ0362"]}]},{"name":"the Natural Science Foundation of Hunan Province","award":["2021JJ40806"],"award-info":[{"award-number":["2021JJ40806"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is the most common fatal muscle disease, with an estimated incidence of 1\/3500\u20131\/5000 male births, and it is associated with mutations in the X-linked DMD gene encoding dystrophin, the largest known human gene. There is currently no cure for DMD. The large size of the DMD gene hampers exogenous gene addition and delivery. The genetic correction of DMD patient-derived induced pluripotent stem cells (DMD-iPSCs) and differentiation into suitable cells for transplantation is a promising autologous therapeutic strategy for DMD. In this study, using CRISPR\/Cas9, the full-length dystrophin coding sequence was reconstructed in an exon-50-deleted DMD-iPSCs by the targeted addition of exon 50 at the junction of exon 49 and intron 49 via homologous-directed recombination (HDR), with a high targeting efficiency of 5\/15, and the genetically corrected iPSCs were differentiated into cardiomyocytes (iCMs). Importantly, the full-length dystrophin expression and membrane localization were restored in genetically corrected iPSCs and iCMs. Thus, this is the first study demonstrating that full-length dystrophin can be restored in iPSCs and iCMs via targeted exon addition, indicating potential clinical prospects for DMD gene therapy.<\/jats:p>","DOI":"10.3390\/ijms23169176","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T03:40:32Z","timestamp":1660621232000},"page":"9176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Full-Length Dystrophin Restoration via Targeted Exon Addition in DMD-Patient Specific iPSCs and Cardiomyocytes"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1929-0784","authenticated-orcid":false,"given":"Rou","family":"Xiao","sequence":"first","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6636-6000","authenticated-orcid":false,"given":"Miaojin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baitao","family":"Zeng","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingqian","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqing","family":"Hu","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desheng","family":"Liang","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/0167-5273(90)90082-G","article-title":"The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy","volume":"26","author":"Nigro","year":"1990","journal-title":"Int. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/s41582-019-0203-3","article-title":"Therapeutic developments for Duchenne muscular dystrophy","volume":"15","author":"Verhaart","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1001\/jamaneurol.2020.1484","article-title":"Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial","volume":"77","author":"Mendell","year":"2020","journal-title":"JAMA Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16105","DOI":"10.1038\/ncomms16105","article-title":"Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy","volume":"8","author":"Servais","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_5","first-page":"43","article-title":"Read-through approach for stop mutations in Duchenne muscular dystrophy. An Update","volume":"40","author":"Politano","year":"2021","journal-title":"Acta Myol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gagliardi, M., and Ashizawa, A.T. (2021). The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040433"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1161\/CIRCULATIONAHA.117.028382","article-title":"Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic","volume":"136","author":"McNally","year":"2017","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4939-8651-4_2","article-title":"An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases","volume":"1828","author":"Rodrigues","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaap9004","DOI":"10.1126\/sciadv.aap9004","article-title":"Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing","volume":"4","author":"Long","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2147\/DDDT.S97635","article-title":"Eteplirsen in the treatment of Duchenne muscular dystrophy","volume":"11","author":"Rowel","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00204-021-03184-z","article-title":"Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: An update","volume":"96","author":"Sheikh","year":"2022","journal-title":"Arch. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1126\/science.1254445","article-title":"Prevention of muscular dystrophy in mice by CRISPR\/Cas9\u2013mediated editing of germline DNA","volume":"345","author":"Long","year":"2014","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1126\/science.aau1549","article-title":"Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy","volume":"362","author":"Amoasii","year":"2018","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nmeth.3684","article-title":"Creating and evaluating accurate CRISPR-Cas9 scalpels for genomic surgery","volume":"13","author":"Bolukbasi","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"814174","DOI":"10.3389\/fneur.2021.814174","article-title":"Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence","volume":"12","author":"Manini","year":"2021","journal-title":"Front. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/978-1-4939-8651-4_12","article-title":"Restoration of Dystrophin Protein Expression by Exon Skipping Utilizing CRISPR-Cas9 in Myoblasts Derived from DMD Patient iPS Cells","volume":"1828","author":"Ifuku","year":"2018","journal-title":"Methods. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.stem.2016.01.021","article-title":"A Single CRISPR-Cas9 Deletion Strategy that Targets the Majority of DMD Patients Restores Dystrophin Function in hiPSC-Derived Muscle Cells","volume":"18","author":"Young","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/mt.2008.264","article-title":"Cardiac Expression of a Mini-dystrophin That Normalizes Skeletal Muscle Force Only Partially Restores Heart Function in Aged Mdx Mice","volume":"17","author":"Bostick","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.csbj.2020.03.012","article-title":"Effective restoration of dystrophin expression in iPSC Mdx-derived muscle progenitor cells using the CRISPR\/Cas9 system and homology-directed repair technology","volume":"18","author":"Jin","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bbrc.2021.01.056","article-title":"Targeted addition of mini-dystrophin into rDNA locus of Duchenne muscular dystrophy patient-derived iPSCs","volume":"545","author":"Zeng","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41587-020-0741-7","article-title":"A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells","volume":"39","author":"Nguyen","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1016\/j.ymthe.2020.07.009","article-title":"Broader Implications of Progressive Liver Dysfunction and Lethal Sepsis in Two Boys following Systemic High-Dose AAV","volume":"28","author":"Morales","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1089\/hum.2017.144","article-title":"Cardiac-Specific Expression of \u0394H2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy","volume":"29","author":"Wasala","year":"2018","journal-title":"Hum. Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/cvr\/cvz109","article-title":"Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells","volume":"116","author":"Pioner","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.yjmcc.2012.12.009","article-title":"Cardiac phenotype of Duchenne Muscular Dystrophy: Insights from cellular studies","volume":"58","author":"Shirokova","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12364","DOI":"10.1074\/jbc.271.21.12364","article-title":"The Association of Cardiac Dystrophin with Myofibrils\/Z-disc Regions in Cardiac Muscle Suggests a Novel Role in the Contractile Apparatus","volume":"271","author":"Meng","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2586","DOI":"10.1161\/01.CIR.101.22.2586","article-title":"Distinct Patterns of Dystrophin Organization in Myocyte Sarcolemma and Transverse Tubules of Normal and Diseased Human Myocardium","volume":"101","author":"Kaprielian","year":"2000","journal-title":"Circulation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/nmeth.4278","article-title":"CIRCLE-seq: A highly sensitive in vitro screen for genome-wide CRISPR\u2013Cas9 nuclease off-targets","volume":"14","author":"Tsai","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nbt.3117","article-title":"GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases","volume":"33","author":"Tsai","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"ref_30","first-page":"e59432","article-title":"CRISPR\/Cas9 Technology in Restoring Dystrophin Expression in iPSC-Derived Muscle Progenitors","volume":"151","author":"Jin","year":"2019","journal-title":"J. Vis. Exp."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1126\/science.1114758","article-title":"Direct Isolation of Satellite Cells for Skeletal Muscle Regeneration","volume":"309","author":"Montarras","year":"2005","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.stemcr.2015.07.016","article-title":"Human Satellite Cell Transplantation and Regeneration from Diverse Skeletal Muscles","volume":"5","author":"Xu","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1016\/j.celrep.2018.10.067","article-title":"A Myogenic Double-Reporter Human Pluripotent Stem Cell Line Allows Prospective Isolation of Skeletal Muscle Progenitors","volume":"25","author":"Wu","year":"2018","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.actbio.2019.06.025","article-title":"Co-delivery of Wnt7a and muscle stem cells using synthetic bioadhesive hydrogel enhances murine muscle regeneration and cell migration during engraftment","volume":"94","author":"Han","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.stemcr.2019.01.007","article-title":"Combined Notch and PDGF Signaling Enhances Migration and Expression of Stem Cell Markers while Inducing Perivascular Cell Features in Muscle Satellite Cells","volume":"12","author":"Gerli","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.stemcr.2015.08.004","article-title":"Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells","volume":"5","author":"Charville","year":"2015","journal-title":"Stem Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/nature19815","article-title":"Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts","volume":"538","author":"Shiba","year":"2016","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.biomaterials.2018.04.055","article-title":"Placenta-derived mesenchymal stromal cells and their exosomes exert therapeutic effects in Duchenne muscular dystrophy","volume":"174","author":"Bier","year":"2018","journal-title":"Biomaterials"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/mt.2011.181","article-title":"Long-term Engraftment of Multipotent Mesenchymal Stromal Cells That Differentiate to Form Myogenic Cells in Dogs with Duchenne Muscular Dystrophy","volume":"20","author":"Okada","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1089\/scd.2020.0161","article-title":"Transplantation of Dystrophin Expressing Chimeric Human Cells of Myoblast\/Mesenchymal Stem Cell Origin Improves Function in Duchenne Muscular Dystrophy Model","volume":"30","author":"Siemionow","year":"2021","journal-title":"Stem Cells Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1097\/FJC.0000000000000183","article-title":"MicroRNA-133a Engineered Mesenchymal Stem Cells Augment Cardiac Function and Cell Survival in the Infarct Heart","volume":"65","author":"Dakhlallah","year":"2015","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4593","DOI":"10.1038\/s41598-020-58126-z","article-title":"Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation","volume":"10","author":"Yoshida","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/nbt.2647","article-title":"DNA targeting specificity of RNA-guided Cas9 nucleases","volume":"31","author":"Hsu","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"W171","DOI":"10.1093\/nar\/gkz365","article-title":"CHOPCHOP v3: Expanding the CRISPR web toolbox beyond genome editing","volume":"47","author":"Labun","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4014","DOI":"10.1093\/bioinformatics\/btv537","article-title":"Cas-Designer: A web-based tool for choice of CRISPR-Cas9 target sites","volume":"31","author":"Park","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"srep18865","DOI":"10.1038\/srep18865","article-title":"In situ genetic correction of F8 intron 22 inversion in hemophilia A patient-specific iPSCs","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1093\/bioinformatics\/btu048","article-title":"Cas-OFFinder: A fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases","volume":"30","author":"Bae","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1038\/s41596-018-0076-8","article-title":"Use of human induced pluripotent stem cell\u2013derived cardiomyocytes to assess drug cardiotoxicity","volume":"13","author":"Sharma","year":"2018","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9176\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:09:13Z","timestamp":1760141353000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9176"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,16]]},"references-count":48,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169176"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169176","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,16]]}}}