{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T20:13:33Z","timestamp":1762460013012,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Parent Project aps, Italy","award":["n.a."],"award-info":[{"award-number":["n.a."]}]},{"name":"Altucell Inc., Dix Hills, NY, USA","award":["n.a."],"award-info":[{"award-number":["n.a."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene translating in lack of functional dystrophin and resulting in susceptibility of myofibers to rupture during contraction. Inflammation and fibrosis are critical hallmarks of DMD muscles, which undergo progressive degeneration leading to loss of independent ambulation in childhood and death by early adulthood. We reported that intraperitoneal injection of microencapsulated Sertoli cells (SeC) in dystrophic mice translates into recovery of muscle morphology and performance thanks to anti-inflammatory effects and induction of the dystrophin paralogue, utrophin at the muscle level, opening new avenues in the treatment of DMD. The aim of this study is to obtain information about the direct effects of SeC on myoblasts\/myotubes, as a necessary step in view of a translational application of SeC-based approaches to DMD. We show that (i) SeC-derived factors stimulate cell proliferation in the early phase of differentiation in C2C12, and human healthy and DMD myoblasts; (ii) SeC delay the expression of differentiation markers in the early phase nevertheless stimulating terminal differentiation in DMD myoblasts; (iii) SeC restrain the fibrogenic potential of fibroblasts, and inhibit myoblast-myofibroblast transdifferentiation; and, (iv) SeC provide functional replacement of dystrophin in preformed DMD myotubes regardless of the mutation by inducing heregulin \u03b21\/ErbB2\/ERK1\/2-dependent utrophin expression. Altogether, these results show that SeC are endowed with promyogenic and antifibrotic effects on dystrophic myoblasts, further supporting their potential use in the treatment of DMD patients. Our data also suggest that SeC-based approaches might be useful in improving the early phase of muscle regeneration, during which myoblasts have to adequately proliferate to replace the damaged muscle mass.<\/jats:p>","DOI":"10.3390\/biom11101504","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T04:51:57Z","timestamp":1634100717000},"page":"1504","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sertoli Cells Improve Myogenic Differentiation, Reduce Fibrogenic Markers, and Induce Utrophin Expression in Human DMD Myoblasts"],"prefix":"10.3390","volume":"11","author":[{"given":"Laura","family":"Salvadori","sequence":"first","affiliation":[{"name":"Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy"},{"name":"Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Chiappalupi","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy"},{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"},{"name":"Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iva","family":"Arato","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Mancuso","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Calvitti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Cristina","family":"Marchetti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7908-3379","authenticated-orcid":false,"given":"Francesca","family":"Riuzzi","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy"},{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"},{"name":"Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Calafiore","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"},{"name":"Centro Biotecnologico Internazionale di Ricerca Traslazionale ad Indirizzo Endocrino, Metabolico ed Embrio-Riproduttivo (CIRTEMER), 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Luca","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"},{"name":"Centro Biotecnologico Internazionale di Ricerca Traslazionale ad Indirizzo Endocrino, Metabolico ed Embrio-Riproduttivo (CIRTEMER), 06132 Perugia, Italy"},{"name":"Centro Universitario di Ricerca sulla Genomica Funzionale (CURGeF), 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1973-9679","authenticated-orcid":false,"given":"Guglielmo","family":"Sorci","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy"},{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"},{"name":"Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy"},{"name":"Centro Biotecnologico Internazionale di Ricerca Traslazionale ad Indirizzo Endocrino, Metabolico ed Embrio-Riproduttivo (CIRTEMER), 06132 Perugia, Italy"},{"name":"Centro Universitario di Ricerca sulla Genomica Funzionale (CURGeF), 06132 Perugia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0960-8966(91)90039-U","article-title":"Population frequencies of inherited neuromuscular diseases\u2014A world survey","volume":"1","author":"Emery","year":"1991","journal-title":"Neuromuscul. Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/ana.23528","article-title":"Evidence-based path to newborn screening for Duchenne muscular dystrophy","volume":"71","author":"Mendell","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41572-021-00248-3","article-title":"Duchenne muscular dystrophy","volume":"7","author":"Duan","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1242\/dmm.018424","article-title":"Animal models of Duchenne muscular dystrophy: From basic mechanisms to gene therapy","volume":"8","author":"McGreevy","year":"2015","journal-title":"Dis. Model Mech."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/cphy.c170052","article-title":"Immunobiology of Inherited Muscular Dystrophies","volume":"8","author":"Tidball","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bello, L., and Pegoraro, E. (2019). The \u201cUsual Suspects\u201d: Genes for Inflammation, Fibrosis, Regeneration, and Muscle Strength Modify Duchenne Muscular Dystrophy. J. Clin. Med., 8.","DOI":"10.3390\/jcm8050649"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s13023-017-0631-3","article-title":"The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: An evidence review","volume":"12","author":"Ryder","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e12599","DOI":"10.1111\/cpr.12599","article-title":"Do porcine Sertoli cells represent an opportunity for Duchenne muscular dystrophy?","volume":"52","author":"Chiappalupi","year":"2019","journal-title":"Cell Prolif."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1590\/0004-282x20190088","article-title":"Duchenne muscular dystrophy: An historical treatment review","volume":"77","author":"Werneck","year":"2019","journal-title":"Arq. Neuro-Psiquiatria"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.dib.2015.11.016","article-title":"Effects of intraperitoneal injection of microencapsulated Sertoli cells on chronic and presymptomatic dystrophic mice","volume":"5","author":"Chiappalupi","year":"2015","journal-title":"Data Brief"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.biomaterials.2015.10.029","article-title":"Intraperitoneal injection of microencapsulated Sertoli cells restores muscle morphology and performance in dystrophic mice","volume":"75","author":"Chiappalupi","year":"2016","journal-title":"Biomaterials"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/biolre\/ioy027","article-title":"50 years of spermatogenesis: Sertoli cells and their interactions with germ cells","volume":"99","author":"Griswold","year":"2018","journal-title":"Biol. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1530\/REP-09-0384","article-title":"Immunoprotective sertoli cells: Making allogeneic and xenogeneic transplantation feasible","volume":"139","author":"Mital","year":"2010","journal-title":"Reproduction"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.semcdb.2014.02.011","article-title":"Sertoli cells-immunological sentinels of spermatogenesis","volume":"30","author":"Kaur","year":"2014","journal-title":"Semin Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/andr.12484","article-title":"Sertoli cells for cell transplantation: Pre-clinical studies and future perspectives","volume":"6","author":"Luca","year":"2018","journal-title":"Andrology"},{"key":"ref_17","unstructured":"Chiappalupi, S., Salvadori, L., Mancuso, F., Arato, I., Calvitti, M., Riuzzi, F., Calafiore, R., Luca, G., and Sorci, G. Microencapsulated Sertoli cells sustain myoblast proliferation without affecting the myogenic potential. In vitro data, Data Brief, submitted."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Salvadori, L., Mandrone, M., Manenti, T., Ercolani, C., Cornioli, L., Lianza, M., Tomasi, P., Chiappalupi, S., Di Filippo, E.S., and Fulle, S. (2020). Identification of Withania somnifera-Silybum marianum-Trigonella foenum-graecum Formulation as a Nutritional Supplement to Contrast Muscle Atrophy and Sarcopenia. Nutrients, 13.","DOI":"10.3390\/nu13010049"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/jcsm.12561","article-title":"Targeting RAGE prevents muscle wasting and prolongs survival in cancer cachexia","volume":"11","author":"Chiappalupi","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_20","first-page":"572","article-title":"Human ontogenesis. 3. Cell death in fetal muscle","volume":"81","author":"Goebel","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/S0002-9440(10)63188-4","article-title":"Transforming growth factor-beta1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle: A key event in muscle fibrogenesis","volume":"164","author":"Li","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0960-8966(98)00093-5","article-title":"Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophies","volume":"9","author":"Bernasconi","year":"1999","journal-title":"Neuromuscul. Disord."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14661","DOI":"10.1016\/S0021-9258(17)36676-0","article-title":"Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin","volume":"269","author":"Sliwkowski","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Washburn, R.L., Hibler, T., Thompson, L.A., Kaur, G., and Dufour, J.M. (2021). Therapeutic application of Sertoli cells for treatment of various diseases. Semin Cell Dev. Biol.","DOI":"10.1016\/j.semcdb.2021.04.007"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chiappalupi, S., Salvadori, L., Luca, G., Riuzzi, F., Calafiore, R., Donato, R., and Sorci, G. (2017). Employment of Microencapsulated Sertoli Cells as a New Tool to Treat Duchenne Muscular Dystrophy. J. Funct. Morphol. Kinesiol., 2.","DOI":"10.3390\/jfmk2040047"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2511","DOI":"10.1084\/jem.20090134","article-title":"Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone","volume":"206","author":"Fallarino","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jconrel.2012.08.028","article-title":"Reversal of experimental Laron Syndrome by xenotransplantation of microencapsulated porcine Sertoli cells","volume":"165","author":"Luca","year":"2013","journal-title":"J. Control Release"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1111\/cns.12569","article-title":"Terapeutic Potential of Microencapsulated Sertoli Cells in Huntington Disease","volume":"22","author":"Luca","year":"2016","journal-title":"CNS Neurosci. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/xen.12274","article-title":"Xenograft of microencapsulated Sertoli cells restores glucose homeostasis in db\/db mice with spontaneous diabetes mellitus","volume":"23","author":"Luca","year":"2016","journal-title":"Xenotransplantation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"299rv4","DOI":"10.1126\/scitranslmed.aaa7322","article-title":"Immune-mediated pathology in Duchenne muscular dystrophy","volume":"7","author":"Rosenberg","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1023\/A:1025425823322","article-title":"Myoblast transplantation: The current status of a potential therapeutic tool for myopathies","volume":"24","author":"Skuk","year":"2003","journal-title":"J. Muscle Res. Cell. Motil."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1016\/j.ymthe.2018.07.011","article-title":"Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy","volume":"26","author":"Duan","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sun, C., Shen, L., Zhang, Z., and Xie, X. (2020). Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update. Genes, 11.","DOI":"10.3390\/genes11080837"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1152\/physrev.00043.2011","article-title":"Satellite cells and the muscle stem cell niche","volume":"93","author":"Yin","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Cappellari, O., Mantuano, P., and De Luca, A. (2020). \u201cThe Social Network\u201d and Muscular Dystrophies: The Lesson Learnt about the Niche Environment as a Target for Therapeutic Strategies. Cells, 9.","DOI":"10.3390\/cells9071659"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1152\/physrev.00019.2003","article-title":"Cellular and molecular regulation of muscle regeneration","volume":"84","author":"Rudnicki","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1242\/jcs.084491","article-title":"S100B protein regulates myoblast proliferation and differentiation by activating FGFR1 in a bFGF-dependent manner","volume":"124","author":"Riuzzi","year":"2011","journal-title":"J. Cell. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/cdd.2010.95","article-title":"BMP signalling permits population expansion by preventing premature myogenic differentiation in muscle satellite cells","volume":"18","author":"Ono","year":"2011","journal-title":"Cell. Death Differ."},{"key":"ref_40","first-page":"481","article-title":"Growth hormone and the insulin-like growth factor system in myogenesis","volume":"17","author":"Florini","year":"1996","journal-title":"Endocr. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.bbamcr.2018.10.012","article-title":"Epidermal Growth Factor-based adhesion substrates elicit myoblast scattering, proliferation, differentiation and promote satellite cell myogenic activation","volume":"1866","author":"Sciancalepore","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.stem.2019.01.002","article-title":"EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions","volume":"24","author":"Wang","year":"2019","journal-title":"Cell Stem Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/mus.1072","article-title":"Prosaposin is immunolocalized to muscle and prosaptides promote myoblast fusion and attenuate loss of muscle mass after nerve injury","volume":"24","author":"Rende","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/s41467-020-20290-1","article-title":"TGF\u03b2 signalling acts as a molecular brake of myoblast fusion","volume":"12","author":"Melendez","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S0002-9440(10)64250-2","article-title":"Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle","volume":"161","author":"Li","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1002\/jcp.21324","article-title":"Skeletal muscle cells express the profibrotic cytokine connective tissue growth factor (CTGF\/CCN2), which induces their dedifferentiation","volume":"215","author":"Vial","year":"2008","journal-title":"J. Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Hillege, M.M.G., Galli Caro, R.A., Offringa, C., de Wit, G.M.J., Jaspers, R.T., and Hoogaars, W.M.H. (2020). TGF-\u03b2 Regulates Collagen Type I Expression in Myoblasts and Myotubes via Transient Ctgf and Fgf-2 Expression. Cells, 9.","DOI":"10.3390\/cells9020375"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1038\/nrd3978","article-title":"Extracellular vesicles: Biology and emerging therapeutic opportunities","volume":"12","author":"Breakefield","year":"2013","journal-title":"Nat. Rev. Drug. Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/humu.22758","article-title":"The TREAT-NMD DMD Global Database: Analysis of more than 7,000 Duchenne muscular dystrophy mutations","volume":"36","author":"Bladen","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/21678707.2018.1438261","article-title":"The potential of utrophin modulators for the treatment of Duchenne muscular dystrophy","volume":"6","author":"Guiraud","year":"2018","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4714","DOI":"10.1128\/MCB.22.13.4714-4722.2002","article-title":"ErbB2 is required for muscle spindle and myoblast cell survival","volume":"22","author":"Andrechek","year":"2002","journal-title":"Mol. Cell. Biol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/10\/1504\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:12:18Z","timestamp":1760166738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/10\/1504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,12]]},"references-count":51,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["biom11101504"],"URL":"https:\/\/doi.org\/10.3390\/biom11101504","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2021,10,12]]}}}