{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T21:05:02Z","timestamp":1783717502853,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T00:00:00Z","timestamp":1596585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010014","name":"Manchester Metropolitan University","doi-asserted-by":"publisher","award":["CF-SciEng-APL-2017-1"],"award-info":[{"award-number":["CF-SciEng-APL-2017-1"]}],"id":[{"id":"10.13039\/100010014","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Maladaptive endoplasmic reticulum (ER) stress is associated with modified reactive oxygen species (ROS) generation and mitochondrial abnormalities; and is postulated as a potential mechanism involved in muscle weakness in myositis, an acquired autoimmune neuromuscular disease. This study investigates the impact of ROS generation in an in vitro model of ER stress in skeletal muscle, using the ER stress inducer tunicamycin (24 h) in the presence or absence of a superoxide dismutase\/catalase mimetic Eukarion (EUK)-134. Tunicamycin induced maladaptive ER stress, which was mitigated by EUK-134 at the transcriptional level. ER stress promoted mitochondrial dysfunction, described by substantial loss of mitochondrial membrane potential, as well as a reduction in respiratory control ratio, reserve capacity, phosphorylating respiration, and coupling efficiency, which was ameliorated by EUK-134. Tunicamycin induced ROS-mediated biogenesis and fusion of mitochondria, which, however, had high propensity of fragmentation, accompanied by upregulated mRNA levels of fission-related markers. Increased cellular ROS generation was observed under ER stress that was prevented by EUK-134, even though no changes in mitochondrial superoxide were noticeable. These findings suggest that targeting ROS generation using EUK-134 can amend aspects of ER stress-induced changes in mitochondrial dynamics and function, and therefore, in instances of chronic ER stress, such as in myositis, quenching ROS generation may be a promising therapy for muscle weakness and dysfunction.<\/jats:p>","DOI":"10.3390\/antiox9080710","type":"journal-article","created":{"date-parts":[[2020,8,5]],"date-time":"2020-08-05T15:13:18Z","timestamp":1596640398000},"page":"710","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Eukarion-134 Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Dysfunction in Human Skeletal Muscle Cells"],"prefix":"10.3390","volume":"9","author":[{"given":"Anastasia","family":"Thoma","sequence":"first","affiliation":[{"name":"Musculoskeletal Science &amp; Sports Medicine Research Centre, Department of Life Sciences, Faculty of Science &amp; Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Lyon","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasser","family":"Al-Shanti","sequence":"additional","affiliation":[{"name":"Musculoskeletal Science &amp; Sports Medicine Research Centre, Department of Life Sciences, Faculty of Science &amp; Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4508-0406","authenticated-orcid":false,"given":"Gareth A.","family":"Nye","sequence":"additional","affiliation":[{"name":"Chester Medical School, University of Chester, Chester CH1 4BJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L7 8TX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1501-7879","authenticated-orcid":false,"given":"Adam P.","family":"Lightfoot","sequence":"additional","affiliation":[{"name":"Musculoskeletal Science &amp; Sports Medicine Research Centre, Department of Life Sciences, Faculty of Science &amp; Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.tibs.2017.10.006","article-title":"How are proteins reduced in the endoplasmic reticulum?","volume":"43","author":"Ellgaard","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sicari, D., Igbaria, A., and Chevet, E. (2019). Control of protein homeostasis in the early secretory pathway: Current status and challenges. Cells, 8.","DOI":"10.3390\/cells8111347"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.tibs.2015.01.002","article-title":"UPR, autophagy, and mitochondria crosstalk underlies the ER stress response","volume":"40","author":"Senft","year":"2015","journal-title":"Trends Biochem. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"434","DOI":"10.3390\/ijms14010434","article-title":"An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases","volume":"14","author":"Bhandary","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10495-016-1296-4","article-title":"The role of endoplasmic reticulum stress in neurodegenerative disease","volume":"22","author":"Xiang","year":"2017","journal-title":"Apoptosis"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1016\/j.bbadis.2017.06.009","article-title":"ER stress disturbs SR\/ER-mitochondria Ca2+ transfer: Implications in Duchenne muscular dystrophy","volume":"1863","author":"Pauly","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.cell.2010.02.034","article-title":"Endoplasmic reticulum stress and the inflammatory basis of metabolic disease","volume":"140","author":"Hotamisligil","year":"2010","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1002\/art.21103","article-title":"Activation of the endoplasmic reticulum stress response in autoimmune myositis: Potential role in muscle fiber damage and dysfunction","volume":"52","author":"Nagaraju","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1089\/ars.2014.5851","article-title":"Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease","volume":"21","author":"Cao","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.biocel.2011.10.012","article-title":"Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics","volume":"44","author":"Bravo","year":"2012","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1242\/jcs.080762","article-title":"Increased ER\u2013mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress","volume":"124","author":"Bravo","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_13","first-page":"193","article-title":"Tunicamycin-induced ER stress mediates mitochondrial dysfunction in human adipocytes","volume":"Volume 44","author":"Jackisch","year":"2016","journal-title":"Proceedings of the Society for Endocrinology BES 2016"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.redox.2018.11.003","article-title":"Enhanced inter-compartmental Ca2+ flux modulates mitochondrial metabolism and apoptotic threshold during aging","volume":"20","author":"Bourguignon","year":"2019","journal-title":"Redox Biol."},{"key":"ref_15","first-page":"215","article-title":"Synthetic combined superoxide dismutase\/catalase mimetics are protective as a delayed treatment in a rat stroke model: A key role for reactive oxygen species in ischemic brain injury","volume":"284","author":"Baker","year":"1998","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/2044-5040-1-34","article-title":"Immortalized pathological human myoblasts: Towards a universal tool for the study of neuromuscular disorders","volume":"1","author":"Mamchaoui","year":"2011","journal-title":"Skelet. Muscle"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1089\/152308604771978507","article-title":"Combined superoxide dismutase\/catalase mimetics alter fetal pulmonary arterial smooth muscle cell growth","volume":"6","author":"Wedgwood","year":"2004","journal-title":"Antioxid. Redox Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00426-16","DOI":"10.1128\/MCB.00426-16","article-title":"Deletion of Pofut1 in mouse skeletal myofibers induces muscle aging-related phenotypes in cis and in trans","volume":"37","author":"Zygmunt","year":"2017","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"760","DOI":"10.7150\/ijbs.25052","article-title":"MiR-487b-3p suppresses the proliferation and differentiation of myoblasts by targeting IRS1 in skeletal muscle myogenesis","volume":"14","author":"Wang","year":"2018","journal-title":"Int. J. Biol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Debaud, C., Salga, M., Begot, L., Holy, X., Chedik, M., De l\u2019Escalopier, N., Torossian, F., Levesque, J.P., Lataillade, J.J., and Le Bousse-Kerdiles, M.C. (2017). Peripheral denervation participates in heterotopic ossification in a spinal cord injury model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182454"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13843","DOI":"10.1074\/jbc.M808515200","article-title":"Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission","volume":"284","author":"Dagda","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e3128","DOI":"10.21769\/BioProtoc.3128","article-title":"Analysis of the mitochondrial membrane potential using the cationic JC-1 dye as a sensitive fluorescent probe","volume":"9","author":"Sivandzade","year":"2019","journal-title":"Bio Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.redox.2013.12.028","article-title":"Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity","volume":"2","author":"Dott","year":"2014","journal-title":"Redox Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1161\/CIRCRESAHA.116.306374","article-title":"How mitochondrial dynamism orchestrates mitophagy","volume":"116","author":"Shirihai","year":"2015","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.4049\/jimmunol.174.7.4333","article-title":"HIV-1 transactivator of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis","volume":"174","author":"Perry","year":"2005","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2533","DOI":"10.1242\/jcs.070490","article-title":"New insights into the role of mitochondria in aging: Mitochondrial dynamics and more","volume":"123","author":"Seo","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101451","DOI":"10.1016\/j.redox.2020.101451","article-title":"Redox-dependent regulation of mitochondrial dynamics by DJ-1 paralogs in Saccharomyces cerevisiae","volume":"32","author":"Bankapalli","year":"2020","journal-title":"Redox Biol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Westrate, L.M., Drocco, J.A., Martin, K.R., Hlavacek, W.S., and MacKeigan, J.P. (2014). Mitochondrial morphological features are associated with fission and fusion events. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095265"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pearson, T., Kabayo, T., Ng, R., Chamberlain, J., McArdle, A., and Jackson, M.J. (2014). Skeletal muscle contractions induce acute changes in cytosolic superoxide, but slower responses in mitochondrial superoxide and cellular hydrogen peroxide. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096378"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s10495-007-0756-2","article-title":"Mitochondria, oxidative stress and cell death","volume":"12","author":"Ott","year":"2007","journal-title":"Apoptosis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.freeradbiomed.2012.01.015","article-title":"Amplification of proinflammatory phenotype, damage, and weakness by oxidative stress in the diaphragm muscle of mdx mice","volume":"52","author":"Kim","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R470","DOI":"10.1152\/ajpregu.00371.2013","article-title":"EUK-134 ameliorates nNOS\u03bc translocation and skeletal muscle fiber atrophy during short-term mechanical unloading","volume":"306","author":"Lawler","year":"2014","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13395-015-0045-7","article-title":"Muscle dysfunction associated with adjuvant-induced arthritis is prevented by antioxidant treatment","volume":"5","author":"Yamada","year":"2015","journal-title":"Skelet. Muscle"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Himori, K., Abe, M., Tatebayashi, D., Lee, J., Westerblad, H., Lanner, J.T., and Yamada, T. (2017). Superoxide dismutase\/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169146"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3105","DOI":"10.1016\/S0021-9258(19)81080-3","article-title":"Relationship of the structure and biological activity of the natural homologues of tunicamycin","volume":"257","author":"Duksin","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e989","DOI":"10.1038\/cddis.2013.522","article-title":"JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death","volume":"5","author":"Win","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.bbrc.2015.06.065","article-title":"Melatonin inhibits tunicamycin-induced endoplasmic reticulum stress and insulin resistance in skeletal muscle cells","volume":"463","author":"Quan","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s00125-011-2328-9","article-title":"Endoplasmic reticulum stress does not mediate palmitate-induced insulin resistance in mouse and human muscle cells","volume":"55","author":"Hassan","year":"2012","journal-title":"Diabetologia"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Deldicque, L., Bertrand, L., Patton, A., Francaux, M., and Baar, K. (2011). ER stress induces anabolic resistance in muscle cells through PKB-induced blockade of mTORC1. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020993"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/s41418-018-0133-4","article-title":"Increased mitochondrial respiration promotes survival from endoplasmic reticulum stress","volume":"26","author":"Knupp","year":"2019","journal-title":"Cell Death Differ."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"BSR20170898","DOI":"10.1042\/BSR20170898","article-title":"Sigmar1 regulates endoplasmic reticulum stress-induced C\/EBP-homologous protein expression in cardiomyocytes","volume":"37","author":"Alam","year":"2017","journal-title":"Biosci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1515\/hsz-2012-0198","article-title":"Integration of cellular bioenergetics with mitochondrial quality control and autophagy","volume":"393","author":"Hill","year":"2012","journal-title":"Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.freeradbiomed.2014.10.505","article-title":"Nitric oxide availability is increased in contracting skeletal muscle from aged mice, but does not differentially decrease muscle superoxide","volume":"78","author":"Pearson","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"68191","DOI":"10.18632\/oncotarget.19277","article-title":"Tunicamycin induced endoplasmic reticulum stress promotes apoptosis of prostate cancer cells by activating mTORC1","volume":"8","author":"Guha","year":"2017","journal-title":"Oncotarget"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1159\/000076547","article-title":"EUK-134 reduces renal dysfunction and injury caused by oxidative and nitrosative stress of the kidney","volume":"24","author":"Chatterjee","year":"2004","journal-title":"Am. J. Nephrol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7542","DOI":"10.3390\/ijms14047542","article-title":"Protein tyrosine nitration and thiol oxidation by peroxynitrite\u2014Strategies to prevent these oxidative modifications","volume":"14","author":"Daiber","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Trnka, J., Elkalaf, M., and And\u011bl, M. (2015). Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121837"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15066","DOI":"10.1073\/pnas.232591499","article-title":"Increased mitochondrial mass in mitochondrial myopathy mice","volume":"99","author":"Wredenberg","year":"2002","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Jadiya, P., and Tomar, D. (2020). Mitochondrial Protein Quality Control Mechanisms. Genes, 11.","DOI":"10.3390\/genes11050563"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Marino Gammazza, A., Macaluso, F., Di Felice, V., Cappello, F., and Barone, R. (2018). Hsp60 in skeletal muscle fiber biogenesis and homeostasis: From physical exercise to skeletal muscle pathology. Cells, 7.","DOI":"10.3390\/cells7120224"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"19781","DOI":"10.1038\/srep19781","article-title":"Skeletal muscle Heat shock protein 60 increases after endurance training and induces peroxisome proliferator-activated receptor gamma coactivator 1 \u03b11 expression","volume":"6","author":"Barone","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1530\/JME-19-0207","article-title":"Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis","volume":"64","author":"Xiao","year":"2020","journal-title":"J. Mol. Endocrinol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"C1176","DOI":"10.1152\/ajpcell.00017.2014","article-title":"Oxidative stress-induced mitochondrial fragmentation and movement in skeletal muscle myoblasts","volume":"306","author":"Iqbal","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1016\/j.freeradbiomed.2010.08.024","article-title":"H2O2-induced mitochondrial fragmentation in C2C12 myocytes","volume":"49","author":"Fan","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1016\/j.celrep.2018.02.055","article-title":"The PERK arm of the unfolded protein response regulates mitochondrial morphology during acute endoplasmic reticulum stress","volume":"22","author":"Lebeau","year":"2018","journal-title":"Cell Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/ncb2220","article-title":"During autophagy mitochondria elongate, are spared from degradation and sustain cell viability","volume":"13","author":"Gomes","year":"2011","journal-title":"Nat. Cell Biol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/8\/710\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:54:36Z","timestamp":1760176476000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/8\/710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,5]]},"references-count":57,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["antiox9080710"],"URL":"https:\/\/doi.org\/10.3390\/antiox9080710","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.06.10.143958","asserted-by":"object"}]},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,5]]}}}