{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:12:42Z","timestamp":1791655962863,"version":"4.3.4"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Program","award":["I01 BX003507"],"award-info":[{"award-number":["I01 BX003507"]}]},{"name":"NIA, NIH","award":["AG064078"],"award-info":[{"award-number":["AG064078"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Degeneration and death of motor neurons in Amyotrophic Lateral Sclerosis (ALS) are associated with increased lipid peroxidation. Lipid peroxidation is the driver of ferroptosis, an iron-dependent oxidative mode of cell death. However, the importance of ferroptosis in motor neuron degeneration of ALS remains unclear. Glutathione peroxidase 4 (Gpx4) is a key enzyme in suppressing ferroptosis by reducing phospholipid hydroperoxides in membranes. To assess the effect of increased protection against ferroptosis on motor neuron disease, we generated SOD1<jats:sup>G93A<\/jats:sup>GPX4 double transgenic mice by cross-breeding GPX4 transgenic mice with SOD1<jats:sup>G93A<\/jats:sup> mice, a widely used ALS mouse model. Compared with control SOD1<jats:sup>G93A<\/jats:sup> mice, both male and female SOD1<jats:sup>G93A<\/jats:sup>GPX4 mice had extended lifespans. SOD1<jats:sup>G93A<\/jats:sup>GPX4 mice also showed delayed disease onset and increased motor function, which were correlated with ameliorated spinal motor neuron degeneration and reduced lipid peroxidation. Moreover, cell toxicity induced by SOD1<jats:sup>G93A<\/jats:sup> was ameliorated by Gpx4 overexpression and by chemical inhibitors of ferroptosis in vitro. We further found that the anti-ferroptosis defense system in spinal cord tissues of symptomatic SOD1<jats:sup>G93A<\/jats:sup> mice and sporadic ALS patients might be compromised due to deficiency of Gpx4. Thus, our results suggest that ferroptosis plays a key role in motor neuron degeneration of ALS.<\/jats:p>","DOI":"10.1038\/s41598-021-92369-8","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T10:03:33Z","timestamp":1624010613000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Overexpression of ferroptosis defense enzyme Gpx4 retards motor neuron disease of SOD1G93A mice"],"prefix":"10.1038","volume":"11","author":[{"given":"Liuji","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren","family":"Na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Danae McLane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody Sylvester","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinglong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qitao","family":"Ran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,18]]},"reference":[{"key":"92369_CR1","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1016\/S0140-6736(10)61156-7","volume":"377","author":"MC Kiernan","year":"2011","unstructured":"Kiernan, M. C. et al. Amyotrophic lateral sclerosis. Lancet 377, 942\u2013955 (2011).","journal-title":"Lancet"},{"key":"92369_CR2","first-page":"49","volume":"6","author":"AA Alsultan","year":"2016","unstructured":"Alsultan, A. A., Waller, R., Heath, P. R. & Kirby, J. The genetics of amyotrophic lateral sclerosis: Current insights. Degener. Neurol. Neuromuscul. Dis 6, 49\u201364 (2016).","journal-title":"Degener. Neurol. Neuromuscul. Dis"},{"key":"92369_CR3","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrneurol.2011.152","volume":"7","author":"L Ferraiuolo","year":"2011","unstructured":"Ferraiuolo, L., Kirby, J., Grierson, A. J., Sendtner, M. & Shaw, P. J. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat. Rev. Neurol. 7, 616\u2013630 (2011).","journal-title":"Nat. Rev. Neurol."},{"issue":"Suppl 1","key":"92369_CR4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3109\/21678421.2013.778554","volume":"14","author":"MR Turner","year":"2013","unstructured":"Turner, M. R. et al. Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph. Lateral. Scler. Frontotemporal. Degener 14(Suppl 1), 19\u201332 (2013).","journal-title":"Amyotroph. Lateral. Scler. Frontotemporal. Degener"},{"key":"92369_CR5","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","volume":"79","author":"SC Ling","year":"2013","unstructured":"Ling, S. C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron 79, 416\u2013438 (2013).","journal-title":"Neuron"},{"key":"92369_CR6","doi-asserted-by":"publisher","first-page":"68","DOI":"10.3389\/fnagi.2017.00068","volume":"9","author":"D Petrov","year":"2017","unstructured":"Petrov, D., Mansfield, C., Moussy, A. & Hermine, O. ALS clinical trials review: 20 years of failure. Are we any closer to registering a new treatment?. Front. Aging Neurosci. 9, 68 (2017).","journal-title":"Front. Aging Neurosci."},{"key":"92369_CR7","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1016\/j.freeradbiomed.2004.12.021","volume":"38","author":"M Perluigi","year":"2005","unstructured":"Perluigi, M. et al. Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice\u2013a model of familial amyotrophic lateral sclerosis. Free Radic. Biol. Med 38, 960\u2013968 (2005).","journal-title":"Free Radic. Biol. Med"},{"key":"92369_CR8","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1080\/17482960801933942","volume":"9","author":"H Mitsumoto","year":"2008","unstructured":"Mitsumoto, H. et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph. Lateral. Scler 9, 177\u2013183 (2008).","journal-title":"Amyotroph. Lateral. Scler"},{"key":"92369_CR9","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","volume":"149","author":"SJ Dixon","year":"2012","unstructured":"Dixon, S. J. et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 149, 1060\u20131072 (2012).","journal-title":"Cell"},{"key":"92369_CR10","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.tcb.2015.10.014","volume":"26","author":"WS Yang","year":"2016","unstructured":"Yang, W. S. & Stockwell, B. R. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol 26, 165\u2013176 (2016).","journal-title":"Trends Cell Biol"},{"key":"92369_CR11","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","volume":"171","author":"BR Stockwell","year":"2017","unstructured":"Stockwell, B. R. et al. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273\u2013285 (2017).","journal-title":"Cell"},{"key":"92369_CR12","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/S0891-5849(99)00173-2","volume":"27","author":"R Brigelius-Flohe","year":"1999","unstructured":"Brigelius-Flohe, R. Tissue-specific functions of individual glutathione peroxidases. Free Radic. Biol. Med 27, 951\u2013965 (1999).","journal-title":"Free Radic. Biol. Med"},{"key":"92369_CR13","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","volume":"156","author":"WS Yang","year":"2014","unstructured":"Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317\u2013331 (2014).","journal-title":"Cell"},{"key":"92369_CR14","doi-asserted-by":"publisher","first-page":"28097","DOI":"10.1074\/jbc.M115.680090","volume":"290","author":"L Chen","year":"2015","unstructured":"Chen, L., Hambright, W. S., Na, R. & Ran, Q. Ablation of the ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J. Biol. Chem 290, 28097\u201328106 (2015).","journal-title":"J. Biol. Chem"},{"key":"92369_CR15","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/362059a0","volume":"362","author":"DR Rosen","year":"1993","unstructured":"Rosen, D. R. et al. Mutations in Cu\/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59\u201362 (1993).","journal-title":"Nature"},{"key":"92369_CR16","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1126\/science.8209258","volume":"264","author":"ME Gurney","year":"1994","unstructured":"Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu Zn superoxide dismutase mutation. Science 264, 1772\u20131775 (1994).","journal-title":"Science"},{"key":"92369_CR17","doi-asserted-by":"publisher","first-page":"55137","DOI":"10.1074\/jbc.M410387200","volume":"279","author":"Q Ran","year":"2004","unstructured":"Ran, Q. et al. Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis. J. Biol. Chem 279, 55137\u201355146 (2004).","journal-title":"J. Biol. Chem"},{"key":"92369_CR18","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1002\/jnr.20868","volume":"84","author":"Q Ran","year":"2006","unstructured":"Ran, Q. et al. Glutathione peroxidase 4 protects cortical neurons from oxidative injury and amyloid toxicity. J. Neurosci. Res 84, 202\u2013208 (2006).","journal-title":"J. Neurosci. Res"},{"key":"92369_CR19","unstructured":"Leitner, M., Menzies, S. & Lutz, C. in The Jackson Laboratory (2009)."},{"key":"92369_CR20","doi-asserted-by":"publisher","first-page":"e9541","DOI":"10.1371\/journal.pone.0009541","volume":"5","author":"JC Stevens","year":"2010","unstructured":"Stevens, J. C. et al. Modification of superoxide dismutase 1 (SOD1) properties by a GFP tag\u2013implications for research into amyotrophic lateral sclerosis (ALS). PLoS ONE 5, e9541 (2010).","journal-title":"PLoS ONE"},{"key":"92369_CR21","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1021\/acscentsci.7b00028","volume":"3","author":"O Zilka","year":"2017","unstructured":"Zilka, O. et al. On the mechanism of cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent Sci 3, 232\u2013243 (2017).","journal-title":"ACS Cent Sci"},{"key":"92369_CR22","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1038\/ncb3064","volume":"16","author":"JP Friedmann Angeli","year":"2014","unstructured":"Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol 16, 1180\u20131191 (2014).","journal-title":"Nat. Cell Biol"},{"key":"92369_CR23","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1038\/mt.2013.211","volume":"21","author":"KD Foust","year":"2013","unstructured":"Foust, K. D. et al. Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression and extends survival in models of inherited ALS. Mol. Ther. 21, 2148\u20132159 (2013).","journal-title":"Mol. Ther."},{"key":"92369_CR24","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.neulet.2016.07.059","volume":"636","author":"B van Zundert","year":"2017","unstructured":"van Zundert, B. & Brown, R. H. Jr. Silencing strategies for therapy of SOD1-mediated ALS. Neurosci. Lett. 636, 32\u201339 (2017).","journal-title":"Neurosci. Lett."},{"key":"92369_CR25","doi-asserted-by":"publisher","first-page":"42292","DOI":"10.1038\/srep42292","volume":"7","author":"JB Hilton","year":"2017","unstructured":"Hilton, J. B. et al. Cu(II)(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord. Sci. Rep. 7, 42292 (2017).","journal-title":"Sci. Rep."},{"key":"92369_CR26","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1212\/WNL.62.10.1758","volume":"62","author":"EP Simpson","year":"2004","unstructured":"Simpson, E. P., Henry, Y. K., Henkel, J. S., Smith, R. G. & Appel, S. H. Increased lipid peroxidation in sera of ALS patients: A potential biomarker of disease burden. Neurology 62, 1758\u20131765 (2004).","journal-title":"Neurology"},{"key":"92369_CR27","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1002\/ana.410440518","volume":"44","author":"WA Pedersen","year":"1998","unstructured":"Pedersen, W. A. et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann. Neurol 44, 819\u2013824 (1998).","journal-title":"Ann. Neurol"},{"key":"92369_CR28","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1038\/s41598-019-39739-5","volume":"9","author":"D Devos","year":"2019","unstructured":"Devos, D. et al. A ferroptosis-based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis. Sci. Rep. 9, 2918 (2019).","journal-title":"Sci. Rep."},{"key":"92369_CR29","doi-asserted-by":"publisher","first-page":"776","DOI":"10.2174\/1389450121666200220123305","volume":"21","author":"S Spasi\u0107","year":"2020","unstructured":"Spasi\u0107, S. et al. Edaravone may prevent ferroptosis in ALS. Curr. Drug Targets 21, 776\u2013780 (2020).","journal-title":"Curr. Drug Targets"},{"key":"92369_CR30","doi-asserted-by":"publisher","first-page":"111592","DOI":"10.1016\/j.yexcr.2019.111592","volume":"384","author":"T Homma","year":"2019","unstructured":"Homma, T., Kobayashi, S., Sato, H. & Fujii, J. Edaravone, a free radical scavenger, protects against ferroptotic cell death in vitro. Exp. Cell Res. 384, 111592 (2019).","journal-title":"Exp. Cell Res."},{"key":"92369_CR31","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1159\/000323469","volume":"8","author":"Q Wang","year":"2011","unstructured":"Wang, Q. et al. Prevention of motor neuron degeneration by novel iron chelators in SOD1(G93A) transgenic mice of amyotrophic lateral sclerosis. Neurodegener. Dis. 8, 310\u2013321 (2011).","journal-title":"Neurodegener. Dis."},{"key":"92369_CR32","doi-asserted-by":"publisher","first-page":"3766","DOI":"10.1096\/fj.09-130047","volume":"23","author":"L Kupershmidt","year":"2009","unstructured":"Kupershmidt, L. et al. Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 23, 3766\u20133779 (2009).","journal-title":"FASEB J."},{"key":"92369_CR33","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.nbd.2011.04.025","volume":"43","author":"MR Vargas","year":"2011","unstructured":"Vargas, M. R., Johnson, D. A. & Johnson, J. A. Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1(G93A) mice model. Neurobiol. Dis. 43, 543\u2013551 (2011).","journal-title":"Neurobiol. Dis."},{"key":"92369_CR34","doi-asserted-by":"publisher","first-page":"3289","DOI":"10.1016\/j.bbagen.2012.11.020","volume":"1830","author":"R Brigelius-Flohe","year":"2013","unstructured":"Brigelius-Flohe, R. & Maiorino, M. Glutathione peroxidases. Biochim. Biophys. Acta 1830, 3289\u20133303 (2013).","journal-title":"Biochim. Biophys. Acta"},{"key":"92369_CR35","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1212\/WNL.59.5.729","volume":"59","author":"ME Cudkowicz","year":"2002","unstructured":"Cudkowicz, M. E. et al. Survival in transgenic ALS mice does not vary with CNS glutathione peroxidase activity. Neurology 59, 729\u2013734 (2002).","journal-title":"Neurology"},{"key":"92369_CR36","doi-asserted-by":"publisher","first-page":"29771","DOI":"10.1074\/jbc.M504039200","volume":"280","author":"A Tiwari","year":"2005","unstructured":"Tiwari, A., Xu, Z. & Hayward, L. J. Aberrantly increased hydrophobicity shared by mutants of Cu, Zn-superoxide dismutase in familial amyotrophic lateral sclerosis. J. Biol. Chem. 280, 29771\u201329779 (2005).","journal-title":"J. Biol. Chem."},{"key":"92369_CR37","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1126\/science.288.5464.335","volume":"288","author":"M Li","year":"2000","unstructured":"Li, M. et al. Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288, 335\u2013339 (2000).","journal-title":"Science"},{"key":"92369_CR38","doi-asserted-by":"crossref","unstructured":"Pasinelli, P., Houseweart, M.K., Brown, R.H., & Cleveland, D.W. Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. U. S. A 97, 13901\u201313906 (2000).","DOI":"10.1073\/pnas.240305897"},{"key":"92369_CR39","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1172\/JCI200317610","volume":"111","author":"C Guegan","year":"2003","unstructured":"Guegan, C. & Przedborski, S. Programmed cell death in amyotrophic lateral sclerosis. J. Clin. Invest 111, 153\u2013161 (2003).","journal-title":"J. Clin. Invest"},{"key":"92369_CR40","doi-asserted-by":"publisher","first-page":"2996","DOI":"10.1073\/pnas.1819728116","volume":"116","author":"Z Wu","year":"2019","unstructured":"Wu, Z. et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc Natl Acad Sci U S A 116, 2996\u20133005 (2019).","journal-title":"Proc Natl Acad Sci U S A"},{"key":"92369_CR41","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.brainres.2007.06.045","volume":"1167","author":"N Morimoto","year":"2007","unstructured":"Morimoto, N. et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res. 1167, 112\u2013117 (2007).","journal-title":"Brain Res."},{"key":"92369_CR42","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1007\/s12035-013-8623-3","volume":"49","author":"T An","year":"2014","unstructured":"An, T. et al. Oxidative stress and autophagic alteration in brainstem of SOD1-G93A mouse model of ALS. Mol. Neurobiol. 49, 1435\u20131448 (2014).","journal-title":"Mol. Neurobiol."},{"key":"92369_CR43","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1080\/17482960701856300","volume":"9","author":"S Scott","year":"2008","unstructured":"Scott, S. et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph. Lateral Scler. 9, 4\u201315 (2008).","journal-title":"Amyotroph. Lateral Scler."},{"key":"92369_CR44","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1111\/j.1474-9726.2008.00432.x","volume":"7","author":"L Chen","year":"2008","unstructured":"Chen, L. et al. Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice. Aging Cell 7, 866\u2013878 (2008).","journal-title":"Aging Cell"},{"key":"92369_CR45","doi-asserted-by":"publisher","first-page":"7728","DOI":"10.1016\/S0021-9258(20)89509-X","volume":"266","author":"M Maiorino","year":"1991","unstructured":"Maiorino, M. et al. Phospholipid hydroperoxide glutathione peroxidase is the 18-kDa selenoprotein expressed in human tumor cell lines. J. Biol. Chem 266, 7728\u20137732 (1991).","journal-title":"J. Biol. Chem"},{"key":"92369_CR46","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.redox.2017.01.021","volume":"12","author":"WS Hambright","year":"2017","unstructured":"Hambright, W. S., Fonseca, R. S., Chen, L., Na, R. & Ran, Q. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox. Biol 12, 8\u201317 (2017).","journal-title":"Redox. Biol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92369-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92369-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92369-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T09:53:01Z","timestamp":1670061181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-92369-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,18]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["92369"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-92369-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,18]]},"assertion":[{"value":"10 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12890"}}