{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T09:12:52Z","timestamp":1785834772762,"version":"3.56.0"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Department of Animal Medicine, Production and Health, University of Padua","award":["BIRD187958\/18"],"award-info":[{"award-number":["BIRD187958\/18"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A new pandemic caused by the betacoronavirus SARS-CoV-2 originated in China in late 2019. Although often asymptomatic, a relevant percentage of affected people can develop severe pneumonia. Initial evidence suggests that dysregulation of the immune response could contribute to the pathogenesis, as previously demonstrated for SARS-CoV. The presence of genome composition features involved in delaying viral recognition is herein investigated for human coronaviruses (HCoVs), with a special emphasis on SARS-CoV-2. A broad collection of HCoVs polyprotein, envelope, matrix, nucleocapsid and spike coding sequences was downloaded and several statistics representative of genome composition and codon bias were investigated. A model able to evaluate and test the presence of a significant under- or over-representation of dinucleotide pairs while accounting for the underlying codon bias and protein sequence was also implemented. The study revealed the significant under-representation of CpG dinucleotide pair in all HcoV, but especially in SARS-CoV and even more in SARS-CoV-2. The presence of forces acting to minimize CpG content was confirmed by relative synonymous codon usage pattern. Codons containing the CpG pair were severely under-represented, primarily in the polyprotein and spike coding sequences of SARS-CoV-2. Additionally, a significant under-representation of the TpA pair was observed in the N and S region of SARS-CoV and SARS-CoV-2. Increasing experimental evidence has proven that CpG and TpA are targeted by innate antiviral host defences, contributing both to RNA degradation and RIG-1 mediated interferon production. The low content of these dinucleotides could contribute to a delayed interferon production, dysregulated immune response, higher viral replication and poor outcome. Significantly, the RIG-1 signalling pathway was proven to be defective in elderlies, suggesting a likely interaction between limited viral recognition and lower responsiveness in interferon production that could justify the higher disease severity and mortality in older patients.<\/jats:p>","DOI":"10.1038\/s41598-021-90278-4","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T10:02:50Z","timestamp":1621591370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["SARS-CoV-2 and other human coronavirus show genome patterns previously associated to reduced viral recognition and altered immune response"],"prefix":"10.1038","volume":"11","author":[{"given":"Giovanni","family":"Franzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"90278_CR1","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3390\/diseases4030026","volume":"4","author":"Y Lim","year":"2016","unstructured":"Lim, Y., Ng, Y., Tam, J. & Liu, D. Human coronaviruses: a review of virus\u2013host interactions. Diseases 4, 26 (2016).","journal-title":"Diseases"},{"key":"90278_CR2","doi-asserted-by":"publisher","first-page":"91","DOI":"10.5772\/26550","volume-title":"Viral Genomes\u2014Molecular Structure, Diversity, Gene Expression Mechanisms and Host\u2013Virus Interactions","author":"E Plant","year":"2012","unstructured":"Plant, E. Ribosomal frameshift signals in viral Genomes. In Viral Genomes\u2014Molecular Structure, Diversity, Gene Expression Mechanisms and Host\u2013Virus Interactions (eds Garcia, M. L. & Romanowski, V.) 91\u2013122 (Intechopen, 2012). https:\/\/doi.org\/10.5772\/26550."},{"key":"90278_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-4939-2438-7_1","volume-title":"Coronaviruses: Methods and Protocols","author":"AR Fehr","year":"2015","unstructured":"Fehr, A. R. & Perlman, S. Coronaviruses: an overview of their replication and pathogenesis. In Coronaviruses: Methods and Protocols (eds Maier, H. J. & Bickerton, E.) 1\u201323 (Springer, 2015). https:\/\/doi.org\/10.1007\/978-1-4939-2438-7_1."},{"key":"90278_CR4","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1111\/resp.13196","volume":"23","author":"Y Yin","year":"2018","unstructured":"Yin, Y. & Wunderink, R. G. MERS, SARS and other coronaviruses as causes of pneumonia. Respirology 23, 130\u2013137 (2018).","journal-title":"Respirology"},{"key":"90278_CR5","doi-asserted-by":"crossref","unstructured":"Van der Hoek, L. Human coronaviruses: what do they cause? Antivir. Ther. 12, 651\u2013658 (2007).","DOI":"10.1177\/135965350701200S01.1"},{"key":"90278_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/bs.aivir.2018.01.001","author":"VM Corman","year":"2018","unstructured":"Corman, V. M., Muth, D., Niemeyer, D. & Drosten, C. Hosts and sources of endemic human coronaviruses. Adv. Virus Res. https:\/\/doi.org\/10.1016\/bs.aivir.2018.01.001 (2018).","journal-title":"Adv. Virus Res."},{"key":"90278_CR7","unstructured":"WHO Guidelines for the Global Surveillance of Severe Acute Respiratory Syndrome (SARS). Updated recommendations, October 2004 (WHO, 2015)."},{"key":"90278_CR8","doi-asserted-by":"publisher","first-page":"124","DOI":"10.7861\/clinmed.2019-coron","volume":"20","author":"MA Lake","year":"2020","unstructured":"Lake, M. A. What we know so far: COVID-19 current clinical knowledge and research. Clin. Med. (Lond.) 20, 124\u2013127 (2020).","journal-title":"Clin. Med. (Lond.)"},{"key":"90278_CR9","unstructured":"Flaxman, S. et al. Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in European countries: technical description update. arXiv:2004.11342 (2020)."},{"key":"90278_CR10","doi-asserted-by":"publisher","first-page":"231","DOI":"10.3390\/pathogens9030231","volume":"9","author":"FA Rabi","year":"2020","unstructured":"Rabi, F. A., Al Zoubi, M. S., Kasasbeh, G. A., Salameh, D. M. & Al-Nasser, A. D. SARS-CoV-2 and coronavirus disease 2019: what we know so far. Pathogens 9, 231 (2020).","journal-title":"Pathogens"},{"key":"90278_CR11","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1002\/jmv.25709","volume":"92","author":"J Liu","year":"2020","unstructured":"Liu, J. et al. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J. Med. Virol. 92, 491\u2013494 (2020).","journal-title":"J. Med. Virol."},{"key":"90278_CR12","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.virusres.2009.07.014","volume":"145","author":"SL Kong","year":"2009","unstructured":"Kong, S. L., Chui, P., Lim, B. & Salto-Tellez, M. Elucidating the molecular physiopathology of acute respiratory distress syndrome in severe acute respiratory syndrome patients. Virus Res. 145, 260\u2013269 (2009).","journal-title":"Virus Res."},{"key":"90278_CR13","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","volume":"395","author":"C Huang","year":"2020","unstructured":"Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 395, 497\u2013506 (2020).","journal-title":"The Lancet"},{"key":"90278_CR14","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1159\/000503030","volume":"12","author":"M Kikkert","year":"2020","unstructured":"Kikkert, M. Innate immune evasion by human respiratory RNA viruses. J. Innate Immun. 12, 4\u201320 (2020).","journal-title":"J. Innate Immun."},{"key":"90278_CR15","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1002\/jmv.25685","volume":"92","author":"G Li","year":"2020","unstructured":"Li, G. et al. Coronavirus infections and immune responses. J. Med. Virol. 92, 424\u2013432 (2020).","journal-title":"J. Med. Virol."},{"key":"90278_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2017.11.002","author":"J Zheng","year":"2018","unstructured":"Zheng, J. & Perlman, S. Immune responses in influenza A virus and human coronavirus infections: an ongoing battle between the virus and host. Curr. Opin. Virol. https:\/\/doi.org\/10.1016\/j.coviro.2017.11.002 (2018).","journal-title":"Curr. Opin. Virol."},{"key":"90278_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2016.01.007","author":"R Channappanavar","year":"2016","unstructured":"Channappanavar, R. et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe https:\/\/doi.org\/10.1016\/j.chom.2016.01.007 (2016).","journal-title":"Cell Host Microbe"},{"key":"90278_CR18","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1146\/annurev.genet.32.1.185","volume":"32","author":"S Karlin","year":"1998","unstructured":"Karlin, S., Campbell, A. M. & Mr\u00e1zek, J. Comparative DNA analysis across diverse genomes. Annu. Rev. Genet. 32, 185\u2013225 (1998).","journal-title":"Annu. Rev. Genet."},{"key":"90278_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ve\/vez038","volume":"5","author":"H Gu","year":"2019","unstructured":"Gu, H., Fan, R. L. Y., Wang, D. & Poon, L. L. M. Dinucleotide evolutionary dynamics in influenza A virus. Virus Evol. 5, 1\u201310 (2019).","journal-title":"Virus Evol."},{"key":"90278_CR20","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1111\/j.1462-2920.2009.01901.x","volume":"11","author":"D Willner","year":"2009","unstructured":"Willner, D., Thurber, R. V. & Rohwer, F. Metagenomic signatures of 86 microbial and viral metagenomes. Environ. Microbiol. 11, 1752\u20131766 (2009).","journal-title":"Environ. Microbiol."},{"key":"90278_CR21","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1146\/annurev.genet.42.110807.091442","volume":"42","author":"R Hershberg","year":"2008","unstructured":"Hershberg, R. & Petrov, D. A. Selection on codon bias. Annu. Rev. Genet. 42, 287\u2013299 (2008).","journal-title":"Annu. Rev. Genet."},{"key":"90278_CR22","doi-asserted-by":"crossref","unstructured":"Roth, A., Anisimova, M. & Cannarozzi, G. M. Measuring codon usage bias. In Codon Evolution Mechanisms and Models 189\u2013217 (2012).","DOI":"10.1093\/acprof:osobl\/9780199601165.003.0013"},{"key":"90278_CR23","doi-asserted-by":"crossref","unstructured":"Plotkin, J. B., Robins, H. & Levine, A. J. Tissue-specific codon usage and the expression of human genes. In Proceedings of the National Academy of Sciences 101(34), 12588\u201312591 (2004).","DOI":"10.1073\/pnas.0404957101"},{"key":"90278_CR24","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.ympev.2017.05.019","volume":"114","author":"G Franzo","year":"2017","unstructured":"Franzo, G., Tucciarone, C. M., Cecchinato, M. & Drigo, M. Canine parvovirus type 2 (CPV-2) and feline panleukopenia virus (FPV) codon bias analysis reveals a progressive adaptation to the new niche after the host jump. Mol. Phylogenet. Evol. 114, 82\u201392 (2017).","journal-title":"Mol. Phylogenet. Evol."},{"key":"90278_CR25","doi-asserted-by":"publisher","first-page":"e0199950","DOI":"10.1371\/journal.pone.0199950","volume":"13","author":"G Franzo","year":"2018","unstructured":"Franzo, G. et al. The analysis of genome composition and codon bias reveals distinctive patterns between avian and mammalian circoviruses which suggest a potential recombinant origin for porcine circovirus 3. PLoS ONE 13, e0199950 (2018).","journal-title":"PLoS ONE"},{"key":"90278_CR26","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1038\/msb.2009.71","volume":"5","author":"I Bahir","year":"2009","unstructured":"Bahir, I., Fromer, M., Prat, Y. & Linial, M. Viral adaptation to host: a proteome-based analysis of codon usage and amino acid preferences. Mol. Syst. Biol. 5, 311 (2009).","journal-title":"Mol. Syst. Biol."},{"key":"90278_CR27","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1186\/1471-2148-10-253","volume":"10","author":"EHM Wong","year":"2010","unstructured":"Wong, E. H. M., Smith, D. K., Rabadan, R., Peiris, M. & Poon, L. L. M. Codon usage bias and the evolution of influenza A viruses. Codon usage biases of influenza virus. BMC Evol. Biol. 10, 253 (2010).","journal-title":"BMC Evol. Biol."},{"key":"90278_CR28","doi-asserted-by":"crossref","unstructured":"Kenrie P. Y. H. et al. Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir. Med. 8(7), 687\u2013695 (2020).","DOI":"10.1016\/S2213-2600(20)30193-4"},{"key":"90278_CR29","doi-asserted-by":"publisher","first-page":"e1000079","DOI":"10.1371\/journal.ppat.1000079","volume":"4","author":"BD Greenbaum","year":"2008","unstructured":"Greenbaum, B. D., Levine, A. J., Bhanot, G. & Rabadan, R. Patterns of evolution and host gene mimicry in influenza and other RNA viruses. PLoS Pathog. 4, e1000079 (2008).","journal-title":"PLoS Pathog."},{"key":"90278_CR30","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.1093\/molbev\/msaa094","volume":"37","author":"X Xia","year":"2020","unstructured":"Xia, X. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol. Biol. Evol. 37, 2699\u20132705 (2020).","journal-title":"Mol. Biol. Evol."},{"key":"90278_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ve\/veaa057","volume":"6","author":"P Digard","year":"2020","unstructured":"Digard, P., Lee, H. M., Sharp, C., Grey, F. & Gaunt, E. Intra-genome variability in the dinucleotide composition of SARS-CoV-2. Virus Evol. 6, 1\u201310 (2020).","journal-title":"Virus Evol."},{"key":"90278_CR32","doi-asserted-by":"publisher","first-page":"e74109","DOI":"10.1371\/journal.pone.0074109","volume":"8","author":"X Cheng","year":"2013","unstructured":"Cheng, X. et al. CpG usage in RNA viruses: data and hypotheses. PLoS ONE 8, e74109 (2013).","journal-title":"PLoS ONE"},{"key":"90278_CR33","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1007\/s00239-005-0221-1","volume":"62","author":"LA Shackelton","year":"2006","unstructured":"Shackelton, L. A., Parrish, C. R. & Holmes, E. C. Evolutionary basis of codon usage and nucleotide composition bias in vertebrate DNA viruses. J. Mol. Evol. 62, 551\u2013563 (2006).","journal-title":"J. Mol. Evol."},{"key":"90278_CR34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-019-56847-4","volume":"10","author":"Y Wang","year":"2020","unstructured":"Wang, Y. et al. Human SARS-CoV-2 has evolved to reduce CG dinucleotide in its open reading frames. Sci. Rep. 10, 1\u201310 (2020).","journal-title":"Sci. Rep."},{"key":"90278_CR35","doi-asserted-by":"publisher","first-page":"4527","DOI":"10.1093\/nar\/gku075","volume":"42","author":"NJ Atkinson","year":"2014","unstructured":"Atkinson, N. J., Witteveldt, J., Evans, D. J. & Simmonds, P. The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication. Nucl. Acids Res. 42, 4527\u20134545 (2014).","journal-title":"Nucl. Acids Res."},{"key":"90278_CR36","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/nature24039","volume":"550","author":"MA Takata","year":"2017","unstructured":"Takata, M. A. et al. CG dinucleotide suppression enables antiviral defence targeting non-self RNA. Nature 550, 124\u2013127 (2017).","journal-title":"Nature"},{"key":"90278_CR37","doi-asserted-by":"publisher","first-page":"65","DOI":"10.4161\/rna.5.2.6044","volume":"5","author":"Y Zhu","year":"2014","unstructured":"Zhu, Y. & Gao, G. ZAP-mediated mRNA degradation. RNA Biol. 5, 65\u201367 (2014).","journal-title":"RNA Biol."},{"key":"90278_CR38","doi-asserted-by":"publisher","first-page":"4352","DOI":"10.1073\/pnas.0712276105","volume":"105","author":"G Chen","year":"2008","unstructured":"Chen, G., Guo, X., Lv, F., Xu, Y. & Gao, G. p72 DEAD box RNA helicase is required for optimal function of the zinc-finger antiviral protein. Proc. Natl. Acad. Sci. U. S. A. 105, 4352\u20134357 (2008).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"90278_CR39","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/ni.1963","volume":"12","author":"S Hayakawa","year":"2011","unstructured":"Hayakawa, S. et al. ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses. Nat. Immunol. 12, 37\u201344 (2011).","journal-title":"Nat. Immunol."},{"key":"90278_CR40","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.virusres.2007.05.020","volume":"130","author":"CL Washenberger","year":"2007","unstructured":"Washenberger, C. L. et al. Hepatitis C virus RNA: dinucleotide frequencies and cleavage by RNase L. Virus Res. 130, 85\u201395 (2007).","journal-title":"Virus Res."},{"key":"90278_CR41","doi-asserted-by":"publisher","first-page":"e1000602","DOI":"10.1371\/journal.ppat.1000602","volume":"5","author":"DDC Ireland","year":"2009","unstructured":"Ireland, D. D. C. et al. RNase L mediated protection from virus induced demyelination. PLoS Pathog. 5, e1000602 (2009).","journal-title":"PLoS Pathog."},{"key":"90278_CR42","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1126\/science.aaf3926","volume":"352","author":"PS Pillai","year":"2016","unstructured":"Pillai, P. S. et al. Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease. Science 352, 463\u2013466 (2016).","journal-title":"Science"},{"key":"90278_CR43","doi-asserted-by":"publisher","first-page":"eaan2392","DOI":"10.1126\/scisignal.aan2392","volume":"10","author":"RD Molony","year":"2017","unstructured":"Molony, R. D. et al. Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. Sci. Signal. 10, eaan2392 (2017).","journal-title":"Sci. Signal."},{"key":"90278_CR44","doi-asserted-by":"publisher","first-page":"D593","DOI":"10.1093\/nar\/gkr859","volume":"40","author":"BE Pickett","year":"2012","unstructured":"Pickett, B. E. et al. ViPR: an open bioinformatics database and analysis resource for virology research. Nucl. Acids Res. 40, D593\u2013D598 (2012).","journal-title":"Nucl. Acids Res."},{"key":"90278_CR45","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1093\/bioinformatics\/btp163","volume":"25","author":"PJA Cock","year":"2009","unstructured":"Cock, P. J. A. et al. Biopython: freely available python tools for computational molecular biology and bioinformatics. Bioinformatics 25, 1422\u20131423 (2009).","journal-title":"Bioinformatics"},{"key":"90278_CR46","doi-asserted-by":"crossref","unstructured":"Charif, D. & Lobry, J. R. SeqinR 1.0\u20132: a contributed package to the R project for statistical computing devoted to biological sequences retrieval and analysis. In Structural Approaches to Sequence Evolution 207\u2013232 (Springer, Berlin, Heidelberg, 2007).","DOI":"10.1007\/978-3-540-35306-5_10"},{"key":"90278_CR47","doi-asserted-by":"crossref","unstructured":"Wang, D. et al. A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol. Syst. Biol. 15(2), e8503 (2018).","DOI":"10.15252\/msb.20188503"},{"key":"90278_CR48","doi-asserted-by":"publisher","first-page":"D746","DOI":"10.1093\/nar\/gkv1045","volume":"44","author":"R Petryszak","year":"2016","unstructured":"Petryszak, R. et al. Expression Atlas update\u2014an integrated database of gene and protein expression in humans, animals and plants. Nucl. Acids Res. 44, D746\u2013D752 (2016).","journal-title":"Nucl. Acids Res."},{"key":"90278_CR49","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1111\/j.1467-985X.2010.00676_9.x","volume":"174","author":"C Ginestet","year":"2011","unstructured":"Ginestet, C. ggplot2: elegant graphics for data analysis. J. R. Stat. Soc. A Stat. Soc. 174, 245\u2013246 (2011).","journal-title":"J. R. Stat. Soc. A Stat. Soc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90278-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90278-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90278-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T08:38:35Z","timestamp":1670056715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-90278-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,21]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["90278"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-90278-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,21]]},"assertion":[{"value":"15 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 May 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The author declares no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10696"}}