{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:52:12Z","timestamp":1787003532138,"version":"build-2736575974"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-2113-M-182-003"],"award-info":[{"award-number":["MOST 109-2113-M-182-003"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 106-2320-B-182-029-MY3"],"award-info":[{"award-number":["MOST 106-2320-B-182-029-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chang Gung Memorial Hospital, Linkou, Taiwan","award":["CMRPD1G0133"],"award-info":[{"award-number":["CMRPD1G0133"]}]},{"name":"Chang Gung Memorial Hospital, Linkou, Taiwan","award":["CLRPD1J0012"],"award-info":[{"award-number":["CLRPD1J0012"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and\/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1\u2009\u00b1\u200959.9\u00a0ng\/ml vs. 13.7\u2009\u00b1\u200932.6\u00a0ng\/ml,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-89089-4","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T06:07:04Z","timestamp":1620194824000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Association of urinary ketamine and APOA1 levels with bladder dysfunction in ketamine abusers revealed via proteomics and targeted metabolite analyses"],"prefix":"10.1038","volume":"11","author":[{"given":"Jo-Chuan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ju","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chyi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chao","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Te","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Ken","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivas","family":"Dash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jau-Song","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"89089_CR1","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1097\/ALN.0b013e3181ed09a2","volume":"113","author":"EF Domino","year":"2010","unstructured":"Domino, E. F. Taming the ketamine tiger. 1965. Anesthesiology 113, 678\u2013684. https:\/\/doi.org\/10.1097\/ALN.0b013e3181ed09a2 (2010).","journal-title":"Anesthesiology"},{"key":"89089_CR2","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1124\/dmd.30.7.853","volume":"30","author":"Y Hijazi","year":"2002","unstructured":"Hijazi, Y. & Boulieu, R. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab. Dispos. 30, 853\u2013858. https:\/\/doi.org\/10.1124\/dmd.30.7.853 (2002).","journal-title":"Drug Metab. Dispos."},{"key":"89089_CR3","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.cca.2006.12.013","volume":"379","author":"MH Huang","year":"2007","unstructured":"Huang, M. H. et al. Performance characteristics of ELISAs for monitoring ketamine exposure. Clin. Chim. Acta 379, 59\u201365. https:\/\/doi.org\/10.1016\/j.cca.2006.12.013 (2007).","journal-title":"Clin. Chim. Acta"},{"key":"89089_CR4","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1093\/jat\/33.6.310","volume":"33","author":"N Harun","year":"2009","unstructured":"Harun, N., Anderson, R. A. & Miller, E. I. Validation of an enzyme-linked immunosorbent assay screening method and a liquid chromatography-tandem mass spectrometry confirmation method for the identification and quantification of ketamine and norketamine in urine samples from Malaysia. J. Anal. Toxicol. 33, 310\u2013321. https:\/\/doi.org\/10.1093\/jat\/33.6.310 (2009).","journal-title":"J. Anal. Toxicol."},{"key":"89089_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/s0376-8716(02)00243-0","volume":"69","author":"P Dillon","year":"2003","unstructured":"Dillon, P., Copeland, J. & Jansen, K. Patterns of use and harms associated with non-medical ketamine use. Drug Alcohol Depend. 69, 23\u201328. https:\/\/doi.org\/10.1016\/s0376-8716(02)00243-0 (2003).","journal-title":"Drug Alcohol Depend."},{"key":"89089_CR6","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.urology.2007.01.038","volume":"69","author":"R Shahani","year":"2007","unstructured":"Shahani, R., Streutker, C., Dickson, B. & Stewart, R. J. Ketamine-associated ulcerative cystitis: A new clinical entity. Urology 69, 810\u2013812. https:\/\/doi.org\/10.1016\/j.urology.2007.01.038 (2007).","journal-title":"Urology"},{"key":"89089_CR7","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/j.1360-0443.2011.03576.x","volume":"107","author":"CJ Morgan","year":"2012","unstructured":"Morgan, C. J., Curran, H. V. & Independent Scientific Committee on Drugs. Ketamine use: A review. Addiction 107, 27\u201338. https:\/\/doi.org\/10.1111\/j.1360-0443.2011.03576.x (2012).","journal-title":"Addiction"},{"key":"89089_CR8","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1111\/j.1464-410X.2008.07920.x","volume":"102","author":"PS Chu","year":"2008","unstructured":"Chu, P. S. et al. The destruction of the lower urinary tract by ketamine abuse: A new syndrome?. BJU Int. 102, 1616\u20131622. https:\/\/doi.org\/10.1111\/j.1464-410X.2008.07920.x (2008).","journal-title":"BJU Int."},{"key":"89089_CR9","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.urols.2013.09.001","volume":"24","author":"S-TW En-Meng","year":"2013","unstructured":"En-Meng, S.-T.W., Cha, T.-L., Sun, G.-H., Yu, D.-S. & Chang, S.-Y. A murderer of young bladders: Ketamine-associated cystitis. Urol. Sci. 24, 113\u2013116 (2013).","journal-title":"Urol. Sci."},{"key":"89089_CR10","doi-asserted-by":"publisher","first-page":"7313","DOI":"10.1007\/s11033-014-3616-5","volume":"41","author":"D Gu","year":"2014","unstructured":"Gu, D. et al. Long-term ketamine abuse induces cystitis in rats by impairing the bladder epithelial barrier. Mol. Biol. Rep. 41, 7313\u20137322. https:\/\/doi.org\/10.1007\/s11033-014-3616-5 (2014).","journal-title":"Mol. Biol. Rep."},{"key":"89089_CR11","doi-asserted-by":"publisher","first-page":"e0160578","DOI":"10.1371\/journal.pone.0160578","volume":"11","author":"CC Lin","year":"2016","unstructured":"Lin, C. C., Lin, A. T., Yang, A. H. & Chen, K. K. Microvascular injury in ketamine-induced bladder dysfunction. PLoS ONE 11, e0160578. https:\/\/doi.org\/10.1371\/journal.pone.0160578 (2016).","journal-title":"PLoS ONE"},{"key":"89089_CR12","doi-asserted-by":"publisher","first-page":"2757","DOI":"10.3892\/etm.2017.4913","volume":"14","author":"Q Duan","year":"2017","unstructured":"Duan, Q. et al. Changes to the bladder epithelial barrier are associated with ketamine-induced cystitis. Exp. Ther. Med. 14, 2757\u20132762. https:\/\/doi.org\/10.3892\/etm.2017.4913 (2017).","journal-title":"Exp. Ther. Med."},{"key":"89089_CR13","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1111\/j.1442-2042.2008.02177.x","volume":"16","author":"O Yamaguchi","year":"2009","unstructured":"Yamaguchi, O. et al. Clinical guidelines for overactive bladder. Int. J. Urol. 16, 126\u2013142. https:\/\/doi.org\/10.1111\/j.1442-2042.2008.02177.x (2009).","journal-title":"Int. J. Urol."},{"key":"89089_CR14","doi-asserted-by":"publisher","first-page":"7240","DOI":"10.1038\/s41598-019-43746-x","volume":"9","author":"CC Li","year":"2019","unstructured":"Li, C. C. et al. A survey for ketamine abuse and its relation to the lower urinary tract symptoms in Taiwan. Sci. Rep. 9, 7240. https:\/\/doi.org\/10.1038\/s41598-019-43746-x (2019).","journal-title":"Sci. Rep."},{"key":"89089_CR15","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1016\/j.ajpath.2015.12.014","volume":"186","author":"SC Baker","year":"2016","unstructured":"Baker, S. C., Shabir, S., Georgopoulos, N. T. & Southgate, J. Ketamine-induced apoptosis in normal human urothelial cells: A direct, N-methyl-d-aspartate receptor-independent pathway characterized by mitochondrial stress. Am. J. Pathol. 186, 1267\u20131277. https:\/\/doi.org\/10.1016\/j.ajpath.2015.12.014 (2016).","journal-title":"Am. J. Pathol."},{"key":"89089_CR16","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20190595","author":"L Cui","year":"2019","unstructured":"Cui, L. et al. Ketamine induces endoplasmic reticulum stress in rats and SV-HUC-1 human uroepithelial cells by activating NLRP3\/TXNIP aix. Biosci. Rep. https:\/\/doi.org\/10.1042\/BSR20190595 (2019)."},{"key":"89089_CR17","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1111\/iju.12100","volume":"20","author":"D Gu","year":"2013","unstructured":"Gu, D. et al. Effects of long-term ketamine administration on rat bladder protein levels: A proteomic investigation using two-dimensional difference gel electrophoresis system. Int. J. Urol. 20, 1024\u20131031. https:\/\/doi.org\/10.1111\/iju.12100 (2013).","journal-title":"Int. J. Urol."},{"key":"89089_CR18","doi-asserted-by":"publisher","first-page":"887","DOI":"10.3892\/mmr.2014.2823","volume":"11","author":"CH Shen","year":"2015","unstructured":"Shen, C. H. et al. Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamineinjected mice. Mol. Med. Rep. 11, 887\u2013895. https:\/\/doi.org\/10.3892\/mmr.2014.2823 (2015).","journal-title":"Mol. Med. Rep."},{"key":"89089_CR19","doi-asserted-by":"publisher","first-page":"1880","DOI":"10.3892\/mmr.2016.5482","volume":"14","author":"CH Shen","year":"2016","unstructured":"Shen, C. H. et al. Evaluation of urinary bladder fibrogenesis in a mouse model of long-term ketamine injection. Mol. Med. Rep. 14, 1880\u20131890. https:\/\/doi.org\/10.3892\/mmr.2016.5482 (2016).","journal-title":"Mol. Med. Rep."},{"key":"89089_CR20","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201600085","author":"HH Yang","year":"2017","unstructured":"Yang, H. H., Zhai, W. J. & Kuo, H. C. The putative involvement of actin-binding proteins and cytoskeleton proteins in pathological mechanisms of ketamine cystitis-Revealed by a prospective pilot study using proteomic approaches. Proteomics Clin. Appl. https:\/\/doi.org\/10.1002\/prca.201600085 (2017).","journal-title":"Proteomics Clin. Appl."},{"key":"89089_CR21","doi-asserted-by":"publisher","first-page":"4237285","DOI":"10.1155\/2019\/4237285","volume":"2019","author":"J Liu","year":"2019","unstructured":"Liu, J. et al. FibroAtlas: A database for the exploration of fibrotic diseases and their genes. Cardiol. Res. Pract. 2019, 4237285. https:\/\/doi.org\/10.1155\/2019\/4237285 (2019).","journal-title":"Cardiol. Res. Pract."},{"key":"89089_CR22","doi-asserted-by":"publisher","first-page":"257","DOI":"10.3389\/fimmu.2015.00257","volume":"6","author":"NS Merle","year":"2015","unstructured":"Merle, N. S., Noe, R., Halbwachs-Mecarelli, L., Fremeaux-Bacchi, V. & Roumenina, L. T. Complement system part II: Role in immunity. Front. Immunol. 6, 257. https:\/\/doi.org\/10.3389\/fimmu.2015.00257 (2015).","journal-title":"Front. Immunol."},{"key":"89089_CR23","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1074\/mcp.R800001-MCP200","volume":"7","author":"S Decramer","year":"2008","unstructured":"Decramer, S. et al. Urine in clinical proteomics. Mol. Cell Proteomics 7, 1850\u20131862. https:\/\/doi.org\/10.1074\/mcp.R800001-MCP200 (2008).","journal-title":"Mol. Cell Proteomics"},{"key":"89089_CR24","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.jchromb.2007.02.005","volume":"852","author":"PS Cheng","year":"2007","unstructured":"Cheng, P. S., Fu, C. Y., Lee, C. H., Liu, C. & Chien, C. S. GC-MS quantification of ketamine, norketamine, and dehydronorketamine in urine specimens and comparative study using ELISA as the preliminary test methodology. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 852, 443\u2013449. https:\/\/doi.org\/10.1016\/j.jchromb.2007.02.005 (2007).","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"issue":"Suppl 1","key":"89089_CR25","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/j.1757-5672.2011.00122.x","volume":"4","author":"E Meng","year":"2012","unstructured":"Meng, E., Lin, W. Y., Lee, W. C. & Chuang, Y. C. Pathophysiology of overactive bladder. Low Urin Tract Symptoms 4(Suppl 1), 48\u201355. https:\/\/doi.org\/10.1111\/j.1757-5672.2011.00122.x (2012).","journal-title":"Low Urin Tract Symptoms"},{"key":"89089_CR26","doi-asserted-by":"publisher","first-page":"6568","DOI":"10.4049\/jimmunol.1003756","volume":"186","author":"K Kambas","year":"2011","unstructured":"Kambas, K. et al. Endothelin-1 signaling promotes fibrosis in vitro in a bronchopulmonary dysplasia model by activating the extrinsic coagulation cascade. J. Immunol. 186, 6568\u20136575. https:\/\/doi.org\/10.4049\/jimmunol.1003756 (2011).","journal-title":"J. Immunol."},{"key":"89089_CR27","doi-asserted-by":"publisher","first-page":"103801","DOI":"10.1016\/j.jprot.2020.103801","volume":"223","author":"S Huang","year":"2020","unstructured":"Huang, S. et al. TMT-labelled quantitative proteomic analysis to identify the proteins underlying radiation-induced colorectal fibrosis in rats. J. Proteomics 223, 103801. https:\/\/doi.org\/10.1016\/j.jprot.2020.103801 (2020).","journal-title":"J. Proteomics"},{"key":"89089_CR28","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1016\/S0006-3495(97)78264-X","volume":"73","author":"JC Phillips","year":"1997","unstructured":"Phillips, J. C., Wriggers, W., Li, Z., Jonas, A. & Schulten, K. Predicting the structure of apolipoprotein A-I in reconstituted high-density lipoprotein disks. Biophys. J. 73, 2337\u20132346. https:\/\/doi.org\/10.1016\/S0006-3495(97)78264-X (1997).","journal-title":"Biophys. J."},{"key":"89089_CR29","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/nrd2353","volume":"7","author":"KM Wasan","year":"2008","unstructured":"Wasan, K. M., Brocks, D. R., Lee, S. D., Sachs-Barrable, K. & Thornton, S. J. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: Implications for drug discovery. Nat. Rev. Drug Discov. 7, 84\u201399. https:\/\/doi.org\/10.1038\/nrd2353 (2008).","journal-title":"Nat. Rev. Drug Discov."},{"key":"89089_CR30","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s12291-015-0513-1","volume":"31","author":"M Mangaraj","year":"2016","unstructured":"Mangaraj, M., Nanda, R. & Panda, S. Apolipoprotein A-I: A molecule of diverse function. Indian J. Clin. Biochem. 31, 253\u2013259. https:\/\/doi.org\/10.1007\/s12291-015-0513-1 (2016).","journal-title":"Indian J. Clin. Biochem."},{"key":"89089_CR31","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1182\/blood.v97.8.2381","volume":"97","author":"N Hyka","year":"2001","unstructured":"Hyka, N. et al. Apolipoprotein A-I inhibits the production of interleukin-1beta and tumor necrosis factor-alpha by blocking contact-mediated activation of monocytes by T lymphocytes. Blood 97, 2381\u20132389. https:\/\/doi.org\/10.1182\/blood.v97.8.2381 (2001).","journal-title":"Blood"},{"key":"89089_CR32","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1164\/rccm.200905-0659OC","volume":"182","author":"TH Kim","year":"2010","unstructured":"Kim, T. H. et al. Role of lung apolipoprotein A-I in idiopathic pulmonary fibrosis: Antiinflammatory and antifibrotic effect on experimental lung injury and fibrosis. Am. J. Respir. Crit. Care Med. 182, 633\u2013642. https:\/\/doi.org\/10.1164\/rccm.200905-0659OC (2010).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"89089_CR33","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.jchromb.2008.09.036","volume":"876","author":"MC Parkin","year":"2008","unstructured":"Parkin, M. C. et al. Detection of ketamine and its metabolites in urine by ultra high pressure liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 876, 137\u2013142. https:\/\/doi.org\/10.1016\/j.jchromb.2008.09.036 (2008).","journal-title":"J. Chromatogr. B Anal. Technol. Biomed. Life Sci."},{"key":"89089_CR34","doi-asserted-by":"publisher","first-page":"5803","DOI":"10.1021\/pr100576x","volume":"9","author":"YT Chen","year":"2010","unstructured":"Chen, Y. T. et al. Discovery of novel bladder cancer biomarkers by comparative urine proteomics using iTRAQ technology. J. Proteome Res. 9, 5803\u20135815. https:\/\/doi.org\/10.1021\/pr100576x (2010).","journal-title":"J. Proteome Res."},{"key":"89089_CR35","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","volume":"4","author":"W da Huang","year":"2009","unstructured":"da Huang, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44\u201357. https:\/\/doi.org\/10.1038\/nprot.2008.211 (2009).","journal-title":"Nat. Protoc."},{"key":"89089_CR36","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa, M. & Goto, S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27\u201330. https:\/\/doi.org\/10.1093\/nar\/28.1.27 (2000).","journal-title":"Nucleic Acids Res."},{"key":"89089_CR37","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","volume":"47","author":"D Szklarczyk","year":"2019","unstructured":"Szklarczyk, D. et al. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47, D607\u2013D613. https:\/\/doi.org\/10.1093\/nar\/gky1131 (2019).","journal-title":"Nucleic Acids Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89089-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89089-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89089-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T02:38:00Z","timestamp":1670035080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-89089-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,5]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["89089"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-89089-4","relation":{"references":[{"id-type":"uri","id":"","asserted-by":"subject"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,5]]},"assertion":[{"value":"22 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 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":"9583"}}