{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:48:32Z","timestamp":1792648112746,"version":"4.5.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31671194"],"award-info":[{"award-number":["31671194"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970616"],"award-info":[{"award-number":["81970616"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81720108007"],"award-info":[{"award-number":["81720108007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81600513"],"award-info":[{"award-number":["81600513"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Exosomes are increasingly recognized as vehicles of intercellular communication. However, the role of exosome in maintaining cellular homeostasis under stress conditions remained unclear. Here we show that Rab27a expression was upregulated exclusively in tubular epithelial cells (TECs) during proteinuria nephropathy established by adriamycin (ADR) injection and 5\/6 nephrectomy as well as in chronic kidney disease patients, leading to the increased secretion of exosomes carrying albumin. The active exosome production promoted tubule injury and inflammation in neighboring and the producing cells. Interferon regulatory factor 1 (IRF-1) was found as the transcription factor contributed to the upregulation of Rab27a. Albumin could be detected in exosome fraction and co-localized with exosome marker CD63 indicating the secretion of albumin into extracellular space by exosomes. Interestingly, inhibition of exosome release accelerated albumin degradation which reversed tubule injury with albumin overload, while lysosome suppression augmented exosome secretion and tubule inflammation. Our findings revealed that IRF-1\/Rab27a mediated exosome secretion constituted a coordinated approach to lysosome degradation for albumin handling, which lead to the augment of albumin toxicity as a maladaptive response to maintain cell homeostasis. The findings may suggest a novel therapeutic strategy for proteinuric kidney disease by targeting exosome secretion.<\/jats:p>","DOI":"10.1038\/s41419-020-2709-4","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T11:05:11Z","timestamp":1594206311000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Rab27a dependent exosome releasing participated in albumin handling as a coordinated approach to lysosome in kidney disease"],"prefix":"10.1038","volume":"11","author":[{"given":"Ye","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao-Tao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuo-Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Feng","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ri-Ning","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Cheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-Li","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,8]]},"reference":[{"key":"2709_CR1","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1016\/j.cell.2016.01.043","volume":"164","author":"M Tkach","year":"2016","unstructured":"Tkach, M. & Thery, C. Communication by extracellular vesicles: where we are and where we need to go. Cell 164, 1226\u20131232 (2016).","journal-title":"Cell"},{"key":"2709_CR2","doi-asserted-by":"publisher","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","volume":"7","author":"C The\u0301ry","year":"2018","unstructured":"The\u0301ry, C. et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018).","journal-title":"J. Extracell. Vesicles"},{"key":"2709_CR3","doi-asserted-by":"publisher","first-page":"27066","DOI":"10.3402\/jev.v4.27066","volume":"4","author":"M Yanez-Mo","year":"2015","unstructured":"Yanez-Mo, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).","journal-title":"J. Extracell. Vesicles"},{"key":"2709_CR4","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1080\/19336918.2016.1251000","volume":"11","author":"G Desdin-Mico","year":"2017","unstructured":"Desdin-Mico, G. & Mittelbrunn, M. Role of exosomes in the protection of cellular homeostasis. Cell Adh Migr. 11, 127\u2013134 (2017).","journal-title":"Cell Adh Migr."},{"key":"2709_CR5","first-page":"1","volume":"2012","author":"A Zhang","year":"2012","unstructured":"Zhang, A. & Huang, S. Progress in pathogenesis of proteinuria. Int J. Nephrol. 2012, 1\u201314 (2012).","journal-title":"Int J. Nephrol."},{"key":"2709_CR6","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.1097\/01.ASN.0000069223.98703.8E","volume":"14","author":"H Shimizu","year":"2003","unstructured":"Shimizu, H. et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. J. Am. Soc. Nephrol. 14, 1496\u20131505 (2003).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR7","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1056\/NEJM199811123392007","volume":"339","author":"G Remuzzi","year":"1998","unstructured":"Remuzzi, G. & Bertani, T. Pathophysiology of progressive nephropathies. N. Engl. J. Med. 339, 1448\u20131456 (1998).","journal-title":"N. Engl. J. Med."},{"key":"2709_CR8","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/nrneph.2010.174","volume":"7","author":"RJ Baines","year":"2011","unstructured":"Baines, R. J. & Brunskill, N. J. Tubular toxicity of proteinuria. Nat. Rev. Nephrol. 7, 177\u2013180 (2011).","journal-title":"Nat. Rev. Nephrol."},{"key":"2709_CR9","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.kint.2015.11.007","volume":"89","author":"R Nielsen","year":"2016","unstructured":"Nielsen, R., Christensen, E. I. & Birn, H. Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int 89, 58\u201367 (2016).","journal-title":"Kidney Int"},{"key":"2709_CR10","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1681\/ASN.2013010018","volume":"24","author":"V Tenten","year":"2013","unstructured":"Tenten, V. et al. Albumin is recycled from the primary urine by tubular transcytosis. J. Am. Soc. Nephrol. 24, 1966\u20131980 (2013).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR11","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1159\/000490223","volume":"47","author":"FF He","year":"2018","unstructured":"He, F. F. et al. A new pathogenesis of albuminuria: role of transcytosis. Cell. Physiol. Biochem. 47, 1274\u20131286 (2018).","journal-title":"Cell. Physiol. Biochem."},{"key":"2709_CR12","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1681\/ASN.2006040377","volume":"17","author":"M Abbate","year":"2006","unstructured":"Abbate, M., Zoja, C. & Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 17, 2974\u20132984 (2006).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR13","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1681\/ASN.2012101031","volume":"24","author":"FT Borges","year":"2013","unstructured":"Borges, F. T. et al. TGF-beta1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J. Am. Soc. Nephrol. 24, 385\u2013392 (2013).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR14","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.kint.2018.09.013","volume":"95","author":"ZL Li","year":"2019","unstructured":"Li, Z. L. et al. HIF-1alpha inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation. Kidney Int 95, 388\u2013404 (2019).","journal-title":"Kidney Int"},{"key":"2709_CR15","doi-asserted-by":"crossref","unstructured":"Lv, L. L. et al. Exosomal miRNA-19b-3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury. Cell Death Differ. 27, 210\u2013226 (2019).","DOI":"10.1038\/s41418-019-0349-y"},{"key":"2709_CR16","doi-asserted-by":"publisher","first-page":"403","DOI":"10.3389\/fimmu.2014.00403","volume":"5","author":"F Baixauli","year":"2014","unstructured":"Baixauli, F., Lopez-Otin, C. & Mittelbrunn, M. Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front Immunol. 5, 403 (2014).","journal-title":"Front Immunol."},{"key":"2709_CR17","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/boc.201500030","volume":"107","author":"SA Bellingham","year":"2015","unstructured":"Bellingham, S. A., Guo, B. & Hil, A. F. The secret life of extracellular vesicles in metal homeostasis and neurodegeneration. Biol. Cell 107, 389\u2013418 (2015).","journal-title":"Biol. Cell"},{"key":"2709_CR18","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/ncb3112","volume":"17","author":"L Murrow","year":"2015","unstructured":"Murrow, L., Malhotra, R. & Debnath, J. ATG12-ATG3 interacts with Alix to promote basal autophagic flux and late endosome function. Nat. Cell Biol. 17, 300\u2013310 (2015).","journal-title":"Nat. Cell Biol."},{"key":"2709_CR19","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.1681\/ASN.2018030324","volume":"29","author":"Y Guo","year":"2018","unstructured":"Guo, Y. et al. Podocyte-specific induction of Kr\u00fcppel-like factor 15 restores differentiation markers and attenuates kidney injury in proteinuric kidney disease. J. Am. Soc. Nephrol. 29, 2529\u20132545 (2018).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR20","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1681\/ASN.2017050523","volume":"29","author":"LL Lv","year":"2018","unstructured":"Lv, L. L. et al. Exosomal CCL2 from tubular epithelial cells is critical for albumin-induced tubulointerstitial inflammation. J. Am. Soc. Nephrol. 29, 919\u2013935 (2018).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR21","doi-asserted-by":"publisher","unstructured":"Ding, W., Yousefi, K. & Shehadeh, L. A. Isolation, characterization, and high throughput extracellular flux analysis of mouse primary renal tubular epithelial cells. J. Vis. Exp. https:\/\/doi.org\/10.3791\/57718 (2018).","DOI":"10.3791\/57718"},{"key":"2709_CR22","doi-asserted-by":"publisher","first-page":"30829","DOI":"10.3402\/jev.v5.30829","volume":"5","author":"K Iwai","year":"2016","unstructured":"Iwai, K., Minamisawa, T., Suga, K., Yajima, Y. & Shiba, K. Isolation of human salivary extracellular vesicles by iodixanol density gradient ultracentrifugation and their characterizations. J. Extracell. Vesicles 5, 30829 (2016).","journal-title":"J. Extracell. Vesicles"},{"key":"2709_CR23","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1038\/ki.2008.463","volume":"74","author":"C Slattery","year":"2008","unstructured":"Slattery, C. et al. In vivo visualization of albumin degradation in the proximal tubule. Kidney Int. 74, 1480\u20131486 (2008).","journal-title":"Kidney Int."},{"key":"2709_CR24","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1111\/j.1440-1797.2010.01383.x","volume":"16","author":"VW Lee","year":"2011","unstructured":"Lee, V. W. & Harris, D. C. Adriamycin nephropathy: a model of focal segmental glomerulosclerosis. Nephrol. (Carlton) 16, 30\u201338 (2011).","journal-title":"Nephrol. (Carlton)"},{"key":"2709_CR25","first-page":"5553","volume":"126","author":"M Colombo","year":"2013","unstructured":"Colombo, M. et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126, 5553\u20135565 (2013).","journal-title":"J. Cell Sci."},{"key":"2709_CR26","doi-asserted-by":"publisher","first-page":"3455","DOI":"10.1074\/jbc.M114.605253","volume":"290","author":"BB Guo","year":"2015","unstructured":"Guo, B. B., Bellingham, S. A. & Hill, A. F. The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. J. Biol. Chem. 290, 3455\u20133467 (2015).","journal-title":"J. Biol. Chem."},{"key":"2709_CR27","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/ncb2000","volume":"12","author":"M Ostrowski","year":"2010","unstructured":"Ostrowski, M. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19\u201330 (2010).","journal-title":"Nat. Cell Biol."},{"key":"2709_CR28","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1002\/hep.29605","volume":"67","author":"MQ Yang","year":"2018","unstructured":"Yang, M. Q. et al. Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia\/reperfusion injury. Hepatology 67, 1056\u20131070 (2018).","journal-title":"Hepatology"},{"key":"2709_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09720-x","volume":"10","author":"L Song","year":"2019","unstructured":"Song, L. et al. KIBRA controls exosome secretion via inhibiting the proteasomal degradation of Rab27a. Nat. Commun. 10, 1639 (2019).","journal-title":"Nat. Commun."},{"key":"2709_CR30","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/978-1-4939-2569-8_11","volume":"1298","author":"T Yasuda","year":"2015","unstructured":"Yasuda, T., Mrozowska, P. S. & Fukuda, M. Functional analysis of Rab27A and its effector Slp2-a in renal epithelial cells. Methods Mol. Biol. 1298, 127\u2013139 (2015).","journal-title":"Methods Mol. Biol."},{"key":"2709_CR31","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1083\/jcb.201512024","volume":"213","author":"PS Mrozowska","year":"2016","unstructured":"Mrozowska, P. S. & Fukuda, M. Regulation of podocalyxin trafficking by Rab small GTPases in 2D and 3D epithelial cell cultures. J. Cell Biol. 213, 355\u2013369 (2016).","journal-title":"J. Cell Biol."},{"key":"2709_CR32","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.1016\/j.cell.2012.11.024","volume":"151","author":"V Luga","year":"2012","unstructured":"Luga, V. et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151, 1542\u20131556 (2012).","journal-title":"Cell"},{"key":"2709_CR33","doi-asserted-by":"publisher","first-page":"18018","DOI":"10.1074\/jbc.M115.662064","volume":"290","author":"D Liu","year":"2015","unstructured":"Liu, D. et al. Megalin\/cubulin-lysosome-mediated albumin reabsorption is involved in the tubular cell activation of NLRP3 inflammasome and tubulointerstitial inflammation. J. Biol. Chem. 290, 18018\u201318028 (2015).","journal-title":"J. Biol. Chem."},{"key":"2709_CR34","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1681\/ASN.2011040396","volume":"23","author":"JK Guo","year":"2012","unstructured":"Guo, J. K. et al. Increased tubular proliferation as an adaptive response to glomerular albuminuria. J. Am. Soc. Nephrol. 23, 429\u2013437 (2012).","journal-title":"J. Am. Soc. Nephrol."},{"key":"2709_CR35","doi-asserted-by":"publisher","unstructured":"Babuta, M. et al. Dysregulated autophagy and lysosome function are linked to exosome production by micro-RNA 155 in alcoholic liver disease. Hepatology, https:\/\/doi.org\/10.1002\/hep.30766 (2019).","DOI":"10.1002\/hep.30766"},{"key":"2709_CR36","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1038\/s41591-018-0194-4","volume":"24","author":"C Qiu","year":"2018","unstructured":"Qiu, C. et al. Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat. Med. 24, 1721\u20131731 (2018).","journal-title":"Nat. Med."},{"key":"2709_CR37","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1038\/ki.2013.218","volume":"84","author":"R Nielsen","year":"2013","unstructured":"Nielsen, R. et al. Increased lysosomal proteolysis counteracts protein accumulation in the proximal tubule during focal segmental glomerulosclerosis. Kidney Int. 84, 902\u2013910 (2013).","journal-title":"Kidney Int"},{"key":"2709_CR38","doi-asserted-by":"publisher","first-page":"F1009","DOI":"10.1152\/ajprenal.00601.2012","volume":"304","author":"D Lee","year":"2013","unstructured":"Lee, D. et al. Limited capacity of proximal tubular proteolysis in mice with proteinuria. Am. J. Physiol. Ren. Physiol. 304, F1009\u2013F1019 (2013).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2709_CR39","doi-asserted-by":"publisher","first-page":"F639","DOI":"10.1152\/ajprenal.00383.2014","volume":"308","author":"WJ Liu","year":"2015","unstructured":"Liu, W. J. et al. Urinary proteins induce lysosomal membrane permeabilization and lysosomal dysfunction in renal tubular epithelial cells. Am. J. Physiol. Ren. Physiol. 308, F639\u2013F649 (2015).","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"2709_CR40","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.2215\/CJN.03250807","volume":"3","author":"GL Bakris","year":"2008","unstructured":"Bakris, G. L. Slowing nephropathy progression: focus on proteinuria reduction. Clin. J. Am. Soc. Nephrol. 3, S3\u2013S10 (2008).","journal-title":"Clin. J. Am. Soc. Nephrol."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2709-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2709-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2709-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T08:38:28Z","timestamp":1760085508000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2709-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,8]]},"references-count":40,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["2709"],"URL":"https:\/\/doi.org\/10.1038\/s41419-020-2709-4","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,8]]},"assertion":[{"value":"5 January 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"513"}}