{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T19:27:20Z","timestamp":1793993240835,"version":"4.8.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T00:00:00Z","timestamp":1611792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.<\/jats:p>","DOI":"10.1038\/s41419-020-03382-0","type":"journal-article","created":{"date-parts":[[2021,1,28]],"date-time":"2021-01-28T08:11:29Z","timestamp":1611821489000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Extracellular vesicles-released parathyroid hormone-related protein from Lewis lung carcinoma induces lipolysis and adipose tissue browning in cancer cachexia"],"prefix":"10.1038","volume":"12","author":[{"given":"Wenjun","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyuan","family":"Ru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kairu","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quansheng","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0924-5795","authenticated-orcid":false,"given":"Hongmei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,28]]},"reference":[{"key":"3382_CR1","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/nrc3829","volume":"14","author":"JM Argiles","year":"2014","unstructured":"Argiles, J. M., Busquets, S., Stemmler, B. & Lopez-Soriano, F. J. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14, 754\u2013762 (2014).","journal-title":"Nat. Rev. Cancer"},{"key":"3382_CR2","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.pharmthera.2017.02.020","volume":"174","author":"L Barile","year":"2017","unstructured":"Barile, L. & Vassalli, G. Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol. Ther. 174, 63\u201378 (2017).","journal-title":"Pharmacol. Ther."},{"key":"3382_CR3","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1016\/j.ccell.2016.10.009","volume":"30","author":"A Becker","year":"2016","unstructured":"Becker, A. et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer cell 30, 836\u2013848 (2016).","journal-title":"Cancer cell"},{"key":"3382_CR4","doi-asserted-by":"publisher","first-page":"4920","DOI":"10.1158\/0008-5472.CAN-12-0925","volume":"72","author":"A Bobrie","year":"2012","unstructured":"Bobrie, A. et al. Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res. 72, 4920\u20134930 (2012).","journal-title":"Cancer Res."},{"key":"3382_CR5","doi-asserted-by":"publisher","first-page":"4900","DOI":"10.1210\/endo.142.11.8515","volume":"142","author":"GK Chan","year":"2001","unstructured":"Chan, G. K., Deckelbaum, R. A., Bolivar, I., Goltzman, D. & Karaplis, A. C. PTHrP inhibits adipocyte differentiation by down-regulating PPAR gamma activity via a MAPK-dependent pathway. Endocrinology 142, 4900\u20134909 (2001).","journal-title":"Endocrinology"},{"key":"3382_CR6","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1097\/PPO.0000000000000306","volume":"24","author":"J Clancy","year":"2018","unstructured":"Clancy, J. & D\u2019Souza-Schorey, C. Extracellular vesicles in cancer: purpose and promise. Cancer J. 24, 65\u201369 (2018).","journal-title":"Cancer J."},{"key":"3382_CR7","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1016\/j.bbadis.2015.08.010","volume":"1852","author":"K Essandoh","year":"2015","unstructured":"Essandoh, K. et al. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction. Biochim. Biophys. Acta 1852, 2362\u20132371 (2015).","journal-title":"Biochim. Biophys. Acta"},{"key":"3382_CR8","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.cmet.2012.06.011","volume":"16","author":"KC Fearon","year":"2012","unstructured":"Fearon, K. C., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153\u2013166 (2012).","journal-title":"Cell Metab."},{"key":"3382_CR9","doi-asserted-by":"publisher","first-page":"2189","DOI":"10.1002\/cncr.21013","volume":"103","author":"M Fouladiun","year":"2005","unstructured":"Fouladiun, M. et al. Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care-correlations with food intake, metabolism, exercise capacity, and hormones. Cancer 103, 2189\u20132198 (2005).","journal-title":"Cancer"},{"key":"3382_CR10","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1146\/annurev-pharmtox-010814-124630","volume":"55","author":"B Gyorgy","year":"2015","unstructured":"Gyorgy, B., Hung, M. E., Breakefield, X. O. & Leonard, J. N. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu. Rev. Pharmacol. Toxicol. 55, 439\u2013464 (2015).","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"3382_CR11","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1002\/ijc.1425","volume":"94","author":"H Iguchi","year":"2001","unstructured":"Iguchi, H., Onuma, E., Sato, K., Sato, K. & Ogata, E. Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen. Int. J. cancer 94, 24\u201327 (2001).","journal-title":"Int. J. cancer"},{"key":"3382_CR12","doi-asserted-by":"publisher","first-page":"5311","DOI":"10.1158\/1078-0432.CCR-17-0577","volume":"23","author":"X Jin","year":"2017","unstructured":"Jin, X. et al. Evaluation of tumor-derived exosomal miRNA as potential diagnostic biomarkers for early-stage non-small cell lung cancer using next-generation sequencing. Clin. Cancer Res. 23, 5311\u20135319 (2017).","journal-title":"Clin. Cancer Res."},{"key":"3382_CR13","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nature13528","volume":"513","author":"S Kir","year":"2014","unstructured":"Kir, S. et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513, 100\u2013104 (2014).","journal-title":"Nature"},{"key":"3382_CR14","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.cmet.2015.11.003","volume":"23","author":"S Kir","year":"2016","unstructured":"Kir, S. et al. PTH\/PTHrP receptor mediates cachexia in models of kidney failure and cancer. Cell Metab. 23, 315\u2013323 (2016).","journal-title":"Cell Metab."},{"key":"3382_CR15","doi-asserted-by":"publisher","first-page":"26913","DOI":"10.3402\/jev.v3.26913","volume":"3","author":"J Lotvall","year":"2014","unstructured":"Lotvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicles 3, 26913 (2014).","journal-title":"J. Extracell. Vesicles"},{"key":"3382_CR16","doi-asserted-by":"publisher","first-page":"2535","DOI":"10.3892\/or.2016.5066","volume":"36","author":"Y Matsumoto","year":"2016","unstructured":"Matsumoto, Y. et al. Quantification of plasma exosome is a potential prognostic marker for esophageal squamous cell carcinoma. Oncol. Rep. 36, 2535\u20132543 (2016).","journal-title":"Oncol. Rep."},{"key":"3382_CR17","doi-asserted-by":"publisher","first-page":"24534","DOI":"10.1074\/jbc.M115.679217","volume":"290","author":"L Montermini","year":"2015","unstructured":"Montermini, L. et al. Inhibition of oncogenic epidermal growth factor receptor kinase triggers release of exosome-like extracellular vesicles and impacts their phosphoprotein and DNA content. J. Biol. Chem. 290, 24534\u201324546 (2015).","journal-title":"J. Biol. Chem."},{"key":"3382_CR18","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1681\/ASN.2007090981","volume":"19","author":"GR Mundy","year":"2008","unstructured":"Mundy, G. R. & Edwards, J. R. PTH-related peptide (PTHrP) in hypercalcemia. J. Am. Soc. Nephrol. 19, 672\u2013675 (2008).","journal-title":"J. Am. Soc. Nephrol."},{"key":"3382_CR19","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.clnu.2009.11.006","volume":"29","author":"RA Murphy","year":"2010","unstructured":"Murphy, R. A. et al. Loss of adipose tissue and plasma phospholipids: relationship to survival in advanced cancer patients. Clin. Nutr. 29, 482\u2013487 (2010).","journal-title":"Clin. Nutr."},{"key":"3382_CR20","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). sup pp 1\u201313.","journal-title":"Nat. Cell Biol."},{"key":"3382_CR21","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.1200\/JCO.1993.11.10.2043","volume":"11","author":"L Ovesen","year":"1993","unstructured":"Ovesen, L., Allingstrup, L., Hannibal, J., Mortensen, E. L. & Hansen, O. P. Effect of dietary counseling on food intake, body weight, response rate, survival, and quality of life in cancer patients undergoing chemotherapy: a prospective, randomized study. J. Clin. Oncol. 11, 2043\u20132049 (1993).","journal-title":"J. Clin. Oncol."},{"key":"3382_CR22","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/nm.2753","volume":"18","author":"H Peinado","year":"2012","unstructured":"Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883\u2013891 (2012).","journal-title":"Nat. Med."},{"key":"3382_CR23","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1038\/s41375-018-0015-2","volume":"32","author":"D Peng","year":"2018","unstructured":"Peng, D. et al. miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding. Leukemia 32, 1180\u20131188 (2018).","journal-title":"Leukemia"},{"key":"3382_CR24","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.cmet.2014.06.011","volume":"20","author":"M Petruzzelli","year":"2014","unstructured":"Petruzzelli, M. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433\u2013447 (2014).","journal-title":"Cell Metab."},{"key":"3382_CR25","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1172\/JCI87316","volume":"126","author":"JM Pitt","year":"2016","unstructured":"Pitt, J. M., Kroemer, G. & Zitvogel, L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J. Clin. Invest. 126, 1139\u20131143 (2016).","journal-title":"J. Clin. Invest."},{"key":"3382_CR26","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1002\/cncr.23802","volume":"113","author":"M Ryden","year":"2008","unstructured":"Ryden, M. et al. Lipolysis-not inflammation, cell death, or lipogenesis-is involved in adipose tissue loss in cancer cachexia. Cancer 113, 1695\u20131704 (2008).","journal-title":"Cancer"},{"key":"3382_CR27","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.jconrel.2015.09.031","volume":"220","author":"H Saari","year":"2015","unstructured":"Saari, H. et al. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells. J. Control. Release 220, 727\u2013737 (2015).","journal-title":"J. Control. Release"},{"key":"3382_CR28","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1136\/gutjnl-2014-308350","volume":"65","author":"G Sagar","year":"2016","unstructured":"Sagar, G. et al. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. Gut 65, 1165\u20131174 (2016).","journal-title":"Gut"},{"key":"3382_CR29","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/pmic.201600375","volume":"17","author":"P Samuel","year":"2017","unstructured":"Samuel, P., Fabbri, M. & Carter, D. R. F. Mechanisms of drug resistance in cancer: the role of extracellular vesicles. Proteomics 17, 23\u201324 (2017).","journal-title":"Proteomics"},{"key":"3382_CR30","doi-asserted-by":"publisher","first-page":"C101","DOI":"10.1152\/ajpcell.00344.2015","volume":"311","author":"R Sun","year":"2016","unstructured":"Sun, R. et al. Valproic acid attenuates skeletal muscle wasting by inhibiting C\/EBPbeta-regulated atrogin1 expression in cancer cachexia. Am. J. Physiol. Cell Physiol. 311, C101\u2013C115 (2016).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"3382_CR31","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ygyno.2008.04.033","volume":"110","author":"DD Taylor","year":"2008","unstructured":"Taylor, D. D. & Gercel-Taylor, C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol. Oncol. 110, 13\u201321 (2008).","journal-title":"Gynecol. Oncol."},{"key":"3382_CR32","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1097\/MCO.0000000000000357","volume":"20","author":"SS Thomas","year":"2017","unstructured":"Thomas, S. S. & Mitch, W. E. Parathyroid hormone stimulates adipose tissue browning: a pathway to muscle wasting. Curr. Opin. Clin. Nutr. Metab. Care 20, 153\u2013157 (2017).","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"3382_CR33","doi-asserted-by":"publisher","first-page":"22258","DOI":"10.1074\/jbc.M114.588046","volume":"289","author":"T Tian","year":"2014","unstructured":"Tian, T. et al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem. 289, 22258\u201322267 (2014).","journal-title":"J. Biol. Chem."},{"key":"3382_CR34","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1093\/jnci\/89.23.1763","volume":"89","author":"MJ Tisdale","year":"1997","unstructured":"Tisdale, M. J. Biology of cachexia. J. Natl Cancer Inst. 89, 1763\u20131773 (1997).","journal-title":"J. Natl Cancer Inst."},{"key":"3382_CR35","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":"3382_CR36","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.semcdb.2015.10.039","volume":"54","author":"M Tsoli","year":"2016","unstructured":"Tsoli, M., Swarbrick, M. M. & Robertson, G. R. Lipolytic and thermogenic depletion of adipose tissue in cancer cachexia. Semin. Cell Dev. Biol. 54, 68\u201381 (2016).","journal-title":"Semin. Cell Dev. Biol."},{"key":"3382_CR37","doi-asserted-by":"publisher","DOI":"10.4161\/23723548.2014.965624","volume":"1","author":"CR Walkley","year":"2014","unstructured":"Walkley, C. R., Walia, M. K., Ho, P. W. & Martin, T. J. PTHrP, its receptor, and protein kinase A activation in osteosarcoma. Mol. Cell. Oncol. 1, e965624 (2014).","journal-title":"Mol. Cell. Oncol."},{"key":"3382_CR38","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s11010-017-3056-3","volume":"435","author":"S Wang","year":"2017","unstructured":"Wang, S., Li, X., Xu, M., Wang, J. & Zhao, R. C. Reduced adipogenesis after lung tumor exosomes priming in human mesenchymal stem cells via TGFbeta signaling pathway. Mol. Cell. Biochem. 435, 59\u201366 (2017).","journal-title":"Mol. Cell. Biochem."},{"key":"3382_CR39","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.bbcan.2017.10.001","volume":"1868","author":"K Wu","year":"2017","unstructured":"Wu, K., Xing, F., Wu, S. Y. & Watabe, K. Extracellular vesicles as emerging targets in cancer: recent development from bench to bedside. Biochim. Biophys. Acta Rev. Cancer 1868, 538\u2013563 (2017).","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"3382_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00726-x","volume":"8","author":"G Zhang","year":"2017","unstructured":"Zhang, G. et al. Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90. Nat. Commun. 8, 589 (2017).","journal-title":"Nat. Commun."},{"key":"3382_CR41","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/cdd.2016.113","volume":"24","author":"X Zhang","year":"2017","unstructured":"Zhang, X., Cheng, Q., Wang, Y., Leung, P. S. & Mak, K. K. Hedgehog signaling in bone regulates whole-body energy metabolism through a bone-adipose endocrine relay mediated by PTHrP and adiponectin. Cell Death Differ. 24, 225\u2013237 (2017).","journal-title":"Cell Death Differ."},{"key":"3382_CR42","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1126\/science.1100747","volume":"306","author":"R Zimmermann","year":"2004","unstructured":"Zimmermann, R. et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306, 1383\u20131386 (2004).","journal-title":"Science"},{"key":"3382_CR43","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1053\/meta.2000.6740","volume":"49","author":"SD Zuijdgeest-van Leeuwen","year":"2000","unstructured":"Zuijdgeest-van Leeuwen, S. D. et al. Lipolysis and lipid oxidation in weight-losing cancer patients and healthy subjects. Metabolism 49, 931\u2013936 (2000).","journal-title":"Metabolism"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03382-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03382-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03382-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T13:24:15Z","timestamp":1669901055000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-03382-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,28]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["3382"],"URL":"https:\/\/doi.org\/10.1038\/s41419-020-03382-0","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,28]]},"assertion":[{"value":"1 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 December 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 January 2021","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"}},{"value":"Ethics approval was obtained from the Animal Care and Use Committee of Tongji Medical College of Huazhong University of Science and Technology (approval no. S2392).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"134"}}