{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:46:59Z","timestamp":1791946019380,"version":"4.3.4"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771647"],"award-info":[{"award-number":["81771647"]}],"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":["81801525"],"award-info":[{"award-number":["81801525"]}],"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":["81571426"],"award-info":[{"award-number":["81571426"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LQ17H040004"],"award-info":[{"award-number":["LQ17H040004"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Sci&Tech Plan Project of Zhejiang Province","award":["2018KY039"],"award-info":[{"award-number":["2018KY039"]}]},{"name":"Health Sci&Tech Plan Project of Zhejiang Province","award":["2019KY363"],"award-info":[{"award-number":["2019KY363"]}]},{"name":"Special Project for the Research Institutions of Zhejiang Province","award":["C11920D-04"],"award-info":[{"award-number":["C11920D-04"]}]},{"name":"Zhejiang Province Program for the Cultivation of High-level innovative Health talents"},{"name":"start-up fund of Hangzhou Medical College","award":["C11904Q-04"],"award-info":[{"award-number":["C11904Q-04"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Reprod Biol Endocrinol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Heat shock protein 90 (Hsp90) is a highly abundant eukaryotic molecular chaperone that plays important roles in client protein maturation, protein folding and degradation, and signal transduction. Previously, we found that both Hsp90 and its co-chaperone cell division cycle protein 37 (Cdc37) were expressed in human sperm. Hsp90 is known to be involved in human sperm capacitation via unknown underlying mechanism(s). As Cdc37 was a kinase-specific co-chaperone of Hsp90, Hsp90 may regulate human sperm capacitation via other kinases. It has been reported that two major mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase 1\/2 (Erk1\/2) and p38, are expressed in human sperm in the same locations as Hsp90 and Cdc37. Phosphorylated Erk1\/2 has been shown to promote sperm hyperactivated motility and acrosome reaction, while phosphorylated p38 inhibits sperm motility. Therefore, in this study we explored whether Hsp90 modulates human sperm capacitation via the Erk1\/2 and p38 MAPK signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human sperm was treated with the Hsp90-specific inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) during capacitation. Computer-assisted sperm analyzer (CASA) was used to detect sperm motility and hyperactivation. The sperm acrosome reaction was analyzed by using fluorescein isothiocyanate-conjugated\n                      <jats:italic>Pisum sativum<\/jats:italic>\n                      agglutinin (PSA-FITC) staining. The interactions between Hsp90, Cdc37, Erk1\/2 and p38 were assessed using co-immunoprecipitation (Co-IP) experiments. Western blotting analysis was used to evaluate the levels of protein expression and phosphorylation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Human sperm hyperactivation and acrosome reaction were inhibited by 17-AAG, suggesting that Hsp90 is involved in human sperm capacitation. In addition, Co-IP experiments revealed that 17-AAG reduced the interaction between Hsp90 and Cdc37, leading to the dissociation of Erk1\/2 from the Hsp90-Cdc37 protein complex. Western blotting analysis revealed that levels of Erk1\/2 and its phosphorylated form were subsequently decreased. Decreasing of Hsp90-Cdc37 complex also affected the interaction between Hsp90 and p38. Nevertheless, p38 dissociated from the Hsp90 protein complex and was activated by autophosphorylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Taken together, our findings indicate that Hsp90 is involved in human sperm hyperactivation and acrosome reaction. In particular, Hsp90 and its co-chaperone Cdc37 form a protein complex with Erk1\/2 and p38 to regulate their kinase activity. These results suggest that Hsp90 regulates human sperm capacitation via the Erk1\/2 and p38 MAPK signaling pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12958-021-00723-2","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T03:02:58Z","timestamp":1614826978000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Hsp90 modulates human sperm capacitation via the Erk1\/2 and p38 MAPK signaling pathways"],"prefix":"10.1186","volume":"19","author":[{"given":"Peibei","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"723_CR1","doi-asserted-by":"crossref","unstructured":"De Jonge C. Biological basis for human capacitation-revisited. Human reproduction update. 2017 May 1;23(3):289 \u2013 99.","DOI":"10.1093\/humupd\/dmw048"},{"key":"723_CR2","doi-asserted-by":"crossref","unstructured":"Bragado MJ, Gil MC, Martin-Hidalgo D, Hurtado de Llera A, Bravo N, Moreno AD, et al. Src family tyrosine kinase regulates acrosome reaction but not motility in porcine spermatozoa. Reproduction. 2012 Jul;144(1):67\u201375.","DOI":"10.1530\/REP-11-0075"},{"key":"723_CR3","doi-asserted-by":"crossref","unstructured":"Andrisani A, Dona G, Tibaldi E, Brunati AM, Sabbadin C, Armanini D, et al. Astaxanthin Improves Human Sperm Capacitation by Inducing Lyn Displacement and Activation. Marine drugs. 2015 Aug 25;13(9):5533\u201351.","DOI":"10.3390\/md13095533"},{"key":"723_CR4","doi-asserted-by":"crossref","unstructured":"Strunker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, et al. The CatSper channel mediates progesterone-induced Ca2 + influx in human sperm. Nature. 2011 Mar 17;471(7338):382\u20136.","DOI":"10.1038\/nature09769"},{"key":"723_CR5","doi-asserted-by":"crossref","unstructured":"Lishko PV, Botchkina IL, Kirichok Y. Progesterone activates the principal Ca2 + channel of human sperm. Nature. 2011 Mar 17;471(7338):387\u201391.","DOI":"10.1038\/nature09767"},{"key":"723_CR6","doi-asserted-by":"crossref","unstructured":"Xu WM, Shi QX, Chen WY, Zhou CX, Ni Y, Rowlands DK, et al. Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility. Proc Natl Acad Sci USA. 2007 Jun;5(23):9816\u201321. 104(.","DOI":"10.1073\/pnas.0609253104"},{"key":"723_CR7","doi-asserted-by":"crossref","unstructured":"Ickowicz D, Finkelstein M, Breitbart H. Mechanism of sperm capacitation and the acrosome reaction: role of protein kinases. Asian journal of andrology. 2012 Nov;14(6):816\u201321.","DOI":"10.1038\/aja.2012.81"},{"key":"723_CR8","doi-asserted-by":"crossref","unstructured":"Taipale M, Jarosz DF, Lindquist S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature reviews Molecular cell biology. 2010 Jul;11(7):515\u201328.","DOI":"10.1038\/nrm2918"},{"key":"723_CR9","doi-asserted-by":"crossref","unstructured":"Colombo G, Paladino A, Woodford MR, Backe SJ, Sager RA, Kancherla P, et al. Chemical Perturbation of Oncogenic Protein Folding: from the Prediction of Locally Unstable Structures to the Design of Disruptors of Hsp90-Client Interactions. Chemistry. 2020 Mar 13.","DOI":"10.1002\/chem.202000615"},{"key":"723_CR10","doi-asserted-by":"crossref","unstructured":"Dunn DM, Woodford MR, Truman AW, Jensen SM, Schulman J, Caza T, et al. c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells. Cell reports. 2015 Aug 11;12(6):1006-18.","DOI":"10.1016\/j.celrep.2015.07.004"},{"key":"723_CR11","doi-asserted-by":"crossref","unstructured":"Zierer BK, Rubbelke M, Tippel F, Madl T, Schopf FH, Rutz DA, et al. Importance of cycle timing for the function of the molecular chaperone Hsp90. Nature structural molecular biology. 2016 Nov;23(11):1020\u20138.","DOI":"10.1038\/nsmb.3305"},{"issue":"12","key":"723_CR12","doi-asserted-by":"publisher","first-page":"e115841","DOI":"10.1371\/journal.pone.0115841","volume":"9","author":"K Li","year":"2014","unstructured":"Li K, Xue Y, Chen A, Jiang Y, Xie H, Shi Q, et al. Heat shock protein 90 has roles in intracellular calcium homeostasis, protein tyrosine phosphorylation regulation, and progesterone-responsive sperm function in human sperm. PloS one. 2014;9(12):e115841.","journal-title":"PloS one"},{"key":"723_CR13","doi-asserted-by":"crossref","unstructured":"Sagare-Patil V, Bhilawadikar R, Galvankar M, Zaveri K, Hinduja I, Modi D. Progesterone requires heat shock protein 90 (HSP90) in human sperm to regulate motility and acrosome reaction. Journal of assisted reproduction and genetics. 2017 Feb 24.","DOI":"10.1007\/s10815-017-0879-5"},{"key":"723_CR14","doi-asserted-by":"crossref","unstructured":"Eckl JM, Scherr MJ, Freiburger L, Daake MA, Sattler M, Richter K. Hsp90.Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites. The Journal of biological chemistry. 2015 Dec 25;290(52):30843\u201354.","DOI":"10.1074\/jbc.M115.693150"},{"key":"723_CR15","doi-asserted-by":"crossref","unstructured":"Pearl LH. Hsp90 and Cdc37 -- a chaperone cancer conspiracy. Current opinion in genetics & development. 2005 Feb;15(1):55\u201361.","DOI":"10.1016\/j.gde.2004.12.011"},{"key":"723_CR16","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1146\/annurev.pharmtox.37.1.297","volume":"37","author":"WB Pratt","year":"1997","unstructured":"Pratt WB. The role of the hsp90-based chaperone system in signal transduction by nuclear receptors and receptors signaling via MAP kinase. Annu Rev Pharmacol Toxicol. 1997;37:297\u2013326.","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"723_CR17","doi-asserted-by":"crossref","unstructured":"Boczek EE, Reefschlager LG, Dehling M, Struller TJ, Hausler E, Seidl A, et al. Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90. Proceedings of the National Academy of Sciences of the United States of America. 2015 Jun 23;112(25):E3189-98.","DOI":"10.1073\/pnas.1424342112"},{"issue":"1","key":"723_CR18","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cellimm.2009.05.012","volume":"259","author":"S Fang","year":"2009","unstructured":"Fang S, Fu J, Yuan X, Han C, Shi L, Xin Y, et al. Heat shock protein 90 regulates the stability of MEKK3 in HEK293 cells. Cellular immunology. 2009;259(1):49\u201355.","journal-title":"Cellular immunology"},{"issue":"6","key":"723_CR19","doi-asserted-by":"publisher","first-page":"3885","DOI":"10.1074\/jbc.M806715200","volume":"284","author":"S Sreeramulu","year":"2008","unstructured":"Sreeramulu S, Jonker HRA, Langer T, Richter C, Lancaster CRD, Schwalbe H. The Human Cdc37{middle dot}Hsp90 Complex Studied by Heteronuclear NMR Spectroscopy. J Biol Chem. 2008;284(6):3885\u201396.","journal-title":"J Biol Chem"},{"key":"723_CR20","doi-asserted-by":"crossref","unstructured":"Li K, Sun P, Wang Y, Gao T, Zheng D, Liu A, et al. Hsp90 interacts with Cdc37, is phosphorylated by PKA\/PKC, and regulates Src phosphorylation in human sperm capacitation. Andrology. 2020.","DOI":"10.1111\/andr.12862"},{"key":"723_CR21","doi-asserted-by":"crossref","unstructured":"Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nature reviews Immunology. 2013 Sep;13(9):679\u201392.","DOI":"10.1038\/nri3495"},{"key":"723_CR22","doi-asserted-by":"crossref","unstructured":"Nan X, Tamguney TM, Collisson EA, Lin LJ, Pitt C, Galeas J, et al. Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway. Proceedings of the National Academy of Sciences of the United States of America. 2015 Jun 30;112(26):7996\u20138001.","DOI":"10.1073\/pnas.1509123112"},{"key":"723_CR23","doi-asserted-by":"crossref","unstructured":"Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014 Nov 15;120(22):3446\u201356.","DOI":"10.1002\/cncr.28864"},{"key":"723_CR24","doi-asserted-by":"crossref","unstructured":"Schulte TW, Blagosklonny MV, Romanova L, Mushinski JF, Monia BP, Johnston JF, et al. Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Molecular cellular biology. 1996 Oct;16(10):5839\u201345.","DOI":"10.1128\/MCB.16.10.5839"},{"key":"723_CR25","doi-asserted-by":"crossref","unstructured":"Grammatikakis N, Lin JH, Grammatikakis A, Tsichlis PN, Cochran BH. p50(cdc37) acting in concert with Hsp90 is required for Raf-1 function. Molecular and cellular biology. 1999 Mar;19(3):1661\u201372.","DOI":"10.1128\/MCB.19.3.1661"},{"key":"723_CR26","doi-asserted-by":"crossref","unstructured":"Ota A, Zhang J, Ping P, Han J, Wang Y. Specific regulation of noncanonical p38alpha activation by Hsp90-Cdc37 chaperone complex in cardiomyocyte. Circulation research. 2010 Apr 30;106(8):1404\u201312.","DOI":"10.1161\/CIRCRESAHA.109.213769"},{"key":"723_CR27","doi-asserted-by":"crossref","unstructured":"Almog T, Lazar S, Reiss N, Etkovitz N, Milch E, Rahamim N, et al. Identification of extracellular signal-regulated kinase 1\/2 and p38 MAPK as regulators of human sperm motility and acrosome reaction and as predictors of poor spermatozoan quality. The Journal of biological chemistry. 2008 May 23;283(21):14479-89.","DOI":"10.1074\/jbc.M710492200"},{"key":"723_CR28","doi-asserted-by":"crossref","unstructured":"Li MW, Mruk DD, Cheng CY. Mitogen-activated protein kinases in male reproductive function. Trends in molecular medicine. 2009 Apr;15(4):159\u201368.","DOI":"10.1016\/j.molmed.2009.02.002"},{"key":"723_CR29","doi-asserted-by":"crossref","unstructured":"Almog T, Naor Z. The role of Mitogen activated protein kinase (MAPK) in sperm functions. Molecular and cellular endocrinology. 2010 Jan 27;314(2):239\u201343.","DOI":"10.1016\/j.mce.2009.05.009"},{"key":"723_CR30","doi-asserted-by":"crossref","unstructured":"Verba KA, Wang RY, Arakawa A, Liu Y, Shirouzu M, Yokoyama S, et al. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science. 2016 Jun 24;352(6293):1542-7.","DOI":"10.1126\/science.aaf5023"},{"issue":"3","key":"723_CR31","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/aja.2010.69","volume":"13","author":"PE Visconti","year":"2011","unstructured":"Visconti PE, Krapf D, de la Vega-Beltr\u00e1n JL, Acevedo JJ, Darszon A. Ion channels, phosphorylation and mammalian sperm capacitation. Asian journal of andrology. 2011;13(3):395\u2013405.","journal-title":"Asian journal of andrology"},{"key":"723_CR32","doi-asserted-by":"crossref","unstructured":"Salvador JM, Mittelstadt PR, Guszczynski T, Copeland TD, Yamaguchi H, Appella E, et al. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nature immunology. 2005 Apr;6(4):390\u20135.","DOI":"10.1038\/ni1177"},{"key":"723_CR33","doi-asserted-by":"crossref","unstructured":"Stival C, Puga Molina Ldel C, Paudel B, Buffone MG, Visconti PE, Krapf D. Sperm Capacitation and Acrosome Reaction in Mammalian Sperm. Advances in anatomy, embryology, and cell biology. 2016;220:93\u2013106.","DOI":"10.1007\/978-3-319-30567-7_5"},{"key":"723_CR34","doi-asserted-by":"crossref","unstructured":"Battistone MA, Da Ros VG, Salicioni AM, Navarrete FA, Krapf D, Visconti PE, et al. Functional human sperm capacitation requires both bicarbonate-dependent PKA activation and down-regulation of Ser\/Thr phosphatases by Src family kinases. Molecular human reproduction. 2013 Sep;19(9):570\u201380.","DOI":"10.1093\/molehr\/gat033"},{"key":"723_CR35","doi-asserted-by":"crossref","unstructured":"Eckl JM, Rutz DA, Haslbeck V, Zierer BK, Reinstein J, Richter K. Cdc37 (cell division cycle 37) restricts Hsp90 (heat shock protein 90) motility by interaction with N-terminal and middle domain binding sites. J Biol Chem. 2013 May;31(22):16032\u201342. 288(.","DOI":"10.1074\/jbc.M112.439257"},{"key":"723_CR36","doi-asserted-by":"crossref","unstructured":"Zhang T, Hamza A, Cao X, Wang B, Yu S, Zhan CG, et al. A novel Hsp90 inhibitor to disrupt Hsp90\/Cdc37 complex against pancreatic cancer cells. Molecular cancer therapeutics. 2008 Jan;7(1):162\u201370.","DOI":"10.1158\/1535-7163.MCT-07-0484"},{"issue":"7","key":"723_CR37","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1080\/01635581.2011.596645","volume":"63","author":"Y Li","year":"2011","unstructured":"Li Y, Zhang T, Schwartz SJ, Sun D. Sulforaphane Potentiates the Efficacy of 17-Allylamino 17-Demethoxygeldanamycin Against Pancreatic Cancer Through Enhanced Abrogation of Hsp90 Chaperone Function. Nutr Cancer. 2011;63(7):1151\u20139.","journal-title":"Nutr Cancer"},{"key":"723_CR38","doi-asserted-by":"crossref","unstructured":"Karkoulis PK, Stravopodis DJ, Margaritis LH, Voutsinas GE. 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC cancer. 2010 Sep 09;10:481.","DOI":"10.1186\/1471-2407-10-481"},{"key":"723_CR39","doi-asserted-by":"crossref","unstructured":"Georgakis GV, Li Y, Rassidakis GZ, Martinez-Valdez H, Medeiros LJ, Younes A. Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin\u2019s lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death. Clinical cancer research: an official journal of the American Association for Cancer Research. 2006 Jan 15;12(2):584 \u2013 90.","DOI":"10.1158\/1078-0432.CCR-05-1194"},{"key":"723_CR40","doi-asserted-by":"crossref","unstructured":"Tamura S, Marunouchi T, Tanonaka K. Heat-shock protein 90 modulates cardiac ventricular hypertrophy via activation of MAPK pathway. J Mol Cell Cardiol. 2019 Feb;127:134\u201342.","DOI":"10.1016\/j.yjmcc.2018.12.010"},{"key":"723_CR41","doi-asserted-by":"crossref","unstructured":"Hioki T, Tokuda H, Nakashima D, Fujita K, Kawabata T, Sakai G, et al. HSP90 inhibitors strengthen extracellular ATP-stimulated synthesis of interleukin\u20106 in osteoblasts: Amplification of p38 MAP kinase. Cell Biochemistry and Function. 2020.","DOI":"10.1002\/cbf.3566"}],"container-title":["Reproductive Biology and Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12958-021-00723-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12958-021-00723-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12958-021-00723-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T19:00:26Z","timestamp":1671476426000},"score":1,"resource":{"primary":{"URL":"https:\/\/rbej.biomedcentral.com\/articles\/10.1186\/s12958-021-00723-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["723"],"URL":"https:\/\/doi.org\/10.1186\/s12958-021-00723-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-97403\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.3.rs-97403\/v2","asserted-by":"object"}]},"ISSN":["1477-7827"],"issn-type":[{"value":"1477-7827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,4]]},"assertion":[{"value":"17 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Medical Ethics Committee of the Zhejiang Academy of Medical Sciences. Informed consents were signed by healthy male donors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"39"}}