{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T22:45:29Z","timestamp":1792709129862,"version":"4.5.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T00:00:00Z","timestamp":1438646400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T00:00:00Z","timestamp":1438646400000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Osteoclasts play an important role in diseases involving bone loss. In this study, we assessed the effect of a plant-derived natural alkaloid (lycorine, or LY) on osteoclastogenesis <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Our <jats:italic>in vitro<\/jats:italic> study showed that receptor activator of nuclear factor-\u03baB ligand (RANKL)-induced osteoclastogenesis could be inhibited by LY; this effect was due to inhibition of mitogen-activated protein kinase (MAPK) signalling via MAP kinase kinases (MKKs). The MAPK agonist anisomycin could partially rescue the inhibitory effect of LY. Furthermore, LY also played a protective role in both a murine ovariectomy (OVX)-induced osteoporosis model and a titanium particle-induced osteolysis model. These results confirmed that LY was effective in preventing osteoclast-related diseases <jats:italic>in vivo<\/jats:italic>. In conclusion, our results show that LY is effective in suppressing osteoclastogenesis and therefore could be used to treat OVX-induced osteoporosis and wear particle-induced osteolysis.<\/jats:p>","DOI":"10.1038\/srep12853","type":"journal-article","created":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T10:16:20Z","timestamp":1438683380000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Lycorine suppresses RANKL-induced osteoclastogenesis in vitro and prevents ovariectomy-induced osteoporosis and titanium particle-induced osteolysis in vivo"],"prefix":"10.1038","volume":"5","author":[{"given":"Shuai","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gu","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Mao","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Jun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Zhen","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Jie","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Jun","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-Wu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,8,4]]},"reference":[{"key":"BFsrep12853_CR1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature01658","volume":"423","author":"WJ Boyle","year":"2003","unstructured":"Boyle, W. J., Simonet, W. S. & Lacey, D. L. Osteoclast differentiation and activation. Nature 423, 337\u2013342 (2003).","journal-title":"Nature"},{"key":"BFsrep12853_CR2","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nrg1122","volume":"4","author":"SL Teitelbaum","year":"2003","unstructured":"Teitelbaum, S. L. & Ross, F. P. Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638\u2013649 (2003).","journal-title":"Nat Rev Genet"},{"key":"BFsrep12853_CR3","first-page":"129","volume":"80","author":"N Takahashi","year":"2003","unstructured":"Takahashi, N., Udagawa, N., Tanaka, S. & Suda, T. Generating murine osteoclasts from bone marrow. Methods Mol Med 80, 129\u2013144 (2003).","journal-title":"Methods Mol Med"},{"key":"BFsrep12853_CR4","doi-asserted-by":"crossref","first-page":"7724","DOI":"10.1074\/jbc.274.12.7724","volume":"274","author":"BG Darnay","year":"1999","unstructured":"Darnay, B. G., Ni, J., Moore, P. A. & Aggarwal, B. B. Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem 274, 7724\u20137731 (1999).","journal-title":"J Biol Chem"},{"key":"BFsrep12853_CR5","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1128\/MCB.21.7.2475-2484.2001","volume":"21","author":"G Takaesu","year":"2001","unstructured":"Takaesu, G. et al. Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway. Mol Cell Biol 21, 2475\u20132484 (2001).","journal-title":"Mol Cell Biol"},{"key":"BFsrep12853_CR6","first-page":"153","volume":"22","author":"G Pearson","year":"2001","unstructured":"Pearson, G. et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22, 153\u2013183 (2001).","journal-title":"Endocr Rev"},{"key":"BFsrep12853_CR7","doi-asserted-by":"crossref","first-page":"35081","DOI":"10.1074\/jbc.C500353200","volume":"280","author":"P Monje","year":"2005","unstructured":"Monje, P., Hernandez-Losa, J., Lyons, R. J., Castellone, M. D. & Gutkind, J. S. Regulation of the transcriptional activity of c-Fos by ERK. A novel role for the prolyl isomerase PIN1. J Biol Chem 280, 35081\u201335084 (2005).","journal-title":"J Biol Chem"},{"key":"BFsrep12853_CR8","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","volume":"3","author":"H Takayanagi","year":"2002","unstructured":"Takayanagi, H. et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 3, 889\u2013901 (2002).","journal-title":"Dev Cell"},{"key":"BFsrep12853_CR9","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/nrd3244","volume":"9","author":"R Rizzoli","year":"2010","unstructured":"Rizzoli, R., Yasothan, U. & Kirkpatrick, P. Denosumab. Nature Reviews. Drug Discovery 9, 591\u2013592 (2010).","journal-title":"Nature Reviews. Drug Discovery"},{"key":"BFsrep12853_CR10","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1345\/aph.1G226","volume":"40","author":"AM Whelan","year":"2006","unstructured":"Whelan, A. M., Jurgens, T. M. & Bowles, S. K. Natural health products in the prevention and treatment of osteoporosis: systematic review of randomized controlled trials. Ann Pharmacother 40, 836\u2013849 (2006).","journal-title":"Ann Pharmacother"},{"key":"BFsrep12853_CR11","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.phymed.2010.03.014","volume":"17","author":"M Kumar","year":"2010","unstructured":"Kumar, M. et al. Anti-osteoporotic constituents from Indian medicinal plants. Phytomedicine 17, 993\u2013999 (2010).","journal-title":"Phytomedicine"},{"key":"BFsrep12853_CR12","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.joms.2006.01.017","volume":"64","author":"RW Wong","year":"2006","unstructured":"Wong, R. W. & Rabie, A. B. Traditional Chinese medicines and bone formation--a review. J Oral Maxillofac Surg 64, 828\u2013837 (2006).","journal-title":"J Oral Maxillofac Surg"},{"key":"BFsrep12853_CR13","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/ptr.2030","volume":"21","author":"SE Putnam","year":"2007","unstructured":"Putnam, S. E., Scutt, A. M., Bicknell, K., Priestley, C. M. & Williamson, E. M. Natural products as alternative treatments for metabolic bone disorders and for maintenance of bone health. Phytother Res 21, 99\u2013112 (2007).","journal-title":"Phytother Res"},{"key":"BFsrep12853_CR14","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.bcp.2014.06.009","volume":"90","author":"Z Ouyang","year":"2014","unstructured":"Ouyang, Z. et al. Hypericin suppresses osteoclast formation and wear particle-induced osteolysis via modulating ERK signalling pathway. Biochemical Pharmacology 90, 276\u2013287 (2014).","journal-title":"Biochemical Pharmacology"},{"key":"BFsrep12853_CR15","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.bbrc.2013.12.029","volume":"443","author":"X Qu","year":"2014","unstructured":"Qu, X. et al. Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades. Biochemical and Biophysical Research Communications 443, 658\u2013665 (2014).","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"BFsrep12853_CR16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s10549-014-2844-7","volume":"144","author":"Z Zhai","year":"2014","unstructured":"Zhai, Z. et al. Andrographolide prevents human breast cancer-induced osteoclastic bone loss via attenuated RANKL signaling. Breast Cancer Research and Treatment 144, 33\u201345 (2014).","journal-title":"Breast Cancer Research and Treatment"},{"key":"BFsrep12853_CR17","first-page":"41","volume":"23","author":"I Zupko","year":"2009","unstructured":"Zupko, I. et al. Antitumor activity of alkaloids derived from Amaryllidaceae species. In Vivo 23, 41\u201348 (2009).","journal-title":"In Vivo"},{"key":"BFsrep12853_CR18","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.fitote.2011.09.008","volume":"83","author":"GS Citoglu","year":"2012","unstructured":"Citoglu, G. S., Acikara, O. B., Yilmaz, B. S. & Ozbek, H. Evaluation of analgesic, anti-inflammatory and hepatoprotective effects of lycorine from Sternbergia fisheriana (Herbert) Rupr. Fitoterapia 83, 81\u201387 (2012).","journal-title":"Fitoterapia"},{"key":"BFsrep12853_CR19","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1186\/1743-422X-8-483","volume":"8","author":"J Liu","year":"2011","unstructured":"Liu, J. et al. Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol J 8, 483 (2011).","journal-title":"Virol J"},{"key":"BFsrep12853_CR20","doi-asserted-by":"crossref","first-page":"10182","DOI":"10.1016\/j.bmc.2008.10.061","volume":"16","author":"Y Toriizuka","year":"2008","unstructured":"Toriizuka, Y. et al. New lycorine-type alkaloid from Lycoris traubii and evaluation of antitrypanosomal and antimalarial activities of lycorine derivatives. Bioorg Med Chem 16, 10182\u201310189 (2008).","journal-title":"Bioorg Med Chem"},{"key":"BFsrep12853_CR21","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.toxlet.2013.01.018","volume":"218","author":"Z Cao","year":"2013","unstructured":"Cao, Z. et al. Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity. Toxicol Lett 218, 174\u2013185 (2013).","journal-title":"Toxicol Lett"},{"key":"BFsrep12853_CR22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1475-2867-12-49","volume":"12","author":"L Li","year":"2012","unstructured":"Li, L. et al. Lycorine induces cell-cycle arrest in the G0\/G1 phase in K562 cells via HDAC inhibition. Cancer Cell Int 12, 49 (2012).","journal-title":"Cancer Cell Int"},{"key":"BFsrep12853_CR23","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1111\/j.1755-148X.2012.01036.x","volume":"25","author":"R Liu","year":"2012","unstructured":"Liu, R. et al. Lycorine hydrochloride inhibits metastatic melanoma cell-dominant vasculogenic mimicry. Pigment Cell Melanoma Res 25, 630\u2013638 (2012).","journal-title":"Pigment Cell Melanoma Res"},{"key":"BFsrep12853_CR24","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.intimp.2011.11.018","volume":"12","author":"J Kang","year":"2012","unstructured":"Kang, J. et al. Lycorine inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in RAW264.7 cells through suppressing P38 and STATs activation and increases the survival rate of mice after LPS challenge. Int Immunopharmacol 12, 249\u2013256 (2012).","journal-title":"Int Immunopharmacol"},{"key":"BFsrep12853_CR25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/ar2110","volume":"9","author":"G Schett","year":"2007","unstructured":"Schett, G. Cells of the synovium in rheumatoid arthritis. Osteoclasts. Arthritis Res Ther 9, 203 (2007).","journal-title":"Arthritis Res Ther"},{"key":"BFsrep12853_CR26","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1126\/science.289.5484.1504","volume":"289","author":"SL Teitelbaum","year":"2000","unstructured":"Teitelbaum, S. L. Bone Resorption by Osteoclasts. Science 289, 1504\u20131508 (2000).","journal-title":"Science"},{"key":"BFsrep12853_CR27","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/bph.12463","volume":"171","author":"ZJ Zhai","year":"2014","unstructured":"Zhai, Z. J. et al. Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo. Br J Pharmacol 171, 663\u2013675 (2014).","journal-title":"Br J Pharmacol"},{"key":"BFsrep12853_CR28","doi-asserted-by":"crossref","first-page":"463","DOI":"10.2147\/PPA.S46192","volume":"8","author":"T Miyazaki","year":"2014","unstructured":"Miyazaki, T., Tokimura, F. & Tanaka, S. A review of denosumab for the treatment of osteoporosis. Patient Prefer Adherence 8, 463\u2013471 (2014).","journal-title":"Patient Prefer Adherence"},{"key":"BFsrep12853_CR29","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1056\/NEJM199712043372301","volume":"337","author":"PD Delmas","year":"1997","unstructured":"Delmas, P. D. et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations and uterine endometrium in postmenopausal women. N Engl J Med 337, 1641\u20131647 (1997).","journal-title":"N Engl J Med"},{"key":"BFsrep12853_CR30","doi-asserted-by":"crossref","first-page":"4879","DOI":"10.1210\/jc.2003-031672","volume":"89","author":"MR McClung","year":"2004","unstructured":"McClung, M. R. et al. Prevention of postmenopausal bone loss: six-year results from the Early Postmenopausal Intervention Cohort Study. J Clin Endocrinol Metab 89, 4879\u20134885 (2004).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep12853_CR31","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1016\/S0140-6736(02)08827-X","volume":"359","author":"PD Delmas","year":"2002","unstructured":"Delmas, P. D. Treatment of postmenopausal osteoporosis. Lancet 359, 2018\u20132026 (2002).","journal-title":"Lancet"},{"key":"BFsrep12853_CR32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/j.1749-6632.1997.tb48598.x","volume":"833","author":"GA Colditz","year":"1997","unstructured":"Colditz, G. A. Hormone replacement therapy increases the risk of breast cancer. Ann N Y Acad Sci 833, 129\u2013136 (1997).","journal-title":"Ann N Y Acad Sci"},{"key":"BFsrep12853_CR33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1001\/jama.288.3.321","volume":"288","author":"JE Rossouw","year":"2002","unstructured":"Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288, 321\u2013333 (2002).","journal-title":"JAMA"},{"key":"BFsrep12853_CR34","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.drudis.2013.08.010","volume":"19","author":"E Verron","year":"2014","unstructured":"Verron, E. & Bouler, J. M. Is bisphosphonate therapy compromised by the emergence of adverse bone disorders? Drug Discov Today 19, 312\u2013319 (2014).","journal-title":"Drug Discov Today"},{"key":"BFsrep12853_CR35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1586\/erp.12.76","volume":"13","author":"M Hiligsmann","year":"2013","unstructured":"Hiligsmann, M., Boonen, A., Dirksen, C. D., Ben Sedrine, W. & Reginster, J. Y. Cost-effectiveness of denosumab in the treatment of postmenopausal osteoporotic women. Expert Rev Pharmacoecon Outcomes Res 13, 19\u201328 (2013).","journal-title":"Expert Rev Pharmacoecon Outcomes Res"},{"key":"BFsrep12853_CR36","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1016\/j.bbamcr.2014.01.009","volume":"1843","author":"NJ Darling","year":"2014","unstructured":"Darling, N. J. & Cook, S. J. The role of MAPK signalling pathways in the response to endoplasmic reticulum stress. Biochim Biophys Acta 1843, 2150\u20132163 (2014).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep12853_CR37","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.bcp.2014.06.009","volume":"90","author":"Z Ouyang","year":"2014","unstructured":"Ouyang, Z. et al. Hypericin suppresses osteoclast formation and wear particle-induced osteolysis via modulating ERK signalling pathway. Biochem Pharmacol 90, 276\u2013287 (2014).","journal-title":"Biochem Pharmacol"},{"key":"BFsrep12853_CR38","doi-asserted-by":"crossref","first-page":"31155","DOI":"10.1074\/jbc.M001229200","volume":"275","author":"M Matsumoto","year":"2000","unstructured":"Matsumoto, M., Sudo, T., Saito, T., Osada, H. & Tsujimoto, M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem 275, 31155\u201331161 (2000).","journal-title":"J Biol Chem"},{"key":"BFsrep12853_CR39","doi-asserted-by":"crossref","first-page":"4317","DOI":"10.1242\/jcs.00082","volume":"115","author":"JP David","year":"2002","unstructured":"David, J. P., Sabapathy, K., Hoffmann, O., Idarraga, M. H. & Wagner, E. F. JNK1 modulates osteoclastogenesis through both c-Jun phosphorylation-dependent and -independent mechanisms. J Cell Sci 115, 4317\u20134325 (2002).","journal-title":"J Cell Sci"},{"key":"BFsrep12853_CR40","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.cyto.2008.01.006","volume":"42","author":"YC Lu","year":"2008","unstructured":"Lu, Y. C., Yeh, W. C. & Ohashi, P. S. LPS\/TLR4 signal transduction pathway. Cytokine 42, 145\u2013151 (2008).","journal-title":"Cytokine"},{"key":"BFsrep12853_CR41","doi-asserted-by":"crossref","first-page":"45969","DOI":"10.1074\/jbc.M408795200","volume":"279","author":"M Matsumoto","year":"2004","unstructured":"Matsumoto, M. et al. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem 279, 45969\u201345979 (2004).","journal-title":"J Biol Chem"},{"key":"BFsrep12853_CR42","doi-asserted-by":"crossref","first-page":"32905","DOI":"10.1074\/jbc.M505820200","volume":"280","author":"Y Kim","year":"2005","unstructured":"Kim, Y. et al. Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis. J Biol Chem 280, 32905\u201332913 (2005).","journal-title":"J Biol Chem"},{"key":"BFsrep12853_CR43","doi-asserted-by":"crossref","first-page":"e34132","DOI":"10.1371\/journal.pone.0034132","volume":"7","author":"A Qin","year":"2012","unstructured":"Qin, A. et al. Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption. PLoS One 7, e34132 (2012).","journal-title":"PLoS One"},{"key":"BFsrep12853_CR44","doi-asserted-by":"crossref","first-page":"E817","DOI":"10.1097\/BRS.0000000000000362","volume":"39","author":"S Chen","year":"2014","unstructured":"Chen, S. et al. Upregulation of tumor necrosis factor alpha and ADAMTS-5, but not ADAMTS-4, in human intervertebral cartilage endplate with modic changes. Spine (Phila Pa 1976) 39, E817\u2013825 (2014).","journal-title":"Spine (Phila Pa 1976)"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep12853","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep12853.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep12853.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T21:43:58Z","timestamp":1672955038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep12853"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,4]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,10,16]]}},"alternative-id":["BFsrep12853"],"URL":"https:\/\/doi.org\/10.1038\/srep12853","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,4]]},"assertion":[{"value":"27 March 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"12853"}}