{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T23:22:55Z","timestamp":1772148175898,"version":"3.50.1"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T00:00:00Z","timestamp":1460419200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T00:00:00Z","timestamp":1460419200000},"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>Cleidocranial dysplasia (CCD), a skeletal disorder characterized by delayed permanent tooth eruption and other dental abnormalities, is caused by heterozygous<jats:italic>RUNX2<\/jats:italic>mutations. As an osteoblast-specific transcription factor,<jats:italic>RUNX2<\/jats:italic>plays a role in bone remodeling, tooth formation and tooth eruption. To investigate the crosstalk between<jats:italic>RUNX2<\/jats:italic>and 1\u03b1,25-dihydroxyvitamin D3 (1\u03b1,25-(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>) in human dental follicle cells (hDFCs) during osteoclast formation, we established a co-culture system of hDFCs from CCD patient and healthy donors with peripheral blood mononuclear cells (PBMCs). Expression of the osteoclast-associated genes and the number of TRAP<jats:sup>+<\/jats:sup>cells were reduced in CCD hDFCs, indicating its suppressed osteoclast-inductive ability, which was reflected by the downregulated RANKL\/OPG ratio. In addition, 1\u03b1,25-(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-stimulation elevated the expression of osteoclast-related genes, as well as<jats:italic>RANKL<\/jats:italic>mRNA levels and RANKL\/OPG ratios in control hDFCs. Conversely,<jats:italic>RUNX2<\/jats:italic>mutation abolished this 1\u03b1,25-(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-induced<jats:italic>RANKL<\/jats:italic>gene activation and osteoclast formation in CCD hDFCs. Therefore,<jats:italic>RUNX2<\/jats:italic>haploinsufficiency impairs dental follicle-induced osteoclast formation capacity through RANKL\/OPG signaling, which may be partially responsible for delayed permanent tooth eruption in CCD patients. Furthermore, this abnormality was not rescued by 1\u03b1,25-(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>application because 1\u03b1,25-(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-induced RANKL activation in hDFCs is mediated principally via the<jats:italic>RUNX2<\/jats:italic>-dependent pathway.<\/jats:p>","DOI":"10.1038\/srep24225","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T09:36:07Z","timestamp":1460453767000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["RUNX2 Mutation Impairs 1\u03b1,25-Dihydroxyvitamin D3 mediated Osteoclastogenesis in Dental Follicle Cells"],"prefix":"10.1038","volume":"6","author":[{"given":"X. Z.","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X. Y.","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. Y.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"X.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. J.","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. H.","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. G.","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,4,12]]},"reference":[{"key":"BFsrep24225_CR1","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/S0092-8674(00)80260-3","volume":"5","author":"S Mundlos","year":"1997","unstructured":"Mundlos, S., Otto, F., Mundlos, C. & Al, E. Mutations involving the transcription factor Cbfal cause cleidocranial dysplasia. Cell 5, 773\u2013779 (1997).","journal-title":"Cell"},{"key":"BFsrep24225_CR2","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.oooo.2012.07.435","volume":"115","author":"T Roberts","year":"2013","unstructured":"Roberts, T., Stephen, L. & Beighton, P. Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience. Oral Surg Oral Med Oral Pathol Oral Radiol. 115, 46\u201355 (2013).","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol."},{"key":"BFsrep24225_CR3","first-page":"177","volume":"36","author":"S Mundlos","year":"1999","unstructured":"Mundlos, S. Cleidocranial dysplasia: Clinical and molecular genetics. J Med Genet. 36, 177\u2013182 (1999).","journal-title":"J Med Genet."},{"key":"BFsrep24225_CR4","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.1128\/MCB.15.4.1858","volume":"4","author":"P Ducy","year":"1995","unstructured":"Ducy, P. & Karsenty, G. Two distinct osteoblast-specific cisactingelements control expression of a mouse osteocalcin gene. Mol Cell Biol. 4, 1858\u20131869 (1995).","journal-title":"Mol Cell Biol."},{"key":"BFsrep24225_CR5","first-page":"1057","volume":"8","author":"YW Guo","year":"2015","unstructured":"Guo, Y. W., Chiu, C. Y., Liu, C. L., Jap, T. S. & Lin, L. Y. Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia. Int J Clin Exp Pathol. 8, 1057\u20131062 (2015).","journal-title":"Int J Clin Exp Pathol."},{"key":"BFsrep24225_CR6","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1016\/S0092-8674(00)80258-5","volume":"5","author":"T Komori","year":"1997","unstructured":"Komori, T., Yagi, H. & Nomura, S. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 5, 755\u2013764 (1997).","journal-title":"Cell"},{"key":"BFsrep24225_CR7","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/S0092-8674(00)80259-7","volume":"5","author":"F Otto","year":"1997","unstructured":"Otto, F., Thornell, A. & Crompton, T. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 5, 765\u2013771 (1997).","journal-title":"Cell"},{"key":"BFsrep24225_CR8","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/S0925-4773(00)00562-1","volume":"1\u20132","author":"A Bronckers","year":"2001","unstructured":"Bronckers, A., Engelse, M. & Cavender, A. Cell-specific patterns of Cbfa1 mRNA and protein expression in postnatal murine dental tissues. Mech Dev. s 1\u20132, 255\u2013258 (2001).","journal-title":"Mech Dev. s"},{"key":"BFsrep24225_CR9","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1242\/dev.126.13.2911","volume":"13","author":"R D\u2019 Souza","year":"1999","unstructured":"D\u2019 Souza, R., Aberg, T. & Gaikwad, J. Cbfa1 is required for epithelial mesenchymal interactions regulating tooth development in mice. Development 13, 2911\u20132920 (1999).","journal-title":"Development"},{"key":"BFsrep24225_CR10","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.archoralbio.2004.01.010","volume":"49","author":"S Yoda","year":"2004","unstructured":"Yoda, S., Suda, N., Kitahara, Y., Komori, T. & Ohyama, K. Delayed tooth eruption and suppressed osteoclast number in the eruption pathway of heterozygous Runx2\/Cbfa1 knockout mice. Arch Oral Biol. 49, 435\u2013442 (2004).","journal-title":"Arch Oral Biol."},{"key":"BFsrep24225_CR11","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1111\/j.1600-0714.1980.tb00377.x","volume":"9","author":"DR Cahill","year":"1980","unstructured":"Cahill, D. R. & Marks, S. C. Tooth eruption: evidence for the central role of dental follicle. J Oral Pathol. 9, 189\u2013200 (1980).","journal-title":"J Oral Pathol."},{"key":"BFsrep24225_CR12","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1111\/j.1601-6343.2009.01439.x","volume":"12","author":"GE Wise","year":"2009","unstructured":"Wise, G. E. Cellular and molecular basis of tooth eruption. Orthod Craniofac Res. 12, 67\u201373 (2009).","journal-title":"Orthod Craniofac Res."},{"key":"BFsrep24225_CR13","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s00774-003-0481-z","volume":"22","author":"T Suzuki","year":"2004","unstructured":"Suzuki, T., Suda, N. & Ohyama, K. Osteoclastogenesis during mouse tooth germ development is mediated by receptor activator of NFKappa-B ligand (RANKL). J Bone Miner Metab. 22, 185\u2013191 (2004).","journal-title":"J Bone Miner Metab."},{"key":"BFsrep24225_CR14","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1016\/j.archoralbio.2005.02.007","volume":"10","author":"J Heinrich","year":"2005","unstructured":"Heinrich, J., Bsoul, S., Barnes, J., Woodruff, K. & S, A. CSF-1, RANKL and OPG regulate osteoclastogenesis during murine tooth eruption. Arch Oral Biol. 10, 897\u2013908 (2005).","journal-title":"Arch Oral Biol."},{"key":"BFsrep24225_CR15","doi-asserted-by":"publisher","first-page":"2524","DOI":"10.1089\/scd.2014.0127","volume":"23","author":"B Li","year":"2014","unstructured":"Li, B. et al. Periodontal ligament stem cells modulate root resorption of human primary teeth via Runx2 regulating RANKL\/OPG system. Stem Cells Dev. 23, 2524\u20132534 (2014).","journal-title":"Stem Cells Dev."},{"key":"BFsrep24225_CR16","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1210\/en.2012-1542","volume":"154","author":"Y Yamamoto","year":"2013","unstructured":"Yamamoto, Y. et al. Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology 154, 1008\u20131020 (2013).","journal-title":"Endocrinology"},{"key":"BFsrep24225_CR17","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.jbspin.2012.09.011","volume":"80","author":"TH Kim","year":"2013","unstructured":"Kim, T. H. et al. 1,25-Dihydroxyvitamin D3 inhibits directly human osteoclastogenesis by down-regulation of the c-Fms and RANK expression. Joint Bone Spine 80, 307\u2013314 (2013).","journal-title":"Joint Bone Spine"},{"key":"BFsrep24225_CR18","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1007\/s00774-008-0018-6","volume":"27","author":"C Vincent","year":"2009","unstructured":"Vincent, C., Kogawa, M., Findlay, D. M. & Atkins, G. J. The generation of osteoclasts from RAW 264.7 precursors in defined, serum-free conditions. J Bone Miner Metab. 27, 114\u2013119 (2009).","journal-title":"J Bone Miner Metab."},{"key":"BFsrep24225_CR19","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.jsbmb.2010.03.048","volume":"121","author":"M Kogawa","year":"2010","unstructured":"Kogawa, M., Anderson, P. H., Findlay, D. M., Morris, H. A. & Atkins, G. J. The metabolism of 25-(OH)vitamin D3 by osteoclasts and their precursors regulates the differentiation of osteoclasts. J Steroid Biochem Mol Biol. 121, 277\u2013280 (2010).","journal-title":"J Steroid Biochem Mol Biol."},{"key":"BFsrep24225_CR20","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.matbio.2004.12.004","volume":"24","author":"C Morsczeck","year":"2005","unstructured":"Morsczeck, C. et al. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol. 24, 155\u2013165 (2005).","journal-title":"Matrix Biol."},{"key":"BFsrep24225_CR21","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1111\/j.1365-2184.2010.00670.x","volume":"43","author":"K Pan","year":"2010","unstructured":"Pan, K. et al. Multilineage differentiation of dental follicle cells and the roles of Runx2 over-expression in enhancing osteoblast \u2044cementoblast-related gene expression in dental follicle cells. Cell Prolif. 43, 219\u2013228 (2010).","journal-title":"Cell Prolif."},{"key":"BFsrep24225_CR22","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/mutage\/geq044","volume":"25","author":"C Zhang","year":"2010","unstructured":"Zhang, C. et al. Mutational analysis of RUNX2 gene in Chinese patients with cleidocranial dysplasia. Mutagenesis 25, 589\u2013594 (2010).","journal-title":"Mutagenesis"},{"key":"BFsrep24225_CR23","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1177\/0022034514566655","volume":"94","author":"WJ Yan","year":"2015","unstructured":"Yan, W. J. et al. Abnormal differentiation of dental pulp cells in cleidocranial dysplasia. J Dent Res. 94, 577\u2013583 (2015).","journal-title":"J Dent Res."},{"key":"BFsrep24225_CR24","doi-asserted-by":"publisher","first-page":"4058","DOI":"10.1210\/endo.137.9.8756585","volume":"137","author":"Y Fujikawa","year":"1996","unstructured":"Fujikawa, Y., Quinn, J. M., Sabokbar, A., McGee, J. O. & Athanasou, N. A. The human osteoclast precursor circulates in the monocyte fraction. Endocrinology 137, 4058\u20134060 (1996).","journal-title":"Endocrinology"},{"key":"BFsrep24225_CR25","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/ocr.12000","volume":"16","author":"D Dorotheou","year":"2013","unstructured":"Dorotheou, D. et al. Tooth eruption: altered gene expression in the dental follicle of patients with cleidocranial dysplasia. Orthod Craniofac Res. 16, 20\u201327 (2013).","journal-title":"Orthod Craniofac Res."},{"key":"BFsrep24225_CR26","doi-asserted-by":"publisher","first-page":"2416","DOI":"10.1210\/endo.134.6.8194468","volume":"134","author":"JM Quinn","year":"1994","unstructured":"Quinn, J. M., McGee, J. O. & Athanasou, N. A. Cellular and hormonal factors influencing monocyte differentiation to osteoclastic bone-resorbing cells. Endocrinology 134, 2416\u20132423 (1994).","journal-title":"Endocrinology"},{"key":"BFsrep24225_CR27","doi-asserted-by":"publisher","first-page":"7260","DOI":"10.1073\/pnas.87.18.7260","volume":"87","author":"N Udagawa","year":"1990","unstructured":"Udagawa, N., Takahashi, N. & Akatsu, T. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrowderived stromal cells. Proc Natl Acad Sci. 87, 7260\u20137264 (1990).","journal-title":"Proc Natl Acad Sci."},{"key":"BFsrep24225_CR28","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s002239900473","volume":"62","author":"JM Quinn","year":"1998","unstructured":"Quinn, J. M., Neale, S., Fujikawa, Y., McGee, J. O. & Athanasou, N. A. Human osteoclast formation from blood monocytes, peritoneal macrophages, and bone marrow cells. Calcif Tissue Int. 62, 527\u2013531 (1998).","journal-title":"Calcif Tissue Int."},{"key":"BFsrep24225_CR29","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1002\/jcp.21971","volume":"222","author":"V Bloemen","year":"2010","unstructured":"Bloemen, V., Schoenmaker, T., de Vries, T. J. & Everts, V. Direct cell-cell contact between periodontal ligament fibroblasts and osteoclast precursors synergistically increases the expression of genes related to osteoclastogenesis. J Cell Physiol. 222, 565\u2013573 (2010).","journal-title":"J Cell Physiol."},{"key":"BFsrep24225_CR30","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1177\/0022034509340008","volume":"88","author":"M Uchiyama","year":"2009","unstructured":"Uchiyama, M., Nakamichi, Y. & Nakamura, M. Dental Pulp and Periodontal Ligament Cells Support Osteoclastic Differentiation. J Dent Res. 88, 609\u2013614 (2009).","journal-title":"J Dent Res."},{"key":"BFsrep24225_CR31","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1177\/0022034515578908","volume":"7","author":"J Ge","year":"2015","unstructured":"Ge, J. et al. Dental Follicle Cells Participate in Tooth Eruption via the RUNX2-MiR-31-SATB2 Loop. J Dent Res. 7, 936\u2013944 (2015).","journal-title":"J Dent Res."},{"key":"BFsrep24225_CR32","doi-asserted-by":"publisher","first-page":"25163","DOI":"10.1074\/jbc.M000322200","volume":"275","author":"K Thirunavukkarasu","year":"2000","unstructured":"Thirunavukkarasu, K., Halladay, D. & Miles, R. The osteoblast-specific transcription factor Cbfa1 contributes to the expression of osteoprotegerin, a potent inhibitor of osteoclast differentiation and function. J Biol Chem. 275, 25163\u201325172 (2000).","journal-title":"J Biol Chem."},{"key":"BFsrep24225_CR33","doi-asserted-by":"publisher","first-page":"36241","DOI":"10.1074\/jbc.M104319200","volume":"39","author":"K Thirunavukkarasu","year":"2001","unstructured":"Thirunavukkarasu, K., Miles, R. & Halladay, D. Stimulation of osteoprotegerin (OPG) gene expression by transforming growth factor-beta (TGF-beta). Mapping of the OPG promoter region that mediates TGF-beta effects. J Biol Chem. 39, 36241\u201336250 (2001).","journal-title":"J Biol Chem."},{"key":"BFsrep24225_CR34","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1161\/ATVBAHA.110.222547","volume":"31","author":"CH Byon","year":"2011","unstructured":"Byon, C. H. et al. Runx2-upregulated receptor activator of nuclear factor kappaB ligand in calcifying smooth muscle cells promotes migration and osteoclastic differentiation of macrophages. Arterioscler Thromb Vasc Biol. 31, 1387\u20131396 (2011).","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"BFsrep24225_CR35","doi-asserted-by":"publisher","first-page":"23971","DOI":"10.1074\/jbc.M302457200","volume":"26","author":"H Enomoto","year":"2003","unstructured":"Enomoto, H., Shiojiri, S., Hoshi, K. & Komori, T. Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2\u2212\/\u2212 mice by RANKL transgene. J Biol Chem. 26, 23971\u201323977 (2003).","journal-title":"J Biol Chem."},{"key":"BFsrep24225_CR36","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.archoralbio.2009.04.009","volume":"54","author":"X Tang","year":"2009","unstructured":"Tang, X. & Meng, H. Osteogenic induction and 1,25-dihydroxyvitamin D3 oppositely regulate the proliferation and expression of RANKL and the vitamin D receptor of human periodontal ligament cells. Arch Oral Biol. 54, 625\u2013633 (2009).","journal-title":"Arch Oral Biol."},{"key":"BFsrep24225_CR37","doi-asserted-by":"publisher","first-page":"e83510","DOI":"10.1371\/annotation\/39606c88-c2a1-45e7-8b2d-9b8f7df6f05f","volume":"8","author":"MS Han","year":"2013","unstructured":"Han, M. S. et al. Functional cooperation between vitamin D receptor and Runx2 in vitamin D-induced vascular calcification. Plos One. 8, e83510\u2013e83584 (2013).","journal-title":"Plos One."},{"key":"BFsrep24225_CR38","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.bone.2015.02.007","volume":"75","author":"A Martin","year":"2015","unstructured":"Martin, A. et al. Estrogens antagonize RUNX2-mediated osteoblast-driven osteoclastogenesis through regulating RANKL membrane association. Bone. 75, 96\u2013104 (2015).","journal-title":"Bone."},{"key":"BFsrep24225_CR39","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1006\/excr.2002.5474","volume":"274","author":"H Drissi","year":"2002","unstructured":"Drissi, H. et al. 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2\/Cbfa1 gene promoter. Exp Cell Res. 274, 323\u2013333 (2002).","journal-title":"Exp Cell Res."},{"key":"BFsrep24225_CR40","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1002\/jcb.21929","volume":"105","author":"R Kitazawa","year":"2008","unstructured":"Kitazawa, R., Mori, K., Yamaguchi, A., Kondo, T. & Kitazawa, S. Modulation of mouse RANKL gene expression by Runx2 and vitamin D3. J Cell Biochem. 105, 1289\u20131297 (2008).","journal-title":"J Cell Biochem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep24225.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24225","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep24225.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T17:25:38Z","timestamp":1718472338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep24225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,12]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,26]]}},"alternative-id":["BFsrep24225"],"URL":"https:\/\/doi.org\/10.1038\/srep24225","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,12]]},"assertion":[{"value":"4 December 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 April 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24225"}}