{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T06:23:29Z","timestamp":1770963809365,"version":"3.50.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T00:00:00Z","timestamp":1474329600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T00:00:00Z","timestamp":1474329600000},"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>Y<jats:sub>1<\/jats:sub> receptor (Y<jats:sub>1<\/jats:sub>R)-signalling pathway plays a pivotal role in the regulation of bone metabolism. The lack of Y<jats:sub>1<\/jats:sub>R-signalling stimulates bone mass accretion that has been mainly attributed to Y<jats:sub>1<\/jats:sub>R disruption from bone-forming cells. Still, the involvement of Y<jats:sub>1<\/jats:sub>R-signalling in the control of bone-resorbing cells remained to be explored. Therefore, in this study we assessed the role of Y<jats:sub>1<\/jats:sub>R deficiency in osteoclast formation and resorption activity. Here we demonstrate that Y<jats:sub>1<\/jats:sub>R germline deletion (Y<jats:sub>1<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup>) led to increased formation of highly multinucleated (n\u2009&gt;\u20098) osteoclasts and enhanced surface area, possibly due to monocyte chemoattractant protein-1 (MCP-1) overexpression regulated by RANKL-signalling. Interestingly, functional studies revealed that these giant Y<jats:sub>1<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> multinucleated cells produce poorly demineralized eroded pits, which were associated to reduce expression of osteoclast matrix degradation markers, such as tartrate-resistant acid phosphatase-5b (TRAcP5b), matrix metalloproteinase-9 (MMP-9) and cathepsin-K (CTSK). Tridimensional (3D) morphologic analyses of resorption pits, using an in-house developed quantitative computational tool (BonePit), showed that Y<jats:sub>1<\/jats:sub>R<jats:sup>\u2212\/\u2212<\/jats:sup> resorption pits displayed a marked reduction in surface area, volume and depth. Together, these data demonstrates that the lack of Y<jats:sub>1<\/jats:sub>Rs stimulates the formation of larger multinucleated osteoclasts <jats:italic>in vitro<\/jats:italic> with reduced bone-resorbing activity, unveiling a novel therapeutic option for osteoclastic bone diseases based on Y<jats:sub>1<\/jats:sub>R-signalling ablation.<\/jats:p>","DOI":"10.1038\/srep33470","type":"journal-article","created":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T09:13:48Z","timestamp":1474362828000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Ablation of Y1 receptor impairs osteoclast bone-resorbing activity"],"prefix":"10.1038","volume":"6","author":[{"given":"Daniela M.","family":"Sousa","sequence":"first","affiliation":[]},{"given":"Francisco","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[]},{"given":"Diana I.","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Lu\u00eds","family":"Leit\u00e3o","sequence":"additional","affiliation":[]},{"given":"Estrela","family":"Neto","sequence":"additional","affiliation":[]},{"given":"Cec\u00edlia J.","family":"Alves","sequence":"additional","affiliation":[]},{"given":"In\u00eas S.","family":"Alencastre","sequence":"additional","affiliation":[]},{"given":"Herbert","family":"Herzog","sequence":"additional","affiliation":[]},{"given":"Paulo","family":"Aguiar","sequence":"additional","affiliation":[]},{"given":"Meriem","family":"Lamghari","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,9,20]]},"reference":[{"key":"BFsrep33470_CR1","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1177\/0022034513500306","volume":"92","author":"BF Boyce","year":"2013","unstructured":"Boyce, B. F. Advances in the Regulation of Osteoclasts and Osteoclast Functions. J. Dent. Res. 92, 860\u2013867 (2013).","journal-title":"J. Dent. Res."},{"key":"BFsrep33470_CR2","first-page":"481","volume":"3","author":"NA Sims","year":"2014","unstructured":"Sims, N. A. & Martin, T. J. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKEy Rep. 3, 481 (2014).","journal-title":"BoneKEy Rep"},{"key":"BFsrep33470_CR3","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1111\/j.1365-2362.2012.02717.x","volume":"42","author":"BF Boyce","year":"2012","unstructured":"Boyce, B. F., Rosenberg, E., de Papp, A. E. & Duong, L. T. The osteoclast, bone remodelling and treatment of metabolic bone disease. Eur. J. Clin. Invest. 42, 1332\u20131341 (2012).","journal-title":"Eur. J. Clin. Invest."},{"key":"BFsrep33470_CR4","doi-asserted-by":"publisher","first-page":"24571","DOI":"10.1074\/jbc.M202561200","volume":"277","author":"S-M K\u00e4k\u00f6nen","year":"2002","unstructured":"K\u00e4k\u00f6nen, S.-M. et al. Transforming Growth Factor-\u03b2 Stimulates Parathyroid Hormone-related Protein and Osteolytic Metastases via Smad and Mitogen-activated Protein Kinase Signaling Pathways. J Biol. Chem. 277, 24571\u201324578 (2002).","journal-title":"J Biol. Chem."},{"key":"BFsrep33470_CR5","first-page":"943","volume":"152","author":"EM Gravallese","year":"1998","unstructured":"Gravallese, E. M. et al. Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am. J. Pathol. 152, 943\u2013951 (1998).","journal-title":"Am. J. Pathol."},{"key":"BFsrep33470_CR6","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.abb.2008.03.016","volume":"473","author":"F Elefteriou","year":"2008","unstructured":"Elefteriou, F. Regulation of bone remodeling by the central and peripheral nervous system. Arch. Biochem. Biophys. 473, 231\u2013236 (2008).","journal-title":"Arch. Biochem. Biophys."},{"key":"BFsrep33470_CR7","doi-asserted-by":"publisher","first-page":"19092","DOI":"10.1074\/jbc.M700644200","volume":"282","author":"PA Baldock","year":"2007","unstructured":"Baldock, P. A. et al. Novel Role of Y1 Receptors in the Coordinated Regulation of Bone and Energy Homeostasis. J. Biol. Chem. 282, 19092\u201319102 (2007).","journal-title":"J. Biol. Chem."},{"key":"BFsrep33470_CR8","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.bone.2010.10.174","volume":"48","author":"NJ Lee","year":"2011","unstructured":"Lee, N. J. et al. Osteoblast specific Y1 receptor deletion enhances bone mass. Bone 48, 461\u2013467 (2011).","journal-title":"Bone"},{"key":"BFsrep33470_CR9","doi-asserted-by":"publisher","first-page":"9","DOI":"10.2174\/138945009787122888","volume":"10","author":"DM Sousa","year":"2009","unstructured":"Sousa, D. M., Herzog, H. & Lamghari, M. NPY signalling pathway in bone homeostasis: Y1 receptor as a potential drug target. Curr. Drug Targets 10, 9\u201319 (2009).","journal-title":"Curr. Drug Targets"},{"key":"BFsrep33470_CR10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.bone.2012.03.020","volume":"51","author":"DM Sousa","year":"2012","unstructured":"Sousa, D. M. et al. Neuropeptide Y Y1 receptor antagonism increases bone mass in mice. Bone 51, 8\u201316 (2012).","journal-title":"Bone"},{"key":"BFsrep33470_CR11","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1002\/jcb.22194","volume":"107","author":"L Teixeira","year":"2009","unstructured":"Teixeira, L. et al. NPY revealed as a critical modulator of osteoblast function in vitro: new insights into the role of Y1 and Y2 receptors. J. Cell. Biochem. 107, 908\u2013916 (2009).","journal-title":"J. Cell. Biochem."},{"key":"BFsrep33470_CR12","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1002\/jbmr.61","volume":"25","author":"NJ Lee","year":"2010","unstructured":"Lee, N. J. et al. Critical role for Y1 receptors in mesenchymal progenitor cell differentiation and osteoblast activity. J. Bone Miner. Res. 25, 1736\u20131747 (2010).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep33470_CR13","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1084\/jem.20051971","volume":"202","author":"J Wheway","year":"2005","unstructured":"Wheway, J. et al. A fundamental bimodal role for neuropeptide Y1 receptor in the immune system. J. Exp. Med. 202, 1527\u20131538 (2005).","journal-title":"J. Exp. Med."},{"key":"BFsrep33470_CR14","doi-asserted-by":"publisher","first-page":"3228","DOI":"10.2337\/db12-0156","volume":"61","author":"L Macia","year":"2012","unstructured":"Macia, L. et al. Neuropeptide Y1 receptor in immune cells regulates inflammation and insulin resistance associated with diet-induced obesity. Diabetes 61, 3228\u20133238 (2012).","journal-title":"Diabetes"},{"key":"BFsrep33470_CR15","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1359\/jbmr.2000.15.8.1477","volume":"15","author":"S Takeshita","year":"2000","unstructured":"Takeshita, S., Kaji, K. & Kudo, A. Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J. Bone Miner. Res. 15, 1477\u20131488 (2000).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep33470_CR16","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1172\/JCI36809","volume":"119","author":"H Kim","year":"2009","unstructured":"Kim, H. et al. Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. J. Clin. Invest. 119, 813\u2013825 (2009).","journal-title":"J. Clin. Invest."},{"key":"BFsrep33470_CR17","doi-asserted-by":"publisher","first-page":"212","DOI":"10.5312\/wjo.v3.i12.212","volume":"3","author":"L Xing","year":"2012","unstructured":"Xing, L., Xiu, Y. & Boyce, B. F. Osteoclast fusion and regulation by RANKL-dependent and independent factors. World J. Orthop. 3, 212\u2013222 (2012).","journal-title":"World J. Orthop"},{"key":"BFsrep33470_CR18","doi-asserted-by":"publisher","first-page":"16163","DOI":"10.1074\/jbc.M412713200","volume":"280","author":"MS Kim","year":"2005","unstructured":"Kim, M. S., Day, C. J. & Morrison, N. A. MCP-1 is induced by receptor activator of nuclear factor-{kappa}B ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation. J. Biol. Chem. 280, 16163\u201316169 (2005).","journal-title":"J. Biol. Chem."},{"key":"BFsrep33470_CR19","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1007\/s00223-013-9786-7","volume":"93","author":"M Rumpler","year":"2013","unstructured":"Rumpler, M. et al. Osteoclasts on bone and dentin in vitro: mechanism of trail formation and comparison of resorption behavior. Calcif. Tissue Int. 93, 526\u2013539 (2013).","journal-title":"Calcif. Tissue Int."},{"key":"BFsrep33470_CR20","unstructured":"Schneider, R. In Surface and Thin Film Analysis: Principles, Instrumentation, Applications (eds Buhert, H. et al.) Ch. 2.3, 293\u2013310 (Wiley-VCH Verlag GmbH & Co. KGaA, 2011)."},{"key":"BFsrep33470_CR21","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1002\/jbmr.326","volume":"26","author":"JS Nyman","year":"2011","unstructured":"Nyman, J. S. et al. Differential effects between the loss of MMP-2 and MMP-9 on structural and tissue-level properties of bone. J. Bone Miner. Res. 26, 1252\u20131260 (2011).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep33470_CR22","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1016\/j.bone.2008.11.019","volume":"44","author":"J Morko","year":"2009","unstructured":"Morko, J. et al. Overexpression of cathepsin K accelerates the resorption cycle and osteoblast differentiation in vitro. Bone 44, 717\u2013728 (2009).","journal-title":"Bone"},{"key":"BFsrep33470_CR23","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1359\/jbmr.1997.12.6.972","volume":"12","author":"G Caselli","year":"1997","unstructured":"Caselli, G. et al. Tartronates: a new generation of drugs affecting bone metabolism. J. Bone Miner. Res. 12, 972\u2013981 (1997).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep33470_CR24","doi-asserted-by":"publisher","first-page":"3597","DOI":"10.1073\/pnas.95.7.3597","volume":"95","author":"H Yasuda","year":"1998","unstructured":"Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin\/osteoclastogenesis-inhibitory factor and is identical to TRANCE\/RANKL. Proc. Natl. Acad. Sci. USA 95, 3597\u20133602 (1998).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep33470_CR25","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1016\/j.archoralbio.2015.06.002","volume":"60","author":"Y Yamashita","year":"2015","unstructured":"Yamashita, Y. et al. RANKL pretreatment plays an important role in the differentiation of pit-forming osteoclasts induced by TNF-alpha on murine bone marrow macrophages. Arch. Oral Biol. 60, 1273\u20131282 (2015).","journal-title":"Arch. Oral Biol."},{"key":"BFsrep33470_CR26","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.bbagen.2007.02.009","volume":"1770","author":"S Amano","year":"2007","unstructured":"Amano, S., Arai, M., Goto, S. & Togari, A. Inhibitory effect of NPY on isoprenaline-induced osteoclastogenesis in mouse bone marrow cells. Biochim. Biophys. Acta 1770, 966\u2013973 (2007).","journal-title":"Biochim. Biophys. Acta"},{"key":"BFsrep33470_CR27","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1359\/jbmr.2003.18.10.1905","volume":"18","author":"AR Hayman","year":"2003","unstructured":"Hayman, A. R. & Cox, T. M. Tartrate-resistant acid phosphatase knockout mice. J. Bone Miner. Res. 18, 1905\u20131907 (2003).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep33470_CR28","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/S0344-0338(87)80107-3","volume":"182","author":"K Metze","year":"1987","unstructured":"Metze, K., Ciplea, A. G., Hettwer, H. & Barckhaus, R. H. Size dependent enzyme activities of multinucleated (osteoclastic) giant cells in bone tumors. Pathol. Res. Pract. 182, 214\u2013221 (1987).","journal-title":"Pathol. Res. Pract."},{"key":"BFsrep33470_CR29","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.bbrc.2009.04.020","volume":"383","author":"K Miyamoto","year":"2009","unstructured":"Miyamoto, K. et al. MCP-1 expressed by osteoclasts stimulates osteoclastogenesis in an autocrine\/paracrine manner. Biochem. Biophys. Res. Commun. 383, 373\u2013377 (2009).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFsrep33470_CR30","doi-asserted-by":"crossref","unstructured":"Khan, U. A., Hashimi, S. M., Bakr, M. M., Forwood, M. R. & Morrison, N. A. CCL2 and CCR2 are Essential for the Formation of Osteoclasts and Foreign Body Giant Cells. J. Cell. Biochem. (2015).","DOI":"10.1002\/jcb.25282"},{"key":"BFsrep33470_CR31","doi-asserted-by":"publisher","first-page":"13453","DOI":"10.1073\/pnas.95.23.13453","volume":"95","author":"P Saftig","year":"1998","unstructured":"Saftig, P. et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl. Acad. Sci. USA 95, 13453\u201313458 (1998).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep33470_CR32","doi-asserted-by":"publisher","first-page":"4123","DOI":"10.1242\/dev.00559","volume":"130","author":"C Colnot","year":"2003","unstructured":"Colnot, C., Thompson, Z., Miclau, T., Werb, Z. & Helms, J. A. Altered fracture repair in the absence of MMP9. Development 130, 4123\u20134133 (2003).","journal-title":"Development"},{"key":"BFsrep33470_CR33","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.bone.2012.09.018","volume":"52","author":"X Wang","year":"2013","unstructured":"Wang, X. et al. MMP9 regulates the cellular response to inflammation after skeletal injury. Bone 52, 111\u2013119 (2013).","journal-title":"Bone"},{"key":"BFsrep33470_CR34","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1242\/dmm.004226","volume":"3","author":"N Ortega","year":"2010","unstructured":"Ortega, N., Wang, K., Ferrara, N., Werb, Z. & Vu, T. H. Complementary interplay between matrix metalloproteinase-9, vascular endothelial growth factor and osteoclast function drives endochondral bone formation. Dis. Model. Mech. 3, 224\u2013235 (2010).","journal-title":"Dis. Model. Mech."},{"key":"BFsrep33470_CR35","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1002\/jbmr.1889","volume":"28","author":"MM McDonald","year":"2013","unstructured":"McDonald, M. M. et al. Matrix metalloproteinase-driven endochondral fracture union proceeds independently of osteoclast activity. J. Bone Miner. Res. 28, 1550\u20131560 (2013).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep33470_CR36","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1002\/jor.22400","volume":"31","author":"DM Sousa","year":"2013","unstructured":"Sousa, D. M. et al. Neuropeptide Y modulates fracture healing through Y1 receptor signaling. J. Orthop. Res. 31, 1570\u20131578 (2013).","journal-title":"J. Orthop. Res."},{"key":"BFsrep33470_CR37","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1210\/endo.143.5.8813","volume":"143","author":"P Boissy","year":"2002","unstructured":"Boissy, P., Saltel, F., Bouniol, C., Jurdic, P. & Machuca-Gayet, I. Transcriptional activity of nuclei in multinucleated osteoclasts and its modulation by calcitonin. Endocrin. 143, 1913\u20131921 (2002).","journal-title":"Endocrin"},{"key":"BFsrep33470_CR38","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/BF00185977","volume":"186","author":"K Piper","year":"1992","unstructured":"Piper, K., Boyde, A. & Jones, S. J. The relationship between the number of nuclei of an osteoclast and its resorptive capability in vitro. Anat. Embryol. (Berl) 186, 291\u2013299 (1992).","journal-title":"Anat. Embryol. (Berl)"},{"key":"BFsrep33470_CR39","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1111\/j.1365-2443.2010.01441.x","volume":"15","author":"MY Youn","year":"2010","unstructured":"Youn, M. Y., Takada, I., Imai, Y., Yasuda, H. & Kato, S. Transcriptionally active nuclei are selective in mature multinucleated osteoclasts. Genes Cells 15, 1025\u20131035 (2010).","journal-title":"Genes Cells"},{"key":"BFsrep33470_CR40","doi-asserted-by":"crossref","unstructured":"Long, C. L. & Humphrey, M. B. Osteoimmunology: the expanding role of immunoreceptors in osteoclasts and bone remodeling. Bonekey Rep. 1 (2012).","DOI":"10.1038\/bonekey.2012.59"},{"key":"BFsrep33470_CR41","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1038\/nri2062","volume":"7","author":"H Takayanagi","year":"2007","unstructured":"Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292\u2013304 (2007).","journal-title":"Nat. Rev. Immunol."},{"key":"BFsrep33470_CR42","doi-asserted-by":"publisher","first-page":"15032","DOI":"10.1038\/boneres.2015.32","volume":"3","author":"DM Merrild","year":"2015","unstructured":"Merrild, D. M. et al. Pit- and trench-forming osteoclasts: a distinction that matters. Bone Res. 3, 15032 (2015).","journal-title":"Bone Res."},{"key":"BFsrep33470_CR43","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1007\/s00223-012-9674-6","volume":"92","author":"J Vanderoost","year":"2013","unstructured":"Vanderoost, J., Soe, K., Merrild, D. M., Delaisse, J. M. & van Lenthe, G. H. Glucocorticoid-induced changes in the geometry of osteoclast resorption cavities affect trabecular bone stiffness. Calcif. Tissue Int. 92, 240\u2013250 (2013).","journal-title":"Calcif. Tissue Int."},{"key":"BFsrep33470_CR44","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1046\/j.1471-4159.2003.01895.x","volume":"86","author":"OW Howell","year":"2003","unstructured":"Howell, O. W. et al. Neuropeptide Y is neuroproliferative for post-natal hippocampal precursor cells. J. Neurochem. 86, 646\u2013659 (2003).","journal-title":"J. Neurochem."},{"key":"BFsrep33470_CR45","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1016\/j.actbio.2010.12.029","volume":"7","author":"KB Fonseca","year":"2011","unstructured":"Fonseca, K. B., Bidarra, S. J., Oliveira, M. J., Granja, P. L. & Barrias, C. C. Molecularly designed alginate hydrogels susceptible to local proteolysis as three-dimensional cellular microenvironments. Acta Biomater. 7, 1674\u20131682 (2011).","journal-title":"Acta Biomater"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep33470.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep33470","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep33470.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T06:49:05Z","timestamp":1672901345000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep33470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,20]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,16]]}},"alternative-id":["BFsrep33470"],"URL":"https:\/\/doi.org\/10.1038\/srep33470","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,20]]},"assertion":[{"value":"25 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 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":"33470"}}