{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T16:53:25Z","timestamp":1759683205951},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,24]],"date-time":"2016-08-24T00:00:00Z","timestamp":1471996800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,24]],"date-time":"2016-08-24T00:00:00Z","timestamp":1471996800000},"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>Surgical brain injury (SBI) defines complications induced by intracranial surgery, such as cerebral edema and other secondary injuries. In our study, intrathymic and hepatic portal vein injection of allogeneic myelin basic protein (MBP) or autogeneic brain cell suspensions were administered to a standard SBI model. Serum pro-inflammatory IL-2, anti-inflammatory IL-4 concentrations and the CD4<jats:sup>+<\/jats:sup>T\/CD8<jats:sup>+<\/jats:sup>T ratio were measured at 1, 3, 7, 14 and 21\u2009d after surgery to verify the establishment of immune tolerance. Furthermore, we confirmed neuroprotective effects by evaluating neurological scores at 1, 3, 7, 14 and 21\u2009d after SBI. Anti-Fas ligand (FasL) immunohistochemistry and TUNEL assays of brain sections were tested at 21\u2009d after surgery. Intrathymic injections of MBP or autogeneic brain cell suspensions functioned by both suppressing secondary inflammatory reactions and improving prognoses, whereas hepatic portal vein injections of autogeneic brain cell suspensions exerted a better effect than MBP. Intrathymic and hepatic portal vein injections of MBP had equal effects on reducing secondary inflammation and improving prognoses. Otherwise, hepatic portal vein injections of autogeneic brain cell suspensions had better outcomes than intrathymic injections of autogeneic brain cell suspensions. Moreover, the benefit of injecting antigens into the thymus was outweighed by hepatic portal vein injections.<\/jats:p>","DOI":"10.1038\/srep32030","type":"journal-article","created":{"date-parts":[[2016,8,24]],"date-time":"2016-08-24T10:32:47Z","timestamp":1472034767000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Treatment of surgical brain injury by immune tolerance induced by intrathymic and hepatic portal vein injection of brain antigens"],"prefix":"10.1038","volume":"6","author":[{"given":"Weijian","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baolong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huajun","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,8,24]]},"reference":[{"key":"BFsrep32030_CR1","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s00281-015-0520-6","volume":"37","author":"SM Brendecke","year":"2015","unstructured":"Brendecke, S. M. & Prinz, M. Do not judge a cell by its cover-diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation. Semin. Immunopathol. 37, 591\u2013605 (2015).","journal-title":"Semin. Immunopathol."},{"key":"BFsrep32030_CR2","doi-asserted-by":"crossref","first-page":"10390","DOI":"10.1523\/JNEUROSCI.0546-15.2015","volume":"35","author":"L Huang","year":"2015","unstructured":"Huang, L. et al. Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury. J. Neurosci. 35, 10390\u201310401 (2015).","journal-title":"J. Neurosci."},{"key":"BFsrep32030_CR3","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.bbadis.2015.10.010","volume":"1862","author":"CD Troletti","year":"2016","unstructured":"Troletti, C. D., de Goede, P., Kamermans, A. & de Vries, H. E. Molecular alterations of the blood-brain barrier under inflammatory conditions: The role of endothelial to mesenchymal transition. Biochim. Biophys. Acta. 1862, 452\u2013460 (2016).","journal-title":"Biochim. Biophys. Acta."},{"key":"BFsrep32030_CR4","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1089\/neu.2008.0738","volume":"26","author":"BJ Blyth","year":"2009","unstructured":"Blyth, B. J. et al. Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J. Neurotrauma. 26, 1497\u20131507 (2009).","journal-title":"J. Neurotrauma."},{"key":"BFsrep32030_CR5","first-page":"97","volume":"11","author":"D Lozano","year":"2015","unstructured":"Lozano, D. et al. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences and therapeutic opportunities. Neuropsychiatr. Dis. Treat. 11, 97\u2013106 (2015).","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"BFsrep32030_CR6","doi-asserted-by":"crossref","first-page":"685","DOI":"10.3760\/cma.j.issn.0366-6999.20132851","volume":"127","author":"Y Zheng","year":"2014","unstructured":"Zheng, Y. et al. An experimental study on thymus immune tolerance to treat surgical brain injury. Chin. Med. J. (Engl). 127, 685\u2013690 (2014).","journal-title":"Chin. Med. J. (Engl)."},{"key":"BFsrep32030_CR7","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/nrneurol.2015.144","volume":"11","author":"Y Fu","year":"2015","unstructured":"Fu, Y., Liu, Q., Anrather, J. & Shi, F. D. Immune interventions in stroke. Nat. Rev. Neurol. 11, 524\u2013535 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"BFsrep32030_CR8","doi-asserted-by":"crossref","first-page":"246","DOI":"10.3171\/2011.8.JNS11883","volume":"116","author":"RE Ayer","year":"2012","unstructured":"Ayer, R. E. et al. Preoperative mucosal tolerance to brain antigens and a neuroprotective immune response following surgical brain injury. J. Neurosurg. 116, 246\u2013253 (2012).","journal-title":"J. Neurosurg."},{"key":"BFsrep32030_CR9","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jss.2013.06.015","volume":"185","author":"H Huang","year":"2013","unstructured":"Huang, H. et al. Combined intrathymic and intravenous injection of mesenchymal stem cells can prolong the survival of rat cardiac allograft associated with decrease in miR-155 expression. J. Surg. Res. 185, 896\u2013903 (2013).","journal-title":"J. Surg. Res."},{"key":"BFsrep32030_CR10","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.trim.2006.09.033","volume":"17","author":"GV Mazariegos","year":"2007","unstructured":"Mazariegos, G. V., Sindhi, R., Thomson, A. W. & Marcos, A. Clinical tolerance following liver transplantation: long term results and future prospects. Transpl. Immunol. 17, 114\u2013119 (2007).","journal-title":"Transpl. Immunol."},{"key":"BFsrep32030_CR11","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1001\/jama.2011.2014","volume":"307","author":"S Feng","year":"2012","unstructured":"Feng, S. et al. Complete immunosuppression withdrawal and subsequent allograft function among pediatric recipients of parental living donor liver transplants. JAMA . 307, 283\u2013293 (2012).","journal-title":"JAMA"},{"key":"BFsrep32030_CR12","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/eci.12430","volume":"45","author":"MA van Delft","year":"2015","unstructured":"van Delft, M. A., Huitema, L. F. & Tas, S. W. The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur. J. Clin. Invest. 45, 529\u2013539 (2015).","journal-title":"Eur. J. Clin. Invest."},{"key":"BFsrep32030_CR13","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1053\/j.seminoncol.2012.10.001","volume":"39","author":"O Alpdogan","year":"2012","unstructured":"Alpdogan, O. & van den Brink, M. R. Immune tolerance and transplantation. Semin. Oncol. 39, 629\u2013642 (2012).","journal-title":"Semin. Oncol."},{"key":"BFsrep32030_CR14","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.immuni.2015.04.021","volume":"42","author":"BE Oftedal","year":"2015","unstructured":"Oftedal, B. E. et al. Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases. Immunity . 42, 1185\u20131196 (2015).","journal-title":"Immunity"},{"key":"BFsrep32030_CR15","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.jaut.2015.08.020","volume":"66","author":"DG Doherty","year":"2016","unstructured":"Doherty, D. G. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J. Autoimmun. 66, 60\u201375 (2016).","journal-title":"J. Autoimmun."},{"key":"BFsrep32030_CR16","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1038\/cmi.2013.7","volume":"4","author":"F Li","year":"2013","unstructured":"Li, F. & Tian, Z. The liver works as a school to educate regulatory immune cells. Cell Mol Immunol . 4, 292\u2013302 (2013).","journal-title":"Cell Mol Immunol"},{"key":"BFsrep32030_CR17","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/223472a0","volume":"223","author":"RY Calne","year":"1969","unstructured":"Calne, R. Y. et al. Induction of immunological tolerance by porcine liver allografts. Nature . 223, 472\u2013476 (1969).","journal-title":"Nature"},{"key":"BFsrep32030_CR18","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1007\/s00018-006-6094-7","volume":"63","author":"JM Boggs","year":"2006","unstructured":"Boggs, J. M. Myelin basic protein: a multifunctional protein. Cell Mol. Life Sci. 63, 1945\u20131961 (2006).","journal-title":"Cell Mol. Life Sci."},{"key":"BFsrep32030_CR19","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.intimp.2014.02.021","volume":"20","author":"MM Dai","year":"2014","unstructured":"Dai, M. M. et al. Effects and mechanisms of Geniposide on rats with adjuvant arthritis. Int. Immunopharmacol. 20, 46\u201353 (2014).","journal-title":"Int. Immunopharmacol."},{"key":"BFsrep32030_CR20","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.trim.2015.08.004","volume":"33","author":"SF Yang","year":"2015","unstructured":"Yang, S. F. et al. Induction of tolerance and prolongation of islet allograft survival by syngeneic hematopoietic stem cell transplantation in mice. Transpl. Immunol. 33, 130\u2013139 (2015).","journal-title":"Transpl. Immunol."},{"key":"BFsrep32030_CR21","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1186\/1472-6882-14-316","volume":"14","author":"YH Gao","year":"2014","unstructured":"Gao, Y. H. et al. NK cells mediate the cumulative analgesic effect of electroacupuncture in a rat model of neuropathic pain. BMC Complement Altern. Med. 14, 316 (2014).","journal-title":"BMC Complement Altern. Med."},{"key":"BFsrep32030_CR22","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1142\/S0192415X10007713","volume":"38","author":"J Li","year":"2010","unstructured":"Li, J., Du, J., Sun, L., Liu, J. & Quan, Z. Anti-inflammatory function of Nodosin via inhibition of IL-2. Am. J. Chin. Med. 38, 127\u2013142 (2010).","journal-title":"Am. J. Chin. Med."},{"key":"BFsrep32030_CR23","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.1111\/ajt.13382","volume":"15","author":"Y Yamada","year":"2015","unstructured":"Yamada, Y. et al. Repeated Injections of IL-2 Break Renal Allograft Tolerance Induced via Mixed Hematopoietic Chimerism in Monkeys. Am. J. Transplant. 15, 3055\u20133066 (2015).","journal-title":"Am. J. Transplant."},{"key":"BFsrep32030_CR24","doi-asserted-by":"crossref","first-page":"7331","DOI":"10.4049\/jimmunol.0803917","volume":"182","author":"AD Wells","year":"2009","unstructured":"Wells, A. D. New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors and epigenetic imprinting. J. Immunol. 182, 7331\u20137341 (2009).","journal-title":"J. Immunol."},{"key":"BFsrep32030_CR25","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/362245a0","volume":"362","author":"M Kopf","year":"1993","unstructured":"Kopf, M., Le, G. G., Bachmann, M., Lamers, M. C., Bluethmann, H. & Kohler, G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature . 362, 245\u2013248 (1993).","journal-title":"Nature"},{"key":"BFsrep32030_CR26","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1172\/JCI76210","volume":"125","author":"JT Walsh","year":"2015","unstructured":"Walsh, J. T. et al. MHCII-independent CD4+T cells protect injured CNS neurons via IL-4. J. Clin. Invest. 125, 699\u2013714 (2015).","journal-title":"J. Clin. Invest."},{"key":"BFsrep32030_CR27","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1161\/CIRCULATIONAHA.105.593046","volume":"113","author":"G Yilmaz","year":"2006","unstructured":"Yilmaz, G., Arumugam, T. V., Stokes, K. Y. & Granger, D. N. Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation . 113, 2105\u20132112 (2006).","journal-title":"Circulation"},{"key":"BFsrep32030_CR28","doi-asserted-by":"crossref","first-page":"6997","DOI":"10.1007\/s11033-013-2819-5","volume":"40","author":"Y Zhang","year":"2013","unstructured":"Zhang, Y. et al. Remifentanil preconditioning alleviating brain damage of cerebral ischemia reperfusion rats by regulating the JNK signal pathway and TNF-alpha\/TNFR1 signal pathway. Mol. Biol. Rep. 40, 6997\u20137006 (2013).","journal-title":"Mol. Biol. Rep."},{"key":"BFsrep32030_CR29","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1634\/stemcells.22-6-908","volume":"22","author":"O Bohana-Kashtan","year":"2004","unstructured":"Bohana-Kashtan, O. & Civin, C. I. Fas ligand as a tool for immunosuppression and generation of immune tolerance. Stem Cells . 22, 908\u201324 (2004).","journal-title":"Stem Cells"},{"key":"BFsrep32030_CR30","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1126\/science.270.5239.1189","volume":"270","author":"TS Griffith","year":"1995","unstructured":"Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R. & Ferguson, T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science . 270, 1189\u20131192 (1995).","journal-title":"Science"},{"key":"BFsrep32030_CR31","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/377630a0","volume":"377","author":"D Bellgrau","year":"1995","unstructured":"Bellgrau, D. et al. A role for CD95 ligand in preventing graft rejection. Nature . 377, 630\u2013632 (1995).","journal-title":"Nature"},{"key":"BFsrep32030_CR32","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.stem.2012.03.007","volume":"10","author":"K Akiyama","year":"2012","unstructured":"Akiyama, K. et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-\/FAS-mediated T cell apoptosis. Cell Stem Cell . 10, 544\u2013555 (2012).","journal-title":"Cell Stem Cell"},{"key":"BFsrep32030_CR33","doi-asserted-by":"crossref","first-page":"3443","DOI":"10.4049\/jimmunol.179.6.3443","volume":"179","author":"RA Derks","year":"2007","unstructured":"Derks, R. A., Jankowska-Gan, E., Xu, Q. & Burlingham, W. J. Dendritic cell type determines the mechanism of bystander suppression by adaptive T regulatory cells specific for the minor antigen HA-1. J. Immunol. 179, 3443\u20133451 (2007).","journal-title":"J. Immunol."},{"key":"BFsrep32030_CR34","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1136\/ard.2010.136994","volume":"70","author":"E Zonneveld-Huijssoon","year":"2011","unstructured":"Zonneveld-Huijssoon, E. et al. Bystander suppression of experimental arthritis by nasal administration of a heat shock protein peptide. Ann. Rheum. Dis. 70, 2199\u20132206 (2011).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep32030_CR35","doi-asserted-by":"crossref","first-page":"831","DOI":"10.4103\/0366-6999.178955","volume":"129","author":"ZQ Cui","year":"2016","unstructured":"Cui, Z. Q. et al. Could Intrathymic Injection of Myelin Basic Protein Suppress Inflammatory Response After Co-culture of T Lymphocytes and BV-2 Microglia Cells? Chin Med J (Engl). 129, 831\u2013837 (2016).","journal-title":"Chin Med J (Engl)."},{"key":"BFsrep32030_CR36","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1161\/STROKEAHA.107.501486","volume":"39","author":"JM Gee","year":"2008","unstructured":"Gee, J. M., Kalil, A., Thullbery, M. & Becker, K. J. Induction of immunologic tolerance to myelin basic protein prevents central nervous system autoimmunity and improves outcome after stroke. Stroke . 39, 1575\u20131582 (2008).","journal-title":"Stroke"},{"key":"BFsrep32030_CR37","first-page":"3403","volume":"118","author":"S L\u00fcth","year":"2008","unstructured":"L\u00fcth, S. et al. Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs. J Clin Invest . 118, 3403\u20133410 (2008).","journal-title":"J Clin Invest"},{"key":"BFsrep32030_CR38","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/cmi.2015.112","volume":"13","author":"AK Horst","year":"2016","unstructured":"Horst, A. K., Neumann, K., Diehl, L. & Tiegs, G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol . 13, 277\u2013292 (2016).","journal-title":"Cell Mol Immunol"},{"key":"BFsrep32030_CR39","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.jneuroim.2010.06.002","volume":"227","author":"JP Peron","year":"2010","unstructured":"Peron, J. P. et al. Oral tolerance reduces Th17 cells as well as the overall inflammation in the central nervous system of EAE mice. J. Neuroimmunol. 227, 10\u201317 (2010).","journal-title":"J. Neuroimmunol."},{"key":"BFsrep32030_CR40","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1111\/j.1467-7652.2011.00613.x","volume":"9","author":"K Suzuki","year":"2011","unstructured":"Suzuki, K. et al. Prevention of allergic asthma by vaccination with transgenic rice seed expressing mite allergen: induction of allergen-specific oral tolerance without bystander suppression. Plant Biotechnol. J. 9, 982\u2013990 (2011).","journal-title":"Plant Biotechnol. J."},{"key":"BFsrep32030_CR41","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1016\/j.ultrasmedbio.2014.11.011","volume":"41","author":"AZ Tuckett","year":"2015","unstructured":"Tuckett, A. Z., Zakrzewski, J. L., Li, D., van den Brink, M. R. & Thornton, R. H. Free-hand ultrasound guidance permits safe and efficient minimally invasive intrathymic injections in both young and aged mice. Ultrasound Med Biol . 41, 1105\u20131111 (2015).","journal-title":"Ultrasound Med Biol"},{"key":"BFsrep32030_CR42","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.nbd.2015.11.003","volume":"85","author":"P Sherchan","year":"2016","unstructured":"Sherchan, P. et al. Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model. Neurobiol. Dis. 85, 164\u2013173 (2016).","journal-title":"Neurobiol. Dis."},{"key":"BFsrep32030_CR43","doi-asserted-by":"crossref","first-page":"6323","DOI":"10.18632\/oncotarget.6319","volume":"7","author":"Y Wang","year":"2016","unstructured":"Wang, Y. et al. Decreased TPD52 expression is associated with poor prognosis in primary hepatocellular carcinoma. Oncotarget . 7, 6323\u20136334 (2016).","journal-title":"Oncotarget"},{"key":"BFsrep32030_CR44","doi-asserted-by":"crossref","first-page":"e0142561","DOI":"10.1371\/journal.pone.0142561","volume":"10","author":"H Wang","year":"2015","unstructured":"Wang, H. et al. Effect of ATM and HDAC Inhibition on Etoposide-Induced DNA Damage in Porcine Early Preimplantation Embryos. PLoS One . 10, e0142561 (2015).","journal-title":"PLoS One"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep32030","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep32030.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep32030.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,19]],"date-time":"2024-06-19T01:23:35Z","timestamp":1718760215000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep32030"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,24]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,10,17]]}},"alternative-id":["BFsrep32030"],"URL":"https:\/\/doi.org\/10.1038\/srep32030","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,24]]},"assertion":[{"value":"21 March 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 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":"32030"}}