{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:46:52Z","timestamp":1771260412928,"version":"3.50.1"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T00:00:00Z","timestamp":1470182400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T00:00:00Z","timestamp":1470182400000},"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>Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to \u03b2-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become \u03b2-sheet conformation after 10 days <jats:italic>in vitro<\/jats:italic> incubation and 14 days <jats:italic>in vivo<\/jats:italic> subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent \u03b2-sheet transition induces cell apoptosis <jats:italic>in vitro<\/jats:italic>. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated <jats:italic>in vitro<\/jats:italic> and in an <jats:italic>in vivo<\/jats:italic> chick chorioallantoic membrane model for tumor formation. <jats:italic>In vivo<\/jats:italic>, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials.<\/jats:p>","DOI":"10.1038\/srep31037","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T10:05:49Z","timestamp":1470218749000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":76,"title":["Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels"],"prefix":"10.1038","volume":"6","author":[{"given":"Le-Ping","family":"Yan","sequence":"first","affiliation":[]},{"given":"Joana","family":"Silva-Correia","sequence":"additional","affiliation":[]},{"given":"Viviana P.","family":"Ribeiro","sequence":"additional","affiliation":[]},{"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Cristina","family":"Correia","sequence":"additional","affiliation":[]},{"given":"Alain","family":"da Silva Morais","sequence":"additional","affiliation":[]},{"given":"Rui A.","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Rui M.","family":"Reis","sequence":"additional","affiliation":[]},{"given":"Ana L.","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Joaquim M.","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Rui L.","family":"Reis","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2016,8,3]]},"reference":[{"key":"BFsrep31037_CR1","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/S0939-6411(00)00090-4","volume":"50","author":"NA Peppas","year":"2000","unstructured":"Peppas, N. A., Bures, P., Leobandung, W. & Ichikawa, H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm 50, 27\u201346 (2000).","journal-title":"Eur J Pharm Biopharm"},{"key":"BFsrep31037_CR2","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1126\/science.1214804","volume":"336","author":"D Seliktar","year":"2012","unstructured":"Seliktar, D. Designing cell-compatible hydrogels for biomedical applications. Science 336, 1124\u20131128 (2012).","journal-title":"Science"},{"key":"BFsrep31037_CR3","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1016\/j.addr.2006.09.020","volume":"58","author":"D Schmaljohann","year":"2006","unstructured":"Schmaljohann, D. Thermo- and pH-responsive polymers in drug delivery. Advanced Drug Delivery Reviews 58, 1655\u20131670 (2006).","journal-title":"Advanced Drug Delivery Reviews"},{"key":"BFsrep31037_CR4","doi-asserted-by":"publisher","first-page":"3136","DOI":"10.1021\/nl2011627","volume":"11","author":"A Riedinger","year":"2011","unstructured":"Riedinger, A. et al. \u201cNanohybrids\u201d Based on pH-Responsive Hydrogels and Inorganic Nanoparticles for Drug Delivery and Sensor Applications. Nano Letters 11, 3136\u20133141 (2011).","journal-title":"Nano Letters"},{"key":"BFsrep31037_CR5","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/nmat1092","volume":"3","author":"Y Luo","year":"2004","unstructured":"Luo, Y. & Shoichet, M. S. A photolabile hydrogel for guided three-dimensional cell growth and migration. Nat Mater 3, 249\u2013253 (2004).","journal-title":"Nat Mater"},{"key":"BFsrep31037_CR6","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1126\/science.1169494","volume":"324","author":"AM Kloxin","year":"2009","unstructured":"Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59\u201363 (2009).","journal-title":"Science"},{"key":"BFsrep31037_CR7","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/nchem.1174","volume":"3","author":"CA DeForest","year":"2011","unstructured":"DeForest, C. A. & Anseth, K. S. Cytocompatible click-based hydrogels with dynamically tunable properties through orthogonal photoconjugation and photocleavage reactions. Nat Chem 3, 925\u2013931 (2011).","journal-title":"Nat Chem"},{"key":"BFsrep31037_CR8","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nmat1352","volume":"4","author":"JD Ehrick","year":"2005","unstructured":"Ehrick, J. D. et al. Genetically engineered protein in hydrogels tailors stimuli-responsive characteristics. Nat Mater 4, 298\u2013302 (2005).","journal-title":"Nat Mater"},{"key":"BFsrep31037_CR9","doi-asserted-by":"publisher","first-page":"3066","DOI":"10.1002\/anie.200604808","volume":"46","author":"WL Murphy","year":"2007","unstructured":"Murphy, W. L., Dillmore, W. S., Modica, J. & Mrksich, M. Dynamic Hydrogels: Translating a Protein Conformational Change into Macroscopic Motion. Angewandte Chemie International Edition 46, 3066\u20133069 (2007).","journal-title":"Angewandte Chemie International Edition"},{"key":"BFsrep31037_CR10","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.1002\/adfm.200701288","volume":"18","author":"Z Sui","year":"2008","unstructured":"Sui, Z., King, W. J. & Murphy, W. L. Protein-Based Hydrogels with Tunable Dynamic Responses. Advanced Functional Materials 18, 1824\u20131831 (2008).","journal-title":"Advanced Functional Materials"},{"key":"BFsrep31037_CR11","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1038\/nm1066","volume":"10","author":"CA Ross","year":"2004","unstructured":"Ross, C. A. & Poirier, M. A. Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl S10\u2013S17 (2004).","journal-title":"Nat Med"},{"key":"BFsrep31037_CR12","doi-asserted-by":"publisher","first-page":"112","DOI":"10.4161\/pri.2.3.7488","volume":"2","author":"RN Rambaran","year":"2008","unstructured":"Rambaran, R. N. & Serpell, L. C. Amyloid fibrils: Abnormal protein assembly. Prion 2, 112\u2013117 (2008).","journal-title":"Prion"},{"key":"BFsrep31037_CR13","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.progpolymsci.2007.05.013","volume":"32","author":"C Vepari","year":"2007","unstructured":"Vepari, C. & Kaplan, D. L. Silk as a biomaterial. Progress in Polymer Science 32, 991\u20131007 (2007).","journal-title":"Progress in Polymer Science"},{"key":"BFsrep31037_CR14","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1038\/418741a","volume":"418","author":"Z Shao","year":"2002","unstructured":"Shao, Z. & Vollrath, F. Materials: Surprising strength of silkworm silk. Nature 418, 741\u2013741 (2002).","journal-title":"Nature"},{"key":"BFsrep31037_CR15","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1021\/bm0345460","volume":"5","author":"UJ Kim","year":"2004","unstructured":"Kim, U. J. et al. Structure and properties of silk hydrogels. Biomacromolecules 5, 786\u2013792 (2004).","journal-title":"Biomacromolecules"},{"key":"BFsrep31037_CR16","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1163\/1568562041271075","volume":"15","author":"A Motta","year":"2004","unstructured":"Motta, A. et al. Fibroin hydrogels for biomedical applications: preparation, characterization and in vitro cell culture studies. J Biomater Sci Polym Ed 15, 851\u2013864 (2004).","journal-title":"J Biomater Sci Polym Ed"},{"key":"BFsrep31037_CR17","doi-asserted-by":"publisher","first-page":"3100","DOI":"10.1021\/bm050431f","volume":"6","author":"Y Tamada","year":"2005","unstructured":"Tamada, Y. New process to form a silk fibroin porous 3-D structure. Biomacromolecules 6, 3100\u20133106 (2005).","journal-title":"Biomacromolecules"},{"key":"BFsrep31037_CR18","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.jbiosc.2009.02.015","volume":"108","author":"K Makaya","year":"2009","unstructured":"Makaya, K., Terada, S., Ohgo, K. & Asakura, T. Comparative study of silk fibroin porous scaffolds derived from salt\/water and sucrose\/hexafluoroisopropanol in cartilage formation. Journal of Bioscience and Bioengineering 108, 68\u201375 (2009).","journal-title":"Journal of Bioscience and Bioengineering"},{"key":"BFsrep31037_CR19","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1016\/j.biomaterials.2011.10.067","volume":"33","author":"LS Teixeira","year":"2012","unstructured":"Teixeira, L. S., Feijen, J., van Blitterswijk, C. A., Dijkstra, P. J. & Karperien, M. Enzyme-catalyzed crosslinkable hydrogels: emerging strategies for tissue engineering. Biomaterials 33, 1281\u20131290 (2012).","journal-title":"Biomaterials"},{"key":"BFsrep31037_CR20","first-page":"57","volume":"66","author":"SO Andersen","year":"1965","unstructured":"Andersen, S. O. 7. Biosynthesis of the cross-links in reslin. Acta Physiologica Scandinavica 66, 57\u201363 (1965).","journal-title":"Acta Physiologica Scandinavica"},{"key":"BFsrep31037_CR21","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/0304-4165(64)90289-2","volume":"93","author":"SO Andersen","year":"1964","unstructured":"Andersen, S. O. The Cross-Links in Resilin Identified As Dityrosine and Trityrosine. Biochimica et biophysica acta 93, 213\u2013215 (1964).","journal-title":"Biochimica et biophysica acta"},{"key":"BFsrep31037_CR22","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/0005-2795(76)90064-7","volume":"439","author":"R Aeschbach","year":"1976","unstructured":"Aeschbach, R., Amado, R. & Neukom, H. Formation of dityrosine cross-links in proteins by oxidation of tyrosine residues. Biochimica et biophysica acta 439, 292\u2013301 (1976).","journal-title":"Biochimica et biophysica acta"},{"key":"BFsrep31037_CR23","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/BF01024835","volume":"3","author":"G Matheis","year":"1984","unstructured":"Matheis, G. & Whitaker, J. Peroxidase-catalyzed cross linking of proteins. J Protein Chem 3, 35\u201348 (1984).","journal-title":"J Protein Chem"},{"key":"BFsrep31037_CR24","first-page":"14","volume":"7","author":"LP Yan","year":"2013","unstructured":"Yan, L. P. et al. Injectable and dual-stimuli-responsive silk fibroin hydrogels for tissue engineering and regenerative medicine applications. J Tissue Eng Regen Med 7(S1), 14 (2013).","journal-title":"J Tissue Eng Regen Med"},{"key":"BFsrep31037_CR25","unstructured":"Reis, R. L. et al. In ventors; A4TEC Association, assignee. Hydrogels derived from silk fibroin: Methods and uses thereof. Portuguese patent PT107426. 2014 Apr 29."},{"key":"BFsrep31037_CR26","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/nmat2619","volume":"9","author":"DW Hutmacher","year":"2010","unstructured":"Hutmacher, D. W. Biomaterials offer cancer research the third dimension. Nat Mater 9, 90\u201393 (2010).","journal-title":"Nat Mater"},{"key":"BFsrep31037_CR27","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1002\/adma.200902643","volume":"22","author":"GG Leisk","year":"2010","unstructured":"Leisk, G. G., Lo, T. J., Yucel, T., Lu, Q. & Kaplan, D. L. Electrogelation for protein adhesives. Adv Mater 22, 711\u2013715 (2010).","journal-title":"Adv Mater"},{"key":"BFsrep31037_CR28","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1002\/adfm.200400405","volume":"15","author":"HJ Jin","year":"2005","unstructured":"Jin, H. J. et al. Water-Stable Silk Films with Reduced \u03b2-Sheet Content. Advanced Functional Materials 15, 1241\u20131247 (2005).","journal-title":"Advanced Functional Materials"},{"key":"BFsrep31037_CR29","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1021\/ma00152a009","volume":"18","author":"T Asakura","year":"1985","unstructured":"Asakura, T., Kuzuhara, A., Tabeta, R. & Saito, H. Conformational characterization of Bombyx mori silk fibroin in the solid state by high-frequency carbon-13 cross polarization-magic angle spinning NMR, x-ray diffraction, and infrared spectroscopy. Macromolecules 18, 1841\u20131845 (1985).","journal-title":"Macromolecules"},{"key":"BFsrep31037_CR30","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1038\/nmat1762","volume":"5","author":"C Holland","year":"2006","unstructured":"Holland, C., Terry, A. E., Porter, D. & Vollrath, F. Comparing the rheology of native spider and silkworm spinning dope. Nat Mater 5, 870\u2013874 (2006).","journal-title":"Nat Mater"},{"key":"BFsrep31037_CR31","doi-asserted-by":"publisher","first-page":"7806","DOI":"10.1016\/j.actbio.2013.04.033","volume":"9","author":"S Bai","year":"2013","unstructured":"Bai, S. et al. Controllable transition of silk fibroin nanostructures: An insight into in vitro silk self-assembly process. Acta Biomaterialia 9, 7806\u20137813 (2013).","journal-title":"Acta Biomaterialia"},{"key":"BFsrep31037_CR32","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1089\/ten.tea.2011.0632","volume":"18","author":"J Silva-Correia","year":"2012","unstructured":"Silva-Correia, J. et al. Angiogenic potential of gellan-gum-based hydrogels for application in nucleus pulposus regeneration: in vivo study. Tissue Eng Part A 18, 1203\u20131212 (2012).","journal-title":"Tissue Eng Part A"},{"key":"BFsrep31037_CR33","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1002\/cyto.1099","volume":"46","author":"Z Maciorowski","year":"2001","unstructured":"Maciorowski, Z. et al. Comparative image and flow cytometric TUNEL analysis of fine needle samples of breast carcinoma. Cytometry 46, 150\u2013156 (2001).","journal-title":"Cytometry"},{"key":"BFsrep31037_CR34","doi-asserted-by":"publisher","first-page":"2791","DOI":"10.1016\/j.biomaterials.2007.02.032","volume":"28","author":"R Jin","year":"2007","unstructured":"Jin, R., Hiemstra, C., Zhong, Z. & Feijen, J. Enzyme-mediated fast in situ formation of hydrogels from dextran-tyramine conjugates. Biomaterials 28, 2791\u20132800 (2007).","journal-title":"Biomaterials"},{"key":"BFsrep31037_CR35","doi-asserted-by":"publisher","first-page":"2622","DOI":"10.1021\/bm070300+","volume":"8","author":"S Sakai","year":"2007","unstructured":"Sakai, S., Hashimoto, I., Ogushi, Y. & Kawakami, K. Peroxidase-catalyzed cell encapsulation in subsieve-size capsules of alginate with phenol moieties in water-immiscible fluid dissolving H2O2 . Biomacromolecules 8, 2622\u20132626 (2007).","journal-title":"Biomacromolecules"},{"key":"BFsrep31037_CR36","doi-asserted-by":"publisher","first-page":"3523","DOI":"10.1016\/j.biomaterials.2009.03.004","volume":"30","author":"M Hu","year":"2009","unstructured":"Hu, M. et al. Cell immobilization in gelatin-hydroxyphenylpropionic acid hydrogel fibers. Biomaterials 30, 3523\u20133531 (2009).","journal-title":"Biomaterials"},{"key":"BFsrep31037_CR37","doi-asserted-by":"publisher","first-page":"2544","DOI":"10.1016\/j.biomaterials.2009.01.020","volume":"30","author":"R Jin","year":"2009","unstructured":"Jin, R. et al. Injectable chitosan-based hydrogels for cartilage tissue engineering. Biomaterials 30, 2544\u20132551 (2009).","journal-title":"Biomaterials"},{"key":"BFsrep31037_CR38","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/j.biomaterials.2007.11.003","volume":"29","author":"X Wang","year":"2008","unstructured":"Wang, X., Kluge, J. A., Leisk, G. G. & Kaplan, D. L. Sonication-induced gelation of silk fibroin for cell encapsulation. Biomaterials 29, 1054\u20131064 (2008).","journal-title":"Biomaterials"},{"key":"BFsrep31037_CR39","doi-asserted-by":"publisher","first-page":"4615","DOI":"10.1002\/adfm.201400526","volume":"24","author":"BP Partlow","year":"2014","unstructured":"Partlow, B. P. et al. Highly Tunable Elastomeric Silk Biomaterials. Adv. Funct. Mater 24, 4615\u20134624 (2014).","journal-title":"Adv. Funct. Mater"},{"key":"BFsrep31037_CR40","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nmat2778","volume":"9","author":"S Zhang","year":"2010","unstructured":"Zhang, S. et al. A self-assembly pathway to aligned monodomain gels. Nat Mater 9, 594\u2013601 (2010).","journal-title":"Nat Mater"},{"key":"BFsrep31037_CR41","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/nmat2479","volume":"8","author":"EF Banwell","year":"2009","unstructured":"Banwell, E. F. et al. Rational design and application of responsive alpha-helical peptide hydrogels. Nat Mater 8, 596\u2013600 (2009).","journal-title":"Nat Mater"},{"key":"BFsrep31037_CR42","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1053\/sonc.2002.37263","volume":"29","author":"J Folkman","year":"2002","unstructured":"Folkman, J. Role of angiogenesis in tumor growth and metastasis. Seminars in Oncology 29, 15\u201318 (2002).","journal-title":"Seminars in Oncology"},{"key":"BFsrep31037_CR43","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.actbio.2011.09.037","volume":"8","author":"LP Yan","year":"2012","unstructured":"Yan, L. P. et al. Macro\/microporous silk fibroin scaffolds with potential for articular cartilage and meniscus tissue engineering applications. Acta Biomater 8, 289\u2013301 (2012).","journal-title":"Acta Biomater"},{"key":"BFsrep31037_CR44","doi-asserted-by":"publisher","first-page":"3527","DOI":"10.1016\/j.biomaterials.2004.09.040","volume":"26","author":"M Fini","year":"2005","unstructured":"Fini, M. et al. The healing of confined critical size cancellous defects in the presence of silk fibroin hydrogel. Biomaterials 26, 3527\u20133536 (2005).","journal-title":"Biomaterials"},{"key":"BFsrep31037_CR45","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1016\/j.bpj.2009.07.028","volume":"97","author":"T Yucel","year":"2009","unstructured":"Yucel, T., Cebe, P. & Kaplan, D. L. Vortex-induced injectable silk fibroin hydrogels. Biophys J 97, 2044\u20132050 (2009).","journal-title":"Biophys J"},{"key":"BFsrep31037_CR46","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1021\/bm300006r","volume":"13","author":"I Karakutuk","year":"2012","unstructured":"Karakutuk, I., Ak, F. & Okay, O. Diepoxide-triggered conformational transition of silk fibroin: formation of hydrogels. Biomacromolecules 13, 1122\u20131128 (2012).","journal-title":"Biomacromolecules"},{"key":"BFsrep31037_CR47","doi-asserted-by":"publisher","first-page":"2185","DOI":"10.1016\/j.actbio.2012.03.007","volume":"8","author":"X Wu","year":"2012","unstructured":"Wu, X. et al. Sodium dodecyl sulfate-induced rapid gelation of silk fibroin. Acta Biomater 8, 2185\u20132192 (2012).","journal-title":"Acta Biomater"},{"key":"BFsrep31037_CR48","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1016\/j.carbpol.2013.07.028","volume":"98","author":"CH Park","year":"2013","unstructured":"Park, C. H., Jeong, L., Cho, D., Kwon, O. H. & Park, W. H. Effect of methylcellulose on the formation and drug release behavior of silk fibroin hydrogel. Carbohydr Polym 98, 1179\u20131185 (2013).","journal-title":"Carbohydr Polym"},{"key":"BFsrep31037_CR49","doi-asserted-by":"publisher","first-page":"055003","DOI":"10.1088\/1748-6041\/8\/5\/055003","volume":"8","author":"B Kundu","year":"2013","unstructured":"Kundu, B. & Kundu, S. C. Bio-inspired fabrication of fibroin cryogels from the muga silkworm Antheraea assamensis for liver tissue engineering. Biomed Mater 8, 055003 (2013).","journal-title":"Biomed Mater"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep31037.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31037","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31037.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:37:12Z","timestamp":1672897032000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep31037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,3]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,8,30]]}},"alternative-id":["BFsrep31037"],"URL":"https:\/\/doi.org\/10.1038\/srep31037","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,3]]},"assertion":[{"value":"22 January 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 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":"31037"}}