{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:17:57Z","timestamp":1790054277321,"version":"4.0.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,7,8]],"date-time":"2015-07-08T00:00:00Z","timestamp":1436313600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,7,8]],"date-time":"2015-07-08T00:00:00Z","timestamp":1436313600000},"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>Deregulation of inflammasome activation was recently identified to be involved in the pathogenesis of various inflammatory diseases. Although macrolide antibiotics display well described immunomodulatory properties, presumably involved in their clinical effects, their impact on inflammasome activation has not been investigated. We compared the influence of macrolides on cytokine induction in human monocytes. The role of intracellular azithromycin-accumulation was examined by interference with Ca<jats:sup>++<\/jats:sup>-dependent uptake. We have also analysed the signalling cascades involved in inflammasome activation and substantiated the findings in a murine sepsis model. Azithromycin, but not clarithromycin or roxithromycin, specifically inhibited IL-1\u03b1 and IL-1\u03b2 secretion upon LPS stimulation. Interference with Ca<jats:sup>++<\/jats:sup>-dependent uptake abolished the cytokine-modulatory effect, suggesting a role of intracellular azithromycin accumulation in the modulatory role of this macrolide. Azithromycin\u2019s inhibiting effects were observed upon LPS, but not upon flagellin, stimulation. Consistent with this observation, we found impaired induction of the LPS-sensing caspase-4 whereas NF-\u03baB signalling was unaffected. Furthermore, azithromycin specifically affected IL-1\u03b2 levels in a murine endotoxin sepsis model. We provide the first evidence of a differential impact of macrolides on the inflammasome\/IL-1\u03b2 axis, which may be of relevance in inflammasome-driven diseases such as chronic obstructive pulmonary disease or asthma.<\/jats:p>","DOI":"10.1038\/srep12016","type":"journal-article","created":{"date-parts":[[2015,7,8]],"date-time":"2015-07-08T11:08:45Z","timestamp":1436353725000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Azithromycin inhibits IL-1 secretion and non-canonical inflammasome activation"],"prefix":"10.1038","volume":"5","author":[{"given":"Guido A.","family":"Gualdoni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilman","family":"Lingscheid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus G.","family":"Schmetterer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Hennig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Steinberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard J.","family":"Zlabinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,8]]},"reference":[{"key":"BFsrep12016_CR1","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1128\/CMR.00078-09","volume":"23","author":"S Kanoh","year":"2010","unstructured":"Kanoh, S. & Rubin, B. K. Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications. Clin. Microbiol. Rev. 23, 590\u2013615 (2010).","journal-title":"Clin. Microbiol. Rev."},{"key":"BFsrep12016_CR2","doi-asserted-by":"publisher","first-page":"7438","DOI":"10.1038\/srep07438","volume":"4","author":"F Ratzinger","year":"2014","unstructured":"Ratzinger, F. et al. Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity. Sci. Rep. 4, 7438 (2014).","journal-title":"Sci. Rep."},{"key":"BFsrep12016_CR3","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1164\/rccm.200801-145OC","volume":"178","author":"TAR Seemungal","year":"2008","unstructured":"Seemungal, T. A. R. et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am. J. Respir. Crit. Care Med. 178, 1139\u20131147 (2008).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFsrep12016_CR4","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1056\/NEJMoa1104623","volume":"365","author":"RK Albert","year":"2011","unstructured":"Albert, R. K. et al. Azithromycin for prevention of exacerbations of COPD. N. Engl. J. Med. 365, 689\u2013698 (2011).","journal-title":"N. Engl. J. Med."},{"key":"BFsrep12016_CR5","doi-asserted-by":"publisher","first-page":"59","DOI":"10.2165\/00151829-200403010-00007","volume":"3","author":"D Banerjee","year":"2004","unstructured":"Banerjee, D., Honeybourne, D. & Khair, O. A. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat. Respir. Med. 3, 59\u201365 (2004).","journal-title":"Treat. Respir. Med."},{"key":"BFsrep12016_CR6","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1378\/chest.120.3.730","volume":"120","author":"T Suzuki","year":"2001","unstructured":"Suzuki, T. et al. Erythromycin and common cold in COPD. Chest 120, 730\u2013733 (2001).","journal-title":"Chest"},{"key":"BFsrep12016_CR7","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/S0140-6736(12)60953-2","volume":"380","author":"C Wong","year":"2012","unstructured":"Wong, C. et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. The Lancet 380, 660\u2013667 (2012).","journal-title":"The Lancet"},{"key":"BFsrep12016_CR8","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1093\/jac\/dkr040","volume":"66","author":"Y Cai","year":"2011","unstructured":"Cai, Y. et al. Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review. J. Antimicrob. Chemother. 66, 968\u2013978 (2011).","journal-title":"J. Antimicrob. Chemother."},{"key":"BFsrep12016_CR9","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.jaip.2014.06.002","volume":"2","author":"DR Rollins","year":"2014","unstructured":"Rollins, D. R., Good, J. T. & Martin, R. J. The role of atypical infections and macrolide therapy in patients with asthma. J. Allergy Clin. Immunol. Pract. 2, 511\u2013517 (2014).","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"BFsrep12016_CR10","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/nature10759","volume":"481","author":"T Strowig","year":"2012","unstructured":"Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278\u2013286 (2012).","journal-title":"Nature"},{"key":"BFsrep12016_CR11","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.mib.2013.04.004","volume":"16","author":"Y Aachoui","year":"2013","unstructured":"Aachoui, Y., Sagulenko, V., Miao, E. A. & Stacey, K. J. Inflammasome-mediated pyroptotic and apoptotic cell death and defense against infection. Curr. Opin. Microbiol. 16, 319\u2013326 (2013).","journal-title":"Curr. Opin. Microbiol."},{"key":"BFsrep12016_CR12","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1016\/j.cell.2014.04.007","volume":"157","author":"M Lamkanfi","year":"2014","unstructured":"Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013\u20131022 (2014).","journal-title":"Cell"},{"key":"BFsrep12016_CR13","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1126\/science.1240248","volume":"341","author":"N Kayagaki","year":"2013","unstructured":"Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246\u20131249 (2013).","journal-title":"Science"},{"key":"BFsrep12016_CR14","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/nature13683","volume":"514","author":"J Shi","year":"2014","unstructured":"Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187\u2013192 (2014).","journal-title":"Nature"},{"key":"BFsrep12016_CR15","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.mib.2012.11.008","volume":"16","author":"GI Vladimer","year":"2013","unstructured":"Vladimer, G. I., Marty-Roix, R., Ghosh, S., Weng, D. & Lien, E. Inflammasomes and host defenses against bacterial infections. Curr. Opin. Microbiol. 16, 23\u201331 (2013).","journal-title":"Curr. Opin. Microbiol."},{"key":"BFsrep12016_CR16","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1093\/infdis\/jir846","volume":"205","author":"C Kebaier","year":"2012","unstructured":"Kebaier, C. et al. Staphylococcus aureus \u03b1-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome. J. Infect. Dis. 205, 807\u2013817 (2012).","journal-title":"J. Infect. Dis."},{"key":"BFsrep12016_CR17","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.molmed.2010.11.001","volume":"17","author":"PJ Shaw","year":"2011","unstructured":"Shaw, P. J., McDermott, M. F. & Kanneganti, T.-D. Inflammasomes and autoimmunity. Trends Mol. Med. 17, 57\u201364 (2011).","journal-title":"Trends Mol. Med."},{"key":"BFsrep12016_CR18","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1084\/jem.20130084","volume":"210","author":"D Jankovic","year":"2013","unstructured":"Jankovic, D. et al. The Nlrp3 inflammasome regulates acute graft-versus-host disease. J. Exp. Med. 210, 1899\u20131910 (2013).","journal-title":"J. Exp. Med."},{"key":"BFsrep12016_CR19","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/ni.1935","volume":"11","author":"SL Masters","year":"2010","unstructured":"Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1\u03b2 in type 2 diabetes. Nat. Immunol. 11, 897\u2013904 (2010).","journal-title":"Nat. Immunol."},{"key":"BFsrep12016_CR20","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1378\/chest.13-1885","volume":"145","author":"GG Brusselle","year":"2014","unstructured":"Brusselle, G. G., Provoost, S., Bracke, K. R., Kuchmiy, A. & Lamkanfi, M. Inflammasomes in respiratory disease: from bench to bedside. Chest 145, 1121\u20131133 (2014).","journal-title":"Chest"},{"key":"BFsrep12016_CR21","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1183\/09031936.00158110","volume":"38","author":"NS Pauwels","year":"2011","unstructured":"Pauwels, N. S. et al. Role of IL-1\u03b1 and the Nlrp3\/caspase-1\/IL-1\u03b2 axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur. Respir. J. 38, 1019\u20131028 (2011).","journal-title":"Eur. Respir. J."},{"key":"BFsrep12016_CR22","doi-asserted-by":"publisher","first-page":"e28457","DOI":"10.1371\/journal.pone.0028457","volume":"6","author":"FM Botelho","year":"2011","unstructured":"Botelho, F. M. et al. IL-1\u03b1\/IL-1R1 Expression in Chronic Obstructive Pulmonary Disease and Mechanistic Relevance to Smoke-Induced Neutrophilia in Mice. PLoS ONE 6, e28457 (2011).","journal-title":"PLoS ONE"},{"key":"BFsrep12016_CR23","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1183\/09031936.00019207","volume":"31","author":"H Imaoka","year":"2008","unstructured":"Imaoka, H. et al. Interleukin-18 production and pulmonary function in COPD. Eur. Respir. J. 31, 287\u2013297 (2008).","journal-title":"Eur. Respir. J."},{"key":"BFsrep12016_CR24","doi-asserted-by":"publisher","first-page":"e24097","DOI":"10.1371\/journal.pone.0024097","volume":"6","author":"S Eltom","year":"2011","unstructured":"Eltom, S. et al. P2\u2009\u00d77 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke. PloS One 6, e24097 (2011).","journal-title":"PloS One"},{"key":"BFsrep12016_CR25","doi-asserted-by":"publisher","first-page":"125","DOI":"10.2332\/allergolint.10-RAI-0190","volume":"59","author":"A Nambu","year":"2010","unstructured":"Nambu, A. & Nakae, S. IL-1 and Allergy. Allergol. Int. Off. J. Jpn. Soc. Allergol. 59, 125\u2013135 (2010).","journal-title":"Allergol. Int. Off. J. Jpn. Soc. Allergol."},{"key":"BFsrep12016_CR26","doi-asserted-by":"publisher","first-page":"3473","DOI":"10.1182\/blood-2013-05-502229","volume":"122","author":"E Asgari","year":"2013","unstructured":"Asgari, E. et al. C3a modulates IL-1\u03b2 secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood 122, 3473\u20133481 (2013).","journal-title":"Blood"},{"key":"BFsrep12016_CR27","doi-asserted-by":"publisher","first-page":"2324","DOI":"10.1182\/blood-2008-03-146720","volume":"113","author":"MG Netea","year":"2009","unstructured":"Netea, M. G. et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood 113, 2324\u20132335 (2009).","journal-title":"Blood"},{"key":"BFsrep12016_CR28","first-page":"S24","volume":"1","author":"MT Labro","year":"1996","unstructured":"Labro, M. T. Intracellular bioactivity of macrolides. Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis. 1 Suppl 1, S24\u2013S30 (1996).","journal-title":"Clin. Microbiol. Infect. Off. Publ. Eur. Soc. Clin. Microbiol. Infect. Dis."},{"key":"BFsrep12016_CR29","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.1128\/AAC.49.6.2372-2377.2005","volume":"49","author":"M Bosnar","year":"2005","unstructured":"Bosnar, M., Kelneri\u0107, \u017d., Muni\u0107, V., Erakovi\u0107, V. & Parnham, M. J. Cellular Uptake and Efflux of Azithromycin, Erythromycin, Clarithromycin, Telithromycin and Cethromycin. Antimicrob. Agents Chemother. 49, 2372\u20132377 (2005).","journal-title":"Antimicrob. Agents Chemother."},{"key":"BFsrep12016_CR30","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1128\/AAC.39.8.1676","volume":"39","author":"EM Mtairag","year":"1995","unstructured":"Mtairag, E. M., Abdelghaffar, H., Douhet, C. & Labro, M. T. Role of extracellular calcium in in vitro uptake and intraphagocytic location of macrolides. Antimicrob. Agents Chemother. 39, 1676\u20131682 (1995).","journal-title":"Antimicrob. Agents Chemother."},{"key":"BFsrep12016_CR31","doi-asserted-by":"publisher","first-page":"2099","DOI":"10.1128\/AAC.41.10.2099","volume":"41","author":"D Vazifeh","year":"1997","unstructured":"Vazifeh, D., Abdelghaffar, H. & Labro, M. T. Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin. Antimicrob. Agents Chemother. 41, 2099\u20132107 (1997).","journal-title":"Antimicrob. Agents Chemother."},{"key":"BFsrep12016_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1164\/rccm.201406-1014ED","volume":"190","author":"MI Restrepo","year":"2014","unstructured":"Restrepo, M. I. & Anzueto, A. Macrolide antibiotics for prevention of chronic obstructive pulmonary disease exacerbations: are we there yet? Am. J. Respir. Crit. Care Med. 190, 1\u20132 (2014).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFsrep12016_CR33","first-page":"CD002203","volume":"11","author":"KW Southern","year":"2012","unstructured":"Southern, K. W., Barker, P. M., Solis-Moya, A. & Patel, L. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst. Rev. 11, CD002203 (2012).","journal-title":"Cochrane Database Syst. Rev."},{"key":"BFsrep12016_CR34","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1111\/j.1476-5381.2011.01576.x","volume":"165","author":"M Vran\u010di\u0107","year":"2012","unstructured":"Vran\u010di\u0107, M. et al. Azithromycin distinctively modulates classical activation of human monocytes in vitro. Br. J. Pharmacol. 165, 1348\u20131360 (2012).","journal-title":"Br. J. Pharmacol."},{"key":"BFsrep12016_CR35","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1093\/jac\/dkf008","volume":"49","author":"T Kikuchi","year":"2002","unstructured":"Kikuchi, T. et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-\u03baB transcription factors. J. Antimicrob. Chemother. 49, 745\u2013755 (2002).","journal-title":"J. Antimicrob. Chemother."},{"key":"BFsrep12016_CR36","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/S0924-8579(98)00091-0","volume":"11","author":"A Khan","year":"1999","unstructured":"Khan, A., Slifer, T., Araujo, F. & Remington, J. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int. J. Antimicrob. Agents 11, 121\u2013132 (1999).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"BFsrep12016_CR37","doi-asserted-by":"publisher","first-page":"1736","DOI":"10.1128\/AAC.02011-12","volume":"57","author":"P Matzneller","year":"2013","unstructured":"Matzneller, P. et al. Blood, Tissue and Intracellular Concentrations of Azithromycin during and after End of Therapy. Antimicrob. Agents Chemother. 57, 1736\u20131742 (2013).","journal-title":"Antimicrob. Agents Chemother."},{"key":"BFsrep12016_CR38","doi-asserted-by":"publisher","first-page":"23","DOI":"10.2165\/0003088-200948010-00002","volume":"48","author":"M Zeitlinger","year":"2009","unstructured":"Zeitlinger, M., Wagner, C. C. & Heinisch, B. Ketolides--the modern relatives of macrolides : the pharmacokinetic perspective. Clin. Pharmacokinet. 48, 23\u201338 (2009).","journal-title":"Clin. Pharmacokinet."},{"key":"BFsrep12016_CR39","doi-asserted-by":"publisher","first-page":"S11","DOI":"10.1016\/S0924-8579(01)00410-1","volume":"18","author":"GW Amsden","year":"2001","unstructured":"Amsden, G. W. Advanced-generation macrolides: tissue-directed antibiotics. Int. J. Antimicrob. Agents 18 Suppl 1, S11\u201315 (2001).","journal-title":"Int. J. Antimicrob. Agents"},{"key":"BFsrep12016_CR40","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1124\/jpet.112.200733","volume":"345","author":"Y Kobayashi","year":"2013","unstructured":"Kobayashi, Y. et al. A Novel Macrolide Solithromycin Exerts Superior Anti-inflammatory Effect via NF-\u03baB Inhibition. J. Pharmacol. Exp. Ther. 345, 76\u201384 (2013).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"BFsrep12016_CR41","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1002\/eji.201343800","volume":"43","author":"E Vigan\u00f2","year":"2013","unstructured":"Vigan\u00f2, E. & Mortellaro, A. Caspase-11: the driving factor for noncanonical inflammasomes. Eur. J. Immunol. 43, 2240\u20132245 (2013).","journal-title":"Eur. J. Immunol."},{"key":"BFsrep12016_CR42","first-page":"335","volume":"193","author":"Y Kajiwara","year":"2014","unstructured":"Kajiwara, Y. et al. A critical role for human caspase-4 in endotoxin sensitivity. J. Immunol. Baltim. Md 1950 193, 335\u2013343 (2014).","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"BFsrep12016_CR43","doi-asserted-by":"publisher","first-page":"1992","DOI":"10.4049\/jimmunol.1101620","volume":"188","author":"G Sollberger","year":"2012","unstructured":"Sollberger, G., Strittmatter, G. E., Kistowska, M., French, L. E. & Beer, H.-D. Caspase-4 Is Required for Activation of Inflammasomes. J. Immunol. 188, 1992\u20132000 (2012).","journal-title":"J. Immunol."},{"key":"BFsrep12016_CR44","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.bbagen.2013.09.009","volume":"1840","author":"GA Gualdoni","year":"2014","unstructured":"Gualdoni, G. A. et al. Resveratrol enhances TNF-\u03b1 production in human monocytes upon bacterial stimulation. Biochim. Biophys. Acta 1840, 95\u2013105 (2014).","journal-title":"Biochim. Biophys. Acta"},{"key":"BFsrep12016_CR45","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1182\/blood-2006-05-022954","volume":"109","author":"A J\u00f6rgl","year":"2007","unstructured":"J\u00f6rgl, A. et al. Human Langerhans-cell activation triggered in vitro by conditionally expressed MKK6 is counterregulated by the downstream effector RelB. Blood 109, 185\u2013193 (2007).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep12016","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep12016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep12016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T13:49:21Z","timestamp":1672926561000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep12016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,8]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,18]]}},"alternative-id":["BFsrep12016"],"URL":"https:\/\/doi.org\/10.1038\/srep12016","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7,8]]},"assertion":[{"value":"2 March 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2015","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":"12016"}}