{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:09:24Z","timestamp":1791846564289,"version":"4.3.4"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T00:00:00Z","timestamp":1489708800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T00:00:00Z","timestamp":1489708800000},"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>Activation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. PPEF (bisbenzimidazole) targeting topoisomerase IA is observed to be an effective bactericidal agent against both Gram-positive and Gram-negative bacterial strains and thus can be developed as potent broad-spectrum antibiotic against MDR strains. PPEF treatment did not cause target specific mutation instead it leads to up-regulation of efflux gene in <jats:italic>E. coli<\/jats:italic> K12 as a mechanism of resistance. Microscopy, fluorescence spectroscopy and flow cytometry result demonstrate higher accumulation of PPEF in efflux gene deleted <jats:italic>E. coli<\/jats:italic> K12 mutants, and also suggest that Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP), resist the efflux of PPEF, and thus increases efficacy of PPEF. Herein, we report, PPEF and CCCP synergistically killed the persistent bacterial cells, which are not killed by PPEF alone. The above two compounds together inhibited biofilm formation, eradicate preformed biofilms and kills the biofilm cells of <jats:italic>P. aeruginosa<\/jats:italic>. PPEF and CCCP together reduced bacterial load of <jats:italic>E. coli<\/jats:italic> ATCC25922 by 6 log<jats:sub>10<\/jats:sub> in neutropenic thigh infection model of balb\/c mice. Present study suggests that combination therapy could be a promising antimicrobial strategy to handle MDR pathogenic strains.<\/jats:p>","DOI":"10.1038\/srep44419","type":"journal-article","created":{"date-parts":[[2017,3,17]],"date-time":"2017-03-17T10:12:14Z","timestamp":1489745534000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Synergistic efficacy of Bisbenzimidazole and Carbonyl Cyanide 3-Chlorophenylhydrazone combination against MDR bacterial strains"],"prefix":"10.1038","volume":"7","author":[{"given":"Devapriya","family":"Sinha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuti","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Tiwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirti","family":"Sad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vibha","family":"Tandon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,17]]},"reference":[{"key":"BFsrep44419_CR1","first-page":"476","volume":"12","author":"LB Rice","year":"2009","unstructured":"Rice, L. B. The clinical consequences of antimicrobial resistance. CurrOpin. Microbiol. 12, 476\u2013481 (2009).","journal-title":"CurrOpin. Microbiol"},{"key":"BFsrep44419_CR2","unstructured":"World Health Organization. Antimicrobial resistance: global report on surveillance. WHO, Geneva (2014)."},{"key":"BFsrep44419_CR3","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1126\/science.279.5353.996","volume":"279","author":"W Witte","year":"1998","unstructured":"Witte, W. Medical consequences of antibiotic use in agriculture. Science 279, 996\u2013997 (1998).","journal-title":"Science"},{"key":"BFsrep44419_CR4","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1126\/science.288.5467.792","volume":"288","author":"D Ferber","year":"2000","unstructured":"Ferber, D. Superbugs on the hoof? Science 288, 792\u2013794 (2000).","journal-title":"Science"},{"key":"BFsrep44419_CR5","first-page":"71","volume":"24","author":"LL Silver","year":"2011","unstructured":"Silver, L. L. Challenges of Antibacterial Discovery. ClinMicrobiol Rev. 24, 71\u2013109 (2011).","journal-title":"ClinMicrobiol Rev"},{"key":"BFsrep44419_CR6","first-page":"808","volume":"1794","author":"AH Delcour","year":"2009","unstructured":"Delcour, A. H. Outer membrane permeability and antibiotic resistance. BiochimBiophysActa. 1794, 808\u2013816 (2009).","journal-title":"BiochimBiophysActa"},{"key":"BFsrep44419_CR7","doi-asserted-by":"publisher","first-page":"702","DOI":"10.2174\/1389450116666151001103948","volume":"17","author":"Y Wang","year":"2016","unstructured":"Wang, Y., Venter. H. & Ma, S. Efflux Pump Inhibitors: A Novel Approach to Combat Efflux-Mediated Drug Resistance in Bacteria. Curr Drug Targets. 17, 702\u2013719 (2016).","journal-title":"Curr Drug Targets"},{"key":"BFsrep44419_CR8","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.bbrc.2014.05.090","volume":"17","author":"J Sun","year":"2014","unstructured":"Sun, J., Deng, Z. & Yan, A. Bacterial multidrug efflux pumps: Mechanisms, physiology and pharmacological exploitations. BiochemBiophys Res Commun. 17, 254\u2013267 (2014).","journal-title":"BiochemBiophys Res Commun"},{"key":"BFsrep44419_CR9","first-page":"801","volume":"64","author":"E Peeters","year":"2009","unstructured":"Peeters, E., Nelis, H. J. & Coenye, T. In vitro activity of ceftazidime, ciprofloxacin, meropenem, minocycline, tobramycin and trimethoprim\/sulfamethoxazole against planktonic and sessile Burkholderiacepacia complex bacteria. J AntimicrobChemother 64, 801\u2013809 (2009).","journal-title":"J AntimicrobChemother"},{"key":"BFsrep44419_CR10","first-page":"107","volume":"322","author":"K Lewis","year":"2008","unstructured":"Lewis, K. Multidrug tolerance of biofilms and persister cells. Curr Top MicrobiolImmunol 322, 107\u2013131 (2008).","journal-title":"Curr Top MicrobiolImmunol"},{"key":"BFsrep44419_CR11","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1128\/MMBR.00013-14","volume":"78","author":"D Lebeaux","year":"2014","unstructured":"Lebeaux, D., Ghigo, J. M. & Beloin, C. Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol. Mol. Biol. Rev. 78, 510\u2013543 (2014).","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"BFsrep44419_CR12","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.tim.2014.02.001","volume":"22","author":"H Van Acker","year":"2014","unstructured":"Van Acker, H., Van Dijck, P. & Coenye, T. Molecular mechanisms of antimicrobial tolerance and resistance in bacterial and fungal biofilms. Trends Microbiol. 22, 326\u2013333 (2014).","journal-title":"Trends Microbiol."},{"key":"BFsrep44419_CR13","doi-asserted-by":"publisher","first-page":"14918","DOI":"10.1073\/pnas.0800944105","volume":"105","author":"JB Michel","year":"2008","unstructured":"Michel, J. B. et al. Drug interactions modulate the potential for evolution of resistance. Proc Natl Acad Sci USA 105, 14918\u201314923 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep44419_CR14","doi-asserted-by":"publisher","first-page":"13977","DOI":"10.1073\/pnas.0805965105","volume":"105","author":"M Hegreness","year":"2008","unstructured":"Hegreness, M. et al. Accelerated evolution of resistance in multidrug environments. Proc Natl Acad Sci USA 105, 13977\u201313981 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep44419_CR15","doi-asserted-by":"publisher","first-page":"2882","DOI":"10.1093\/jac\/dks322","volume":"67","author":"S Bansal","year":"2012","unstructured":"Bansal, S. et al. 3,4-dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I. J Antimicrob Chemother. 67, 2882\u20132891 (2012).","journal-title":"J Antimicrob Chemother"},{"key":"BFsrep44419_CR16","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1093\/nar\/gkn936","volume":"37","author":"YC Tse-Dinh","year":"2009","unstructured":"Tse-Dinh, Y. C. Bacterial topoisomerase I as a target for discovery of antibacterial compounds. Nucleic Acids Res. 37, 731\u2013737 (2009).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep44419_CR17","doi-asserted-by":"publisher","first-page":"5238","DOI":"10.1021\/jm5003028","volume":"26","author":"H Nimesh","year":"2014","unstructured":"Nimesh, H. et al. Synthesis and biological evaluation of novel bisbenzimidazoles as Escherichia coli topoisomerase IA inhibitors and potential antibacterial agents. J Med Chem. 26, 5238\u20135257 (2014).","journal-title":"J Med Chem"},{"key":"BFsrep44419_CR18","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1086\/533452","volume":"197","author":"LB Rice","year":"2008","unstructured":"Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J Infect Dis. 197, 1079\u20131081 (2008).","journal-title":"J Infect Dis"},{"key":"BFsrep44419_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1086\/595011","volume":"48","author":"HW Boucher","year":"2009","unstructured":"Boucher, H. W. et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 48, 1\u201312 (2009).","journal-title":"Clin Infect Dis"},{"key":"BFsrep44419_CR20","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1586\/eri.13.12","volume":"11","author":"JN Pendleton","year":"2013","unstructured":"Pendleton, J. N., Gorman, S. P. & Gilmore, B. F. Clinical relevance of the ESKAPE pathogens. Expert Rev. Anti Infect. Ther. 11, 297\u2013308 (2013).","journal-title":"Expert Rev. Anti Infect. Ther"},{"key":"BFsrep44419_CR21","unstructured":"Clinical Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fourth Informational Supplement, M100\u2013S24 (2014)."},{"key":"BFsrep44419_CR22","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1111\/j.1574-6976.2011.00290.x","volume":"36","author":"H Nikaido","year":"2012","unstructured":"Nikaido, H. & Pag\u00e8s, J. M. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol Rev. 36, 340\u2013363 (2012).","journal-title":"FEMS Microbiol Rev"},{"key":"BFsrep44419_CR23","doi-asserted-by":"publisher","first-page":"2643","DOI":"10.1128\/AAC.06003-11","volume":"56","author":"M Balganesh","year":"2012","unstructured":"Balganesh, M., Dinesh, N., Sharma, S. et al. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates. Antimicrob Agents Chemother. 56, 2643\u201351 (2012).","journal-title":"Antimicrob Agents Chemother"},{"key":"BFsrep44419_CR24","first-page":"132","volume":"1344","author":"JW Park","year":"1997","unstructured":"Park, J. W., Lee, S. Y., Yang, J. Y. et al. Effect of carbonyl cyanide m-chlorophenylhydrazone (CCCP) on the dimerization of lipoprotein lipase. BiochimBiophysActa. 1344, 132\u20138 (1997).","journal-title":"BiochimBiophysActa"},{"key":"BFsrep44419_CR25","first-page":"1223","volume":"59","author":"A Mahamoud","year":"2007","unstructured":"Mahamoud, A., Chevalier, J., Alibert-Franco, S. et al. Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J AntimicrobChemother. 59, 1223\u20139 (2007).","journal-title":"J AntimicrobChemother"},{"key":"BFsrep44419_CR26","doi-asserted-by":"publisher","first-page":"157","DOI":"10.2174\/157489106777452692","volume":"1","author":"F Van Bambeke","year":"2006","unstructured":"Van Bambeke, F., Pag\u00e8s, J.-M. & Lee, V. J. Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent Pat Antiinfect Drug Discov. 1, 157\u201375 (2006).","journal-title":"Recent Pat Antiinfect Drug Discov"},{"key":"BFsrep44419_CR27","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1086\/338571","volume":"15","author":"X Zhao","year":"2002","unstructured":"Zhao, X. & Drlica, K. Restricting the selection of antibiotic-resistant mutant bacteria: measurement and potential use of the mutant selection window. J Infect Dis. 15, 561\u2013565 (2002).","journal-title":"J Infect Dis"},{"key":"BFsrep44419_CR28","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1056\/NEJMoa012122","volume":"7","author":"R Davidson","year":"2002","unstructured":"Davidson, R. et al. Resistance to levofloxacin and failure of treatment of Pneumococcal pneumonia. N Engl J Med. 7, 747\u2013750 (2002).","journal-title":"N Engl J Med"},{"key":"BFsrep44419_CR29","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1056\/NEJM199902183400704","volume":"18","author":"K Sieradzki","year":"1999","unstructured":"Sieradzki, K. et al. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl. J. Med. 18, 517\u2013523 (1999).","journal-title":"N Engl. J. Med."},{"key":"BFsrep44419_CR30","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/nrmicro.2016.34","volume":"15","author":"A Brauner","year":"2016","unstructured":"Brauner, A. et al. Distinguishing between resistance tolerance and persistence to antibiotic treatment. Nat Rev Microbiol. 15, 320\u2013330 (2016).","journal-title":"Nat Rev Microbiol"},{"key":"BFsrep44419_CR31","unstructured":"Clinical Laboratory Standards Institute (CLSI). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard. 9 ed. Wayne, PA, USA, CLSI (2012)."},{"key":"BFsrep44419_CR32","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1128\/AAC.19.6.1050","volume":"19","author":"LG Reimer","year":"1981","unstructured":"Reimer, L. G., Stratton, C. W. & Reller, L. B. Minimum inhibitory and bactericidal concentrations of 44 antimicrobial agents against three standard control strains in broth with and without human serum. Antimicrob Agents Chemother. 19, 1050\u22121055 (1981).","journal-title":"Antimicrob Agents Chemother"},{"key":"BFsrep44419_CR33","first-page":"e1002158","volume":"7","author":"E Gullberg","year":"2011","unstructured":"Gullberg, E. et al. Selection of resistant bacteria at very low antibiotic concentrations. PLoSPathog. 7, e1002158 (2011).","journal-title":"PLoSPathog"},{"key":"BFsrep44419_CR34","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/0022-2836(86)90129-4","volume":"5","author":"YC Tse-Dinh","year":"1986","unstructured":"Tse-Dinh, Y. C. & Wang, J. C. Complete nucleotide sequence of the topA gene encoding Escherichia coli DNA topoisomerase I. J. Mol. Biol. 5, 321\u2013331 (1986).","journal-title":"J. Mol. Biol."},{"key":"BFsrep44419_CR35","doi-asserted-by":"publisher","first-page":"e365","DOI":"10.1371\/journal.pone.0000365","volume":"11","author":"M Viveiros","year":"2007","unstructured":"Viveiros, M. et al. Antibiotic stress, genetic response and altered permeability of E. coli . PLoS One. 11, e365 (2007).","journal-title":"PLoS One."},{"key":"BFsrep44419_CR36","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1093\/jac\/dkq169","volume":"65","author":"NG Coldham","year":"2010","unstructured":"Coldham, N. G. et al. A 96-well plate fluorescence assay for assessment of cellular permeability and active efflux in Salmonella entericaserovar Typhimurium and Escherichia coli . J Antimicrob. Chemotherapy. 65, 1655\u20131663 (2010).","journal-title":"J Antimicrob. Chemotherapy"},{"key":"BFsrep44419_CR37","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.molcel.2012.04.027","volume":"46","author":"DJ Dwyer","year":"2012","unstructured":"Dwyer, D. J. et al. Antibiotic-Induced Bacterial Cell Death Exhibits Physiological and Biochemical Hallmarks of Apoptosis. Molecular Cell, 46, 561\u2013572 (2012).","journal-title":"Molecular Cell"},{"key":"BFsrep44419_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12866-015-0376-x","volume":"15","author":"P Stiefel","year":"2015","unstructured":"Stiefel, P. et al. Critical aspects of using bacterial cell viability assays with the fluorophores SYTO9 and propidium iodide. BMC Microbiol. 15, 1\u20139 (2015).","journal-title":"BMC Microbiol."},{"key":"BFsrep44419_CR39","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1128\/AAC.40.9.1973","volume":"40","author":"S Bajaksouzian","year":"1996","unstructured":"Bajaksouzian, S., Visalli, M. A., Jacobs, M. R. & Appelbaum, P. C. Antipneumococcal activities of cefpirome and cefotaxime, alone and in combination with vancomycin and teicoplanin, determined by checkerboard and time-kill methods. Antimicrob Agents Chemother. 40, 1973\u20131976 (1996).","journal-title":"Antimicrob Agents Chemother"},{"key":"BFsrep44419_CR40","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1128\/AAC.41.4.850","volume":"41","author":"N Chin","year":"1997","unstructured":"Chin, N., Weitzman, I. & Della-Latta, P. In vitro activity of fluvastatin, a cholesterol-lowering agent, and synergy with fluconazole and itraconazole against Candida species and Cryptococcus neoformans. Antimicrob Agents Chemother. 41, 850\u2013852 (1997).","journal-title":"Antimicrob Agents Chemother"},{"key":"BFsrep44419_CR41","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1128\/AAC.40.9.1973","volume":"40","author":"S Bajaksouzian","year":"1996","unstructured":"Bajaksouzian, S. et al. Antipneumococcal activities of cefpirome and cefotaxime, alone and in combination with vancomycin and teicoplanin, determined by checkerboard and time-kill methods. Antimicrob Agents Chemother. 40, 1973\u20131976 (1996).","journal-title":"Antimicrob Agents Chemother"},{"key":"BFsrep44419_CR42","unstructured":"National committee for Clinical Laboratory Standards (NCCLS). Methods for determining bactericidal activity of antimicrobial agents. Approved guideline M26-A. Clinical and Laboratory Standards Institute (CLSI), Wayne, PA. (1999)."},{"key":"BFsrep44419_CR43","doi-asserted-by":"publisher","first-page":"18877","DOI":"10.1038\/srep18877","volume":"5","author":"H Mu","year":"2016","unstructured":"Mu, H. et al. Potent Antibacterial Nanoparticles against Biofilm and Intracellular Bacteria. Sci Rep. 5, 18877 (2016).","journal-title":"Sci Rep"},{"key":"BFsrep44419_CR44","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1007\/s00018-013-1291-7","volume":"70","author":"V Luca","year":"2013","unstructured":"Luca, V., Stringaro, A., Colone, M., Pini, A. & Mangoni, M. L. Esculentin (1-21), an amphibian skin membrane-active peptide with potent activity on both planktonic and biofilm cells of the bacterial pathogen Pseudomonas aeruginosa. Cell. Mol. Life Sci. 70, 2773\u20132786 (2013).","journal-title":"Cell. Mol. Life Sci."},{"key":"BFsrep44419_CR45","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1038\/nprot.2006.339","volume":"1","author":"NA Franken","year":"2006","unstructured":"Franken, N. A., Rodermond, H. M., Stap, J., Haveman, J. & van Bree, C. Clonogenic assay of cells in vitro . Nat Protoc. 1, 2315\u20139 (2006).","journal-title":"Nat Protoc."},{"key":"BFsrep44419_CR46","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1093\/jac\/dks538","volume":"68","author":"U Zeidler","year":"2013","unstructured":"Zeidler, U. et al. Synergy of the antibiotic colistin with echinocandin antifungals in Candida species. J Antimicrob. Chemother. 68, 1285\u20131296 (2013).","journal-title":"J Antimicrob. Chemother."},{"key":"BFsrep44419_CR47","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.peptides.2011.01.016","volume":"32","author":"O Cirioni","year":"2011","unstructured":"Cirioni, O. et al. S-thanatin in vitro prevents colistin resistance and improves its efficacy in an animal model of Pseudomonas aeruginosa sepsis. Peptides 32, 697\u2013701 (2011).","journal-title":"Peptides"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep44419.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep44419","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep44419.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T23:48:59Z","timestamp":1671839339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep44419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,17]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,6,1]]}},"alternative-id":["BFsrep44419"],"URL":"https:\/\/doi.org\/10.1038\/srep44419","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,17]]},"assertion":[{"value":"10 October 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 February 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 March 2017","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":"44419"}}