{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T20:26:57Z","timestamp":1780345617686,"version":"3.54.1"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Oswaldo Cruz Foundation, Brazil"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Malaria remains a widespread public health problem in tropical and subtropical regions around the world, and there is still no vaccine available for full protection. In recent years, it has been observed that spores of\n                    <jats:italic>Bacillus subtillis<\/jats:italic>\n                    can act as a vaccine carrier and adjuvant, promoting an elevated humoral response after co-administration with antigens either coupled or integrated to their surface. In our study,\n                    <jats:italic>B. subtillis<\/jats:italic>\n                    spores from the KO7 strain were used to couple the recombinant CSP protein of\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    (r\n                    <jats:italic>Pf<\/jats:italic>\n                    CSP), and the nasal humoral-induced immune response in Balb\/C mice was evaluated. Our results demonstrate that the spores coupled to r\n                    <jats:italic>Pf<\/jats:italic>\n                    CSP increase the immunogenicity of the antigen, which induces high levels of serum IgG, and with balanced Th1\/Th2 immune response, being detected antibodies in serum samples for 250\u00a0days. Therefore, the use of\n                    <jats:italic>B. subtilis<\/jats:italic>\n                    spores appears to be promising for use as an adjuvant in a vaccine formulation.\n                  <\/jats:p>","DOI":"10.1038\/s41598-022-05344-2","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T06:03:15Z","timestamp":1643263395000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Bacillus subtilis spores as delivery system for nasal Plasmodium falciparum circumsporozoite surface protein immunization in a murine model"],"prefix":"10.1038","volume":"12","author":[{"given":"Maria Edilene M.","family":"de Almeida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e9ssia Caroline Souza","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Gabriella Santos","family":"de Vasconcelos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago Serr\u00e3o","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane Corr\u00eaa","family":"Gl\u00f3ria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yury Oliveira","family":"Chaves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter Luiz Lima","family":"Neves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Monteiro","family":"Tarrag\u00f4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falio Nino","family":"de Souza Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spartaco","family":"Astolfi-Filho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemilson Soares","family":"Pontes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f4nio Alcirley","family":"da Silva Balieiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachele","family":"Isticato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Ricca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Andr\u00e9 M.","family":"Mari\u00faba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"5344_CR1","unstructured":"World Health Organization (WHO). World Malaria Report 2020."},{"key":"5344_CR2","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1111\/j.1365-3024.2009.01140.x","volume":"31","author":"B Greenwood","year":"2009","unstructured":"Greenwood, B. & Targett, G. Do we still need a malaria vaccine?. Parasite Immunol. 31, 582\u2013586 (2009).","journal-title":"Parasite Immunol."},{"key":"5344_CR3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/imr.12802","volume":"293","author":"L Kurtovic","year":"2020","unstructured":"Kurtovic, L. et al. Complement in malaria immunity and vaccines. Immunol Rev. 293, 38\u201356 (2020).","journal-title":"Immunol Rev."},{"key":"5344_CR4","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1056\/NEJMoa0807381","volume":"24","author":"P Bejon","year":"2008","unstructured":"Bejon, P. et al. Efficacy of RTS\u2019S\/AS01E vaccine against malaria in children 5 to 17 months of age\u201d. N. Engl. J. Med. 24, 2521\u20132532 (2008).","journal-title":"N. Engl. J. Med."},{"key":"5344_CR5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001685","volume":"11","author":"RTS\u2019S Clinical Trials Partnership","year":"2014","unstructured":"RTS\u2019S Clinical Trials Partnership. Efficacy and safety of the RTS\u2019S\/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 11, e1001685 (2014).","journal-title":"PLoS Med."},{"key":"5344_CR6","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1016\/S0140-6736(21)00943-0","volume":"397","author":"MS Datoo","year":"2021","unstructured":"Datoo, M. S. et al. Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: A randomised controlled trial. Lancet 397, 1809\u20131818 (2021).","journal-title":"Lancet"},{"key":"5344_CR7","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.immuni.2020.08.014","volume":"53","author":"LT Wang","year":"2020","unstructured":"Wang, L. T. et al. A potent anti-malarial human monoclonal antibody targets circumsporozoite protein minor repeats and neutralizes sporozoites in the liver. Immunity 53, 733\u2013744 (2020).","journal-title":"Immunity"},{"key":"5344_CR8","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/1475-2859-12-98","volume":"29","author":"R Isticato","year":"2013","unstructured":"Isticato, R. et al. Non-recombinant display of the B subunit of the heat labile toxin of Escherichia coli on wild type and mutant spores of Bacillus subtilis. Microb. Cell Fact. 29, 98 (2013).","journal-title":"Microb. Cell Fact."},{"key":"5344_CR9","first-page":"9","volume":"12","author":"EM Mauriello","year":"2004","unstructured":"Mauriello, E. M. et al. Display of heterologous antigens on the Bacillus subtilis spore coat using CotC as a fusion partner. Vaccine 12, 9\u201310 (2004).","journal-title":"Vaccine"},{"key":"5344_CR10","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1099\/jmm.0.076430-0","volume":"64","author":"Z Zhou","year":"2015","unstructured":"Zhou, Z. et al. Expression of Helicobacter pylori urease B on the surface of Bacillus subtilis spores. J. Med. Microbiol. 64, 104\u2013110 (2015).","journal-title":"J. Med. Microbiol."},{"key":"5344_CR11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087454","volume":"9","author":"RD De Souza","year":"2014","unstructured":"De Souza, R. D. et al. Bacillus subtilis spores as vaccine adjuvants: further insights into the mechanisms of action. PLoS ONE 9, e87454 (2014).","journal-title":"PLoS ONE"},{"key":"5344_CR12","doi-asserted-by":"publisher","first-page":"346","DOI":"10.3389\/fimmu.2018.00346","volume":"9","author":"A Copland","year":"2018","unstructured":"Copland, A. et al. Mucosal delivery of fusion proteins with Bacillus subtilis spores enhances protection against tuberculosis by Bacillus Calmette-Gu\u00e9rin. Front. Immunol. 9, 346 (2018).","journal-title":"Front. Immunol."},{"key":"5344_CR13","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s12934-020-01308-1","volume":"19","author":"F Santos","year":"2020","unstructured":"Santos, F. et al. A probiotic treatment increases the immune response induced by the nasal delivery of spore-adsorbed TTFC. Microb. Cell Fact. 19, 42 (2020).","journal-title":"Microb. Cell Fact."},{"key":"5344_CR14","doi-asserted-by":"publisher","first-page":"3266","DOI":"10.1016\/j.vaccine.2012.03.016","volume":"9","author":"M Song","year":"2012","unstructured":"Song, M. et al. Killed Bacillus subtilis spores as a mucosal adjuvant for an H5N1 vaccine. Vaccine 9, 3266\u20133277 (2012).","journal-title":"Vaccine"},{"key":"5344_CR15","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s12964-020-0514-4","volume":"18","author":"S Zhang","year":"2020","unstructured":"Zhang, S., Mou, C., Cao, Y., Zhang, E. & Yang, Q. Immune response in piglets orally immunized with recombinant Bacillus subtilis expressing the capsid protein of porcine circovirus type 2. Cell Commun. Signal. 18, 23 (2020).","journal-title":"Cell Commun. Signal."},{"key":"5344_CR16","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1002\/eji.200636875","volume":"37","author":"AG Barnes","year":"2007","unstructured":"Barnes, A. G., Cerovic, V., Hobson, P. S. & Klavinskis, L. S. Bacillus subtilis spores: A novel microparticle adjuvant which can instruct a balanced Th1 and Th2 immune response to specific antigen. Eur. J. Immunol. 37, 1538\u20131547 (2007).","journal-title":"Eur. J. Immunol."},{"key":"5344_CR17","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1016\/j.vaccine.2009.10.127","volume":"28","author":"JM Huang","year":"2010","unstructured":"Huang, J. M. et al. Mucosal delivery of antigens using adsorption to bacterial spores. Vaccine 28, 1021\u20131030 (2010).","journal-title":"Vaccine"},{"key":"5344_CR18","first-page":"10","volume":"39","author":"Y Wang","year":"2019","unstructured":"Wang, Y. et al. Mucosal and systemic immune responses induced by intranasal immunization of recombinant Bacillus subtilis expressing the P97R1, P46 antigens of Mycoplasma hyopneumoniae. Biosci. Rep. 39, 10 (2019).","journal-title":"Biosci. Rep."},{"key":"5344_CR19","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1056\/NEJM199701093360202","volume":"336","author":"JA Stoute","year":"1997","unstructured":"Stoute, J. A. et al. A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS\u2019S Malaria Vaccine Evaluation Group. N. Engl. J. Med. 336, 86\u201391 (1997).","journal-title":"N. Engl. J. Med."},{"key":"5344_CR20","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1186\/1471-2334-14-49","volume":"14","author":"L Sousa","year":"2014","unstructured":"Sousa, L. et al. A novel polyclonal antibody-based sandwich ELISA for detection of Plasmodium vivax developed from two lactate dehydrogenase protein segments. BMC Infect. Dis. 14, 49 (2014).","journal-title":"BMC Infect. Dis."},{"key":"5344_CR21","unstructured":"Sambrook, J., Fritsch, E. R. & Maniatis, T. Molecular Cloning: A Laboratory Manual (2nd ed.). Cold Spring Harbor, (NY: Cold Spring Harbor Laboratory Press 1989)."},{"key":"5344_CR22","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1111\/jam.12744","volume":"118","author":"SK Falahati-Pour","year":"2015","unstructured":"Falahati-Pour, S. K., Lotfi, A. S., Ahmadian, G. & Baghizadeh, A. Covalent immobilization of recombinant organophosphorus hydrolase on spores of Bacillus subtilis. J Appl Microbiol. 118, 976\u2013988 (2015).","journal-title":"J Appl Microbiol."},{"key":"5344_CR23","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1126\/science.2414847","volume":"230","author":"DE Arnot","year":"1985","unstructured":"Arnot, D. E. et al. Circumsporozoite protein of Plasmodium vivax: Gene cloning and characterization of the immunodominant epitope. Science 230, 815\u2013818 (1985).","journal-title":"Science"},{"issue":"10","key":"5344_CR24","doi-asserted-by":"publisher","first-page":"397","DOI":"10.3389\/fimmu.2019.00397","volume":"21","author":"J Heide","year":"2019","unstructured":"Heide, J., Vaughan, K. C., Sette, A., Jacobs, T. & Schulze Zur Wiesch, J. Comprehensive review of human Plasmodium falciparum\u2014Specific CD8+ T cell epitopes. Front Immunol. 21(10), 397 (2019).","journal-title":"Front Immunol."},{"key":"5344_CR25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0107764","volume":"23","author":"AR Noe","year":"2014","unstructured":"Noe, A. R. et al. A full-length Plasmodium falciparum recombinant circumsporozoite protein expressed by Pseudomonas fluorescens platform as a malaria vaccine candidate. PLoS ONE 23, e107764 (2014).","journal-title":"PLoS ONE"},{"key":"5344_CR26","doi-asserted-by":"publisher","first-page":"26951","DOI":"10.1074\/jbc.M109.013706","volume":"284","author":"ML Plassmeyer","year":"2009","unstructured":"Plassmeyer, M. L. et al. Structure of the Plasmodium falciparum circumsporozoite protein, a leading malaria vaccine candidate. J. Biol. Chem. 284, 26951\u201326963 (2009).","journal-title":"J. Biol. Chem."},{"key":"5344_CR27","doi-asserted-by":"publisher","first-page":"E10438","DOI":"10.1073\/pnas.1715812114","volume":"114","author":"D Oyen","year":"2017","unstructured":"Oyen, D. et al. Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein. Proc. Natl. Acad. Sci. USA 114, E10438\u2013E10445 (2017).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"5344_CR28","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.1128\/CVI.00135-10","volume":"17","author":"S Lee","year":"2010","unstructured":"Lee, S. et al. Development of a Bacillus subtilis-based rotavirus vaccine. Clin. Vaccine Immunol. 17, 1647\u20131655 (2010).","journal-title":"Clin. Vaccine Immunol."},{"key":"5344_CR29","doi-asserted-by":"publisher","first-page":"S18","DOI":"10.1016\/j.tube.2016.09.016","volume":"101S","author":"K Das","year":"2016","unstructured":"Das, K., Thomas, T., Garnica, O. & Dhandayuthapani, S. Recombinant Bacillus subtilis spores for the delivery of Mycobacterium tuberculosis Ag85B-CFP10 secretory antigens. Tuberculosis (Edinb). 101S, S18\u2013S27 (2016).","journal-title":"Tuberculosis (Edinb)."},{"key":"5344_CR30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191627","volume":"13","author":"X Dai","year":"2018","unstructured":"Dai, X., Liu, M., Pan, K. & Yang, J. Surface display of OmpC of Salmonella serovar Pullorum on Bacillus subtilis spores. PLoS ONE 13, e0191627 (2018).","journal-title":"PLoS ONE"},{"key":"5344_CR31","doi-asserted-by":"publisher","first-page":"38403","DOI":"10.1038\/srep38403","volume":"6","author":"C Mou","year":"2016","unstructured":"Mou, C. et al. Immune responses induced by recombinant Bacillus subtilis expressing the hemagglutinin protein of H5N1 in chickens. Sci. Rep. 6, 38403 (2016).","journal-title":"Sci. Rep."},{"key":"5344_CR32","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41541-020-00274-4","volume":"6","author":"L Jel\u00ednkov\u00e1","year":"2021","unstructured":"Jel\u00ednkov\u00e1, L. et al. An epitope-based malaria vaccine targeting the junctional region of circumsporozoite protein. NPJ Vaccines 6, 13 (2021).","journal-title":"NPJ Vaccines"},{"key":"5344_CR33","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1038\/s41565-018-0271-3","volume":"12","author":"WC Huang","year":"2018","unstructured":"Huang, W. C. et al. A malaria vaccine adjuvant based on recombinant antigen binding to liposomes. Nat. Nanotechnol. 12, 1174\u20131181 (2018).","journal-title":"Nat. Nanotechnol."},{"key":"5344_CR34","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1146\/annurev.iy.07.040189.002203","volume":"7","author":"H Waldmann","year":"1989","unstructured":"Waldmann, H. Manipulation of T-cell responses with monoclonal antibodies. Annu. Rev. Immunol. 7, 407\u2013444. https:\/\/doi.org\/10.1146\/annurev.iy.07.040189.002203 (1989).","journal-title":"Annu. Rev. Immunol."},{"key":"5344_CR35","doi-asserted-by":"publisher","first-page":"3547","DOI":"10.1128\/iai.59.10.3547-3554","volume":"59","author":"WI White","year":"1991","unstructured":"White, W. I., Evans, C. B. & Taylor, D. W. Antimalarial antibodies of the immunoglobulin G2a isotype modulate parasitemias in mice infected with Plasmodium yoelii. Infect. Immun. 59, 3547\u20133554. https:\/\/doi.org\/10.1128\/iai.59.10.3547-3554 (1991).","journal-title":"Infect. Immun."},{"key":"5344_CR36","doi-asserted-by":"publisher","first-page":"979","DOI":"10.4161\/hv.20694","volume":"8","author":"H Amuguni","year":"2012","unstructured":"Amuguni, H. & Tzipori, S. Bacillus subtilis: A temperature resistant and needle free delivery system of immunogens. Hum. Vaccin. Immunother. 8, 979\u2013986 (2012).","journal-title":"Hum. Vaccin. Immunother."},{"key":"5344_CR37","doi-asserted-by":"publisher","first-page":"4778","DOI":"10.1016\/j.vaccine.2011.04.083","volume":"29","author":"JH Amuguni","year":"2011","unstructured":"Amuguni, J. H. et al. Sublingually administered Bacillus subtilis cells expressing tetanus toxin C fragment induce protective systemic and mucosal antibodies against tetanus toxin in mice. Vaccine 29, 4778\u20134784 (2011).","journal-title":"Vaccine"},{"key":"5344_CR38","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1086\/526787","volume":"197","author":"CC John","year":"2008","unstructured":"John, C. C. et al. Antibodies to pre-erythrocytic Plasmodium falciparum antigens and risk of clinical malaria in Kenyan children. J. Infect. Dis. 197, 519\u2013526 (2008).","journal-title":"J. Infect. Dis."},{"key":"5344_CR39","doi-asserted-by":"publisher","first-page":"671","DOI":"10.3389\/fimmu.2014.00671","volume":"5","author":"D Perez-Mazliah","year":"2015","unstructured":"Perez-Mazliah, D. & Langhorne, J. CD4 T-cell subsets in malaria: TH1\/TH2 revisited. Front. Immunol. 5, 671 (2015).","journal-title":"Front. Immunol."},{"key":"5344_CR40","doi-asserted-by":"publisher","first-page":"439","DOI":"10.3389\/fimmu.2019.00439","volume":"10","author":"C Doba\u00f1o","year":"2019","unstructured":"Doba\u00f1o, C. et al. Differential patterns of IgG subclass responses to Plasmodium falciparum antigens in relation to malaria protection and RTS,S vaccination. Front. Immunol. 10, 439 (2019).","journal-title":"Front. Immunol."},{"key":"5344_CR41","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1007\/s00430-019-00606-9","volume":"208","author":"SH Shabani","year":"2019","unstructured":"Shabani, S. H., Zakeri, S., Mortazavi, Y. & Mehrizi, A. A. Immunological evaluation of two novel engineered Plasmodium vivax circumsporozoite proteins formulated with different human-compatible vaccine adjuvants in C57BL\/6 mice. Med. Microbiol. Immunol. 208, 731\u2013745. https:\/\/doi.org\/10.1007\/s00430-019-00606-9 (2019).","journal-title":"Med. Microbiol. Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-05344-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-05344-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-05344-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T16:41:40Z","timestamp":1669308100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-05344-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["5344"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-05344-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-777937\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]},"assertion":[{"value":"3 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1531"}}