{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:40:48Z","timestamp":1790253648814,"version":"4.1.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,1,15]],"date-time":"2018-01-15T00:00:00Z","timestamp":1515974400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,1,15]],"date-time":"2018-01-15T00:00:00Z","timestamp":1515974400000},"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>The HIV-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands. We propose an exhaustive study of the local structural asymmetry between the two monomers of all available PR2 structures complexed with various inhibitors using a structural alphabet approach. On average, PR2 exhibits asymmetry in 31% of its positions\u2014i.e., exhibiting different backbone\u00a0local conformations in the two monomers. This asymmetry was observed all along its structure, particularly in the elbow and flap regions. We first differentiated structural asymmetry conserved in most PR2 structures from the one specific to some PR2. Then, we explored the origin of the detected asymmetry in PR2. We localized asymmetry that could be induced by PR2\u2019s flexibility, allowing transition from the semi-open to closed conformations and the asymmetry potentially induced by ligand binding. This latter could be important for the PR2\u2019s adaptation to diverse ligands. Our results highlighted some differences between asymmetry of PR2 bound to darunavir and amprenavir that could explain their differences of affinity. This knowledge is critical for a better description of PR2\u2019s recognition and adaptation to various ligands and for a better understanding of the resistance of PR2 to most PR2 inhibitors, a major antiretroviral class.<\/jats:p>","DOI":"10.1038\/s41598-017-18941-3","type":"journal-article","created":{"date-parts":[[2018,1,9]],"date-time":"2018-01-09T10:03:20Z","timestamp":1515492200000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Analysis of the HIV-2 protease\u2019s adaptation to various ligands: characterization of backbone asymmetry using a structural alphabet"],"prefix":"10.1038","volume":"8","author":[{"given":"Dhoha","family":"Triki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario Enrique","family":"Cano Contreras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Flatters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9279-5538","authenticated-orcid":false,"given":"Benoit","family":"Visseaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Descamps","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Claude","family":"Camproux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Regad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,1,15]]},"reference":[{"key":"18941_CR1","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.meegid.2016.08.010","volume":"46","author":"B Visseaux","year":"2016","unstructured":"Visseaux, B., Damond, F., Matheron, S., Descamps, D. & Charpentier, C. Hiv-2 molecular epidemiology. Infect. Genet. Evol. 46, 233\u2013240 (2016).","journal-title":"Infect. Genet. Evol."},{"key":"18941_CR2","doi-asserted-by":"publisher","first-page":"1062","DOI":"10.1128\/JVI.01772-15","volume":"90","author":"DN Raugi","year":"2016","unstructured":"Raugi, D. N., Smith, R. A. & Gottlieb, G. S. University of Washington-Dakar HIV-2 Study Group. Four Amino Acid Changes in HIV-2 Protease Confer Class-Wide Sensitivity to Protease Inhibitors. J. Virol. 90, 1062\u20131069 (2016).","journal-title":"J. Virol."},{"key":"18941_CR3","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1128\/AAC.01284-07","volume":"52","author":"D Desbois","year":"2008","unstructured":"Desbois, D. et al. In vitro phenotypic susceptibility of human immunodeficiency virus type 2 clinical isolates to protease inhibitors. Antimicrob. Agents Chemother. 52, 1545\u20131548 (2008).","journal-title":"Antimicrob. Agents Chemother."},{"key":"18941_CR4","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.1128\/AAC.00146-07","volume":"51","author":"S Masse","year":"2007","unstructured":"Masse, S. et al. In vitro selection and characterization of human immunodeficiency virus type 2 with decreased susceptibility to lopinavir. Antimicrob. Agents Chemother. 51, 3075\u20133080 (2007).","journal-title":"Antimicrob. Agents Chemother."},{"key":"18941_CR5","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1097\/QAD.0b013e32832949f0","volume":"23","author":"A B\u00e9nard","year":"2009","unstructured":"B\u00e9nard, A. et al. Good response to lopinavir\/ritonavir-containing antiretroviral regimens in antiretroviral-naive HIV-2-infected patients. AIDS 23, 1171\u20131179 (2009).","journal-title":"AIDS"},{"key":"18941_CR6","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1093\/jac\/dkl034","volume":"57","author":"B Rod\u00e9s","year":"2006","unstructured":"Rod\u00e9s, B. et al. Susceptibility to protease inhibitors in HIV-2 primary isolates from patients failing antiretroviral therapy. J. Antimicrob. Chemother. 57, 709\u2013713 (2006).","journal-title":"J. Antimicrob. Chemother."},{"key":"18941_CR7","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1111\/j.1747-0285.2008.00647.x","volume":"71","author":"ET Brower","year":"2008","unstructured":"Brower, E. T., Bacha, U. M., Kawasaki, Y. & Freire, E. Inhibition of HIV-2 protease by HIV-1 protease inhibitors in clinical use. Chem. Biol. Drug Des. 71, 298\u2013305 (2008).","journal-title":"Chem. Biol. Drug Des."},{"key":"18941_CR8","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1128\/AAC.01109-08","volume":"53","author":"ML Ntemgwa","year":"2009","unstructured":"Ntemgwa, M. L. et al. Nucleoside and nucleotide analogs select in culture for different patterns of drug resistance in human immunodeficiency virus types 1 and 2. Antimicrob Agents Chemother. 53, 708\u2013715 (2009).","journal-title":"Antimicrob Agents Chemother."},{"key":"18941_CR9","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1006\/jmbi.2000.4018","volume":"301","author":"M Prabu-Jeyabalan","year":"2000","unstructured":"Prabu-Jeyabalan, M., Nalivaika, E. & Schiffer, C. A. How does a symmetric dimer recognize an asymmetric substrate? A substrate complex of HIV-1 protease. J. Mol. Biol. 301, 1207\u20131220 (2000).","journal-title":"J. Mol. Biol."},{"key":"18941_CR10","first-page":"1306","volume":"77","author":"M Prabu-jeyabalan","year":"2003","unstructured":"Prabu-jeyabalan, M. et al. Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy. Society 77, 1306\u20131315 (2003).","journal-title":"Society"},{"key":"18941_CR11","doi-asserted-by":"crossref","first-page":"13103","DOI":"10.1016\/S0021-9258(19)38625-9","volume":"268","author":"AM Mulichak","year":"1993","unstructured":"Mulichak, A. M. et al. The crystallographic structure of the protease from human immunodeficiency virus type 2 with two synthetic peptidic transition state analog inhibitors. J. Biol. Chem. 268, 13103\u201313109 (1993).","journal-title":"J. Biol. Chem."},{"key":"18941_CR12","doi-asserted-by":"publisher","first-page":"8387","DOI":"10.1073\/pnas.90.18.8387","volume":"90","author":"L Tong","year":"1993","unstructured":"Tong, L. et al. Crystal structure of human immunodeficiency virus (HIV) type 2 protease in complex with a reduced amide inhibitor and comparison with HIV-1 protease structures. Proc. Natl. Acad. Sci. USA 90, 8387\u20138391 (1993).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"18941_CR13","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/S0969-2126(01)00133-2","volume":"3","author":"L Tong","year":"1995","unstructured":"Tong, L. et al. Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere. Structure 3, 33\u201340 (1995).","journal-title":"Structure"},{"key":"18941_CR14","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/S0969-2126(01)00169-1","volume":"3","author":"JP Priestle","year":"1995","unstructured":"Priestle, J. P. et al. Comparative analysis of the X-ray structures of HIV-1 and HIV-2 proteases in complex with CGP 53820, a novel pseudosymmetric inhibitor. Structure 3, 381\u2013389 (1995).","journal-title":"Structure"},{"key":"18941_CR15","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.jmb.2004.04.005","volume":"339","author":"A-C Camproux","year":"2004","unstructured":"Camproux, A.-C., Gautier, R. & Tuff\u00e9ry, P. A hidden Markov model derived structural alphabet for proteins. J. Mol. Biol. 339, 591\u2013605 (2004).","journal-title":"J. Mol. Biol."},{"key":"18941_CR16","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6807-8-12","volume":"8","author":"J Martin","year":"2008","unstructured":"Martin, J., Regad, L., Lecornet, H. & Camproux, A.-C. Structural deformation upon protein-protein interaction: a structural alphabet approach. BMC Struct. Biol. 8, 12 (2008).","journal-title":"BMC Struct. Biol."},{"key":"18941_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-247","volume":"12","author":"L Regad","year":"2011","unstructured":"Regad, L., Martin, J. & Camproux, A.-C. Dissecting protein loops with a statistical scalpel suggests a functional implication of some structural motifs. BMC Bioinformatics 12, 247 (2011).","journal-title":"BMC Bioinformatics"},{"key":"18941_CR18","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","volume":"28","author":"HM Berman","year":"2000","unstructured":"Berman, H. M. et al. The Protein Data Bank. Nucleic Acids Res. 28, 235\u2013242 (2000).","journal-title":"Nucleic Acids Res."},{"key":"18941_CR19","doi-asserted-by":"publisher","first-page":"3198","DOI":"10.1016\/j.csda.2007.09.010","volume":"52","author":"L Regad","year":"2008","unstructured":"Regad, L., Guyon, F., Maupetit, J., Tuff\u00e9ry, P. & Camproux, A.-C. A Hidden Markov Model applied to the protein 3D structure analysis. Comput. Stat. Data Anal. 52, 3198\u20133207 (2008).","journal-title":"Comput. Stat. Data Anal."},{"key":"18941_CR20","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-75","volume":"11","author":"L Regad","year":"2010","unstructured":"Regad, L., Martin, J., Nuel, G. & Camproux, A.-C. Mining protein loops using a structural alphabet and statistical exceptionality. BMC Bioinformatics 11, 75 (2010).","journal-title":"BMC Bioinformatics"},{"key":"18941_CR21","doi-asserted-by":"publisher","first-page":"e63730","DOI":"10.1371\/journal.pone.0063730","volume":"8","author":"S P\u00e9rot","year":"2013","unstructured":"P\u00e9rot, S. et al. Insights into an original pocket-ligand pair classification: A promising tool for ligand profile prediction. PLoS One 8, e63730, https:\/\/doi.org\/10.1371\/journal.pone.0063730 (2013).","journal-title":"PLoS One"},{"key":"18941_CR22","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1758-2946-3-33","volume":"3","author":"NM O\u2019Boyle","year":"2011","unstructured":"O\u2019Boyle, N. M. et al. Open Babel: An Open chemical toolbox. J. Cheminform. 3, 33 (2011).","journal-title":"J. Cheminform."},{"key":"18941_CR23","unstructured":"R Development Core Team, in R: A language and environment for statistical computing, Vienna, Austria,, http:\/\/ www.R-project.org\/ (2013)."},{"key":"18941_CR24","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1002\/prot.22806","volume":"78","author":"SK Sadiq","year":"2010","unstructured":"Sadiq, S. K. & de Fabritiis, G. Explicit solvent dynamics and energetics of HIV-1 protease flap opening and closing. Proteins Struct. Funct. Bioinforma. 78, 2873\u20132885 (2010).","journal-title":"Proteins Struct. Funct. Bioinforma."},{"key":"18941_CR25","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1093\/nar\/gkt940","volume":"42","author":"TAP De Beer","year":"2014","unstructured":"De Beer, T. A. P., Berka, K., Thornton, J. M. & Laskowski, R. A. PDBsum additions. Nucleic Acids Res. 42, 292\u2013296 (2014).","journal-title":"Nucleic Acids Res."},{"key":"18941_CR26","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1021\/ci5006004","volume":"55","author":"A Borrel","year":"2015","unstructured":"Borrel, A., Regad, L., Xhaard, H., Petitjean, M. & Camproux, A.-C. PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties. J. Chem. Inf. Model. 55, 882\u2013895 (2015).","journal-title":"J. Chem. Inf. Model."},{"key":"18941_CR27","doi-asserted-by":"publisher","unstructured":"Caumes, G., Borrel, A., AbiHussein, H., Camproux, A.-C. & Regad, L. Investigating the Importance of the Pocket-estimation Method in Pocket-based Approaches: An Illustration Using Pocket-ligand Classification. Mol. Inform. 36, https:\/\/doi.org\/10.1002\/minf.201700025 (2017).","DOI":"10.1002\/minf.201700025"},{"key":"18941_CR28","doi-asserted-by":"publisher","unstructured":"Cerisier, N., Regad, L., Triki, D., Camproux, A.-C. & Petitjean, M. Cavity Versus Ligand Shape Descriptors: Application to Urokinase Binding Pockets. J. Comput. Biol. 36, https:\/\/doi.org\/10.1002\/minf.201700040 (2017).","DOI":"10.1002\/minf.201700040"},{"key":"18941_CR29","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1007\/BF01195768","volume":"72","author":"PA Karplus","year":"1985","unstructured":"Karplus, P. A. & Schulz, G. E. Prediction of chain flexibility in proteins. Naturwissenschaften 72, 212\u2013213 (1985).","journal-title":"Naturwissenschaften"},{"key":"18941_CR30","doi-asserted-by":"publisher","first-page":"2561","DOI":"10.1002\/pro.5560061208","volume":"6","author":"S Parthasarathy","year":"1997","unstructured":"Parthasarathy, S. & Murthy, M. R. Analysis of temperature factor distribution in high-resolution protein structures. Protein Sci. 6, 2561\u20132567 (1997).","journal-title":"Protein Sci."},{"key":"18941_CR31","doi-asserted-by":"publisher","first-page":"11887","DOI":"10.1021\/bi990468i","volume":"38","author":"B Xiao","year":"1999","unstructured":"Xiao, B. et al. Crystal structure of a murine glutathione S-transferase in complex with a glutathione conjugate of 4-hydroxynon, 2-enal in one subunit and glutathione in the other: Evidence of signaling across the dimer interface. Biochemistry 38, 11887\u201311894 (1999).","journal-title":"Biochemistry"},{"key":"18941_CR32","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/S0022-2836(02)00558-2","volume":"320","author":"H Cha","year":"2002","unstructured":"Cha, H., Kopetzki, E., Huber, R., Lanzend\u00f6rfer, M. & Brandstetter, H. Structural basis of the adaptive molecular recognition by MMP9. J. Mol. Biol. 320, 1065\u20131079 (2002).","journal-title":"J. Mol. Biol."},{"key":"18941_CR33","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/(SICI)1097-0134(19991201)37:4<729::AID-PROT21>3.0.CO;2-F","volume":"37","author":"L Jin","year":"1999","unstructured":"Jin, L., Stec, B., Lipscomb, W. N. & Kantrowitz, E. R. Insights into the mechanisms of catalysis and heterotropic regulation of Escherichia coli aspartate transcarbamoylase based upon a structure of the enzyme complexed with the bisubstrate analogue N-phosphonacetyl-L-aspartate at 2.1 \u00c5. Proteins Struct. Funct. Genet. 37, 729\u2013742 (1999).","journal-title":"Proteins Struct. Funct. Genet."},{"key":"18941_CR34","doi-asserted-by":"publisher","first-page":"14250","DOI":"10.1073\/pnas.231465798","volume":"98","author":"M Renatus","year":"2001","unstructured":"Renatus, M., Stennicke, H. R., Scott, F. L., Liddington, R. C. & Salvesen, G. S. Dimer formation drives the activation of the cell death protease caspase 9. Proc. Natl. Acad. Sci. USA 98, 14250\u201314255 (2001).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"18941_CR35","doi-asserted-by":"publisher","first-page":"3048","DOI":"10.1002\/prot.22828","volume":"78","author":"D Pednekar","year":"2010","unstructured":"Pednekar, D. & Durani, S. Protein homomers in point-group assembly: Symmetry making and breaking are specific and distinctive in their codes of chemical alphabet in side chains. Proteins Struct. Funct. Bioinforma. 78, 3048\u20133055 (2010).","journal-title":"Proteins Struct. Funct. Bioinforma."},{"key":"18941_CR36","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/4940","volume":"6","author":"DA King","year":"1999","unstructured":"King, D. A., Zhang, L., Guarente, L. & Marmorstein, R. Structure of a HAP1-DNA complex reveals dramatically asymmetric DNA binding by a homodimeric protein. Nat. Struct. Biol. 6, 64\u201371 (1999).","journal-title":"Nat. Struct. Biol."},{"key":"18941_CR37","doi-asserted-by":"publisher","first-page":"e36688","DOI":"10.1371\/journal.pone.0036688","volume":"7","author":"LS Swapna","year":"2012","unstructured":"Swapna, L. S., Srikeerthana, K. & Srinivasan, N. Extent of structural asymmetry in homodimeric proteins: Prevalence and relevance. PLoS One 7, e36688, https:\/\/doi.org\/10.1371\/journal.pone.0036688 (2012).","journal-title":"PLoS One"},{"key":"18941_CR38","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1021\/jp211768n","volume":"116","author":"P Kar","year":"2012","unstructured":"Kar, P. & Knecht, V. J. Origin of decrease in potency of darunavir and two related antiviral inhibitors against HIV-2 compared to HIV-1 protease. Phys Chem B. 116, 2605\u20132614, https:\/\/doi.org\/10.1021\/jp211768n (2012).","journal-title":"Phys Chem B."},{"key":"18941_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/srep06872","volume":"4","author":"J Chen","year":"2014","unstructured":"Chen, J. et al. Revealing origin of decrease in potency of darunavir and amprenavir against HIV-2 relative to HIV-1 protease by molecular dynamics simulations. Sci Rep. 4, 6872, https:\/\/doi.org\/10.1038\/srep06872 (2014).","journal-title":"Sci Rep."},{"key":"18941_CR40","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1146\/annurev.biophys.29.1.105","volume":"29","author":"DS Goodsell","year":"2000","unstructured":"Goodsell, D. S. & Olson, A. J. Structural symmetry and protein function. Annu. Rev. Biophys. Biomol. Struct. 29, 105 (2000).","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"18941_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1110\/ps.051658406","volume":"15","author":"JH Brown","year":"2006","unstructured":"Brown, J. H. Breaking symmetry in protein dimers: designs and functions. Protein Sci. 15, 1\u201313 (2006).","journal-title":"Protein Sci."},{"key":"18941_CR42","doi-asserted-by":"crossref","unstructured":"Tie, Y. et al. Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors. 21, 339\u2013350 (2012).","DOI":"10.1002\/pro.2019"},{"key":"18941_CR43","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jmb.2008.09.031","volume":"384","author":"AY Kovalevsky","year":"2008","unstructured":"Kovalevsky, A. Y., Louis, J. M., Aniana, A., Ghosh, A. K. & Weber, I. T. Structural evidence for effectiveness of darunavir and two related antiviral inhibitors against HIV-2 protease. J Mol Biol. 384, 178\u2013192 (2008).","journal-title":"J Mol Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18941-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18941-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18941-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:58:53Z","timestamp":1671584333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18941-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,15]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["18941"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-18941-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,15]]},"assertion":[{"value":"19 July 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"710"}}