{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T01:46:06Z","timestamp":1778809566503,"version":"3.51.4"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,12,2]],"date-time":"2016-12-02T00:00:00Z","timestamp":1480636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,12,2]],"date-time":"2016-12-02T00:00:00Z","timestamp":1480636800000},"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>A severe bottleneck exists during HIV-1 mucosal transmission. However, viral properties that determine HIV-1 transmissibility are not fully elucidated. We identified multiple transmitted\/founder (T\/F) viruses in six HIV-1-infected subjects by analyzing whole genome sequences. Comparison of biological phenotypes of different T\/F viruses from the same individual allowed us to more precisely identify critical determinants for viral transmissibility since they were transmitted under similar conditions. All T\/F viruses used coreceptor CCR5, while no T\/F viruses used CXCR4 or GPR15. However, the efficiency for different T\/F viruses from the same individual to use CCR5 was significantly variable, and the differences were even more significant for usage of coreceptors FPRL1, CCR3 and APJ. Resistance to IFN-\u03b1 was also different between T\/F viruses in 2 of 3 individuals. The relative fitness between T\/F viruses from the same subject was highly variable (2\u20136%). Importantly, the levels of coreceptor usage efficiency, resistance to IFN-\u03b1 and viral fitness were not associated with proportions of T\/F viruses in each individual during acute infection. Our results show that the modest but significant differences in coreceptor usage efficiency, IFN-\u03b1 sensitivity and viral fitness each alone may not play a critical role in HIV-1 transmission.<\/jats:p>","DOI":"10.1038\/srep38130","type":"journal-article","created":{"date-parts":[[2016,12,2]],"date-time":"2016-12-02T09:59:57Z","timestamp":1480672797000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Transmission of Multiple HIV-1 Subtype C Transmitted\/founder Viruses into the Same Recipients Was not Determined by Modest Phenotypic Differences"],"prefix":"10.1038","volume":"6","author":[{"given":"Hongshuo","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhavna","family":"Hora","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena E.","family":"Giorgi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangping","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanmoy","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan S.","family":"Perelson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,12,2]]},"reference":[{"key":"BFsrep38130_CR1","doi-asserted-by":"publisher","first-page":"7552","DOI":"10.1073\/pnas.0802203105","volume":"105","author":"BF Keele","year":"2008","unstructured":"Keele, B. F. et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proceedings of the National Academy of Sciences of the United States of America 105, 7552\u20137557 (2008).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep38130_CR2","doi-asserted-by":"publisher","first-page":"e1000890","DOI":"10.1371\/journal.ppat.1000890","volume":"6","author":"H Li","year":"2010","unstructured":"Li, H. et al. High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men. PLoS pathogens 6, e1000890 (2010).","journal-title":"PLoS pathogens"},{"key":"BFsrep38130_CR3","doi-asserted-by":"publisher","first-page":"e1000274","DOI":"10.1371\/journal.ppat.1000274","volume":"5","author":"RE Haaland","year":"2009","unstructured":"Haaland, R. E. et al. Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1. PLoS pathogens 5, e1000274, doi: 10.1371\/journal.ppat.1000274 (2009).","journal-title":"PLoS pathogens"},{"key":"BFsrep38130_CR4","doi-asserted-by":"publisher","first-page":"3556","DOI":"10.1128\/JVI.02132-08","volume":"83","author":"MR Abrahams","year":"2009","unstructured":"Abrahams, M. R. et al. Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants. Journal of virology 83, 3556\u20133567, doi: 10.1128\/JVI.02132-08 (2009).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR5","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1097\/QAI.0000000000000649","volume":"69","author":"Y Chen","year":"2015","unstructured":"Chen, Y. et al. Comprehensive Characterization of the Transmitted\/Founder env Genes From a Single MSM Cohort in China. J Acquir Immune Defic Syndr 69, 403\u2013412, doi: 10.1097\/QAI.0000000000000649 (2015).","journal-title":"J Acquir Immune Defic Syndr"},{"key":"BFsrep38130_CR6","doi-asserted-by":"crossref","unstructured":"Shaw, G. M. & Hunter, E. HIV transmission. Cold Spring Harbor perspectives in medicine 2, doi: 10.1101\/cshperspect.a006965 (2012).","DOI":"10.1101\/cshperspect.a006965"},{"key":"BFsrep38130_CR7","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1126\/science.1093137","volume":"303","author":"CA Derdeyn","year":"2004","unstructured":"Derdeyn, C. A. et al. Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science (New York, N.Y.) 303, 2019\u20132022 (2004).","journal-title":"Science (New York, N.Y.)"},{"key":"BFsrep38130_CR8","doi-asserted-by":"publisher","first-page":"6528","DOI":"10.1128\/JVI.79.10.6528-6531.2005","volume":"79","author":"B Chohan","year":"2005","unstructured":"Chohan, B. et al. Selection for human immunodeficiency virus type 1 envelope glycosylation variants with shorter V1-V2 loop sequences occurs during transmission of certain genetic subtypes and may impact viral RNA levels. Journal of virology 79, 6528\u20136531 (2005).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR9","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1086\/596557","volume":"199","author":"M Sagar","year":"2009","unstructured":"Sagar, M. et al. Selection of HIV variants with signature genotypic characteristics during heterosexual transmission. The Journal of infectious diseases 199, 580\u2013589, doi: 10.1086\/596557 (2009).","journal-title":"The Journal of infectious diseases"},{"key":"BFsrep38130_CR10","doi-asserted-by":"publisher","first-page":"6523","DOI":"10.1128\/JVI.79.10.6523-6527.2005","volume":"79","author":"SD Frost","year":"2005","unstructured":"Frost, S. D. et al. Characterization of human immunodeficiency virus type 1 (HIV-1) envelope variation and neutralizing antibody responses during transmission of HIV-1 subtype B. Journal of virology 79, 6523\u20136527 (2005).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR11","doi-asserted-by":"publisher","first-page":"8514","DOI":"10.1128\/JVI.00736-11","volume":"85","author":"CB Wilen","year":"2011","unstructured":"Wilen, C. B. et al. Phenotypic and immunologic comparison of clade B transmitted\/founder and chronic HIV-1 envelope glycoproteins. Journal of virology 85, 8514\u20138527, doi: 10.1128\/JVI.00736-11 (2011).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR12","doi-asserted-by":"publisher","first-page":"e1002209","DOI":"10.1371\/journal.ppat.1002209","volume":"7","author":"S Gnanakaran","year":"2011","unstructured":"Gnanakaran, S. et al. Recurrent signature patterns in HIV-1 B clade envelope glycoproteins associated with either early or chronic infections. PLoS pathogens 7, e1002209, doi: 10.1371\/journal.ppat.1002209 (2011).","journal-title":"PLoS pathogens"},{"key":"BFsrep38130_CR13","doi-asserted-by":"publisher","first-page":"e23673","DOI":"10.1371\/journal.pone.0023673","volume":"6","author":"M Asmal","year":"2011","unstructured":"Asmal, M. et al. A signature in HIV-1 envelope leader peptide associated with transition from acute to chronic infection impacts envelope processing and infectivity. PloS one 6, e23673, doi: 10.1371\/journal.pone.0023673 (2011).","journal-title":"PloS one"},{"key":"BFsrep38130_CR14","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1084\/jem.20090378","volume":"206","author":"JF Salazar-Gonzalez","year":"2009","unstructured":"Salazar-Gonzalez, J. F. et al. Genetic identity, biological phenotype, and evolutionary pathways of transmitted\/founder viruses in acute and early HIV-1 infection. The Journal of experimental medicine 206, 1273\u20131289 (2009).","journal-title":"The Journal of experimental medicine"},{"key":"BFsrep38130_CR15","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.1128\/JVI.06157-11","volume":"86","author":"C Ochsenbauer","year":"2012","unstructured":"Ochsenbauer, C. et al. Generation of transmitted\/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. Journal of virology 86, 2715\u20132728, doi: 10.1128\/JVI.06157-11 (2012).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR16","doi-asserted-by":"publisher","first-page":"6626","DOI":"10.1073\/pnas.1304288110","volume":"110","author":"NF Parrish","year":"2013","unstructured":"Parrish, N. F. et al. Phenotypic properties of transmitted founder HIV-1. Proceedings of the National Academy of Sciences of the United States of America 110, 6626\u20136633, doi: 10.1073\/pnas.1304288110 (2013).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep38130_CR17","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/1742-4690-10-146","volume":"10","author":"AE Fenton-May","year":"2013","unstructured":"Fenton-May, A. E. et al. Relative resistance of HIV-1 founder viruses to control by interferon-alpha. Retrovirology 10, 146, doi: 10.1186\/1742-4690-10-146 (2013).","journal-title":"Retrovirology"},{"key":"BFsrep38130_CR18","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1186\/1471-2105-11-532","volume":"11","author":"EE Giorgi","year":"2010","unstructured":"Giorgi, E. E. et al. Estimating time since infection in early homogeneous HIV-1 samples using a poisson model. BMC bioinformatics 11, 532, doi: 10.1186\/1471-2105-11-532 (2010).","journal-title":"BMC bioinformatics"},{"key":"BFsrep38130_CR19","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/1742-4690-5-52","volume":"5","author":"N Shimizu","year":"2008","unstructured":"Shimizu, N. et al. A formylpeptide receptor, FPRL1, acts as an efficient coreceptor for primary isolates of human immunodeficiency virus. Retrovirology 5, 52, doi: 10.1186\/1742-4690-5-52 (2008).","journal-title":"Retrovirology"},{"key":"BFsrep38130_CR20","doi-asserted-by":"crossref","first-page":"7934","DOI":"10.1128\/JVI.72.10.7934-7940.1998","volume":"72","author":"AL Edinger","year":"1998","unstructured":"Edinger, A. L. et al. An orphan seven-transmembrane domain receptor expressed widely in the brain functions as a coreceptor for human immunodeficiency virus type 1 and simian immunodeficiency virus. Journal of virology 72, 7934\u20137940 (1998).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR21","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/385645a0","volume":"385","author":"J He","year":"1997","unstructured":"He, J. et al. CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature 385, 645\u2013649, doi: 10.1038\/385645a0 (1997).","journal-title":"Nature"},{"key":"BFsrep38130_CR22","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/S0092-8674(00)81313-6","volume":"85","author":"H Choe","year":"1996","unstructured":"Choe, H. et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135\u20131148 (1996).","journal-title":"Cell"},{"key":"BFsrep38130_CR23","doi-asserted-by":"publisher","first-page":"6626","DOI":"10.1073\/pnas.1304288110","volume":"110","author":"NF Parrish","year":"2013","unstructured":"Parrish, N. F. et al. Phenotypic properties of transmitted founder HIV-1. Proceedings of the National Academy of Sciences of the United States of America 110, 6626\u20136633, doi: 10.1073\/pnas.1304288110 (2013).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep38130_CR24","doi-asserted-by":"publisher","first-page":"e1005154","DOI":"10.1371\/journal.ppat.1005154","volume":"11","author":"MJ Deymier","year":"2015","unstructured":"Deymier, M. J. et al. Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-alpha Resistance. PLoS pathogens 11, e1005154, doi: 10.1371\/journal.ppat.1005154 (2015).","journal-title":"PLoS pathogens"},{"key":"BFsrep38130_CR25","doi-asserted-by":"publisher","first-page":"10669","DOI":"10.1128\/JVI.05249-11","volume":"85","author":"C Jiang","year":"2011","unstructured":"Jiang, C. et al. Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. Journal of virology 85, 10669\u201310681, doi: 10.1128\/JVI.05249-11 (2011).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR26","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s12977-014-0069-9","volume":"11","author":"AJ Ritchie","year":"2014","unstructured":"Ritchie, A. J. et al. Recombination-mediated escape from primary CD8\u2009+\u2009T cells in acute HIV-1 infection. Retrovirology 11, 69, doi: 10.1186\/s12977-014-0069-9 (2014).","journal-title":"Retrovirology"},{"key":"BFsrep38130_CR27","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/1742-4690-9-89","volume":"9","author":"H Song","year":"2012","unstructured":"Song, H. et al. Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted\/founder genome. Retrovirology 9, 89, doi: 10.1186\/1742-4690-9-89 (2012).","journal-title":"Retrovirology"},{"key":"BFsrep38130_CR28","doi-asserted-by":"publisher","first-page":"e102734","DOI":"10.1371\/journal.pone.0102734","volume":"9","author":"H Song","year":"2014","unstructured":"Song, H. et al. Reversion and T cell escape mutations compensate the fitness loss of a CD8\u2009+\u2009T cell escape mutant in their cognate transmitted\/founder virus. PloS one 9, e102734, doi: 10.1371\/journal.pone.0102734 (2014).","journal-title":"PloS one"},{"key":"BFsrep38130_CR29","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nmeth995","volume":"4","author":"F Cai","year":"2007","unstructured":"Cai, F. et al. Detection of minor drug-resistant populations by parallel allele-specific sequencing. Nature methods 4, 123\u2013125, doi: 10.1038\/nmeth995 (2007).","journal-title":"Nature methods"},{"key":"BFsrep38130_CR30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12977-014-0101-0","volume":"11","author":"D Liu","year":"2014","unstructured":"Liu, D. et al. Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation. Retrovirology 11, 101, doi: 10.1186\/s12977-014-0101-0 (2014).","journal-title":"Retrovirology"},{"key":"BFsrep38130_CR31","doi-asserted-by":"publisher","first-page":"8353","DOI":"10.1128\/JVI.00780-09","volume":"83","author":"R Nedellec","year":"2009","unstructured":"Nedellec, R. et al. Virus entry via the alternative coreceptors CCR3 and FPRL1 differs by human immunodeficiency virus type 1 subtype. Journal of virology 83, 8353\u20138363 (2009).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR32","doi-asserted-by":"publisher","first-page":"8208","DOI":"10.1128\/JVI.00296-09","volume":"83","author":"J Isaacman-Beck","year":"2009","unstructured":"Isaacman-Beck, J. et al. Heterosexual transmission of human immunodeficiency virus type 1 subtype C: Macrophage tropism, alternative coreceptor use, and the molecular anatomy of CCR5 utilization. Journal of virology 83, 8208\u20138220 (2009).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR33","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/nature13554","volume":"511","author":"NG Sandler","year":"2014","unstructured":"Sandler, N. G. et al. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511, 601\u2013605, doi: 10.1038\/nature13554 (2014).","journal-title":"Nature"},{"key":"BFsrep38130_CR34","doi-asserted-by":"publisher","first-page":"12164","DOI":"10.1128\/JVI.79.19.12164-12172.2005","volume":"79","author":"K Abel","year":"2005","unstructured":"Abel, K., Rocke, D. M., Chohan, B., Fritts, L. & Miller, C. J. Temporal and anatomic relationship between virus replication and cytokine gene expression after vaginal simian immunodeficiency virus infection. Journal of virology 79, 12164\u201312172, doi: 10.1128\/JVI.79.19.12164-12172.2005 (2005).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR35","doi-asserted-by":"publisher","first-page":"3719","DOI":"10.1128\/JVI.01844-08","volume":"83","author":"AR Stacey","year":"2009","unstructured":"Stacey, A. R. et al. Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. Journal of virology 83, 3719\u20133733, doi: 10.1128\/JVI.01844-08 (2009).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR36","doi-asserted-by":"crossref","unstructured":"Arnott, A. et al. High viral fitness during acute HIV-1 infection. PloS one 5, doi: 10.1371\/journal.pone.0012631 (2010).","DOI":"10.1371\/journal.pone.0012631"},{"key":"BFsrep38130_CR37","doi-asserted-by":"publisher","first-page":"11609","DOI":"10.1128\/JVI.00952-08","volume":"82","author":"X Kong","year":"2008","unstructured":"Kong, X. et al. The human immunodeficiency virus type 1 envelope confers higher rates of replicative fitness to perinatally transmitted viruses than to nontransmitted viruses. Journal of virology 82, 11609\u201311618 (2008).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR38","doi-asserted-by":"publisher","first-page":"9222","DOI":"10.1128\/JVI.74.19.9222-9233.2000","volume":"74","author":"ME Quinones-Mateu","year":"2000","unstructured":"Quinones-Mateu, M. E. et al. A dual infection\/competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression. Journal of virology 74, 9222\u20139233 (2000).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR39","doi-asserted-by":"publisher","first-page":"8514","DOI":"10.1128\/JVI.00736-11","volume":"85","author":"CB Wilen","year":"2011","unstructured":"Wilen, C. B. et al. Phenotypic and immunologic comparison of clade B transmitted\/founder and chronic HIV-1 envelope glycoproteins. Journal of virology 85, 8514\u20138527, doi: 10.1128\/JVI.00736-11 (2011).","journal-title":"Journal of virology"},{"key":"BFsrep38130_CR40","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.jim.2014.01.004","volume":"409","author":"AM Sanchez","year":"2014","unstructured":"Sanchez, A. M. et al. Development of a contemporary globally diverse HIV viral panel by the EQAPOL program. Journal of immunological methods 409, 117\u2013130, doi: 10.1016\/j.jim.2014.01.004 (2014).","journal-title":"Journal of immunological methods"},{"key":"BFsrep38130_CR41","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.jviromet.2007.02.015","volume":"143","author":"JL Kirchherr","year":"2007","unstructured":"Kirchherr, J. L. et al. High throughput functional analysis of HIV-1 env genes without cloning. J Virol Methods 143, 104\u2013111 (2007).","journal-title":"J Virol Methods"},{"key":"BFsrep38130_CR42","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1097\/QAD.0b013e328326cc0d","volume":"23","author":"N Shimizu","year":"2009","unstructured":"Shimizu, N. et al. Broad usage spectrum of G protein-coupled receptors as coreceptors by primary isolates of HIV. Aids 23, 761\u2013769 (2009).","journal-title":"Aids"},{"key":"BFsrep38130_CR43","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3109\/03602538409015066","volume":"15","author":"JL Steimer","year":"1984","unstructured":"Steimer, J. L., Mallet, A., Golmard, J. L. & Boisvieux, J. F. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug metabolism reviews 15, 265\u2013292, doi: 10.3109\/03602538409015066 (1984).","journal-title":"Drug metabolism reviews"},{"key":"BFsrep38130_CR44","unstructured":"Davidian, M. & Giltinan, D. M. Nonlinear models for repeated measurement data. (Chapman & Hall\/CRC, 1998)."},{"key":"BFsrep38130_CR45","doi-asserted-by":"publisher","first-page":"110","DOI":"10.2307\/3002019","volume":"2","author":"FE Satterthwaite","year":"1946","unstructured":"Satterthwaite, F. E. An approximate distribution of estimates of variance components. Biometrics 2, 110\u2013114 (1946).","journal-title":"Biometrics"},{"key":"BFsrep38130_CR46","unstructured":"Bonferroni, C. E. Teoria statistica delle classi e calcolo delle probabilit\u00e0. (Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze, 1936)."},{"key":"BFsrep38130_CR47","unstructured":"R: A Language and Environment for Statistical Computing, R Core Team, R Foundation for Statistical Computing, Vienna, Austria https:\/\/www.R-project.org (2016)."},{"key":"BFsrep38130_CR48","unstructured":"subplex: Subplex optimization algorithm. R package version 1.1-3. http:\/\/CRAN.R-project.org\/package=subplex (2008)."},{"key":"BFsrep38130_CR49","unstructured":"ucminf: General-purpose unconstrained non-linear optimization. R package version 1.1-3. http:\/\/CRAN.R-project.org\/package=ucminf (2012)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep38130.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep38130","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep38130.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T01:37:44Z","timestamp":1672882664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep38130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,2]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFsrep38130"],"URL":"https:\/\/doi.org\/10.1038\/srep38130","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,2]]},"assertion":[{"value":"4 July 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 November 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 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":"38130"}}