{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T02:20:46Z","timestamp":1790389246605,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T00:00:00Z","timestamp":1589932800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T00:00:00Z","timestamp":1589932800000},"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>Photoreceptors possess ribbon synapses distinct from the conventional synapses in the brain. Little is known about the function of the BBSome, a complex integral in ciliary and intracellular trafficking, in ribbon synaptic formation. We performed immunohistochemistry using retinas from Bardet-Biedl Syndrome (BBS) mouse models and found that BBS mutant animals have significantly fewer ribbon synapses in the outer plexiform layer and increased ectopic synapses in the outer nuclear layer compared to controls. Many ectopic synapses in BBS mutant retinas are associated with horizontal cell axonal processes that aberrantly intrude into the outer nuclear layer. To determine whether this horizontal cell phenotype is a consequence of retinal degeneration, we examined this phenotype in mice with photoreceptor-specific inactivation of the BBSome induced by <jats:italic>Cre<\/jats:italic> recombinase driven by the rhodopsin promoter. At three months of age, despite retinal degeneration, <jats:italic>Bbs8<\/jats:italic><jats:sup><jats:italic>floxed\/floxed<\/jats:italic><\/jats:sup><jats:italic>; Rho-Cre<\/jats:italic><jats:sup>+<\/jats:sup> mice lack the aberrant intrusion of horizontal cell processes. At 6 months, some horizontal cell processes intrude into the outer nuclear layer in <jats:italic>Bbs8<\/jats:italic><jats:sup><jats:italic>floxed\/floxed<\/jats:italic><\/jats:sup><jats:italic>; Rho-Cre<\/jats:italic><jats:sup>+<\/jats:sup> mice, but the phenotype does not recapitulate the phenotypic severity observed in young congenital BBS mutant mice. Therefore, the lack of BBSome function negatively impacts retinal synaptogenesis, and causes horizontal cell defects in a potentially cell-autonomous fashion.<\/jats:p>","DOI":"10.1038\/s41598-020-65233-4","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T10:03:13Z","timestamp":1589968993000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The absence of BBSome function decreases synaptogenesis and causes ectopic synapse formation in the retina"],"prefix":"10.1038","volume":"10","author":[{"given":"Ying","family":"Hsu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janelle E.","family":"Garrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seongjin","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6282-0835","authenticated-orcid":false,"given":"Val C.","family":"Sheffield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,20]]},"reference":[{"key":"65233_CR1","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.molmed.2004.01.003","volume":"10","author":"K Mykytyn","year":"2004","unstructured":"Mykytyn, K. & Sheffield, V. C. Establishing a connection between cilia and Bardet-Biedl Syndrome. Trends Mol Med 10, 106\u2013109, https:\/\/doi.org\/10.1016\/j.molmed.2004.01.003 (2004).","journal-title":"Trends Mol Med"},{"key":"65233_CR2","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1093\/hmg\/10.8.865","volume":"10","author":"DY Nishimura","year":"2001","unstructured":"Nishimura, D. Y. et al. Positional cloning of a novel gene on chromosome 16q causing Bardet\u2013Biedl syndrome (BBS2). Human Molecular Genetics 10, 865\u2013874 (2001).","journal-title":"Human Molecular Genetics"},{"key":"65233_CR3","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1038\/88925","volume":"28","author":"K Mykytyn","year":"2001","unstructured":"Mykytyn, K. et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 28, 188\u2013191 (2001).","journal-title":"Nat Genet"},{"key":"65233_CR4","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1086\/498323","volume":"77","author":"DY Nishimura","year":"2005","unstructured":"Nishimura, D. Y. et al. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. The American Journal of Human Genetics 77, 1021\u20131033 (2005).","journal-title":"The American Journal of Human Genetics"},{"key":"65233_CR5","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1016\/j.cell.2007.03.053","volume":"129","author":"MV Nachury","year":"2007","unstructured":"Nachury, M. V. et al. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201\u20131213, https:\/\/doi.org\/10.1016\/j.cell.2007.03.053 (2007).","journal-title":"Cell"},{"key":"65233_CR6","doi-asserted-by":"publisher","first-page":"20625","DOI":"10.1074\/jbc.M112.341487","volume":"287","author":"QH Zhang","year":"2012","unstructured":"Zhang, Q. H., Yu, D. H., Seo, S. J., Stone, E. M. & Sheffield, V. C. Intrinsic Protein-Protein Interaction-mediated and Chaperonin-assisted Sequential Assembly of Stable Bardet-Biedl Syndrome Protein Complex, the BBSome. Journal of Biological Chemistry 287, 20625\u201320635, https:\/\/doi.org\/10.1074\/jbc.M112.341487 (2012).","journal-title":"Journal of Biological Chemistry"},{"key":"65233_CR7","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1136\/jmedgenet-2013-101785","volume":"51","author":"S Scheidecker","year":"2014","unstructured":"Scheidecker, S. et al. Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet 51, 132\u2013136, https:\/\/doi.org\/10.1136\/jmedgenet-2013-101785 (2014).","journal-title":"J Med Genet"},{"key":"65233_CR8","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1086\/368204","volume":"72","author":"JL Badano","year":"2003","unstructured":"Badano, J. L. et al. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72, 650\u2013658, https:\/\/doi.org\/10.1086\/368204 (2003).","journal-title":"Am J Hum Genet"},{"key":"65233_CR9","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1038\/ng935","volume":"31","author":"K Mykytyn","year":"2002","unstructured":"Mykytyn, K. et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet 31, 435\u2013438, https:\/\/doi.org\/10.1038\/ng935 (2002).","journal-title":"Nat Genet"},{"key":"65233_CR10","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1083\/jcb.200909183","volume":"187","author":"K-F Lechtreck","year":"2009","unstructured":"Lechtreck, K.-F. et al. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. The Journal of cell biology 187, 1117\u20131132 (2009).","journal-title":"The Journal of cell biology"},{"key":"65233_CR11","doi-asserted-by":"publisher","first-page":"E934","DOI":"10.1073\/pnas.1713226115","volume":"115","author":"PW Liu","year":"2018","unstructured":"Liu, P. W. & Lechtreck, K. F. The Bardet-Biedl syndrome protein complex is an adapter expanding the cargo range of intraflagellar transport trains for ciliary export. P Natl Acad Sci USA 115, E934\u2013E943, https:\/\/doi.org\/10.1073\/pnas.1713226115 (2018).","journal-title":"P Natl Acad Sci USA"},{"key":"65233_CR12","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Seo, S., Bugge, K., Stone, E. M. & Sheffield, V. C. BBS proteins interact genetically with the IFT pathway to influence SHH related phenotypes. Human molecular genetics, dds004 (2012).","DOI":"10.1093\/hmg\/dds004"},{"key":"65233_CR13","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.1242\/jcs.111740","volume":"126","author":"QH Zhang","year":"2013","unstructured":"Zhang, Q. H. et al. BBS7 is required for BBSome formation and its absence in mice results in Bardet-Biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking. Journal of Cell Science 126, 2372\u20132380, https:\/\/doi.org\/10.1242\/jcs.111740 (2013).","journal-title":"Journal of Cell Science"},{"key":"65233_CR14","doi-asserted-by":"publisher","first-page":"1847","DOI":"10.1083\/jcb.201709041","volume":"217","author":"F Ye","year":"2018","unstructured":"Ye, F., Nager, A. R. & Nachury, M. V. BBSome trains remove activated GPCRs from cilia by enabling passage through the transition zone. J Cell Biol 217, 1847\u20131868, https:\/\/doi.org\/10.1083\/jcb.201709041 (2018).","journal-title":"J Cell Biol"},{"key":"65233_CR15","doi-asserted-by":"publisher","unstructured":"Guo, D. F. et al. The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane. Plos Genetics 12, https:\/\/doi.org\/10.1371\/journal.pgen.1005890 (2016).","DOI":"10.1371\/journal.pgen.1005890"},{"key":"65233_CR16","doi-asserted-by":"publisher","unstructured":"Starks, R. D. et al. Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins. Plos Genetics 11, https:\/\/doi.org\/10.1371\/journal.pgen.1005311 (2015).","DOI":"10.1371\/journal.pgen.1005311"},{"key":"65233_CR17","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1093\/hmg\/ddi468","volume":"15","author":"HJ Yen","year":"2006","unstructured":"Yen, H. J., Tayeh, M. K., Stone, E. M., Sheffield, V. C. & Slusarski, D. C. Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer\u2019s vesicle cilia function. Human Molecular Genetics 15, 667\u2013677, https:\/\/doi.org\/10.1093\/hmg\/ddi468 (2006).","journal-title":"Human Molecular Genetics"},{"key":"65233_CR18","doi-asserted-by":"publisher","first-page":"10320","DOI":"10.1073\/pnas.1016531108","volume":"108","author":"ALD Tadenev","year":"2011","unstructured":"Tadenev, A. L. D. et al. Loss of Bardet-Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting. P Natl Acad Sci USA 108, 10320\u201310325, https:\/\/doi.org\/10.1073\/pnas.1016531108 (2011).","journal-title":"P Natl Acad Sci USA"},{"key":"65233_CR19","doi-asserted-by":"publisher","unstructured":"Haq, N. et al. Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons. Plos Biol 17, https:\/\/doi.org\/10.1371\/journal.pbio.3000414 (2019).","DOI":"10.1371\/journal.pbio.3000414"},{"key":"65233_CR20","doi-asserted-by":"publisher","first-page":"e1007057","DOI":"10.1371\/journal.pgen.1007057","volume":"13","author":"Y Hsu","year":"2017","unstructured":"Hsu, Y. et al. BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment. PLoS Genet 13, e1007057, https:\/\/doi.org\/10.1371\/journal.pgen.1007057 (2017).","journal-title":"PLoS Genet"},{"key":"65233_CR21","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1093\/hmg\/ddx399","volume":"27","author":"TL Dilan","year":"2018","unstructured":"Dilan, T. L. et al. Bardet-Biedl syndrome-8 (BBS8) protein is crucial for the development of outer segments in photoreceptor neurons. Human Molecular Genetics 27, 283\u2013294, https:\/\/doi.org\/10.1093\/hmg\/ddx399 (2018).","journal-title":"Human Molecular Genetics"},{"key":"65233_CR22","doi-asserted-by":"publisher","first-page":"E4400","DOI":"10.1073\/pnas.1510111112","volume":"112","author":"P Datta","year":"2015","unstructured":"Datta, P. et al. Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet\u2013Biedl syndrome. Proceedings of the National Academy of Sciences 112, E4400\u2013E4409 (2015).","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"65233_CR23","doi-asserted-by":"publisher","first-page":"16588","DOI":"10.1073\/pnas.0405496101","volume":"101","author":"DY Nishimura","year":"2004","unstructured":"Nishimura, D. Y. et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. P Natl Acad Sci USA 101, 16588\u201316593, https:\/\/doi.org\/10.1073\/pnas.0405496101 (2004).","journal-title":"P Natl Acad Sci USA"},{"key":"65233_CR24","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/S0896-6273(00)00159-8","volume":"28","author":"F Schmitz","year":"2000","unstructured":"Schmitz, F., Konigstorfer, A. & Sudhof, T. C. RIBEYE, a component of synaptic ribbons: A protein\u2019s journey through evolution provides insight into synaptic ribbon function. Neuron 28, 857\u2013872, https:\/\/doi.org\/10.1016\/S0896-6273(00)00159-8 (2000).","journal-title":"Neuron"},{"key":"65233_CR25","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1113\/jphysiol.2007.137927","volume":"585","author":"R Heidelberger","year":"2007","unstructured":"Heidelberger, R. Mechanisms of tonic, graded release: lessons from the vertebrate photoreceptor. J Physiol-London 585, 663\u2013667, https:\/\/doi.org\/10.1113\/jphysiol.2007.137927 (2007).","journal-title":"J Physiol-London"},{"key":"65233_CR26","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/S0896-6273(03)00086-2","volume":"37","author":"O Dick","year":"2003","unstructured":"Dick, O. et al. The presynaptic active zone protein bassoon is essential for photoreceptor ribbon synapse formation in the retina. Neuron 37, 775\u2013786, https:\/\/doi.org\/10.1016\/S0896-6273(03)00086-2 (2003).","journal-title":"Neuron"},{"key":"65233_CR27","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.15252\/embj.201592701","volume":"35","author":"S Maxeiner","year":"2016","unstructured":"Maxeiner, S., Luo, F. J., Tan, A., Schmitz, F. & Sudhof, T. C. How to make a synaptic ribbon: RIBEYE deletion abolishes ribbons in retinal synapses and disrupts neurotransmitter release. Embo J 35, 1098\u20131114, https:\/\/doi.org\/10.15252\/embj.201592701 (2016).","journal-title":"Embo J"},{"key":"65233_CR28","doi-asserted-by":"publisher","first-page":"8664","DOI":"10.1073\/pnas.0402354101","volume":"101","author":"K Mykytyn","year":"2004","unstructured":"Mykytyn, K. et al. Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. P Natl Acad Sci USA 101, 8664\u20138669, https:\/\/doi.org\/10.1073\/pnas.0402354101 (2004).","journal-title":"P Natl Acad Sci USA"},{"key":"65233_CR29","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1038\/Nm.2996","volume":"18","author":"CS Carter","year":"2012","unstructured":"Carter, C. S. et al. Abnormal development of NG2(+)PDGFR-alpha(+) neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nature Medicine 18, 1797\u2013+, https:\/\/doi.org\/10.1038\/Nm.2996 (2012).","journal-title":"Nature Medicine"},{"key":"65233_CR30","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/gene.20097","volume":"41","author":"S Li","year":"2005","unstructured":"Li, S. et al. Rhodopsin-iCre transgenic mouse line for Cre-mediated rod-specific gene targeting. Genesis 41, 73\u201380, https:\/\/doi.org\/10.1002\/gene.20097 (2005).","journal-title":"Genesis"},{"key":"65233_CR31","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.ajhg.2009.10.012","volume":"85","author":"MM van Genderen","year":"2009","unstructured":"van Genderen, M. M. et al. Mutations in TRPM1 Are a Common Cause of Complete Congenital Stationary Night Blindness. Am J Hum Genet 85, 730\u2013736, https:\/\/doi.org\/10.1016\/j.ajhg.2009.10.012 (2009).","journal-title":"Am J Hum Genet"},{"key":"65233_CR32","doi-asserted-by":"publisher","first-page":"26461","DOI":"10.1074\/jbc.M801625200","volume":"283","author":"K Alpadi","year":"2008","unstructured":"Alpadi, K. et al. RIBEYE recruits munc119, a mammalian ortholog of the Caenorhabditis elegans protein unc119, to synaptic ribbons of photoreceptor Synapses. Journal of Biological Chemistry 283, 26461\u201326467, https:\/\/doi.org\/10.1074\/jbc.M801625200 (2008).","journal-title":"Journal of Biological Chemistry"},{"key":"65233_CR33","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.mcn.2014.03.002","volume":"60","author":"XQ Liu","year":"2014","unstructured":"Liu, X. Q., Heidelberger, R. & Janz, R. Phosphorylation of syntaxin 3B by CaMKII regulates the formation of t-SNARE complexes. Mol Cell Neurosci 60, 53\u201362, https:\/\/doi.org\/10.1016\/j.mcn.2014.03.002 (2014).","journal-title":"Mol Cell Neurosci"},{"key":"65233_CR34","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1002\/cne.21915","volume":"512","author":"H Regus-Leidig","year":"2009","unstructured":"Regus-Leidig, H., Dieck, S. T., Specht, D., Meyer, L. & Brandstatter, J. H. Early Steps in the Assembly of Photoreceptor Ribbon Synapses in the Mouse Retina: The Involvement of Precursor Spheres. J Comp Neurol 512, 814\u2013824, https:\/\/doi.org\/10.1002\/cne.21915 (2009).","journal-title":"J Comp Neurol"},{"key":"65233_CR35","doi-asserted-by":"publisher","first-page":"e1002358","DOI":"10.1371\/journal.pgen.1002358","volume":"7","author":"S Seo","year":"2011","unstructured":"Seo, S., Zhang, Q., Bugge, K., Breslow, D. K. & Searby, C. C. A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS Genet 7, e1002358\u2013e1002358 (2011).","journal-title":"PLoS Genet"},{"key":"65233_CR36","doi-asserted-by":"publisher","first-page":"11020","DOI":"10.1073\/pnas.190291097","volume":"97","author":"E Strettoi","year":"2000","unstructured":"Strettoi, E. & Pignatelli, V. Modifications of retinal neurons in a mouse model of retinitis pigmentosa. P Natl Acad Sci USA 97, 11020\u201311025, https:\/\/doi.org\/10.1073\/pnas.190291097 (2000).","journal-title":"P Natl Acad Sci USA"},{"key":"65233_CR37","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1242\/jcs.104729","volume":"125","author":"AD Yuan","year":"2012","unstructured":"Yuan, A. D., Rao, M. V., Veeranna & Nixon, R. A. Neurofilaments at a glance. Journal of Cell Science 125, 3257\u20133263, https:\/\/doi.org\/10.1242\/jcs.104729 (2012).","journal-title":"Journal of Cell Science"},{"key":"65233_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/1096-9861(20000814)424:1<1::AID-CNE1>3.0.CO;2-V","volume":"424","author":"S Haverkamp","year":"2000","unstructured":"Haverkamp, S. & Wassle, H. Immunocytochemical analysis of the mouse retina. J Comp Neurol 424, 1\u201323 (2000).","journal-title":"J Comp Neurol"},{"key":"65233_CR39","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1002\/cne.21188","volume":"500","author":"PR Bayley","year":"2007","unstructured":"Bayley, P. R. & Morgans, C. W. Rod bipolar cells and horizontal cells form displaced synaptic contacts with rods in the outer nuclear layer of the nob2 retina. J Comp Neurol 500, 286\u2013298 (2007).","journal-title":"J Comp Neurol"},{"key":"65233_CR40","doi-asserted-by":"publisher","first-page":"2506","DOI":"10.1111\/j.1460-9568.2007.05886.x","volume":"26","author":"D Specht","year":"2007","unstructured":"Specht, D. et al. Structural and functional remodeling in the retina of a mouse with a photoreceptor synaptopathy: plasticity in the rod and degeneration in the cone system. Eur J Neurosci 26, 2506\u20132515, https:\/\/doi.org\/10.1111\/j.1460-9568.2007.05886.x (2007).","journal-title":"Eur J Neurosci"},{"key":"65233_CR41","doi-asserted-by":"publisher","first-page":"7462","DOI":"10.1523\/Jneurosci.0084-18.2018","volume":"38","author":"WW Green","year":"2018","unstructured":"Green, W. W. et al. Peripheral Gene Therapeutic Rescue of an Olfactory Ciliopathy Restores Sensory Input, Axonal Pathfinding, and Odor-Guided Behavior. J Neurosci 38, 7462\u20137475, https:\/\/doi.org\/10.1523\/Jneurosci.0084-18.2018 (2018).","journal-title":"J Neurosci"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65233-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65233-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65233-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T11:51:58Z","timestamp":1670327518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-65233-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,20]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["65233"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-65233-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,20]]},"assertion":[{"value":"23 August 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2020","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":"8321"}}