{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T03:19:43Z","timestamp":1794107983915,"version":"4.8.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T00:00:00Z","timestamp":1717977600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T00:00:00Z","timestamp":1717977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Programme d'investissements d'avenir (PIA) by the Secr\u00e9tariat g\u00e9n\u00e9ral pour l'investissement (SGPI) of the French government"},{"name":"I-STEM is supported by a recurrent annual grant of the Association Fran\u00e7aise contre les Myopathies (AFM-T\u00e9l\u00e9thon)."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the\n                    <jats:italic>SHANK3<\/jats:italic>\n                    gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2\/3 Complex Subunit 2 (ARPC2) with \u00df-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine\u2019s effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.\n                  <\/jats:p>","DOI":"10.1038\/s41398-024-02947-3","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T04:03:03Z","timestamp":1717992183000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacological modulation of developmental and synaptic phenotypes in human SHANK3 deficient stem cell-derived neuronal models"],"prefix":"10.1038","volume":"14","author":[{"given":"Amandine","family":"Thibaudeau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Schmitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Fran\u00e7ois","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Chatrousse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loic","family":"Cousin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Am\u00e9lie","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurore","family":"Vuidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina B.","family":"Jacob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9241-5710","authenticated-orcid":false,"given":"Peter","family":"Sommer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Benchoua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0002-6847","authenticated-orcid":false,"given":"Johannes H.","family":"Wilbertz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,10]]},"reference":[{"key":"2947_CR1","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s11689-021-09370-5","volume":"13","author":"M Burdeus-Olavarrieta","year":"2021","unstructured":"Burdeus-Olavarrieta M, San Jos\u00e9-C\u00e1ceres A, Garc\u00eda-Alc\u00f3n A, Gonz\u00e1lez-Pe\u00f1as J, Hern\u00e1ndez-Jusdado P, Parellada-Redondo M. Characterisation of the clinical phenotype in Phelan-McDermid syndrome. J Neurodev Disord. 2021;13:26.","journal-title":"J Neurodev Disord"},{"key":"2947_CR2","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1159\/000334260","volume":"2","author":"K Phelan","year":"2012","unstructured":"Phelan K, McDermid HE. The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome). Mol Syndromol. 2012;2:186\u2013201.","journal-title":"Mol Syndromol"},{"key":"2947_CR3","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1002\/ajmg.1320430524","volume":"43","author":"MC Phelan","year":"1992","unstructured":"Phelan MC, Thomas GR, Saul RA, Rogers RC, Taylor HA, Wenger DA, et al. Cytogenetic, biochemical, and molecular analyses of a 22q13 deletion. Am J Med Genet. 1992;43:872\u20136.","journal-title":"Am J Med Genet"},{"key":"2947_CR4","doi-asserted-by":"publisher","first-page":"e1004580","DOI":"10.1371\/journal.pgen.1004580","volume":"10","author":"CS Leblond","year":"2014","unstructured":"Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments. PLoS Genet. 2014;10:e1004580.","journal-title":"PLoS Genet"},{"key":"2947_CR5","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1086\/522590","volume":"81","author":"R Moessner","year":"2007","unstructured":"Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, et al. Contribution of SHANK3 Mutations to Autism Spectrum Disorder. Am J Hum Genet. 2007;81:1289\u201397.","journal-title":"Am J Hum Genet"},{"key":"2947_CR6","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/nature12618","volume":"503","author":"A Shcheglovitov","year":"2013","unstructured":"Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, et al. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013;503:267\u201371.","journal-title":"Nature"},{"key":"2947_CR7","doi-asserted-by":"publisher","first-page":"2751","DOI":"10.1038\/s41380-022-01563-1","volume":"27","author":"H Kim","year":"2022","unstructured":"Kim H, Cho B, Park H, Kim J, Kim S, Shin J, et al. Dormant state of quiescent neural stem cells links Shank3 mutation to autism development. Mol Psychiatry. 2022;27:2751\u201365.","journal-title":"Mol Psychiatry"},{"key":"2947_CR8","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1038\/nn.4260","volume":"19","author":"RT Peixoto","year":"2016","unstructured":"Peixoto RT, Wang W, Croney DM, Kozorovitskiy Y, Sabatini BL. Early hyperactivity and precocious maturation of corticostriatal circuits in Shank3B(-\/-) mice. Nat Neurosci. 2016;19:716\u201324.","journal-title":"Nat Neurosci"},{"key":"2947_CR9","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1038\/mp.2017.185","volume":"23","author":"A Kathuria","year":"2018","unstructured":"Kathuria A, Nowosiad P, Jagasia R, Aigner S, Taylor RD, Andreae LC, et al. Stem cell-derived neurons from autistic individuals with SHANK3 mutation show morphogenetic abnormalities during early development. Mol Psychiatry. 2018;23:735\u201346.","journal-title":"Mol Psychiatry"},{"key":"2947_CR10","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-023-02535-x","volume":"13","author":"Y Hussein","year":"2023","unstructured":"Hussein Y, Tripathi U, Choudhary A, Nayak R, Peles D, Rosh I, et al. Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations. Transl Psychiatry. 2023;13:246.","journal-title":"Transl Psychiatry"},{"key":"2947_CR11","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature16971","volume":"530","author":"Y Mei","year":"2016","unstructured":"Mei Y, Monteiro P, Zhou Y, Kim JA, Gao X, Fu Z, et al. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature. 2016;530:481\u20134.","journal-title":"Nature"},{"key":"2947_CR12","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1126\/science.aad5487","volume":"351","author":"M Bidinosti","year":"2016","unstructured":"Bidinosti M, Botta P, Kr\u00fcttner S, Proenca CC, Stoehr N, Bernhard M, et al. CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency. Science. 2016;351:1199\u2013203.","journal-title":"Science"},{"key":"2947_CR13","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.ebiom.2016.05.032","volume":"9","author":"H Darville","year":"2016","unstructured":"Darville H, Poulet A, Rodet-Amsellem F, Chatrousse L, Pernelle J, Boissart C, et al. Human Pluripotent Stem Cell-derived Cortical Neurons for High Throughput Medication Screening in Autism: A Proof of Concept Study in SHANK3 Haploinsufficiency Syndrome. EBioMedicine. 2016;9:293\u2013305.","journal-title":"EBioMedicine"},{"key":"2947_CR14","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.1038\/s41380-020-00979-x","volume":"26","author":"A Mossa","year":"2021","unstructured":"Mossa A, Pagano J, Ponzoni L, Tozzi A, Vezzoli E, Sciaccaluga M, et al. Developmental impaired Akt signaling in the Shank1 and Shank3 double knock-out mice. Mol Psychiatry. 2021;26:1928\u201344.","journal-title":"Mol Psychiatry"},{"key":"2947_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105213","volume":"148","author":"A Torossian","year":"2021","unstructured":"Torossian A, Sar\u00e9 RM, Loutaev I, Smith CB. Increased rates of cerebral protein synthesis in Shank3 knockout mice: Implications for a link between synaptic protein deficit and dysregulated protein synthesis in autism spectrum disorder\/intellectual disability. Neurobiol Dis. 2021;148:105213.","journal-title":"Neurobiol Dis"},{"key":"2947_CR16","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1038\/s41380-018-0325-9","volume":"25","author":"L Wang","year":"2020","unstructured":"Wang L, Adamski CJ, Bondar VV, Craigen E, Collette JR, Pang K, et al. A kinome-wide RNAi screen identifies ERK2 as a druggable regulator of Shank3 stability. Mol Psychiatry. 2020;25:2504\u201316.","journal-title":"Mol Psychiatry"},{"key":"2947_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-022-00493-7","volume":"13","author":"A Kolevzon","year":"2022","unstructured":"Kolevzon A, Breen MS, Siper PM, Halpern D, Frank Y, Rieger H, et al. Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome. Mol Autism. 2022;13:17.","journal-title":"Mol Autism"},{"key":"2947_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/srep03594","volume":"4","author":"M Nakagawa","year":"2014","unstructured":"Nakagawa M, Taniguchi Y, Senda S, Takizawa N, Ichisaka T, Asano K, et al. A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. Sci Rep. 2014;4:3594.","journal-title":"Sci Rep"},{"key":"2947_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2013.71","volume":"3","author":"C Boissart","year":"2013","unstructured":"Boissart C, Poulet A, Georges P, Darville H, Julita E, Delorme R, et al. Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening. Transl Psychiatry. 2013;3:e294.","journal-title":"Transl Psychiatry"},{"key":"2947_CR20","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2023.103209","volume":"72","author":"L Chatrousse","year":"2023","unstructured":"Chatrousse L, Poullion T, El-Kassar L, Giraud-Triboult K, Boissart C, Sanatine P, et al. Establishment of heterozygous and homozygous SHANK3 knockout clonal pluripotent stem cells from the parental hESC line SA001 using CRISPR\/Cas9. Stem Cell Res. 2023;72:103209.","journal-title":"Stem Cell Res"},{"key":"2947_CR21","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676\u201382.","journal-title":"Nat Methods"},{"key":"2947_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36993-x","volume":"9","author":"L Gouder","year":"2019","unstructured":"Gouder L, Vitrac A, Goubran-Botros H, Danckaert A, Tinevez JY, Andr\u00e9-Leroux G, et al. Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations. Sci Rep. 2019;9:94.","journal-title":"Sci Rep"},{"key":"2947_CR23","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nbt.1529","volume":"27","author":"SM Chambers","year":"2009","unstructured":"Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275\u201380.","journal-title":"Nat Biotechnol"},{"key":"2947_CR24","doi-asserted-by":"crossref","unstructured":"Hergenreder E, Zorina Y, Zhao Z, Munguba H, Calder EL, Baggiolini A, et al. Combined small molecule treatment accelerates timing of maturation in human pluripotent stem cell-derived neurons [Internet]. bioRxiv; 2022 [cited 2023 Apr 12]. p. 2022.06.02.494616. Available from: https:\/\/www.biorxiv.org\/content\/10.1101\/2022.06.02.494616v1.","DOI":"10.1101\/2022.06.02.494616"},{"key":"2947_CR25","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","volume":"49","author":"D Szklarczyk","year":"2021","unstructured":"Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets. Nucleic Acids Res. 2021;49:D605\u201312.","journal-title":"Nucleic Acids Res"},{"key":"2947_CR26","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.bcp.2019.01.017","volume":"163","author":"YJ Yoon","year":"2019","unstructured":"Yoon YJ, Han YM, Choi J, Lee YJ, Yun J, Lee SK, et al. Benproperine, an ARPC2 inhibitor, suppresses cancer cell migration and tumor metastasis. Biochem Pharmacol. 2019;163:46\u201359.","journal-title":"Biochem Pharmacol"},{"key":"2947_CR27","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1091\/mbc.e07-09-0964","volume":"19","author":"F Korobova","year":"2008","unstructured":"Korobova F, Svitkina T. Arp2\/3 complex is important for filopodia formation, growth cone motility, and neuritogenesis in neuronal cells. Mol Biol Cell. 2008;19:1561\u201374.","journal-title":"Mol Biol Cell"},{"key":"2947_CR28","first-page":"2741","volume":"143","author":"PS Wang","year":"2016","unstructured":"Wang PS, Chou FS, Ramachandran S, Xia S, Chen HY, Guo F, et al. Crucial roles of the Arp2\/3 complex during mammalian corticogenesis. Dev Camb Engl. 2016;143:2741\u201352.","journal-title":"Dev Camb Engl"},{"key":"2947_CR29","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1038\/nature08231","volume":"460","author":"BJ Nolen","year":"2009","unstructured":"Nolen BJ, Tomasevic N, Russell A, Pierce DW, Jia Z, McCormick CD, et al. Characterization of two classes of small molecule inhibitors of Arp2\/3 complex. Nature. 2009;460:1031\u20134.","journal-title":"Nature"},{"key":"2947_CR30","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1016\/j.stemcr.2022.05.002","volume":"17","author":"FM Aloisio","year":"2022","unstructured":"Aloisio FM, Barber DL. Arp2\/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification. Stem Cell Rep. 2022;17:1318\u201333.","journal-title":"Stem Cell Rep"},{"key":"2947_CR31","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1016\/j.celrep.2019.06.089","volume":"28","author":"S Xia","year":"2019","unstructured":"Xia S, Lim YB, Zhang Z, Wang Y, Zhang S, Lim CT, et al. Nanoscale architecture of the cortical actin cytoskeleton in embryonic stem cells. Cell Rep. 2019;28:1251\u201367.e7.","journal-title":"Cell Rep"},{"key":"2947_CR32","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1016\/j.celrep.2015.04.064","volume":"11","author":"LJ Duffney","year":"2015","unstructured":"Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, et al. Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators. Cell Rep. 2015;11:1400\u201313.","journal-title":"Cell Rep"},{"key":"2947_CR33","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/nature12630","volume":"503","author":"K Han","year":"2013","unstructured":"Han K, Holder JL Jr, Schaaf CP, Lu H, Chen H, Kang H, et al. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013;503:72\u20137.","journal-title":"Nature"},{"key":"2947_CR34","doi-asserted-by":"publisher","first-page":"4956","DOI":"10.1016\/j.cub.2021.09.022","volume":"31","author":"SI Salomaa","year":"2021","unstructured":"Salomaa SI, Miihkinen M, Kremneva E, Paatero I, Lilja J, Jacquemet G, et al. SHANK3 conformation regulates direct actin binding and crosstalk with Rap1 signaling. Curr Biol. 2021;31:4956\u201370.e9.","journal-title":"Curr Biol"},{"key":"2947_CR35","doi-asserted-by":"publisher","first-page":"6081","DOI":"10.1523\/JNEUROSCI.0035-13.2013","volume":"33","author":"IH Kim","year":"2013","unstructured":"Kim IH, Racz B, Wang H, Burianek L, Weinberg R, Yasuda R, et al. Disruption of Arp2\/3 Results in Asymmetric Structural Plasticity of Dendritic Spines and Progressive Synaptic and Behavioral Abnormalities. J Neurosci. 2013;33:6081\u201392.","journal-title":"J Neurosci"},{"key":"2947_CR36","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s13287-018-0957-3","volume":"9","author":"SE Taylor","year":"2018","unstructured":"Taylor SE, Taylor RD, Price J, Andreae LC. Single-molecule fluorescence in-situ hybridization reveals that human SHANK3 mRNA expression varies during development and in autism-associated SHANK3 heterozygosity. Stem Cell Res Ther. 2018;9:206.","journal-title":"Stem Cell Res Ther"},{"key":"2947_CR37","doi-asserted-by":"publisher","first-page":"2376","DOI":"10.1038\/npp.2009.75","volume":"34","author":"M Boldrini","year":"2009","unstructured":"Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, John Mann J, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology. 2009;34:2376\u201389.","journal-title":"Neuropsychopharmacology"},{"key":"2947_CR38","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.biopsych.2012.04.024","volume":"72","author":"M Boldrini","year":"2012","unstructured":"Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ, et al. Hippocampal Angiogenesis and Progenitor Cell Proliferation Are Increased with Antidepressant Use in Major Depression. Biol Psychiatry. 2012;72:562\u201371.","journal-title":"Biol Psychiatry"},{"key":"2947_CR39","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/nn1969","volume":"10","author":"A Sahay","year":"2007","unstructured":"Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110\u20135.","journal-title":"Nat Neurosci"},{"key":"2947_CR40","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.biopsych.2022.08.014","volume":"93","author":"JM Wolter","year":"2023","unstructured":"Wolter JM, Le BD, Matoba N, Lafferty MJ, Ayg\u00fcn N, Liang D, et al. Cellular Genome-wide Association Study Identifies Common Genetic Variation Influencing Lithium-Induced Neural Progenitor Proliferation. Biol Psychiatry. 2023;93:8\u201317.","journal-title":"Biol Psychiatry"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41398-024-02947-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-024-02947-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41398-024-02947-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T04:03:53Z","timestamp":1717992233000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41398-024-02947-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,10]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["2947"],"URL":"https:\/\/doi.org\/10.1038\/s41398-024-02947-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.09.13.557523","asserted-by":"object"}]},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,10]]},"assertion":[{"value":"2 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"AT, KS, DH, LCo, AW, AV, CJ, PS, and JW are or were employees of Ksilink. The remaining authors have no conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"249"}}