{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T01:35:36Z","timestamp":1783042536087,"version":"3.54.6"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T00:00:00Z","timestamp":1553472000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T00:00:00Z","timestamp":1553472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Local Initiative for Excellence Foundation"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Converging evidence suggests bioenergetic defects contribute to the pathophysiology of schizophrenia and may underlie cognitive dysfunction. The transport and metabolism of lactate energetically couples astrocytes and neurons and supports brain bioenergetics. We examined the concentration of lactate in postmortem brain (dorsolateral prefrontal cortex) in subjects with schizophrenia, in two animal models of schizophrenia, the GluN1 knockdown mouse model and mutant disrupted in schizophrenia 1 (DISC1) mouse model, as well as inducible pluripotent stem cells (iPSCs) from a schizophrenia subject with the DISC1 mutation. We found increased lactate in the dorsolateral prefrontal cortex (p\u2009=\u20090.043, n\u2009=\u200916\/group) in schizophrenia, as well as in frontal cortical neurons differentiated from a subject with schizophrenia with the DISC1 mutation (p\u2009=\u20090.032). We also found a decrease in lactate in mice with induced expression of mutant human DISC1 specifically in astrocytes (p\u2009=\u20090.049). These results build upon the body of evidence supporting bioenergetic dysfunction in schizophrenia, and suggests changes in lactate are a key feature of this often devastating severe mental illness.<\/jats:p>","DOI":"10.1038\/s41598-019-41572-9","type":"journal-article","created":{"date-parts":[[2019,3,25]],"date-time":"2019-03-25T11:03:11Z","timestamp":1553511791000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Measurement of lactate levels in postmortem brain, iPSCs, and animal models of schizophrenia"],"prefix":"10.1038","volume":"9","author":[{"given":"Courtney R.","family":"Sullivan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharine A.","family":"Mielnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Funk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinead M.","family":"O\u2019Donovan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Bentea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail","family":"Pletnikov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2717-5279","authenticated-orcid":false,"given":"Amy J.","family":"Ramsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-3845","authenticated-orcid":false,"given":"Zhexing","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M.","family":"Rowland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"McCullumsmith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,25]]},"reference":[{"key":"41572_CR1","unstructured":"Association, A. P. (American Psychiatric Association, Washington, D.C., 2000)."},{"key":"41572_CR2","unstructured":"Buchanan, R. W. & Carpenter, W. T. In Comprehensive Textbook of Psychiatry Vol. 1 (eds Sadock, B. J. & Sadock, V. A.) 1096\u20131110 (Lippincott, Williams, and Wilkins, 2000)."},{"issue":"Spec No 1","key":"41572_CR3","first-page":"12","volume":"26","author":"W Fleischhacker","year":"2000","unstructured":"Fleischhacker, W. Negative symptoms in patients with schizophrenia with special reference to the primary versus secondary distinction. Encephale 26(Spec No 1), 12\u201314 (2000).","journal-title":"Encephale"},{"key":"41572_CR4","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.psychres.2007.10.006","volume":"165","author":"A Zanello","year":"2009","unstructured":"Zanello, A., Curtis, L., Badan Ba, M. & Merlo, M. C. Working memory impairments in first-episode psychosis and chronic schizophrenia. Psychiatry Res 165, 10\u201318, https:\/\/doi.org\/10.1016\/j.psychres.2007.10.006 (2009).","journal-title":"Psychiatry Res"},{"key":"41572_CR5","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.schres.2008.06.001","volume":"105","author":"T Wobrock","year":"2008","unstructured":"Wobrock, T. et al. Reduced cortical inhibition in first-episode schizophrenia. Schizophr Res 105, 252\u2013261, https:\/\/doi.org\/10.1016\/j.schres.2008.06.001 (2008).","journal-title":"Schizophr Res"},{"key":"41572_CR6","doi-asserted-by":"publisher","first-page":"10625","DOI":"10.1073\/pnas.91.22.10625","volume":"91","author":"L Pellerin","year":"1994","unstructured":"Pellerin, L. & Magistretti, P. J. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91, 10625\u201310629 (1994).","journal-title":"Proc Natl Acad Sci USA"},{"key":"41572_CR7","doi-asserted-by":"publisher","first-page":"3843","DOI":"10.1046\/j.1460-9568.2000.00269.x","volume":"12","author":"JY Chatton","year":"2000","unstructured":"Chatton, J. Y., Marquet, P. & Magistretti, P. J. A quantitative analysis of L-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics. Eur J Neurosci 12, 3843\u20133853 (2000).","journal-title":"Eur J Neurosci"},{"key":"41572_CR8","doi-asserted-by":"publisher","first-page":"7337","DOI":"10.1523\/JNEUROSCI.23-19-07337.2003","volume":"23","author":"A Loaiza","year":"2003","unstructured":"Loaiza, A., Porras, O. H. & Barros, L. F. Glutamate triggers rapid glucose transport stimulation in astrocytes as evidenced by real-time confocal microscopy. J Neurosci 23, 7337\u20137342 (2003).","journal-title":"J Neurosci"},{"key":"41572_CR9","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1523\/jneurosci.4687-12.2014","volume":"34","author":"M Nagase","year":"2014","unstructured":"Nagase, M., Takahashi, Y., Watabe, A. M., Kubo, Y. & Kato, F. On-site energy supply at synapses through monocarboxylate transporters maintains excitatory synaptic transmission. J Neurosci 34, 2605\u20132617, https:\/\/doi.org\/10.1523\/jneurosci.4687-12.2014 (2014).","journal-title":"J Neurosci"},{"key":"41572_CR10","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1002\/glia.20528","volume":"55","author":"L Pellerin","year":"2007","unstructured":"Pellerin, L. et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55, 1251\u20131262, https:\/\/doi.org\/10.1002\/glia.20528 (2007).","journal-title":"Glia"},{"key":"41572_CR11","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1159\/000017324","volume":"20","author":"L Pellerin","year":"1998","unstructured":"Pellerin, L. et al. Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci 20, 291\u2013299 (1998).","journal-title":"Dev Neurosci"},{"key":"41572_CR12","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/ncb1881","volume":"11","author":"A Herrero-Mendez","year":"2009","unstructured":"Herrero-Mendez, A. et al. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC\/C-Cdh1. Nature cell biology 11, 747\u2013752, https:\/\/doi.org\/10.1038\/ncb1881 (2009).","journal-title":"Nature cell biology"},{"key":"41572_CR13","doi-asserted-by":"publisher","first-page":"15294","DOI":"10.1073\/pnas.261560998","volume":"98","author":"A Almeida","year":"2001","unstructured":"Almeida, A., Almeida, J., Bolanos, J. P. & Moncada, S. Different responses of astrocytes and neurons to nitric oxide: the role of glycolytically generated ATP in astrocyte protection. Proc Natl Acad Sci USA 98, 15294\u201315299, https:\/\/doi.org\/10.1073\/pnas.261560998 (2001).","journal-title":"Proc Natl Acad Sci USA"},{"key":"41572_CR14","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.cell.2011.02.018","volume":"144","author":"A Suzuki","year":"2011","unstructured":"Suzuki, A. et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 144, 810\u2013823, https:\/\/doi.org\/10.1016\/j.cell.2011.02.018 (2011).","journal-title":"Cell"},{"key":"41572_CR15","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.biopsych.2008.11.010","volume":"65","author":"WT Regenold","year":"2009","unstructured":"Regenold, W. T. et al. Elevated cerebrospinal fluid lactate concentrations in patients with bipolar disorder and schizophrenia: implications for the mitochondrial dysfunction hypothesis. Biol Psychiatry 65, 489\u2013494, https:\/\/doi.org\/10.1016\/j.biopsych.2008.11.010 (2009).","journal-title":"Biol Psychiatry"},{"key":"41572_CR16","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/mp.2010.71","volume":"16","author":"M Herberth","year":"2011","unstructured":"Herberth, M. et al. Impaired glycolytic response in peripheral blood mononuclear cells of first-onset antipsychotic-naive schizophrenia patients. Mol Psychiatry 16, 848\u2013859, https:\/\/doi.org\/10.1038\/mp.2010.71 (2011).","journal-title":"Mol Psychiatry"},{"key":"41572_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.239","volume":"6","author":"LM Rowland","year":"2016","unstructured":"Rowland, L. M. et al. Elevated brain lactate in schizophrenia: a 7T magnetic resonance spectroscopy study. Transl Psychiatry 6, e967, https:\/\/doi.org\/10.1038\/tp.2016.239 (2016).","journal-title":"Transl Psychiatry"},{"issue":"684-697","key":"41572_CR18","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/sj.mp.4001511","volume":"9","author":"S Prabakaran","year":"2004","unstructured":"Prabakaran, S. et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9(684-697), 643, https:\/\/doi.org\/10.1038\/sj.mp.4001511 (2004).","journal-title":"Mol Psychiatry"},{"key":"41572_CR19","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.jneumeth.2007.11.017S0165-0270(07)00560-2","volume":"169","author":"ND Halim","year":"2008","unstructured":"Halim, N. D. et al. Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds. J Neurosci Methods 169, 208\u2013213, https:\/\/doi.org\/10.1016\/j.jneumeth.2007.11.017S0165-0270(07)00560-2 (2008).","journal-title":"J Neurosci Methods"},{"key":"41572_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.226","volume":"6","author":"B Dean","year":"2016","unstructured":"Dean, B., Thomas, N., Scarr, E. & Udawela, M. Evidence for impaired glucose metabolism in the striatum, obtained postmortem, from some subjects with schizophrenia. Transl Psychiatry 6, e949, https:\/\/doi.org\/10.1038\/tp.2016.226 (2016).","journal-title":"Transl Psychiatry"},{"key":"41572_CR21","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/npp.2017.167","volume":"43","author":"H Hagihara","year":"2018","unstructured":"Hagihara, H. et al. Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders. Neuropsychopharmacology 43, 459\u2013468, https:\/\/doi.org\/10.1038\/npp.2017.167 (2018).","journal-title":"Neuropsychopharmacology"},{"key":"41572_CR22","doi-asserted-by":"publisher","first-page":"43","DOI":"10.3389\/fphys.2014.00043","volume":"5","author":"VA Ruffin","year":"2014","unstructured":"Ruffin, V. A., Salameh, A. I., Boron, W. F. & Parker, M. D. Intracellular pH regulation by acid-base transporters in mammalian neurons. Front Physiol 5, 43, https:\/\/doi.org\/10.3389\/fphys.2014.00043 (2014).","journal-title":"Front Physiol"},{"key":"41572_CR23","doi-asserted-by":"publisher","unstructured":"Sullivan, C., Hasselfeld, K., O\u2019Donovan, S., Ramsey, A. & McCullumsmith, R. Neuron-specific deficits of neuroenergetic processes in the dorsolateral prefrontal cortex in schizophrenia. Molecular Psychiatry, https:\/\/doi.org\/10.1038\/s41380-41018-40035-41383 (2019).","DOI":"10.1038\/s41380-41018-40035-41383"},{"key":"41572_CR24","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1111\/j.1600-0404.2006.00671.x","volume":"114","author":"J Finsterer","year":"2006","unstructured":"Finsterer, J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol Scand 114, 217\u2013238, https:\/\/doi.org\/10.1111\/j.1600-0404.2006.00671.x (2006).","journal-title":"Acta Neurol Scand"},{"key":"41572_CR25","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1007\/s00330-016-4454-8","volume":"27","author":"RJ Lunsing","year":"2017","unstructured":"Lunsing, R. J., Strating, K., de Koning, T. J. & Sijens, P. E. Diagnostic value of MRS-quantified brain tissue lactate level in identifying children with mitochondrial disorders. Eur Radiol 27, 976\u2013984, https:\/\/doi.org\/10.1007\/s00330-016-4454-8 (2017).","journal-title":"Eur Radiol"},{"key":"41572_CR26","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.neubiorev.2014.11.005","volume":"48","author":"A Rajasekaran","year":"2015","unstructured":"Rajasekaran, A., Venkatasubramanian, G., Berk, M. & Debnath, M. Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev 48, 10\u201321, https:\/\/doi.org\/10.1016\/j.neubiorev.2014.11.005 (2015).","journal-title":"Neurosci Biobehav Rev"},{"key":"41572_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-018-0123-9","volume":"8","author":"Y Jouroukhin","year":"2018","unstructured":"Jouroukhin, Y. et al. DISC1 regulates lactate metabolism in astrocytes: implications for psychiatric disorders. Transl Psychiatry 8, 76, https:\/\/doi.org\/10.1038\/s41398-018-0123-9 (2018).","journal-title":"Transl Psychiatry"},{"issue":"173-186","key":"41572_CR28","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/sj.mp.4002079","volume":"13","author":"MV Pletnikov","year":"2008","unstructured":"Pletnikov, M. V. et al. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry 13(173-186), 115, https:\/\/doi.org\/10.1038\/sj.mp.4002079 (2008).","journal-title":"Mol Psychiatry"},{"key":"41572_CR29","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1016\/j.biopsych.2017.10.014","volume":"83","author":"CR Sullivan","year":"2018","unstructured":"Sullivan, C. R., O\u2019Donovan, S. M., McCullumsmith, R. E. & Ramsey, A. Defects in Bioenergetic Coupling in Schizophrenia. Biol Psychiatry 83, 739\u2013750, https:\/\/doi.org\/10.1016\/j.biopsych.2017.10.014 (2018).","journal-title":"Biol Psychiatry"},{"key":"41572_CR30","doi-asserted-by":"publisher","unstructured":"Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421\u2013427, https:\/\/doi.org\/10.1038\/nature13595 (2014).","DOI":"10.1038\/nature13595"},{"key":"41572_CR31","doi-asserted-by":"publisher","first-page":"17785","DOI":"10.1073\/pnas.1004361107","volume":"107","author":"YU Park","year":"2010","unstructured":"Park, Y. U. et al. Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proc Natl Acad Sci USA 107, 17785\u201317790, https:\/\/doi.org\/10.1073\/pnas.1004361107 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"41572_CR32","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-018-1390-4","author":"CR Sullivan","year":"2018","unstructured":"Sullivan, C. R. et al. Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments. Mol Neurobiol. https:\/\/doi.org\/10.1007\/s12035-018-1390-4 (2018).","journal-title":"Mol Neurobiol"},{"key":"41572_CR33","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1159\/000441252","volume":"1","author":"BE Hjelm","year":"2015","unstructured":"Hjelm, B. E. et al. Evidence of Mitochondrial Dysfunction within the Complex Genetic Etiology of Schizophrenia. Mol Neuropsychiatry 1, 201\u2013219, https:\/\/doi.org\/10.1159\/000441252 (2015).","journal-title":"Mol Neuropsychiatry"},{"key":"41572_CR34","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s10059-012-2284-3","volume":"33","author":"C Park","year":"2012","unstructured":"Park, C. & Park, S. K. Molecular links between mitochondrial dysfunctions and schizophrenia. Mol Cells 33, 105\u2013110, https:\/\/doi.org\/10.1007\/s10059-012-2284-3 (2012).","journal-title":"Mol Cells"},{"key":"41572_CR35","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s10545-005-5518-0","volume":"28","author":"AA Morris","year":"2005","unstructured":"Morris, A. A. Cerebral ketone body metabolism. J Inherit Metab Dis 28, 109\u2013121, https:\/\/doi.org\/10.1007\/s10545-005-5518-0 (2005).","journal-title":"J Inherit Metab Dis"},{"key":"41572_CR36","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.schres.2015.10.041","volume":"169","author":"AK Kraeuter","year":"2015","unstructured":"Kraeuter, A. K., Loxton, H., Lima, B. C., Rudd, D. & Sarnyai, Z. Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia. Schizophr Res 169, 491\u2013493, https:\/\/doi.org\/10.1016\/j.schres.2015.10.041 (2015).","journal-title":"Schizophr Res"},{"key":"41572_CR37","doi-asserted-by":"publisher","unstructured":"Kraeuter, A. K., van den Buuse, M. & Sarnyai, Z. Ketogenic diet prevents impaired prepulse inhibition of startle in an acute NMDA receptor hypofunction model of schizophrenia. Schizophr Res, https:\/\/doi.org\/10.1016\/j.schres.2018.11.011 (2018).","DOI":"10.1016\/j.schres.2018.11.011"},{"key":"41572_CR38","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.schres.2017.01.053","volume":"189","author":"CM Palmer","year":"2017","unstructured":"Palmer, C. M. Ketogenic diet in the treatment of schizoaffective disorder: Two case studies. Schizophr Res 189, 208\u2013209, https:\/\/doi.org\/10.1016\/j.schres.2017.01.053 (2017).","journal-title":"Schizophr Res"},{"key":"41572_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15761\/CNM.1000105","volume":"1","author":"J Gilbert-Jaramillo","year":"2018","unstructured":"Gilbert-Jaramillo, J. et al. The effects of the ketogenic diet on psychiatric symptomatology, weight and metabolic dysfunction in schizophrenia patients. Clinical Nutrition and Metabolism 1, 1\u20135 (2018).","journal-title":"Clinical Nutrition and Metabolism"},{"key":"41572_CR40","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1002\/syn.20623","volume":"63","author":"RC Roberts","year":"2009","unstructured":"Roberts, R. C., Roche, J. K., Conley, R. R. & Lahti, A. C. Dopaminergic synapses in the caudate of subjects with schizophrenia: relationship to treatment response. Synapse 63, 520\u2013530, https:\/\/doi.org\/10.1002\/syn.20623 (2009).","journal-title":"Synapse"},{"key":"41572_CR41","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1038\/mp.2015.148","volume":"21","author":"RE McCullumsmith","year":"2016","unstructured":"McCullumsmith, R. E. et al. Cell-specific abnormalities of glutamate transporters in schizophrenia: sick astrocytes and compensating relay neurons? Mol Psychiatry 21, 823\u2013830, https:\/\/doi.org\/10.1038\/mp.2015.148 (2016).","journal-title":"Mol Psychiatry"},{"key":"41572_CR42","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","volume":"150","author":"PK Smith","year":"1985","unstructured":"Smith, P. K. et al. Measurement of protein using bicinchoninic acid. Anal Biochem 150, 76\u201385 (1985).","journal-title":"Anal Biochem"},{"key":"41572_CR43","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/S0092-8674(00)81972-8","volume":"98","author":"AR Mohn","year":"1999","unstructured":"Mohn, A. R., Gainetdinov, R. R., Caron, M. G. & Koller, B. H. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 98, 427\u2013436 (1999).","journal-title":"Cell"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41572-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41572-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41572-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T07:58:16Z","timestamp":1671263896000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41572-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,25]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["41572"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-41572-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,25]]},"assertion":[{"value":"31 July 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2019","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":"5087"}}