{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:25:30Z","timestamp":1790673930257,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T00:00:00Z","timestamp":1553644800000},"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>Parkinson\u2019s disease (PD) is the second most common neurodegenerative disorder and is characterized by motor deficits such as tremor, rigidity and bradykinesia. These symptoms are directly caused by the loss of dopaminergic neurons. However, a wealth of clinical evidence indicates that the dopaminergic system is not the only system affected in PD. Postmortem studies of brains from PD patients have revealed the degeneration of noradrenergic neurons in the locus coeruleus (LC) to the same or even greater extent than that observed in the dopaminergic neurons of substantia nigra (SN) and ventral tegmental area (VTA). Moreover, studies performed on rodent models suggest that enhancement of noradrenergic transmission may attenuate the PD-like phenotype induced by MPTP administration, a neurotoxin-based PD model. The aim of this study was to investigate whether chronic treatment with either of two compounds targeting the noradrenergic system (reboxetine or atipamezole) possess the ability to reduce the progression of a PD-like phenotype in a novel mouse model of progressive dopaminergic neurodegeneration induced by the genetic inhibition of rRNA synthesis in dopaminergic neurons, mimicking a PD-like phenotype. The results showed that reboxetine improved the parkinsonian phenotype associated with delayed progression of SN\/VTA dopaminergic neurodegeneration and higher dopamine content in the striatum. Moreover, the alpha1-adrenergic agonist phenylephrine enhanced survival of TH+ neurons in primary cell cultures, supporting the putative neuroprotective effects of noradrenergic stimulation. Our results provide new insights regarding the possible influence of the noradrenergic system on dopaminergic neuron survival and strongly support the hypothesis regarding the neuroprotective role of noradrenaline.<\/jats:p>","DOI":"10.1038\/s41598-019-41756-3","type":"journal-article","created":{"date-parts":[[2019,3,27]],"date-time":"2019-03-27T16:49:55Z","timestamp":1553705395000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Stimulation of noradrenergic transmission by reboxetine is beneficial for a mouse model of progressive parkinsonism"],"prefix":"10.1038","volume":"9","author":[{"given":"Grzegorz","family":"Kreiner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9622-3476","authenticated-orcid":false,"given":"Katarzyna","family":"Rafa-Zab\u0142ocka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Barut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Chmielarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Kot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Bagi\u0144ska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Parlato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W\u0142adys\u0142awa Anna","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Nalepa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,27]]},"reference":[{"key":"41756_CR1","doi-asserted-by":"publisher","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe, W. et al. Parkinson disease. Nat Rev Dis Primers 3, 17013 (2017).","journal-title":"Nat Rev Dis Primers"},{"key":"41756_CR2","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s00441-004-0956-9","volume":"318","author":"H Braak","year":"2004","unstructured":"Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson\u2019s disease-related pathology. Cell and Tissue Research 318, 121\u2013134 (2004).","journal-title":"Cell and Tissue Research"},{"key":"41756_CR3","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1001\/archneur.60.3.337","volume":"60","author":"C Zarow","year":"2003","unstructured":"Zarow, C., Lyness, S. A., Mortimer, J. A. & Chui, H. C. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol-Chicago 60, 337\u2013341 (2003).","journal-title":"Arch Neurol-Chicago"},{"key":"41756_CR4","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1111\/j.1471-4159.2004.02785.x","volume":"91","author":"KS Rommelfanger","year":"2004","unstructured":"Rommelfanger, K. S., Weinshenker, D. & Miller, G. W. Reduced MPTP toxicity in noradrenaline transporter knockout mice. J Neurochem 91, 1116\u20131124 (2004).","journal-title":"J Neurochem"},{"key":"41756_CR5","doi-asserted-by":"publisher","first-page":"2586","DOI":"10.1046\/j.1460-9568.2003.02684.x","volume":"17","author":"J Srinivasan","year":"2003","unstructured":"Srinivasan, J. & Schmidt, W. J. Potentiation of parkinsonian symptoms by depletion of locus coeruleus noradrenaline in 6-hydroxydopamine-induced partial degeneration of substantia nigra in rats. Eur J Neurosci 17, 2586\u20132592 (2003).","journal-title":"Eur J Neurosci"},{"key":"41756_CR6","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/0306-4522(91)90345-O","volume":"41","author":"M Mavridis","year":"1991","unstructured":"Mavridis, M., Degryse, A. D., Lategan, A. J., Marien, M. R. & Colpaert, F. C. Effects of locus coeruleus lesions on parkinsonian signs, striatal dopamine and substantia nigra cell loss after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in monkeys: a possible role for the locus coeruleus in the progression of Parkinson\u2019s disease. Neuroscience 41, 507\u2013523 (1991).","journal-title":"Neuroscience"},{"key":"41756_CR7","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1016\/j.neuroscience.2008.11.019","volume":"158","author":"KS Rommelfanger","year":"2009","unstructured":"Rommelfanger, K. S., Mitrano, D. A., Smith, Y. & Weinshenker, D. Light and electron microscopic localization of alpha-1 adrenergic receptor immunoreactivity in the rat striatum and ventral midbrain. Neuroscience 158, 1530\u20131540 (2009).","journal-title":"Neuroscience"},{"key":"41756_CR8","doi-asserted-by":"publisher","first-page":"31","DOI":"10.3389\/fnsys.2011.00031","volume":"5","author":"C Delaville","year":"2011","unstructured":"Delaville, C., Deurwaerdere, P. D. & Benazzouz, A. Noradrenaline and Parkinson\u2019s disease. Front Syst Neurosci 5, 31 (2011).","journal-title":"Front Syst Neurosci"},{"key":"41756_CR9","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.2174\/092986707781745550","volume":"14","author":"F Fornai","year":"2007","unstructured":"Fornai, F., di Poggio, A. B., Pellegrini, A., Ruggieri, S. & Paparelli, A. Noradrenaline in Parkinson\u2019s disease: from disease progression to current therapeutics. Curr Med Chem 14, 2330\u20132334 (2007).","journal-title":"Curr Med Chem"},{"key":"41756_CR10","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/2047-9158-1-4","volume":"1","author":"PA Lewitt","year":"2012","unstructured":"Lewitt, P. A. Norepinephrine: the next therapeutics frontier for Parkinson\u2019s disease. Transl Neurodegener 1, 4 (2012).","journal-title":"Transl Neurodegener"},{"key":"41756_CR11","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1523\/JNEUROSCI.0590-10.2011","volume":"31","author":"C Rieker","year":"2011","unstructured":"Rieker, C. et al. Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling. J Neurosci 31, 453\u2013460 (2011).","journal-title":"J Neurosci"},{"key":"41756_CR12","doi-asserted-by":"publisher","first-page":"2898","DOI":"10.1096\/fj.11-181958","volume":"25","author":"A Domanskyi","year":"2011","unstructured":"Domanskyi, A. et al. Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson\u2019s disease models. Faseb Journal 25, 2898\u20132910 (2011).","journal-title":"Faseb Journal"},{"key":"41756_CR13","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.pbb.2015.08.001","volume":"137","author":"P Chmielarz","year":"2015","unstructured":"Chmielarz, P. et al. Disruption of glucocorticoid receptors in the noradrenergic system leads to BDNF up-regulation and altered serotonergic transmission associated with a depressive-like phenotype in female GR(DBHCre) mice. Pharmacol Biochem Behav 137, 69\u201377 (2015).","journal-title":"Pharmacol Biochem Behav"},{"key":"41756_CR14","doi-asserted-by":"publisher","first-page":"207","DOI":"10.3389\/fncel.2013.00207","volume":"7","author":"A Kiryk","year":"2013","unstructured":"Kiryk, A. et al. Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons. Front Cell Neurosci 7, 207 (2013).","journal-title":"Front Cell Neurosci"},{"key":"41756_CR15","doi-asserted-by":"publisher","first-page":"e2813","DOI":"10.1038\/cddis.2017.214","volume":"8","author":"P Chmielarz","year":"2017","unstructured":"Chmielarz, P. et al. Dicer and microRNAs protect adult dopamine neurons. Cell Death & Disease 8, e2813 (2017).","journal-title":"Cell Death & Disease"},{"key":"41756_CR16","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.jneumeth.2010.10.005","volume":"194","author":"A Planken","year":"2010","unstructured":"Planken, A., Porokuokka, L. L., Hanninen, A. L., Tuominen, R. K. & Andressoo, J. O. Medium-throughput computer aided micro-island method to assay embryonic dopaminergic neuron cultures in vitro. J Neurosci Meth 194, 122\u2013131 (2010).","journal-title":"J Neurosci Meth"},{"key":"41756_CR17","first-page":"929","volume":"46","author":"KT Minneman","year":"1994","unstructured":"Minneman, K. T., Hollinger, T. L., Han, S. & Esbenshade, C. T. Selectivity of agonists for cloned alpha 1-adrenergic receptor subtypes. Pharmacology and Experimental Therapeutics 46, 929\u2013936 (1994).","journal-title":"Pharmacology and Experimental Therapeutics"},{"key":"41756_CR18","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 9, 676\u2013682 (2012).","journal-title":"Nat Methods"},{"key":"41756_CR19","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/S0014-2999(02)01660-6","volume":"444","author":"I Nalepa","year":"2002","unstructured":"Nalepa, I. et al. Repeated imipramine and electroconvulsive shock increase alpha 1A-adrenoceptor mRNA level in rat prefrontal cortex. Eur J Pharmacol 444, 151\u2013159 (2002).","journal-title":"Eur J Pharmacol"},{"key":"41756_CR20","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1038\/sj.npp.1300924","volume":"31","author":"G Keilhoff","year":"2006","unstructured":"Keilhoff, G., Becker, A., Grecksch, G., Bernstein, H. G. & Wolf, G. Cell proliferation is influenced by bulbectomy and normalized by imipramine treatment in a region-specific manner. Neuropsychopharmacology 31, 1165\u20131176 (2006).","journal-title":"Neuropsychopharmacology"},{"key":"41756_CR21","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1111\/j.1527-3458.2005.tb00047.x","volume":"11","author":"A Pertovaara","year":"2005","unstructured":"Pertovaara, A., Haapalinna, A., Sirvio, J. & Virtanen, R. Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist. CNS drug reviews 11, 273\u2013288 (2005).","journal-title":"CNS drug reviews"},{"key":"41756_CR22","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.psyneuen.2009.08.014","volume":"35","author":"MC Laarakker","year":"2010","unstructured":"Laarakker, M. C., Raai, J. R., van Lith, H. A. & Ohl, F. The role of the alpha 2A-adrenoceptor in mouse stress-coping behaviour. Psychoneuroendocrinology 35, 490\u2013502 (2010).","journal-title":"Psychoneuroendocrinology"},{"key":"41756_CR23","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1111\/j.1471-4159.2004.02691.x","volume":"91","author":"JA Ihalainen","year":"2004","unstructured":"Ihalainen, J. A. & Tanila, H. In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse nucleus accumbens. J Neurochem 91, 49\u201356 (2004).","journal-title":"J Neurochem"},{"key":"41756_CR24","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s00213-005-0093-5","volume":"182","author":"JF Cryan","year":"2005","unstructured":"Cryan, J. F., Page, M. E. & Lucki, I. Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment. Psychopharmacology (Berl) 182, 335\u2013344 (2005).","journal-title":"Psychopharmacology (Berl)"},{"key":"41756_CR25","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/0014-2999(88)90689-9","volume":"151","author":"H Scheinin","year":"1988","unstructured":"Scheinin, H., MacDonald, E. & Scheinin, M. Behavioural and neurochemical effects of antipamezole, a novel alpha 2-adrenoceptor antagonist. Eur J Pharmacol 151, 35\u201342 (1988).","journal-title":"Eur J Pharmacol"},{"key":"41756_CR26","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/0091-3057(93)90095-B","volume":"45","author":"J Sirvio","year":"1993","unstructured":"Sirvio, J. et al. Dose- and parameter-dependent effects of atipamezole, an alpha 2-antagonist, on the performance of rats in a five-choice serial reaction time task. Pharmacol Biochem Behav 45, 123\u2013129 (1993).","journal-title":"Pharmacol Biochem Behav"},{"key":"41756_CR27","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.neubiorev.2005.03.009","volume":"29","author":"JF Cryan","year":"2005","unstructured":"Cryan, J. F., Mombereau, C. & Vassout, A. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neuroscience & Biobehavioral Reviews 29, 571\u2013625 (2005).","journal-title":"Neuroscience & Biobehavioral Reviews"},{"key":"41756_CR28","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1007\/PL00005092","volume":"356","author":"A Haapalinna","year":"1997","unstructured":"Haapalinna, A. et al. Evaluation of the effects of a specific alpha 2-adrenoceptor antagonist, atipamezole, on alpha 1- and alpha 2-adrenoceptor subtype binding, brain neurochemistry and behaviour in comparison with yohimbine. Naunyn Schmiedebergs Arch Pharmacol 356, 570\u2013582 (1997).","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"41756_CR29","doi-asserted-by":"publisher","unstructured":"Bonito-Oliva, A., Masini, D. & Fisone, G. A mouse model of non-motor symptoms in Parkinson\u2019s disease: focus on pharmacological interventions targeting affective dysfunctions. Frontiers in Behavioral Neuroscience 8, https:\/\/doi.org\/10.3389\/fnbeh.2014.00290 (2014).","DOI":"10.3389\/fnbeh.2014.00290"},{"key":"41756_CR30","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.molcel.2005.05.023","volume":"19","author":"X Yuan","year":"2005","unstructured":"Yuan, X. et al. Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis. Mol Cell 19, 77\u201387 (2005).","journal-title":"Mol Cell"},{"key":"41756_CR31","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1038\/cdd.2013.66","volume":"20","author":"G Kreiner","year":"2013","unstructured":"Kreiner, G. et al. A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell Death Differ 20, 1455\u20131464 (2013).","journal-title":"Cell Death Differ"},{"key":"41756_CR32","doi-asserted-by":"publisher","first-page":"12759","DOI":"10.1523\/JNEUROSCI.2439-08.2008","volume":"28","author":"R Parlato","year":"2008","unstructured":"Parlato, R. et al. Activation of an endogenous suicide response after perturbation of rRNA synthesis leads to neurodegeneration in mice. J Neurosci 28, 12759\u201312764 (2008).","journal-title":"J Neurosci"},{"key":"41756_CR33","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1111\/j.1471-4159.2007.04888.x","volume":"103","author":"JL Madrigal","year":"2007","unstructured":"Madrigal, J. L., Kalinin, S., Richardson, J. C. & Feinstein, D. L. Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta. J Neurochem 103, 2092\u20132101 (2007).","journal-title":"J Neurochem"},{"key":"41756_CR34","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1001\/archneur.63.12.1724","volume":"63","author":"J Tong","year":"2006","unstructured":"Tong, J., Hornykiewicz, O. & Kish, S. J. Inverse relationship between brain noradrenaline level and dopamine loss in Parkinson disease: a possible neuroprotective role for noradrenaline. Arch Neurol 63, 1724\u20131728 (2006).","journal-title":"Arch Neurol"},{"key":"41756_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-15-79","volume":"15","author":"N Kadoguchi","year":"2014","unstructured":"Kadoguchi, N. et al. Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson\u2019s disease. BMC Neurosci 15, 79 (2014).","journal-title":"BMC Neurosci"},{"key":"41756_CR36","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1242\/dmm.028092","volume":"10","author":"V Evsyukov","year":"2017","unstructured":"Evsyukov, V. et al. Genetic mutations linked to Parkinson\u2019s disease differentially control nucleolar activity in pre-symptomatic mouse models. Dis Model Mech 10, 633\u2013643 (2017).","journal-title":"Dis Model Mech"},{"key":"41756_CR37","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1186\/s40478-015-0257-4","volume":"3","author":"P Garcia-Esparcia","year":"2015","unstructured":"Garcia-Esparcia, P. et al. Altered machinery of protein synthesis is region- and stage-dependent and is associated with alpha-synuclein oligomers in Parkinson\u2019s disease. Acta Neuropathol Commun 3, 76 (2015).","journal-title":"Acta Neuropathol Commun"},{"key":"41756_CR38","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.brainres.2016.01.036","volume":"1641","author":"CA Mejias-Aponte","year":"2016","unstructured":"Mejias-Aponte, C. A. Specificity and impact of adrenergic projections to the midbrain dopamine system. Brain Research 1641, 258\u2013273 (2016).","journal-title":"Brain Research"},{"key":"41756_CR39","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1111\/j.1527-3458.2003.tb00258.x","volume":"9","author":"ME Page","year":"2003","unstructured":"Page, M. E. The promises and pitfalls of reboxetine. Cns Drug Reviews 9, 327\u2013342 (2003).","journal-title":"Cns Drug Reviews"},{"key":"41756_CR40","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1002\/mds.26048","volume":"29","author":"AJ Espay","year":"2014","unstructured":"Espay, A. J., LeWitt, P. A. & Kaufmann, H. Norepinephrine deficiency in Parkinson\u2019s disease: the case for noradrenergic enhancement. Mov Disord 29, 1710\u20131719 (2014).","journal-title":"Mov Disord"},{"key":"41756_CR41","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.bcp.2007.01.036","volume":"74","author":"KS Rommelfanger","year":"2007","unstructured":"Rommelfanger, K. S. & Weinshenkey, D. Norepinephrine: The redheaded stepchild of \u2018Parkinson\u2019s disease\u2019. Biochemical Pharmacology 74, 177\u2013190 (2007).","journal-title":"Biochemical Pharmacology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41756-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41756-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41756-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T08:14:18Z","timestamp":1671264858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-41756-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,27]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["41756"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-41756-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,27]]},"assertion":[{"value":"8 November 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 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":"5262"}}