{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T01:35:33Z","timestamp":1769218533231,"version":"3.49.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T00:00:00Z","timestamp":1569801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T00:00:00Z","timestamp":1569801600000},"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>Corticosteroid-binding globulin (CBG) is synthesized by the liver and secreted into the bloodstream where binds to glucocorticoids. Thus CBG has the role of glucocorticoid transport and free hormone control. In addition, CBG has been detected in some extrahepatic tissues without a known role. CBG-deficient mice show decreased total corticosterone levels with missing of classical sexual dimorphism, increased free corticosterone, higher adrenal gland size and altered HPA axis response to stress. Our aim was to ascertain whether CBG deficiency could affect the endocrine synthetic activity of adrenal gland and if the adrenal gland produces CBG. We determined the expression in adrenal gland of proteins involved in the cholesterol uptake and its transport to mitochondria and the main enzymes involved in the corticosterone, aldosterone and catecholamine synthesis. The results showed that CBG is synthesized in the adrenal gland. CBG-deficiency reduced the expression of ACTH receptor, SRB1 and the main genes involved in the adrenal hormones synthesis, stronger in females resulting in the loss of sexual dimorphism in corticosteroid adrenal synthesis, despite corticosterone content in adrenal glands from CBG-deficient females was similar to wildtype ones. In conclusion, these results point to an unexplored and relevant role of CBG in the adrenal gland functionality related to corticosterone production and release.<\/jats:p>","DOI":"10.1038\/s41598-019-50355-1","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T10:04:48Z","timestamp":1569837888000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Corticosteroid-Binding Globulin is expressed in the adrenal gland and its absence impairs corticosterone synthesis and secretion in a sex-dependent manner"],"prefix":"10.1038","volume":"9","author":[{"given":"Jos\u00e9","family":"Gulfo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricard","family":"Castel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo","family":"Ledda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda del Mar","family":"Romero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Montserrat","family":"Esteve","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar","family":"Grasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"50355_CR1","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1111\/cen.13138","volume":"85","author":"A Radhakutty","year":"2016","unstructured":"Radhakutty, A. et al. Effects of prednisolone on energy and fat metabolism in patients with rheumatoid arthritis: tissue-specific insulin resistance with commonly used prednisolone doses. Clin. Endocrinol. (Oxf). 85, 741\u2013747 (2016).","journal-title":"Clin. Endocrinol. (Oxf)."},{"key":"50355_CR2","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1159\/000362724","volume":"22","author":"D Cruz-Topete","year":"2015","unstructured":"Cruz-Topete, D. & Cidlowski, J. A. One hormone, two actions: anti- and pro-inflammatory effects of glucocorticoids. Neuroimmunomodulation 22, 20\u201332 (2015).","journal-title":"Neuroimmunomodulation"},{"key":"50355_CR3","first-page":"457","volume":"38","author":"PK Siiteri","year":"1982","unstructured":"Siiteri, P. K. et al. The serum transport of steroid hormones. Recent Prog. Horm. Res. 38, 457\u2013510 (1982).","journal-title":"Recent Prog. Horm. Res."},{"key":"50355_CR4","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1210\/edrv-10-3-232","volume":"10","author":"CM Mendel","year":"1989","unstructured":"Mendel, C. M. The free hormone hypothesis: a physiologically based mathematical model. Endocr. Rev. 10, 232\u201374 (1989).","journal-title":"Endocr. Rev."},{"key":"50355_CR5","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.cccn.2005.03.044","volume":"359","author":"JG Lewis","year":"2005","unstructured":"Lewis, J. G., Bagley, C. J., Elder, P. A., Bachmann, A. W. & Torpy, D. J. Plasma free cortisol fraction reflects levels of functioning corticosteroid-binding globulin. Clin. Chim. Acta. 359, 189\u201394 (2005).","journal-title":"Clin. Chim. Acta."},{"key":"50355_CR6","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1210\/jcem-25-9-1163","volume":"25","author":"BU Musa","year":"1965","unstructured":"Musa, B. U., Seal, U. S. & Doe, R. P. Elevation of certain plasma proteins in man following estrogen administration: a dose-response relationship. J. Clin. Endocrinol. Metab. 25, 1163\u20136 (1965).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR7","doi-asserted-by":"publisher","first-page":"3379","DOI":"10.1210\/jcem.83.9.5100-5","volume":"83","author":"C Tsigos","year":"1998","unstructured":"Tsigos, C., Kyrou, I., Chrousos, G. P. & Papanicolaou, D. A. Prolonged suppression of corticosteroid-binding globulin by recombinant human interleukin-6 in man. J. Clin. Endocrinol. Metab. 83, 3379 (1998).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR8","doi-asserted-by":"publisher","first-page":"3192","DOI":"10.1210\/jcem.84.9.5946","volume":"84","author":"JM Fern\u00e1ndez-Real","year":"1999","unstructured":"Fern\u00e1ndez-Real, J. M. et al. Plasma total and glycosylated corticosteroid-binding globulin levels are associated with insulin secretion. J. Clin. Endocrinol. Metab. 84, 3192\u20136 (1999).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR9","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.jchemneu.2007.03.007","volume":"34","author":"GF Jirikowski","year":"2007","unstructured":"Jirikowski, G. F., Pusch, L., M\u00f6pert, B., Herbert, Z. & Caldwell, J. D. Expression of corticosteroid binding globulin in the rat central nervous system. J. Chem. Neuroanat. 34, 22\u201328 (2007).","journal-title":"J. Chem. Neuroanat."},{"key":"50355_CR10","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1023\/A:1013304223967","volume":"228","author":"M Grasa","year":"2001","unstructured":"Grasa, M. et al. Corticosteroid-binding globulin synthesis and distribution in rat white adipose tissue. Mol. Cell. Biochem. 228, 25\u201331 (2001).","journal-title":"Mol. Cell. Biochem."},{"key":"50355_CR11","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1210\/endo.132.2.8425503","volume":"132","author":"LA Scrocchi","year":"1993","unstructured":"Scrocchi, L. A., Hearn, S. A., Han, V. K. & Hammond, G. L. Corticosteroid-binding globulin biosynthesis in the mouse liver and kidney during postnatal development. Endocrinology 132, 910\u2013916 (1993).","journal-title":"Endocrinology"},{"key":"50355_CR12","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1055\/s-0034-1389957","volume":"47","author":"H Sch\u00e4fer","year":"2014","unstructured":"Sch\u00e4fer, H., Gebhart, V., Hertel, K. & Jirikowski, G. Expression of Corticosteroid-Binding Globulin CBG in the Human Heart. Horm. Metab. Res. 47, 596\u2013599 (2014).","journal-title":"Horm. Metab. Res."},{"key":"50355_CR13","doi-asserted-by":"publisher","first-page":"29594","DOI":"10.1074\/jbc.M705014200","volume":"282","author":"MA Klieber","year":"2007","unstructured":"Klieber, M. A., Underhill, C., Hammond, G. L. & Muller, Y. A. Corticosteroid-binding globulin, a structural basis for steroid transport and proteinase-triggered release. J. Biol. Chem. 282, 29594\u2013603 (2007).","journal-title":"J. Biol. Chem."},{"key":"50355_CR14","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1210\/jcem-71-1-34","volume":"71","author":"GL Hammond","year":"1990","unstructured":"Hammond, G. L., Smith, C. L., Paterson, N. A. & Sibbald, W. J. A role for corticosteroid-binding globulin in delivery of cortisol to activated neutrophils. J. Clin. Endocrinol. Metab. 71, 34\u20139 (1990).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR15","doi-asserted-by":"publisher","first-page":"7236","DOI":"10.1128\/MCB.00400-06","volume":"26","author":"HH Petersen","year":"2006","unstructured":"Petersen, H. H. et al. Hyporesponsiveness to Glucocorticoids in Mice Genetically Deficient for the Corticosteroid Binding Globulin. Mol. Cell. Biol. 26, 7236\u20137245 (2006).","journal-title":"Mol. Cell. Biol."},{"key":"50355_CR16","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1002\/oby.21543","volume":"24","author":"J Gulfo","year":"2016","unstructured":"Gulfo, J. et al. Altered lipid partitioning and glucocorticoid availability in CBG-deficient male mice with diet-induced obesity. Obesity (Silver Spring). 24, 1677\u201386 (2016).","journal-title":"Obesity (Silver Spring)."},{"issue":"1","key":"50355_CR17","doi-asserted-by":"publisher","first-page":"e0146497","DOI":"10.1371\/journal.pone.0146497","volume":"11","author":"Jose Gulfo","year":"2016","unstructured":"Gulfo, J. et al. New roles for corticosteroid binding globulin and opposite expression profiles in lung and liver. PLoS One 11 (2016).","journal-title":"PLOS ONE"},{"key":"50355_CR18","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.psyneuen.2014.07.029","volume":"50","author":"AM Minni","year":"2014","unstructured":"Minni, A. M. et al. Role of corticosteroid binding globulin in emotional reactivity sex differences in mice. Psychoneuroendocrinology 50, 252\u2013263 (2014).","journal-title":"Psychoneuroendocrinology"},{"key":"50355_CR19","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1055\/s-0042-108071","volume":"48","author":"E Meyer","year":"2016","unstructured":"Meyer, E., Nenke, M., Rankin, W., Lewis, J. & Torpy, D. Corticosteroid-Binding Globulin: A Review of Basic and Clinical Advances. Horm. Metab. Res. 48, 359\u2013371 (2016).","journal-title":"Horm. Metab. Res."},{"key":"50355_CR20","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1210\/jc.2011-2022","volume":"97","author":"DJ Torpy","year":"2012","unstructured":"Torpy, D. J. et al. CBG Santiago: A novel CBG mutation. J. Clin. Endocrinol. Metab. 97, 151\u2013155 (2012).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR21","doi-asserted-by":"publisher","first-page":"E1684","DOI":"10.1210\/jc.2011-1321","volume":"96","author":"G Cizza","year":"2011","unstructured":"Cizza, G. et al. Clinical manifestations of highly prevalent corticosteroid-binding globulin mutations in a village in southern Italy. J. Clin. Endocrinol. Metab. 96, E1684\u201393 (2011).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR22","doi-asserted-by":"publisher","first-page":"3692","DOI":"10.1210\/jcem.86.8.7724","volume":"86","author":"DJ Torpy","year":"2001","unstructured":"Torpy, D. J. et al. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J. Clin. Endocrinol. Metab. 86, 3692\u2013700 (2001).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"50355_CR23","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1210\/en.2009-0862","volume":"151","author":"EM Richard","year":"2010","unstructured":"Richard, E. M. et al. Plasma transcortin influences endocrine and behavioral stress responses in mice. Endocrinology 151, 649\u2013659 (2010).","journal-title":"Endocrinology"},{"key":"50355_CR24","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1007\/s00204-018-2207-y","volume":"92","author":"S Sun","year":"2018","unstructured":"Sun, S., Wang, J., Lu, Y. & Dai, J. Corticosteroid-binding globulin, induced in testicular Leydig cells by perfluorooctanoic acid, promotes steroid hormone synthesis. Arch. Toxicol. 92, 2013\u20132025 (2018).","journal-title":"Arch. Toxicol."},{"key":"50355_CR25","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3389\/fphar.2018.00545","volume":"9","author":"A Tchoukaev","year":"2018","unstructured":"Tchoukaev, A. et al. Opposite Expression of Hepatic and Pulmonary Corticosteroid-Binding Globulin in Cystic Fibrosis Patients. Front. Pharmacol. 9, 545 (2018).","journal-title":"Front. Pharmacol."},{"key":"50355_CR26","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.ecl.2015.02.001","volume":"44","author":"Y Xing","year":"2015","unstructured":"Xing, Y., Lerario, A. M., Rainey, W. & Hammer, G. D. Development of adrenal cortex zonation. Endocrinol. Metab. Clin. North Am. 44, 243\u201374 (2015).","journal-title":"Endocrinol. Metab. Clin. North Am."},{"key":"50355_CR27","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1152\/physrev.00042.2006","volume":"89","author":"R Kvetnansky","year":"2009","unstructured":"Kvetnansky, R., Sabban, E. L. & Palkovits, M. Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol. Rev. 89, 535\u2013606 (2009).","journal-title":"Physiol. Rev."},{"key":"50355_CR28","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/0024-3205(73)90313-5","volume":"13","author":"R Kvetnansky","year":"1973","unstructured":"Kvetnansky, R. Transsynaptic and humoral regulation of adrenal catecholamines synthesis in stress. Life Sci. 13, 90\u201392 (1973).","journal-title":"Life Sci."},{"key":"50355_CR29","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1007\/s10571-006-9063-7","volume":"26","author":"R Kvetnansky","year":"2006","unstructured":"Kvetnansky, R. et al. Gene expression of phenylethanolamine N-methyltransferase in corticotropin-releasing hormone knockout mice during stress exposure. Cell. Mol. Neurobiol. 26, 735\u201354 (2006).","journal-title":"Cell. Mol. Neurobiol."},{"key":"50355_CR30","doi-asserted-by":"publisher","first-page":"5597","DOI":"10.1210\/endo.137.12.8940389","volume":"137","author":"B Nankova","year":"1996","unstructured":"Nankova, B. et al. Immobilization stress elevates gene expression for catecholamine biosynthetic enzymes and some neuropeptides in rat sympathetic ganglia: effects of adrenocorticotropin and glucocorticoids. Endocrinology 137, 5597\u2013604 (1996).","journal-title":"Endocrinology"},{"key":"50355_CR31","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0304-3940(03)00361-6","volume":"344","author":"BB Nankova","year":"2003","unstructured":"Nankova, B. B., Kvetnansky, R. & Sabban, E. L. Adrenocorticotropic hormone (MC-2) receptor mRNA is expressed in rat sympathetic ganglia and up-regulated by stress. Neurosci. Lett. 344, 149\u201352 (2003).","journal-title":"Neurosci. Lett."},{"key":"50355_CR32","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1016\/S0021-9258(18)96620-2","volume":"241","author":"RJ Wurtman","year":"1966","unstructured":"Wurtman, R. J. & Axelrod, J. Control of enzymatic synthesis of adrenaline in the adrenal medulla by adrenal cortical steroids. J. Biol. Chem. 241, 2301\u20135 (1966).","journal-title":"J. Biol. Chem."},{"key":"50355_CR33","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1007\/s10571-006-9056-6","volume":"26","author":"DL Wong","year":"2006","unstructured":"Wong, D. L. Epinephrine biosynthesis: hormonal and neural control during stress. Cell. Mol. Neurobiol. 26, 891\u2013900 (2006).","journal-title":"Cell. Mol. Neurobiol."},{"key":"50355_CR34","doi-asserted-by":"publisher","first-page":"4766","DOI":"10.1210\/en.2012-1485","volume":"153","author":"AM Minni","year":"2012","unstructured":"Minni, A. M. et al. Critical role of plasma corticosteroid-binding-globulin during stress to promote glucocorticoid delivery to the brain: Impact on memory retrieval. Endocrinology 153, 4766\u20134774 (2012).","journal-title":"Endocrinology"},{"key":"50355_CR35","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1677\/JME-10-0006","volume":"45","author":"Y Xing","year":"2010","unstructured":"Xing, Y., Parker, C. R., Edwards, M. & Rainey, W. E. ACTH is a potent regulator of gene expression in human adrenal cells. J. Mol. Endocrinol. 45, 59\u201368 (2010).","journal-title":"J. Mol. Endocrinol."},{"key":"50355_CR36","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3389\/fendo.2016.00042","volume":"7","author":"W-J Shen","year":"2016","unstructured":"Shen, W.-J., Azhar, S. & Kraemer, F. B. ACTH Regulation of Adrenal SR-B1. Front. Endocrinol. (Lausanne). 7, 42 (2016).","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"50355_CR37","doi-asserted-by":"publisher","first-page":"106","DOI":"10.3389\/fendo.2016.00106","volume":"7","author":"A Midzak","year":"2016","unstructured":"Midzak, A. & Papadopoulos, V. Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies. Front. Endocrinol. (Lausanne). 7, 106 (2016).","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"50355_CR38","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1016\/0024-3205(85)90304-2","volume":"36","author":"A Armario","year":"1985","unstructured":"Armario, A., Restrepo, C., Castellanos, J. M. & Balasch, J. Dissociation between adrenocorticotropin and corticosterone responses to restraint after previous chronic exposure to stress. Life Sci. 36, 2085\u201392 (1985).","journal-title":"Life Sci."},{"key":"50355_CR39","first-page":"275","volume":"44","author":"AF Turcu","year":"2016","unstructured":"Turcu, A. F. & Auchus, R. J. Adrenal Steroidogenesis and Congenital Adrenal Hyperplasia. Int. J. Pediatr. Endocrinol. 44, 275\u2013296 (2016).","journal-title":"Int. J. Pediatr. Endocrinol."},{"key":"50355_CR40","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/cen.13242","volume":"86","author":"A Nordenstr\u00f6m","year":"2017","unstructured":"Nordenstr\u00f6m, A. et al. Are carriers of CYP21A2 mutations less vulnerable to psychological stress? A population-based national cohort study. Clin. Endocrinol. (Oxf). 86, 317\u2013324 (2017).","journal-title":"Clin. Endocrinol. (Oxf)."},{"key":"50355_CR41","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1210\/en.2014-1429","volume":"156","author":"JM Adams","year":"2015","unstructured":"Adams, J. M. et al. Somatostatin Is Essential for the Sexual Dimorphism of GH Secretion, Corticosteroid-Binding Globulin Production, and Corticosterone Levels in Mice. Endocrinology 156, 1052 (2015).","journal-title":"Endocrinology"},{"key":"50355_CR42","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1006\/frne.1993.1010","volume":"14","author":"MF Dallman","year":"1993","unstructured":"Dallman, M. F. et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front. Neuroendocrinol. 14, 303\u201347 (1993).","journal-title":"Front. Neuroendocrinol."},{"key":"50355_CR43","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/0024-3205(92)90204-3","volume":"50","author":"WM van Weerden","year":"1992","unstructured":"van Weerden, W. M., Bierings, H. G., van Steenbrugge, G. J., de Jong, F. H. & Schr\u00f6der, F. H. Adrenal glands of mouse and rat do not synthesize androgens. Life Sci. 50, 857\u201361 (1992).","journal-title":"Life Sci."},{"key":"50355_CR44","doi-asserted-by":"publisher","first-page":"4056","DOI":"10.1210\/en.2007-0331","volume":"148","author":"M del Mar Grasa","year":"2007","unstructured":"del Mar Grasa, M., Serrano, M., Fern\u00e1ndez-L\u00f3pez, J. A. & Alemany, M. Corticosterone inhibits the lipid-mobilizing effects of oleoyl-estrone in adrenalectomized rats. Endocrinology 148, 4056\u201363 (2007).","journal-title":"Endocrinology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50355-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50355-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50355-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T14:02:21Z","timestamp":1671285741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50355-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,30]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["50355"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-50355-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,30]]},"assertion":[{"value":"23 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 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":"14018"}}