{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:23:28Z","timestamp":1791473008282,"version":"4.3.4"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2017,6,29]],"date-time":"2017-06-29T00:00:00Z","timestamp":1498694400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,29]],"date-time":"2017-06-29T00:00:00Z","timestamp":1498694400000},"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":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autophagy is triggered during nutrient and energy deprivation in a variety of cells as a homeostatic response to metabolic stress. In the CNS, deficient autophagy has been implicated in neurodegenerative diseases and ischemic brain injury. However, its role in hypoglycemic damage is poorly understood and the dynamics of autophagy during the hypoglycemic and the glucose reperfusion periods, has not been fully described. In the present study, we analyzed the changes in the content of the autophagy proteins BECN1, LC3-II and p62\/SQSTM1 by western blot, and autophagosome formation was followed through time-lapse experiments, during glucose deprivation (GD) and glucose reintroduction (GR) in cortical cultures. According to the results, autophagosome formation rapidly increased during GD, and was followed by an active autophagic flux early after glucose replenishment. However, cells progressively died during GR and autophagy inhibition reduced neuronal death. Neurons undergoing apoptosis during GR did not form autophagosomes, while those surviving up to late GR showed autophagosomes. Calpain activity strongly increased during GR and remained elevated during progressive neuronal death. Its activation led to the cleavage of LAMP2 resulting in lysosome membrane permeabilization (LMP) and release of cathepsin B to the cytosol. Calpain inhibition prevented LMP and increased the number of neurons containing lysosomes and autophagosomes increasing cell viability. Taken together, the present results suggest that calpain-mediated lysosome dysfunction during GR turns an adaptive autophagy response to energy stress into a defective autophagy pathway, which contributes to neuronal death. In these conditions, autophagy inhibition results in the improvement of cell survival.<\/jats:p>","DOI":"10.1038\/cddis.2017.299","type":"journal-article","created":{"date-parts":[[2017,6,29]],"date-time":"2017-06-29T15:45:56Z","timestamp":1498751156000},"page":"e2911-e2911","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Autophagy fails to prevent glucose deprivation\/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons"],"prefix":"10.1038","volume":"8","author":[{"given":"Cristian","family":"Ger\u00f3nimo-Olvera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Montiel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Rincon-Heredia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Castro-Obreg\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourdes","family":"Massieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,29]]},"reference":[{"key":"BFcddis2017299_CR1","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1172\/JCI31669","volume":"117","author":"PE Cryer","year":"2007","unstructured":"Cryer PE . Hypoglycemia, functional brain failure and brain death. J Clin Invest 2007; 117: 868\u2013870.","journal-title":"J Clin Invest"},{"key":"BFcddis2017299_CR2","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1007\/BF00688108","volume":"64","author":"RN Auer","year":"1984","unstructured":"Auer RN, Wieloch T, Olsson Y, Siesj\u00f6 BK . The distribution of hypoglycemic brain damage. Acta Neuropathol 1984; 64: 177\u2013191.","journal-title":"Acta Neuropathol"},{"key":"BFcddis2017299_CR3","doi-asserted-by":"publisher","first-page":"10681","DOI":"10.1523\/JNEUROSCI.23-33-10681.2003","volume":"23","author":"S Suh","year":"2003","unstructured":"Suh S, Aoyama K, Che Y, Garnier P, Matsumori Y, Gum E et al. Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neurosci 2003; 23: 10681\u201310690.","journal-title":"J Neurosci"},{"key":"BFcddis2017299_CR4","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1016\/j.neuroscience.2010.02.074","volume":"167","author":"B P\u00e1ramo","year":"2010","unstructured":"P\u00e1ramo B, Hern\u00e1ndez-Fonseca K, Estrada-S\u00e1nchez AM, Jim\u00e9nez N, Hern\u00e1ndez-Cruz A, Massieu L . Pathways involved in the generation of reactive oxygen and nitrogen species during glucose deprivation and its role on the death of cultured hippocampal neurons. Neuroscience 2010; 167: 1057\u20131069.","journal-title":"Neuroscience"},{"key":"BFcddis2017299_CR5","doi-asserted-by":"publisher","first-page":"2596","DOI":"10.1016\/j.biocel.2013.08.013","volume":"45","author":"B P\u00e1ramo","year":"2013","unstructured":"P\u00e1ramo B, Montiel T, Hern\u00e1ndez-Espinosa DR, Rivera-Mart\u00ednez M, Mor\u00e1n J, Massieu L . Calpain activation induced by glucose deprivation is mediated by oxidative stress and contributes to neuronal damage. Int J Biochem Cell Biol 2013; 45: 2596\u20132604.","journal-title":"Int J Biochem Cell Biol"},{"key":"BFcddis2017299_CR6","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1007\/s10495-013-0930-7","volume":"19","author":"S Garc\u00eda de la Cadena","year":"2014","unstructured":"Garc\u00eda de la Cadena S, Hern\u00e1ndez-Fonseca K, Camacho-Arroyo I, Massieu L . Glucose deprivation induces reticulum stress by PERK pathway and caspase-7 and calpain-mediated caspase-12 activation. Apoptosis 2014; 19: 414\u2013427.","journal-title":"Apoptosis"},{"key":"BFcddis2017299_CR7","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1172\/JCI30077","volume":"117","author":"S Suh","year":"2007","unstructured":"Suh S, Gum ET, Hamby AM, Chan PH, Swanson RA . Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of NADPH oxidase. J Clin Invest 2007; 117: 910\u2013918.","journal-title":"J Clin Invest"},{"key":"BFcddis2017299_CR8","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1146\/annurev-genet-102808-114910","volume":"43","author":"C He","year":"2009","unstructured":"He C, Klionsky DJ . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67\u201393.","journal-title":"Annu Rev Genet"},{"key":"BFcddis2017299_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1348-0421.2010.00271.x","volume":"55","author":"I Tanida","year":"2011","unstructured":"Tanida I . Autophagy basics. Microbiol Immunol 2011; 55: 1\u201311.","journal-title":"Microbiol Immunol"},{"key":"BFcddis2017299_CR10","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nature04723","volume":"441","author":"M Komatsu","year":"2006","unstructured":"Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441: 880\u2013884.","journal-title":"Nature"},{"key":"BFcddis2017299_CR11","first-page":"25","volume":"12","author":"P Anglade","year":"1997","unstructured":"Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson\u2019s disease. Histol Histopathol 1997; 12: 25\u201331.","journal-title":"Histol Histopathol"},{"key":"BFcddis2017299_CR12","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nature04724","volume":"441","author":"T Hara","year":"2006","unstructured":"Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006; 441: 885\u2013889.","journal-title":"Nature"},{"key":"BFcddis2017299_CR13","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/ng1362","volume":"36","author":"B Ravikumar","year":"2004","unstructured":"Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and Mouse models of Huntington disease. Nat Genet 2004; 36: 585\u2013595.","journal-title":"Nat Genet"},{"key":"BFcddis2017299_CR14","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.molcel.2010.09.023","volume":"40","author":"G Kroemer","year":"2010","unstructured":"Kroemer G, Mari\u00f1o G, Levine B . Autophagy and the integrated stress response. Mol Cell 2010; 40: 280\u2013293.","journal-title":"Mol Cell"},{"key":"BFcddis2017299_CR15","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/nrn.2016.51","volume":"17","author":"L Galluzi","year":"2016","unstructured":"Galluzi L, Bravo-San Pedro JM, Blomgren K, Kroemer G . Autophagy in acute brain injury. Nat Rev Neurosci 2016; 17: 467\u2013484.","journal-title":"Nat Rev Neurosci"},{"key":"BFcddis2017299_CR16","doi-asserted-by":"publisher","first-page":"566","DOI":"10.2353\/ajpath.2006.051066","volume":"169","author":"F Adhami","year":"2006","unstructured":"Adhami F, Liao G, Morozov YM, Schloemer A, Schmithrost VJ, Lorenz JN et al. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol 2006; 169: 566\u2013583.","journal-title":"Am J Pathol"},{"key":"BFcddis2017299_CR17","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.nbd.2007.08.005","volume":"29","author":"A Rami","year":"2008","unstructured":"Rami A, Langhagen A, Steiger S . Focal cerebral ishcemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis 2008; 29: 132\u2013141.","journal-title":"Neurobiol Dis"},{"key":"BFcddis2017299_CR18","doi-asserted-by":"publisher","first-page":"762","DOI":"10.4161\/auto.6412","volume":"4","author":"YD Wen","year":"2008","unstructured":"Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 2008; 4: 762\u2013769.","journal-title":"Autophagy"},{"key":"BFcddis2017299_CR19","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.nbd.2008.07.022","volume":"32","author":"S Carloni","year":"2008","unstructured":"Carloni S, Buonocore G, Balduini W . Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 2008; 32: 329\u2013339.","journal-title":"Neurobiol Dis"},{"key":"BFcddis2017299_CR20","doi-asserted-by":"publisher","first-page":"738","DOI":"10.4161\/auto.6.6.12573","volume":"6","author":"AP Qin","year":"2010","unstructured":"Qin AP, Liu CF, Qin YY, Hong LZ, Xu M, Yang L et al. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy 2010; 6: 738\u2013753.","journal-title":"Autophagy"},{"key":"BFcddis2017299_CR21","doi-asserted-by":"publisher","first-page":"151","DOI":"10.4161\/auto.5338","volume":"4","author":"DJ Klionsky","year":"2008","unstructured":"Klionsky DJ, Abeliovich H, Agostinis P, Agrawal DK, Aliev G, Askew DS et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4: 151\u2013175.","journal-title":"Autophagy"},{"key":"BFcddis2017299_CR22","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.4161\/auto.21028","volume":"8","author":"LL Chan","year":"2012","unstructured":"Chan LL, Shen D, Wilkinson AR, Patton W, Lai N, Chan E et al. A novel image-based cytometry method for autophagy detection in living cells. Autophagy 2012; 8: 1371\u20131382.","journal-title":"Autophagy"},{"key":"BFcddis2017299_CR23","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1038\/ncb1482","volume":"8","author":"S Yousefi","year":"2006","unstructured":"Yousefi S, Perozzo R, Schmid I, Ziemicki A, Schaffner T, Scapozza L et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006; 8: 1124\u20131132.","journal-title":"Nat Cell Biol"},{"key":"BFcddis2017299_CR24","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.4161\/auto.6.8.13337","volume":"6","author":"JM Norman","year":"2010","unstructured":"Norman JM, Cohen GM, Bampton ET . The in vitro cleavage of the hAtg proteins by cell death proteases. Autophagy 2010; 6: 1042\u20131056.","journal-title":"Autophagy"},{"key":"BFcddis2017299_CR25","doi-asserted-by":"publisher","first-page":"6434","DOI":"10.1038\/onc.2008.310","volume":"27","author":"P Boya","year":"2008","unstructured":"Boya P, Kroemer G . Lysosomal membrane permeabilization in cell death. Oncogene 2008; 27: 6434\u20136451.","journal-title":"Oncogene"},{"key":"BFcddis2017299_CR26","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.arr.2016.05.008","volume":"32","author":"T Yamashima","year":"2016","unstructured":"Yamashima T . Can \u201ccalpain-cathepsin hypothesis\u201d explain Alzheimer neuronal death? Ageing Res Rev 2016; 32: 169\u2013179.","journal-title":"Ageing Res Rev"},{"key":"BFcddis2017299_CR27","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1471-2202-11-21","volume":"11","author":"S Sadasivan","year":"2010","unstructured":"Sadasivan S, Zhang Z, Larner SF, Liu MC, Zheng W, Kobeissy FH et al. Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype. BMC Neurosci 2010; 11: 21.","journal-title":"BMC Neurosci"},{"key":"BFcddis2017299_CR28","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.brainres.2013.10.032","volume":"1542","author":"JR Kulbe","year":"2014","unstructured":"Kulbe JR, Levy JM, Coultrap SJ, Thorburn A, Bayer KU . Excitotoxic glutamate insults block autophagic flux in hippocampal neurons. Brain Res 2014; 1542: 12\u201319.","journal-title":"Brain Res"},{"key":"BFcddis2017299_CR29","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/j.1432-1033.1987.tb11011.x","volume":"164","author":"PJ Plomp","year":"1987","unstructured":"Plomp PJ, Wolvetang EJ, Groen AK, Meijer AJ, Gordon PB, Seglen PO . Energy dependence of autophagic protein degradation in isolated rat hepatocytes. Eur J Biochem 1987; 164: 197\u2013203.","journal-title":"Eur J Biochem"},{"key":"BFcddis2017299_CR30","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1007\/s11064-015-1700-4","volume":"41","author":"L Camberos-Luna","year":"2016","unstructured":"Camberos-Luna L, Ger\u00f3nimo-Olvera C, Montiel T, Rincon-Heredia R, Massieu L . The ketone body b-hydroxybutyrate stimulates the autophagic flux and prevents neuronal death induced by glucose deprivation in cortical cultured neurons. Neurochem Res 2016; 41: 600\u2013609.","journal-title":"Neurochem Res"},{"key":"BFcddis2017299_CR31","doi-asserted-by":"publisher","first-page":"e2618","DOI":"10.1038\/cddis.2017.34","volume":"8","author":"XY Zhou","year":"2017","unstructured":"Zhou XY, Luo Y, Zhu YM, Liu ZH, Kent TA, Rong JG et al. Inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membrane in ischemic astrocytes. Cell Death Dis 2017; 8: e2618.","journal-title":"Cell Death Dis"},{"key":"BFcddis2017299_CR32","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/sj.jcbfm.9600595","volume":"28","author":"MB Bevers","year":"2008","unstructured":"Bevers MB, Neumar RW . Mechanistic role of calpains in postischemic neurodegeneration. J Cereb Blood Flow Metab 2008; 28: 655\u2013673.","journal-title":"J Cereb Blood Flow Metab"},{"key":"BFcddis2017299_CR33","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/j.bbrc.2010.02.087","volume":"393","author":"S Sahara","year":"2010","unstructured":"Sahara S, Yamashima T . Calpain-mediated Hsp70.1 cleavage in hippocampal CA1 neuronal death. Biochem Biophys Res Commun 2010; 393: 806\u2013811.","journal-title":"Biochem Biophys Res Commun"},{"key":"BFcddis2017299_CR34","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1016\/j.bbamcr.2013.05.019","volume":"1833","author":"GE Villalpando Rodr\u00edguez","year":"2013","unstructured":"Villalpando Rodr\u00edguez GE, Torriglia A . Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2. Biochim Biophys Acta 2013; 1833: 2244\u20132253.","journal-title":"Biochim Biophys Acta"},{"key":"BFcddis2017299_CR35","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1038\/cdd.2012.46","volume":"19","author":"T Arnandis","year":"2012","unstructured":"Arnandis T, Ferrer-Vicens I, Garc\u00eda-Trevijano ER, Miralle VJ, Garc\u00eda C, Torres L et al. Calpains mediate epithelial-cell death during mammary gland involution: mitochondria and lysosomal destabilization. Cell Death Differ 2012; 19: 1536\u20131548.","journal-title":"Cell Death Differ"},{"key":"BFcddis2017299_CR36","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1111\/j.1460-9568.1996.tb01337.x","volume":"8","author":"T Yamashima","year":"1996","unstructured":"Yamashima T, Saido TC, Takita M, Miyazawa A, Yamano J, Miyakawa A et al. Transient brain ischaemia provokes Ca2+, PIP2 and calpain responses prior to delayed neuronal death in monkeys. Eur J Neurosci 1996; 8: 1932\u20131944.","journal-title":"Eur J Neurosci"},{"key":"BFcddis2017299_CR37","doi-asserted-by":"publisher","first-page":"1723","DOI":"10.1046\/j.1460-9568.1998.00184.x","volume":"10","author":"T Yamashima","year":"1998","unstructured":"Yamashima T, Kohda Y, Tsuchiya K, Ueno T, Yamashita J, Yoshioka T et al. Inhibition of ischaemic hippocampal neuronal death in primates with cathepsin B inhibitos CA074: a novel strategy for neuroprotection based on \u201ccalpain-cathepsin hypothesis\u201d. Eur J Neurosci 1998; 10: 1723\u20131733.","journal-title":"Eur J Neurosci"},{"key":"BFcddis2017299_CR38","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1042\/bj20021520","volume":"15","author":"W Li","year":"2003","unstructured":"Li W, Yuan XM, Ivanova S, Tracey KJ, Eaton JW, Brunk UT . 3-aminopropanal, formed during cerebral ischaemia is a potent lysosomotropic neurotoxin. Biochem J 2003; 15: 429\u2013436.","journal-title":"Biochem J"},{"key":"BFcddis2017299_CR39","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1002\/jnr.490350513","volume":"35","author":"GJ Brewer","year":"1993","unstructured":"Brewer GJ, Torricelli JR, Evege EK, Price PJ . Optimized survival of hippocampal neurons in B27-suplemented neurobasal, a new serum free medium combination. J Neurosci Res 1993; 35: 567\u2013576.","journal-title":"J Neurosci Res"},{"key":"BFcddis2017299_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0022-1759(83)90300-9","volume":"65","author":"T Mossman","year":"1983","unstructured":"Mossman T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 1\u20132.","journal-title":"J Immunol Methods"},{"key":"BFcddis2017299_CR41","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, Kraynig V, Longair M, Pietzsch T et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012; 9: 676\u2013682.","journal-title":"Nat Methods"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2017299.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017299","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/cddis.2017.299","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017299.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T17:51:29Z","timestamp":1671731489000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2017299"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,29]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["BFcddis2017299"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2017.299","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,29]]},"assertion":[{"value":"3 November 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2017","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2017","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2017","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}