{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:06:00Z","timestamp":1791273960412,"version":"4.1.0"},"reference-count":39,"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>\n                  <jats:p>\n                    c-Jun N-terminal kinase (JNK) mediates hepatotoxicity through interaction of its phospho-activated form with a mitochondrial outer membrane protein, Sh3bp5 or Sab, leading to dephosphorylation of intermembrane Src and consequent impaired mitochondrial respiration and enhanced ROS release. ROS production from mitochondria activates MAP3 kinases, such as MLK3 and ASK1, which continue to activate a pathway to sustain JNK activation, and amplifies the toxic effect of acetaminophen (APAP) and TNF\/galactosamine (TNF\/GalN). Downstream of MAP3K, in various contexts MKK4 activates both JNK and p38 kinases and MKK7 activates only JNK. The relative role of MKK4\n                    <jats:italic>versus<\/jats:italic>\n                    7 in liver injury is largely unexplored, as is the potential role of p38 kinase, which might be a key mediator of toxicity in addition to JNK. Antisense oligonucleotides (ASO) to MKK4, MKK7 and p38 (\n                    <jats:italic>versus<\/jats:italic>\n                    scrambled control) were used for\n                    <jats:italic>in vivo<\/jats:italic>\n                    knockdown, and in some experiments PMH were used after\n                    <jats:italic>in vivo<\/jats:italic>\n                    knockdown. Mice were treated with APAP or TNF\/GalN and injury assessed. MKK4 and MKK7 were expressed in liver and each was efficiently knocked down with two different ASOs. Massive liver injury and ALT elevation were abrogated by MKK4 but not MKK7 ASO pretreatment in both injury models. The protection was confirmed in PMH. Knockdown of MKK4 completely inhibited basal P-p38 in both cytoplasm and mitochondria. However, ALT levels and histologic injury in APAP-treated mice were not altered with p38 knockdown\n                    <jats:italic>versus<\/jats:italic>\n                    scrambled control. p38 knockdown significantly increased P-JNK levels in cytoplasm but not mitochondria after APAP treatment. In conclusion, MKK4 is the major MAP2K, which activates JNK in acute liver injury. p38, the other downstream target of MKK4, does not contribute to liver injury from APAP or TNF\/galactosamine.\n                  <\/jats:p>","DOI":"10.1038\/cddis.2017.295","type":"journal-article","created":{"date-parts":[[2017,6,29]],"date-time":"2017-06-29T11:45:56Z","timestamp":1498736756000},"page":"e2903-e2903","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["The role of MAP2 kinases and p38 kinase in acute murine liver injury models"],"prefix":"10.1038","volume":"8","author":[{"given":"Jun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W M","family":"Min","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Aghajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tin A","family":"Than","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanda","family":"Win","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Kaplowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,29]]},"reference":[{"key":"BFcddis2017295_CR1","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1002\/hep.28486","volume":"63","author":"S Win","year":"2016","unstructured":"Win S, Than TA, Min RW, Aghajan M, Kaplowitz N . c-Jun N-terminal kinase mediates mouse liver injury through a novel Sab (SH3BP5)-dependent pathway leading to inactivation of intramitochondrial Src. Hepatology 2016; 63: 1987\u20132003.","journal-title":"Hepatology"},{"key":"BFcddis2017295_CR2","doi-asserted-by":"publisher","first-page":"35071","DOI":"10.1074\/jbc.M111.276089","volume":"286","author":"S Win","year":"2011","unstructured":"Win S, Than TA, Han D, Petrovic LM, Kaplowitz N . C-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice. J Biol Chem 2011; 286: 35071\u201335078.","journal-title":"J Biol Chem"},{"key":"BFcddis2017295_CR3","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1124\/mol.112.079863","volume":"82","author":"M Sharma","year":"2012","unstructured":"Sharma M, Gadang V, Jaeschke A . Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity. Mol Pharmacol 2012; 82: 1001\u20131007.","journal-title":"Mol Pharmacol"},{"key":"BFcddis2017295_CR4","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1053\/j.gastro.2008.07.006","volume":"135","author":"H Nakagawa","year":"2008","unstructured":"Nakagawa H, Maeda S, Hikiba Y, Ohmae T, Shibata W, Yanai A et al. Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation. Gastroenterology 2008; 135: 1311\u20131321.","journal-title":"Gastroenterology"},{"key":"BFcddis2017295_CR5","doi-asserted-by":"publisher","first-page":"13565","DOI":"10.1074\/jbc.M708916200","volume":"283","author":"N Hanawa","year":"2008","unstructured":"Hanawa N, Shinohara M, Saberi B, Gaarde WA, Han D, Kaplowitz N . Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury. J Biol Chem 2008; 283: 13565\u201313577.","journal-title":"J Biol Chem"},{"key":"BFcddis2017295_CR6","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1002\/hep.20437","volume":"40","author":"K Kon","year":"2004","unstructured":"Kon K, Kim JS, Jaeschke H, Lemasters JJ . Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 2004; 40: 1170\u20131179.","journal-title":"Hepatology"},{"key":"BFcddis2017295_CR7","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.taap.2010.04.015","volume":"246","author":"C Saito","year":"2010","unstructured":"Saito C, Lemasters JJ, Jaeschke H . c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2010; 246: 8\u201317.","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFcddis2017295_CR8","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/sj.cr.7290262","volume":"15","author":"J Liu","year":"2005","unstructured":"Liu J, Lin A . Role of JNK activation in apoptosis: a double edged sword. Cell Res 2005; 15: 36\u201342.","journal-title":"Cell Res"},{"key":"BFcddis2017295_CR9","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1038\/sj.emboj.7600194","volume":"23","author":"F Tsuruta","year":"2004","unstructured":"Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y et al. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J 2004; 23: 1889\u20131899.","journal-title":"EMBO J"},{"key":"BFcddis2017295_CR10","doi-asserted-by":"publisher","first-page":"3172","DOI":"10.1038\/sj.onc.1210410","volume":"26","author":"AJ Whitmarsh","year":"2007","unstructured":"Whitmarsh AJ, Davis RJ . Role of mitogen-activated protein kinase kinase 4 in cancer. Oncogene 2007; 26: 3172\u20133184.","journal-title":"Oncogene"},{"key":"BFcddis2017295_CR11","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1101\/gad.888501","volume":"15","author":"C Tournier","year":"2001","unstructured":"Tournier C, Dong C, Turner TK, Jones SN, Flavell RA, Davis RJ . MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev 2001; 15: 1419\u20131426.","journal-title":"Genes Dev"},{"key":"BFcddis2017295_CR12","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1053\/j.gastro.2015.12.019","volume":"150","author":"FJ Cubero","year":"2016","unstructured":"Cubero FJ, Zoubek ME, Hu W, Peng J, Zhao G, Nevzorova YA et al. Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterology 2016; 150: 968\u2013981.","journal-title":"Gastroenterology"},{"key":"BFcddis2017295_CR13","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1053\/j.gastro.2006.03.045","volume":"131","author":"BK Gunawan","year":"2006","unstructured":"Gunawan BK, Liu ZX, Han D, Hanawa N, Gaarde WA, Kaplowitz N . c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 2006; 131: 165\u2013178.","journal-title":"Gastroenterology"},{"key":"BFcddis2017295_CR14","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1038\/embor.2008.149","volume":"9","author":"J Heinrichsdorff","year":"2008","unstructured":"Heinrichsdorff J, Luedde T, Perdiguero E, Nebreda AR, Pasparakis M . p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep 2008; 9: 1048\u20131054.","journal-title":"EMBO Rep"},{"key":"BFcddis2017295_CR15","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1021\/tx9701687","volume":"11","author":"W Chen","year":"1998","unstructured":"Chen W, Koenigs LL, Thompson SJ, Peter RM, Rettie AE, Trager WF et al. Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. Chem Res Toxicol 1998; 11: 295\u2013301.","journal-title":"Chem Res Toxicol"},{"key":"BFcddis2017295_CR16","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.tips.2013.01.009","volume":"34","author":"D Han","year":"2013","unstructured":"Han D, Dara L, Win S, Than TA, Yuan L, Abbasi SQ et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci 2013; 34: 243\u2013253.","journal-title":"Trends Pharmacol Sci"},{"key":"BFcddis2017295_CR17","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1136\/gut.2008.165647","volume":"58","author":"F Hoffmann","year":"2009","unstructured":"Hoffmann F, Sass G, Zillies J, Zahler S, Tiegs G, Hartkorn A et al. A novel technique for selective NF-kappaB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion. Gut 2009; 58: 1670\u20131678.","journal-title":"Gut"},{"key":"BFcddis2017295_CR18","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.cell.2004.12.041","volume":"120","author":"H Kamata","year":"2005","unstructured":"Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M . Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120: 649\u2013661.","journal-title":"Cell"},{"key":"BFcddis2017295_CR19","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0014-5793(03)00131-5","volume":"538","author":"A Basu","year":"2003","unstructured":"Basu A, Haldar S . Identification of a novel Bcl-xL phosphorylation site regulating the sensitivity of taxol- or 2-methoxyestradiol-induced apoptosis. FEBS Lett 2003; 538: 41\u201347.","journal-title":"FEBS Lett"},{"key":"BFcddis2017295_CR20","doi-asserted-by":"publisher","first-page":"3845","DOI":"10.1128\/MCB.00279-09","volume":"29","author":"C Morel","year":"2009","unstructured":"Morel C, Carlson SM, White FM, Davis RJ . Mcl-1 integrates the opposing actions of signaling pathways that mediate survival and apoptosis. Mol Cell Biol 2009; 29: 3845\u20133852.","journal-title":"Mol Cell Biol"},{"key":"BFcddis2017295_CR21","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1002\/hep.23188","volume":"50","author":"SC Cazanave","year":"2009","unstructured":"Cazanave SC, Gores GJ . The liver's dance with death: two Bcl-2 guardian proteins from the abyss. Hepatology 2009; 50: 1009\u20131013.","journal-title":"Hepatology"},{"key":"BFcddis2017295_CR22","doi-asserted-by":"publisher","first-page":"30039","DOI":"10.1074\/jbc.M109.039545","volume":"284","author":"HC Masuoka","year":"2009","unstructured":"Masuoka HC, Mott J, Bronk SF, Werneburg NW, Akazawa Y, Kaufmann SH et al. Mcl-1 degradation during hepatocyte lipoapoptosis. J Biol Chem 2009; 284: 30039\u201330048.","journal-title":"J Biol Chem"},{"key":"BFcddis2017295_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2015.03.019","volume":"286","author":"Y Xie","year":"2015","unstructured":"Xie Y, Ramachandran A, Breckenridge DG, Liles JT, Lebofsky M, Farhood A et al. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury. Toxicol Appl Pharmacol 2015; 286: 1\u20139.","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFcddis2017295_CR24","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1021\/tx4001013","volume":"26","author":"AD Patterson","year":"2013","unstructured":"Patterson AD, Carlson BA, Li F, Bonzo JA, Yoo MH, Krausz KW et al. Disruption of thioredoxin reductase 1 protects mice from acute acetaminophen-induced hepatotoxicity through enhanced NRF2 activity. Chem Res Toxicol 2013; 26: 1088\u20131096.","journal-title":"Chem Res Toxicol"},{"key":"BFcddis2017295_CR25","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1101\/gad.992302","volume":"16","author":"H Nishitoh","year":"2002","unstructured":"Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 2002; 16: 1345\u20131355.","journal-title":"Genes Dev"},{"key":"BFcddis2017295_CR26","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.molcel.2007.07.008","volume":"27","author":"A Jaeschke","year":"2007","unstructured":"Jaeschke A, Davis RJ . Metabolic stress signaling mediated by mixed-lineage kinases. Mol Cell 2007; 27: 498\u2013508.","journal-title":"Mol Cell"},{"key":"BFcddis2017295_CR27","doi-asserted-by":"publisher","first-page":"3670","DOI":"10.1128\/MCB.25.9.3670-3681.2005","volume":"25","author":"D Brancho","year":"2005","unstructured":"Brancho D, Ventura JJ, Jaeschke A, Doran B, Flavell RA, Davis RJ . Role of MLK3 in the regulation of mitogen-activated protein kinase signaling cascades. Mol Cell Biol 2005; 25: 3670\u20133681.","journal-title":"Mol Cell Biol"},{"key":"BFcddis2017295_CR28","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1002\/hep.21475","volume":"45","author":"C Latchoumycandane","year":"2007","unstructured":"Latchoumycandane C, Goh CW, Ong MM, Boelsterli UA . Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. Hepatology 2007; 45: 412\u2013421.","journal-title":"Hepatology"},{"key":"BFcddis2017295_CR29","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1136\/gut.2006.104372","volume":"56","author":"NC Henderson","year":"2007","unstructured":"Henderson NC, Pollock KJ, Frew J, Mackinnon AC, Flavell RA, Davis RJ et al. Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure. Gut 2007; 56: 982\u2013990.","journal-title":"Gut"},{"key":"BFcddis2017295_CR30","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.bbrc.2008.06.065","volume":"374","author":"M Bourdi","year":"2008","unstructured":"Bourdi M, Korrapati MC, Chakraborty M, Yee SB, Pohl LR . Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury. Biochem Biophys Res Commun 2008; 374: 6\u201310.","journal-title":"Biochem Biophys Res Commun"},{"key":"BFcddis2017295_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2015.03.019","volume":"286","author":"Y Xie","year":"2015","unstructured":"Xie Y, Ramachandran A, Breckenridge DG, Liles JT, Lebofsky M, Farhood A et al. Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury. Toxicol Appl Pharmacol 2015; 286: 1\u20139.","journal-title":"Toxicol Appl Pharmacol"},{"key":"BFcddis2017295_CR32","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1177\/0192623312447551","volume":"40","author":"LM Wancket","year":"2012","unstructured":"Wancket LM, Meng X, Rogers LK, Liu Y . Mitogen-activated protein kinase phosphatase (Mkp)-1 protects mice against acetaminophen-induced hepatic injury. Toxicol Pathol 2012; 40: 1095\u20131105.","journal-title":"Toxicol Pathol"},{"key":"BFcddis2017295_CR33","doi-asserted-by":"publisher","first-page":"e989","DOI":"10.1038\/cddis.2013.522","volume":"5","author":"S Win","year":"2014","unstructured":"Win S, Than TA, Fernandez-Checa JC, Kaplowitz N . JNK interaction with Sab mediates ER stress induced inhibition of mitochondrial respiration and cell death. Cell Death Dis 2014; 5: e989.","journal-title":"Cell Death Dis"},{"key":"BFcddis2017295_CR34","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/j.jhep.2015.01.032","volume":"62","author":"S Win","year":"2015","unstructured":"Win S, Than TA, Le BH, Garc\u00eda-Ruiz C, Fernandez-Checa JC, Kaplowitz N . Sab (Sh3bp5) dependence of JNK mediated inhibition of mitochondrial respiration in palmitic acid induced hepatocyte lipotoxicity. J Hepatol 2015; 62: 1367\u20131374.","journal-title":"J Hepatol"},{"key":"BFcddis2017295_CR35","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.ccell.2016.01.006","volume":"29","author":"N Lalaoui","year":"2016","unstructured":"Lalaoui N, H\u00e4nggi K, Brumatti G, Chau D, Nguyen NY, Vasilikos L et al. Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics. Cancer Cell 2016; 29: 145\u2013158.","journal-title":"Cancer Cell"},{"key":"BFcddis2017295_CR36","doi-asserted-by":"publisher","first-page":"6991","DOI":"10.1073\/pnas.92.15.6991","volume":"92","author":"D Metzger","year":"1995","unstructured":"Metzger D, Clifford J, Chiba H, Chambon P . Conditional site-specific recombination in mammalian cells using a ligand dependent chimeric Cre recombinase. Proc Natl Acad Sci USA 1995; 92: 6991\u20136995.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2017295_CR37","doi-asserted-by":"publisher","first-page":"10887","DOI":"10.1073\/pnas.93.20.10887","volume":"93","author":"R Feil","year":"1996","unstructured":"Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P . Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci USA 1996; 93: 10887\u201310890.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2017295_CR38","doi-asserted-by":"publisher","first-page":"3159","DOI":"10.1038\/nprot.2006.378","volume":"1","author":"I Rahman","year":"2006","unstructured":"Rahman I, Kode A, Biswas SK . Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc 2006; 1: 3159\u20133165.","journal-title":"Nat Protoc"},{"key":"BFcddis2017295_CR39","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1016\/j.freeradbiomed.2006.05.002","volume":"41","author":"D Han","year":"2006","unstructured":"Han D, Hanawa N, Saberi B, Kaplowitz N . Hydrogen peroxide and redox modulation sensitize primary mouse hepatocytes to TNF-induced apoptosis. Free Radic Biol Med 2006; 41: 627\u2013639.","journal-title":"Free Radic Biol Med"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2017295.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017295","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/cddis.2017.295","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2017295.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T12:51:30Z","timestamp":1671713490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2017295"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,29]]},"references-count":39,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2017,6]]}},"alternative-id":["BFcddis2017295"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2017.295","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,29]]},"assertion":[{"value":"17 February 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 May 2017","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 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":"MA is an employee and shareholder of Ionis Pharmaceuticals. The remaining authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}