{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:12:26Z","timestamp":1790507546523,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,28]],"date-time":"2017-09-28T00:00:00Z","timestamp":1506556800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,28]],"date-time":"2017-09-28T00:00:00Z","timestamp":1506556800000},"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>Endoplasmic reticulum (ER) stress preconditioning protects cells against methylmercury (MeHg) cytotoxicity by inducing integrated stress responses such as eIF2\u03b1 phosphorylation, ATF4 accumulation, and nonsense-mediated mRNA decay (NMD) suppression. Here we demonstrated that ER stress preconditioning results in the upregulation of membrane transporters, leading to a decrease in intracellular mercury content. Our analyses showed that ER stress preconditioning upregulated the expression of methionine transporters that affect the cellular influx of MeHg, LAT1, LAT3, and SNAT2; and a membrane transporter that affects the efflux of MeHg, ABCC4, in MeHg-susceptible myogenic cells. Among these, ABCC4 transporter expression exhibited the greatest elevation. The functional significance of ABCC4 transporter in the efflux of MeHg was shown by the ABCC4 inhibition study. Additionally, we identified the role of phospho-eIF2\u03b1\/ATF4 pathway in the upregulation of LAT1, SNAT2, and ABCC4 and the role of NMD suppression in LAT3 upregulation. Further, we detected that ER stress preconditioning amplified membrane transporter expression most likely through the translation of the upregulated mRNAs caused by ATF4-dependent transcription and NMD suppression. Taken together, these results suggested that the phospho-eIF2\u03b1\/ATF4 pathway activation and NMD suppression may represent therapeutic targets for the alleviation of MeHg cytotoxicity by enhancing mercury efflux besides inducing protective stress responses.<\/jats:p>","DOI":"10.1038\/s41598-017-09435-3","type":"journal-article","created":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T14:40:31Z","timestamp":1506091231000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Endoplasmic reticulum stress preconditioning modifies intracellular mercury content by upregulating membrane transporters"],"prefix":"10.1038","volume":"7","author":[{"given":"Fusako","family":"Usuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatake","family":"Fujimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,9,28]]},"reference":[{"key":"9435_CR1","first-page":"37","volume":"17","author":"ST Park","year":"1996","unstructured":"Park, S. T., Lim, K. T., Chung, Y. T. & Kim, S. U. Methylmercury-induced neurotoxicity in cerebral neuron culture is blocked by antioxidants and NMDA receptor antagonists. Neurotoxicology \n                           17, 37\u201345 (1996).","journal-title":"Neurotoxicology"},{"key":"9435_CR2","first-page":"17","volume":"17","author":"S Yee","year":"1996","unstructured":"Yee, S. & Choi, B. H. Oxidative stress in neurotoxic effects of methylmercury poisoning. Neurotoxicology \n                           17, 17\u201326 (1996).","journal-title":"Neurotoxicology"},{"key":"9435_CR3","doi-asserted-by":"publisher","first-page":"2291","DOI":"10.1097\/00001756-199807130-00027","volume":"9","author":"F Usuki","year":"1998","unstructured":"Usuki, F. & Ishiura, S. Expanded CTG repeats in myotonin protein kinase increase susceptibility to oxidative stress. Neuroreport \n                           9, 2291\u20132296 (1998).","journal-title":"Neuroreport"},{"key":"9435_CR4","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1136\/jnnp.69.2.254","volume":"69","author":"F Usuki","year":"2000","unstructured":"Usuki, F. & Maruyama, K. Ataxia caused by mutations in the alpha-tocopherol transfer protein gene. J. Neurol. Neurosurg. Psychiatry \n                           69, 254\u2013256 (2000).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"9435_CR5","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.neuro.2007.08.011","volume":"29","author":"F Usuki","year":"2008","unstructured":"Usuki, F., Fujita, E. & Sasagawa, N. Methylmercury activates ASK1\/JNK signaling pathways, leading to apoptosis due to both mitochondria- and endoplasmic reticulum (ER)-generated processes in myogenic cell lines. Neurotoxicology \n                           29, 22\u201330, doi:10.1016\/j.neuro.2007.08.011 (2008).","journal-title":"Neurotoxicology"},{"key":"9435_CR6","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0169-328X(02)00642-3","volume":"110","author":"G Shanker","year":"2003","unstructured":"Shanker, G. & Aschner, M. Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants. Brain Res. Mol. Brain Res. \n                           110, 85\u201391 (2003).","journal-title":"Brain Res. Mol. Brain Res."},{"key":"9435_CR7","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1006\/exmp.1994.1017","volume":"60","author":"S Yee","year":"1994","unstructured":"Yee, S. & Choi, B. H. Methylmercury poisoning induces oxidative stress in the mouse brain. Exp. Mol. Pathol. \n                           60, 188\u2013196, doi:10.1006\/exmp.1994.1017 (1994).","journal-title":"Exp. Mol. Pathol."},{"key":"9435_CR8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/S0304-3940(01)01764-5","volume":"304","author":"F Usuki","year":"2001","unstructured":"Usuki, F. et al. In vivo protection of a water-soluble derivative of vitamin E, Trolox, against methylmercury-intoxication in the rat. Neurosci. Lett. \n                           304, 199\u2013203 (2001).","journal-title":"Neurosci. Lett."},{"key":"9435_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00401-004-0844-0","volume":"108","author":"F Usuki","year":"2004","unstructured":"Usuki, F., Yasutake, A., Umehara, F. & Higuchi, I. Beneficial effects of mild lifelong dietary restriction on skeletal muscle: prevention of age-related mitochondrial damage, morphological changes, and vulnerability to a chemical toxin. Acta Neuropathol. \n                           108, 1\u20139, doi:10.1007\/s00401-004-0844-0 (2004).","journal-title":"Acta Neuropathol."},{"key":"9435_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.taap.2010.09.011","volume":"250","author":"M Fujimura","year":"2011","unstructured":"Fujimura, M., Usuki, F., Kawamura, M. & Izumo, S. Inhibition of the Rho\/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure. Toxicology and applied pharmacology \n                           250, 1\u20139, doi:10.1016\/j.taap.2010.09.011 (2011).","journal-title":"Toxicology and applied pharmacology"},{"key":"9435_CR11","doi-asserted-by":"publisher","DOI":"10.1038\/srep02346","volume":"3","author":"F Usuki","year":"2013","unstructured":"Usuki, F., Fujimura, M. & Yamashita, A. Endoplasmic reticulum stress preconditioning attenuates methylmercury-induced cellular damage by inducing favorable stress responses. Scientific reports \n                           3, 2346, doi:10.1038\/srep02346 (2013).","journal-title":"Scientific reports"},{"key":"9435_CR12","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/S1097-2765(03)00105-9","volume":"11","author":"HP Harding","year":"2003","unstructured":"Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular cell \n                           11, 619\u2013633 (2003).","journal-title":"Molecular cell"},{"issue":"Suppl 5","key":"9435_CR13","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1289\/ehp.02110s5689","volume":"110","author":"N Ballatori","year":"2002","unstructured":"Ballatori, N. Transport of toxic metals by molecular mimicry. Environmental health perspectives \n                           110(Suppl 5), 689\u2013694 (2002).","journal-title":"Environmental health perspectives"},{"key":"9435_CR14","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1042\/bj20020841","volume":"367","author":"TA Simmons-Willis","year":"2002","unstructured":"Simmons-Willis, T. A., Koh, A. S., Clarkson, T. W. & Ballatori, N. Transport of a neurotoxicant by molecular mimicry: the methylmercury-L-cysteine complex is a substrate for human L-type large neutral amino acid transporter (LAT) 1 and LAT2. The Biochemical journal \n                           367, 239\u2013246, doi:10.1042\/bj20020841 (2002).","journal-title":"The Biochemical journal"},{"key":"9435_CR15","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1111\/j.1471-4159.2008.05683.x","volume":"107","author":"Z Yin","year":"2008","unstructured":"Yin, Z. et al. The methylmercury-L-cysteine conjugate is a substrate for the L-type large neutral amino acid transporter. Journal of neurochemistry \n                           107, 1083\u20131090, doi:10.1111\/j.1471-4159.2008.05683.x (2008).","journal-title":"Journal of neurochemistry"},{"key":"9435_CR16","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.taap.2003.10.008","volume":"195","author":"CL Hammond","year":"2004","unstructured":"Hammond, C. L., Madejczyk, M. S. & Ballatori, N. Activation of plasma membrane reduced glutathione transport in death receptor apoptosis of HepG2 cells. Toxicology and applied pharmacology \n                           195, 12\u201322, doi:10.1016\/j.taap.2003.10.008 (2004).","journal-title":"Toxicology and applied pharmacology"},{"key":"9435_CR17","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.taap.2004.09.008","volume":"204","author":"N Ballatori","year":"2005","unstructured":"Ballatori, N., Hammond, C. L., Cunningham, J. B., Krance, S. M. & Marchan, R. Molecular mechanisms of reduced glutathione transport: role of the MRP\/CFTR\/ABCC and OATP\/SLC21A families of membrane proteins. Toxicology and applied pharmacology \n                           204, 238\u2013255, doi:10.1016\/j.taap.2004.09.008 (2005).","journal-title":"Toxicology and applied pharmacology"},{"key":"9435_CR18","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.bbapap.2005.10.002","volume":"1754","author":"A Yamashita","year":"2005","unstructured":"Yamashita, A., Kashima, I. & Ohno, S. The role of SMG-1 in nonsense-mediated mRNA decay. Biochimica et biophysica acta \n                           1754, 305\u2013315, doi:10.1016\/j.bbapap.2005.10.002 (2005).","journal-title":"Biochimica et biophysica acta"},{"key":"9435_CR19","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1038\/ng1429","volume":"36","author":"JT Mendell","year":"2004","unstructured":"Mendell, J. T., Sharifi, N. A., Meyers, J. L., Martinez-Murillo, F. & Dietz, H. C. Nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise. Nature genetics \n                           36, 1073\u20131078, doi:10.1038\/ng1429 (2004).","journal-title":"Nature genetics"},{"key":"9435_CR20","doi-asserted-by":"crossref","first-page":"C1077","DOI":"10.1152\/ajpcell.2001.281.4.C1077","volume":"281","author":"CA Wagner","year":"2001","unstructured":"Wagner, C. A., Lang, F. & Broer, S. Function and structure of heterodimeric amino acid transporters. American journal of physiology. Cell physiology \n                           281, C1077\u20131093 (2001).","journal-title":"American journal of physiology. Cell physiology"},{"key":"9435_CR21","doi-asserted-by":"publisher","first-page":"888","DOI":"10.2353\/ajpath.2007.060428","volume":"170","author":"D Fukuhara","year":"2007","unstructured":"Fukuhara, D. et al. Protein characterization of NA+ -independent system L amino acid transporter 3 in mice: a potential role in supply of branched-chain amino acids under nutrient starvation. The American journal of pathology \n                           170, 888\u2013898, doi:10.2353\/ajpath.2007.060428 (2007).","journal-title":"The American journal of pathology"},{"key":"9435_CR22","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1152\/japplphysiol.01408.2010","volume":"111","author":"MJ Drummond","year":"2011","unstructured":"Drummond, M. J. et al. Skeletal muscle amino acid transporter expression is increased in young and older adults following resistance exercise. Journal of applied physiology (Bethesda, Md.: 1985) \n                           111, 135\u2013142, doi:10.1152\/japplphysiol.01408.2010 (2011).","journal-title":"Journal of applied physiology (Bethesda, Md.: 1985)"},{"key":"9435_CR23","first-page":"1281","volume":"5","author":"Q Wang","year":"2015","unstructured":"Wang, Q. & Holst, J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. Am. J. Cancer Res. \n                           5, 1281\u20131294 (2015).","journal-title":"Am. J. Cancer Res."},{"key":"9435_CR24","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.bcp.2014.05.023","volume":"91","author":"L Cheung","year":"2014","unstructured":"Cheung, L. et al. High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4). Biochem. Pharmacol. \n                           91, 97\u2013108, doi:10.1016\/j.bcp.2014.05.023 (2014).","journal-title":"Biochem. Pharmacol."},{"key":"9435_CR25","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1101\/gad.1389006","volume":"20","author":"I Kashima","year":"2006","unstructured":"Kashima, I. et al. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes & development \n                           20, 355\u2013367, doi:10.1101\/gad.1389006 (2006).","journal-title":"Genes & development"},{"key":"9435_CR26","doi-asserted-by":"publisher","first-page":"E592","DOI":"10.1152\/ajpendo.90645.2008","volume":"296","author":"J Avruch","year":"2009","unstructured":"Avruch, J. et al. Amino acid regulation of TOR complex 1. Am. J. Physiol. Endocrinol. Metab. \n                           296, E592\u2013602, doi:10.1152\/ajpendo.90645.2008 (2009).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"9435_CR27","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1007\/s00204-015-1528-3","volume":"90","author":"F Usuki","year":"2016","unstructured":"Usuki, F. & Fujimura, M. Decreased plasma thiol antioxidant barrier and selenoproteins as potential biomarkers for ongoing methylmercury intoxication and an individual protective capacity. Arch. Toxicol. \n                           90, 917\u2013926, doi:10.1007\/s00204-015-1528-3 (2016).","journal-title":"Arch. Toxicol."},{"key":"9435_CR28","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1042\/BJ20051867","volume":"395","author":"SS Palii","year":"2006","unstructured":"Palii, S. S., Thiaville, M. M., Pan, Y. X., Zhong, C. & Kilberg, M. S. Characterization of the amino acid response element within the human sodium-coupled neutral amino acid transporter 2 (SNAT2) System A transporter gene. The Biochemical journal \n                           395, 517\u2013527, doi:10.1042\/bj20051867 (2006).","journal-title":"The Biochemical journal"},{"key":"9435_CR29","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.nut.2012.05.008","volume":"29","author":"JQ Luo","year":"2013","unstructured":"Luo, J. Q., Chen, D. W. & Yu, B. Upregulation of amino acid transporter expression induced by L-leucine availability in L6 myotubes is associated with ATF4 signaling through mTORC1-dependent mechanism. Nutrition \n                           29, 284\u2013290, doi:10.1016\/j.nut.2012.05.008 (2013).","journal-title":"Nutrition"},{"key":"9435_CR30","doi-asserted-by":"publisher","first-page":"223s","DOI":"10.3945\/ajcn.113.070086","volume":"99","author":"PM Taylor","year":"2014","unstructured":"Taylor, P. M. Role of amino acid transporters in amino acid sensing. The American journal of clinical nutrition \n                           99, 223s\u2013230s, doi:10.3945\/ajcn.113.070086 (2014).","journal-title":"The American journal of clinical nutrition"},{"key":"9435_CR31","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/hmg\/ddg011","volume":"12","author":"JK Lamba","year":"2003","unstructured":"Lamba, J. K. et al. Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Human molecular genetics \n                           12, 99\u2013109 (2003).","journal-title":"Human molecular genetics"},{"key":"9435_CR32","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1016\/j.bbagrm.2013.02.005","volume":"1829","author":"C Schweingruber","year":"2013","unstructured":"Schweingruber, C., Rufener, S. C., Zund, D., Yamashita, A. & Muhlemann, O. Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochimica et biophysica acta \n                           1829, 612\u2013623, doi:10.1016\/j.bbagrm.2013.02.005 (2013).","journal-title":"Biochimica et biophysica acta"},{"key":"9435_CR33","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1073\/pnas.0136770100","volume":"100","author":"BP Lewis","year":"2003","unstructured":"Lewis, B. P., Green, R. E. & Brenner, S. E. Evidence for the widespread coupling of alternative splicing and nonsense-mediated mRNA decay in humans. Proceedings of the National Academy of Sciences of the United States of America \n                           100, 189\u2013192, doi:10.1073\/pnas.0136770100 (2003).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"9435_CR34","doi-asserted-by":"publisher","first-page":"6641","DOI":"10.1074\/jbc.M110.168872","volume":"286","author":"F Usuki","year":"2011","unstructured":"Usuki, F., Yamashita, A. & Fujimura, M. Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure. The Journal of biological chemistry \n                           286, 6641\u20136649, doi:10.1074\/jbc.M110.168872 (2011).","journal-title":"The Journal of biological chemistry"},{"key":"9435_CR35","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1006\/bbrc.1999.2026","volume":"267","author":"F Usuki","year":"2000","unstructured":"Usuki, F., Takahashi, N., Sasagawa, N. & Ishiura, S. Differential signaling pathways following oxidative stress in mutant myotonin protein kinase cDNA-transfected C2C12 cell lines. Biochemical and biophysical research communications \n                           267, 739\u2013743, doi:10.1006\/bbrc.1999.2026 (2000).","journal-title":"Biochemical and biophysical research communications"},{"key":"9435_CR36","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.ymthe.2006.04.011","volume":"14","author":"F Usuki","year":"2006","unstructured":"Usuki, F. et al. Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. Molecular therapy: the journal of the American Society of Gene Therapy \n                           14, 351\u2013360, doi:10.1016\/j.ymthe.2006.04.011 (2006).","journal-title":"Molecular therapy: the journal of the American Society of Gene Therapy"},{"key":"9435_CR37","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1016\/S1097-2765(03)00443-X","volume":"12","author":"T Ohnishi","year":"2003","unstructured":"Ohnishi, T. et al. Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. Molecular cell \n                           12, 1187\u20131200 (2003).","journal-title":"Molecular cell"},{"key":"9435_CR38","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1101\/gad.1767209","volume":"23","author":"A Yamashita","year":"2009","unstructured":"Yamashita, A. et al. SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes & development \n                           23, 1091\u20131105, doi:10.1101\/gad.1767209 (2009).","journal-title":"Genes & development"},{"key":"9435_CR39","doi-asserted-by":"publisher","first-page":"15037","DOI":"10.1073\/pnas.1300654110","volume":"110","author":"F Usuki","year":"2013","unstructured":"Usuki, F. et al. Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity. Proc. Natl. Acad. Sci. USA \n                           110, 15037\u201315042, doi:10.1073\/pnas.1300654110 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"9435_CR40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm699","volume":"35","author":"M Ichihara","year":"2007","unstructured":"Ichihara, M. et al. Thermodynamic instability of siRNA duplex is a prerequisite for dependable prediction of siRNA activities. Nucleic Acids Res. \n                           35, e123, doi:10.1093\/nar\/gkm699 (2007).","journal-title":"Nucleic Acids Res."},{"key":"9435_CR41","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2012.00127","volume":"3","author":"JG Betancur","year":"2012","unstructured":"Betancur, J. G., Yoda, M. & Tomari, Y. miRNA-like duplexes as RNAi triggers with improved specificity. Frontiers in genetics \n                           3, 127, doi:10.3389\/fgene.2012.00127 (2012).","journal-title":"Frontiers in genetics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09435-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09435-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09435-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:28:46Z","timestamp":1671794926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-09435-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,28]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["9435"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-09435-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,28]]},"assertion":[{"value":"12 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 July 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 September 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12390"}}