48 results found
Slieker RC, Donnelly LA, Fitipaldi H, et al., 2021, Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study, DIABETOLOGIA, ISSN: 0012-186X
Rutter GA, Georgiadou E, Martinez-Sanchez A, et al., 2020, Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity, DIABETOLOGIA, Vol: 63, Pages: 1990-1998, ISSN: 0012-186X
Carrat GR, Haythorne E, Tomas A, et al., 2020, The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Risk alleles for type 2 diabetes at the<jats:italic>STARD10</jats:italic>locus are associated with lowered<jats:italic>STARD10</jats:italic>expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways through which STARD10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used isolated islets from mice deleted selectively in the β-cell for<jats:italic>Stard10</jats:italic>(β<jats:italic>StarD10</jats:italic>KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>β<jats:italic>StarD10</jats:italic>KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased. Amongst the differentially expressed genes in β<jats:italic>StarD10</jats:italic>KO islets, expression of the phosphoinositide binding proteins<jats:italic>Pirt</jats:italic>and<jats:italic>Synaptotagmin 1</jats:
Pullen TJ, Groen N, van Oudenaarden A, et al., 2018, Identification of potential hub beta cells using single-cell RNA-Seq, Publisher: WILEY, Pages: 51-51, ISSN: 0742-3071
Carrat GR, Haythorne E, Chabosseau P, et al., 2018, The Type 2 diabetes genome-wide association study (GWAS) gene STARD10 controls beta cell granule morphogenesis and proinsulin release, Diabetes UK, Publisher: WILEY, Pages: 46-46, ISSN: 0742-3071
Rutter GA, Hodson DJ, Chabosseau P, et al., 2017, Local and regional control of calcium dynamics in the pancreatic islet, Diabetes, Obesity and Metabolism, Vol: 19, Pages: 30-41, ISSN: 1462-8902
Ca2+ is the key intracellular regulator of insulin secretion, acting in the β-cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K+ channel closure and plasma membrane depolarization engage a sophisticated machinery to drive pulsatile cytosolic Ca2+ changes. Voltage-gated Ca2+ channels, Ca2+-activated K+ channels and Na+/Ca2+ exchange all play important roles. The use of targeted Ca2+ probes has revealed that during each cytosolic Ca2+ pulse, uptake of Ca2+ by mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca2+ dynamics and control organellar function. For example, changes in the expression of the Ca2+-binding protein Sorcin appear to provide a link between ER Ca2+ levels and ER stress, affecting β-cell function and survival. Across the islet, intercellular communication between highly interconnected “hubs,” which act as pacemaker β-cells, and subservient “followers,” ensures efficient insulin secretion. Loss of connectivity is seen after the deletion of genes associated with type 2 diabetes (T2D) and follows metabolic and inflammatory insults that characterize this disease. Hubs, which typically comprise ~1%-10% of total β-cells, are repurposed for their specialized role by expression of high glucokinase (Gck) but lower Pdx1 and Nkx6.1 levels. Single cell-omics are poised to provide a deeper understanding of the nature of these cells and of the networks through which they communicate. New insights into the control of both the intra- and intercellular Ca2+ dynamics may thus shed light on T2D pathology and provide novel opportunities for therapy.
pullen T, Huising MO, Rutter GA, 2017, Analysis of purified pancreatic islet beta and alpha cell transcriptomesreveals 11β-hydroxysteroid dehydrogenase (Hsd11b1) as a noveldisallowed gene, Frontiers in Genetics, Vol: 8, ISSN: 1664-8021
We and others have previously identified a group of genes, dubbed “disallowed,” whose expression is markedly lower in pancreatic islets than in other mammalian cell types. Forced mis-expression of several members of this family leads to defective insulin secretion, demonstrating the likely importance of disallowance for normal beta cell function. Up to now, transcriptomic comparisons have been based solely on data from whole islets. This raises the possibilities that (a) there may be important differences in the degree of disallowance of family members between beta and other either neuroendocrine cells; (b) beta (or alpha) cell disallowed genes may have gone undetected. To address this issue, we survey here recent massive parallel sequencing (RNA-Seq) datasets from purified mouse and human islet cells. Our analysis reveals that the most strongly disallowed genes are similar in beta and alpha cells, with 11β-hydroxysteroid dehydrogenase (Hsd11b1) mRNA being essentially undetectable in both cell types. The analysis also reveals that several genes involved in cellular proliferation, including Yap1 and Igfbp4, and previously assumed to be disallowed in both beta and alpha cells, are selectively repressed only in the beta cell. The latter finding supports the view that beta cell growth is selectively restricted in adults, providing a mechanism to avoid excessive insulin production and the risk of hypoglycaemia. Approaches which increase the expression or activity of selected disallowed genes in the beta cell may provide the basis for novel regenerative therapies in type 2 diabetes.
Mitchell RK, Nguyen-Tu MS, Chabosseau P, et al., 2017, The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice., Journal of Biological Chemistry, Vol: 292, Pages: 8892-8906, ISSN: 1083-351X
Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia. While β-cell mass was preserved 8 days post injection, total insulin content and insulin:chromogranin A immunoreactivity were reduced by ~60%, and glucose-stimulated insulin secretion was eliminated. RNAseq and qRT-PCR analyses revealed that whereas the expression of key β cell genes including Ins2, Slc30a8, MafA, Slc2a2, G6pc2 and Glp1r was reduced after Pax6 deletion, that of several genes which are usually selectively repressed ("disallowed") in β-cells, including Slc16a1, was increased. Assessed in intact islets, glucose-induced ATP:ADP increases were significantly reduced (p<0.05) in βPax6KO versus control β cells, and the former displayed attenuated increases in cytosolic Ca2+. Unexpectedly, glucose-induced increases in intercellular connectivity were enhanced after Pax6 deletion, consistent with increases in the expression of the glucose sensor glucokinase, but decreases in that of two transcription factors usually expressed in fully differentiated β-cells, Pdx1 and Nkx6.1, as observed in islet "hub" cells. These results indicate that Pax6 is required for the functional identity of adult β cells. Furthermore, deficiencies in β cell glucose-sensing are likely to contribute to defective insulin secretion in human carriers of PAX6 mutations.
Carrat GR, Hu M, Nguyen-Tu MS, et al., 2017, Decreased STARD10 expression is associated with defective insulin secretion in humans and mice, American Journal of Human Genetics, Vol: 100, Pages: 238-256, ISSN: 1537-6605
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.
Mehta ZB, FIne N, Pullen TJ, et al., 2016, Changes in the expression of the type 2 diabetes-associated gene VPS13C in the β cell are associated with glucose intolerance in humans and mice, American Journal of Physiology-Endocrinology and Metabolism, Vol: 311, Pages: E488-E507, ISSN: 1522-1555
Single nucleotide polymorphisms (SNPs) close to the VPS13C, C2CD4A and C2CD4B genes on chromosome 15q are associated with impaired fasting glucose and increased risk of type 2 diabetes. eQTL analysis revealed an association between possession of risk (C) alleles at a previously implicated causal SNP, rs7163757, and lowered VPS13C and C2CD4A levels in islets from female (n = 40, P < 0.041) but not from male subjects. Explored using promoter-reporter assays in β-cells and other cell lines, the risk variant at rs7163757 lowered enhancer activity. Mice deleted for Vps13c selectively in the β-cell were generated by crossing animals bearing a floxed allele at exon 1 to mice expressing Cre recombinase under Ins1 promoter control (Ins1Cre). Whereas Vps13cfl/fl:Ins1Cre (βVps13cKO) mice displayed normal weight gain compared with control littermates, deletion of Vps13c had little effect on glucose tolerance. Pancreatic histology revealed no significant change in β-cell mass in KO mice vs. controls, and glucose-stimulated insulin secretion from isolated islets was not altered in vitro between control and βVps13cKO mice. However, a tendency was observed in female null mice for lower insulin levels and β-cell function (HOMA-B) in vivo. Furthermore, glucose-stimulated increases in intracellular free Ca2+ were significantly increased in islets from female KO mice, suggesting impaired Ca2+ sensitivity of the secretory machinery. The present data thus provide evidence for a limited role for changes in VPS13C expression in conferring altered disease risk at this locus, particularly in females, and suggest that C2CD4A may also be involved.
Denton RM, Pullen TJ, Armstrong CT, et al., 2016, Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression, Biochemical Journal, Vol: 473, Pages: 1165-1178, ISSN: 1470-8728
The 2-oxoglutarate dehydrogenase (OGDH) complex is an important control point in vertebrate mitochondrial oxidative metabolism, including in the citrate cycle and catabolism of alternative fuels including glutamine. It is subject to allosteric regulation by NADH and the ATP/ADP ratio, and by Ca2+ through binding to the E1 subunit. The latter involves a unique Ca2+-binding site which includes D114ADLD (site 1). Here, we describe three splice variants of E1 in which either the exon expressing this site is replaced with another exon (loss of site 1, LS1) or an additional exon is expressed leading to the insertion of 15 amino acids just downstream of site 1 (Insert), or both changes occur together (LS1/Insert). We show that all three variants are essentially Ca2+-insensitive. Comparison of massive parallel sequence (RNA-Seq) databases demonstrates predominant expression of the Ca2+-sensitive archetype form in heart and skeletal muscle, but substantial expression of the Ca2+-insensitive variants in brain, pancreatic islets and other tissues. Detailed proteomic and activity studies comparing OGDH complexes from rat heart and brain confirmed the substantial difference in expression between these tissues. The evolution of OGDH variants was explored using bioinformatics, and this indicated that Ca2+-sensitivity arose with the emergence of chordates. In all species examined, this was associated with the co-emergence of Ca2+-insensitive variants suggesting a retained requirement for the latter in some settings. Tissue-specific expression of OGDH splice variants may thus provide a mechanism that tunes the control of the enzyme to the specialized metabolic and signalling needs of individual cell types.
Yavari A, Stocker CJ, Ghaffari S, et al., 2016, Chronic activation of γ2 AMPK induces obesity and reduces β cell function., Cell Metabolism, Vol: 23, Pages: 821-836, ISSN: 1932-7420
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.
Martinez-Sanchez A, Pullen TJ, Chabosseau PL, et al., 2016, Disallowance of acyl-CoA thioesterase 7 (Acot7) in beta cells is required for normal insulin secretion and glucose tolerance, DIABETIC MEDICINE, Vol: 33, Pages: 38-38, ISSN: 0742-3071
Rutter GA, 2016, Disallowance of Acot7 in b-Cells is required for normal glucosetolerance and insulin secretion, Diabetes, Vol: 65, Pages: 1268-1282, ISSN: 0012-1797
Acot7, encoding acyl-CoA thioesterase-7, is one of ∼60 genes expressed ubiquitously across tissues but relatively silenced, or “disallowed”, in pancreatic β-cells. The capacity of ACOT7 to hydrolyse long-chain acyl-CoA esters suggests potential roles in β-oxidation, lipid biosynthesis, signal transduction or insulin exocytosis. Here, we explored the physiological relevance of β-cell-specific Acot7 silencing by re-expressing ACOT7 in these cells. ACOT7 overexpression in clonal MIN6 and INS1(832/13) β-cells impaired insulin secretion in response to glucose plus fatty acids. Furthermore, examined in a panel of transgenic mouse lines, we demonstrate that overexpression of mitochondrial ACOT7 selectively in the adult β-cell reduced glucose tolerance dose-dependently and impaired glucose-stimulated insulin secretion. By contrast, depolarisation-induced secretion was unaffected, arguing against a direct action on the exocytotic machinery. Acyl-CoA levels, ATP/ADP increases, membrane depolarization and Ca2+ fluxes were all markedly reduced in transgenic mouse islets, whereas glucose-induced O2-consumption was unchanged. Whilst glucose-induced increases in ATP/ADP ratio were similarly lowered after ACOT7 over-expression in INS1(832/13) cells, changes in mitochondrial membrane potential (ΔΨ) were unaffected, consistent with an action of Acot7 to increase cellular ATP consumption. Since Acot7 mRNA levels are increased in human islets in type 2 diabetes, inhibition of the enzyme might provide a novel therapeutic strategy.
Carrat GR, Tu M-SCN, Chabosseau PL, et al., 2015, Roles of the Type 2 Diabetes-associated Gene Products ARAP1 and STARD10 in the Control of Insulin Secretion, 75th Scientific Sessions of the American-Diabetes-Association, Publisher: AMER DIABETES ASSOC, Pages: A82-A82, ISSN: 0012-1797
Sayers S, Kantor C, Pullen TJ, et al., 2015, Preserved insulin secretion despite impaired glucose signalling after pancreatic beta cell selective deletion of the tumour suppressor LKB1, Publisher: WILEY-BLACKWELL, Pages: 13-13, ISSN: 0742-3071
Rutter GA, Pullen TJ, Hodson DJ, et al., 2015, Pancreatic beta-cell identity, glucose sensing and the control of insulin secretion, BIOCHEMICAL JOURNAL, Vol: 466, Pages: 203-218, ISSN: 0264-6021
Martinez-Sanchez A, Pullen TJ, Nguyen-Tu MS, et al., 2015, Repression of acyl-CoA thioesterase 7 (Acot7) in beta cells is required for normal glucose tolerance and the potentiation of glucose-stimulated insulin secretion by fatty acids, DIABETIC MEDICINE, Vol: 32, Pages: 40-40, ISSN: 0742-3071
Kone M, Sun G, Ibberson M, et al., 2014, LKB1 and AMPK differentially regulate pancreatic beta-cell identity, Faseb Journal, Vol: 28, Pages: 4972-4985, ISSN: 1530-6860
Fully differentiated pancreatic b cellsare essential for normal glucose homeostasis in mammals.Dedifferentiation of these cells has been suggestedto occur in type 2 diabetes, impairing insulinproduction. Since chronic fuel excess (“glucotoxicity”)is implicated in this process, we sought here to identifythe potential roles in b-cell identity of the tumor suppressorliver kinase B1 (LKB1/STK11) and the downstreamfuel-sensitive kinase, AMP-activated proteinkinase (AMPK). Highly b-cell-restricted deletion ofeach kinase in mice, using an Ins1-controlled Cre, wastherefore followed by physiological, morphometric,and massive parallel sequencing analysis. Loss of LKB1strikingly (2.0–12-fold, E<0.01) increased the expressionof subsets of hepatic (Alb, Iyd, Elovl2) and neuronal(Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamatesignaling. These changes were partially recapitulatedby the loss of AMPK, which also up-regulated b-cell“disallowed” genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to3.4-fold (E<0.01). Correspondingly, targeted promoterswere enriched for neuronal (Zfp206; P51.3310233)and hypoxia-regulated (HIF1; P52.5310216) transcriptionfactors. In summary, LKB1 and AMPK, through onlypartly overlapping mechanisms, maintain b-cell identityby suppressing alternate pathways leading to neuronal,hepatic, and other characteristics. Selective targetingof these enzymes may provide a new approach tomaintaining b-cell function in some forms of diabetes.—Kone,M., Pullen, T. J., Sun, G., Ibberson, M.,Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S.,Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J.,Thorens, B., Reimann, F., Gribble, F., McGinty, J. A.,Chen, L., French, P. M., Birzele, F., Hildebrandt, T.,Uphues, I., Rutter, G. A. LKB1 and AMPK differentiallyregulate pancreatic b-cell identity.
Hodson DJ, Mitchell RK, Marselli L, et al., 2014, ADCY5 couples glucose to insulin secretion in human islets, Diabetes, Vol: 63, Pages: 3009-3021, ISSN: 0012-1797
Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, encoding adenylate cyclase 5, are associated with elevated fasting glucose and increased type 2 diabetes (T2D) risk. Despite this, the mechanisms underlying the effects of these polymorphic variants at the level of pancreatic β-cells remain unclear. Here, we show firstly that ADCY5 mRNA expression in islets is lowered by the possession of risk alleles at rs11708067. Next, we demonstrate that ADCY5 is indispensable for coupling glucose, but not GLP-1, to insulin secretion in human islets. Assessed by in situ imaging of recombinant probes, ADCY5 silencing impaired glucose-induced cAMP increases and blocked glucose metabolism toward ATP at concentrations of the sugar >8 mmol/L. However, calcium transient generation and functional connectivity between individual human β-cells were sharply inhibited at all glucose concentrations tested, implying additional, metabolism-independent roles for ADCY5. In contrast, calcium rises were unaffected in ADCY5-depleted islets exposed to GLP-1. Alterations in β-cell ADCY5 expression and impaired glucose signaling thus provide a likely route through which ADCY5 gene polymorphisms influence fasting glucose levels and T2D risk, while exerting more minor effects on incretin action.
Nguyen-Tu M-S, Kantor C, Sayers S, et al., 2014, LKB1 and AMPK regulate Nptx2 expression and glutamate signalling in pancreatic beta cells, DIABETOLOGIA, Vol: 57, Pages: S48-S48, ISSN: 0012-186X
Carrat GRJ, Pullen TJ, Marselli L, et al., 2014, Roles of the type 2 diabetes- associated gene products Arap1 and StarD10 in the control of insulin secretion, DIABETOLOGIA, Vol: 57, Pages: S63-S64, ISSN: 0012-186X
Pullen TJ, Rutter GA, 2014, Roles of IncRNAs in pancreatic beta cell identity and diabetes susceptibility, Frontiers in Genetics, Vol: 5, ISSN: 1664-8021
Type 2 diabetes usually ensues from the inability of pancreatic beta cells to compensate for incipient insulin resistance. The loss of beta cell mass, function, and potentially beta cell identity contribute to this dysfunction to extents which are debated. In recent years, long non-coding RNAs (lncRNAs) have emerged as potentially providing a novel level of gene regulation implicating critical cellular processes such as pluripotency and differentiation. With over 1000 lncRNAs now identified in beta cells, there is growing evidence for their involvement in the above processes in these cells. While functional evidence on individual islet lncRNAs is still scarce, we discuss how lncRNAs could contribute to type 2 diabetes susceptibility, particularly at loci identified through genome-wide association studies as affecting disease risk.
Martinez-Sanchez A, Pullen TJ, Rutter GA, 2014, Repression of Acot7 in beta-Cells Is Required for the Potentiation of GSIS by Fatty Acids, Publisher: AMER DIABETES ASSOC, Pages: A552-A552, ISSN: 0012-1797
Mitchell RK, Marselli L, Pullen TJ, et al., 2014, ADCY5 couples glucose to insulin secretion in human islets, DIABETIC MEDICINE, Vol: 31, Pages: 5-5, ISSN: 0742-3071
Martinez-Sanchez A, Pullen TJ, Rutter GA, 2014, Acyl-CoA thioesterase 7 (Acot7) silencing in beta cells: underlying mechanisms and function, DIABETIC MEDICINE, Vol: 31, Pages: 30-30, ISSN: 0742-3071
Rutter GA, Sun G, Pullen TJ, et al., 2013, LKB1 and AMPK differentially regulate pancreatic beta cell fate, 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S95-S95, ISSN: 0012-186X
Pullen TJ, Rutter GA, 2013, Could IncRNAs contribute to beta-cell identity and its loss in Type 2 diabetes?, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 41, Pages: 797-801, ISSN: 0300-5127
Pullen TJ, Rutter GA, 2013, When less is more: the forbidden fruits of gene repression in the adult beta-cell, DIABETES OBESITY & METABOLISM, Vol: 15, Pages: 503-512, ISSN: 1462-8902
Pullen TJ, Rutter GA, 2012, An islet-specific long non-coding RNA (lncRNA) expressed from the Pdx1 locus regulates Pdx1 activity, DIABETOLOGIA, Vol: 55, Pages: S94-S94, ISSN: 0012-186X
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