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• W2342592802 abstract "See “No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations,” by Zou W-B, Boulling A, Masamune A, et al, on page 1558. See “No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations,” by Zou W-B, Boulling A, Masamune A, et al, on page 1558. Over the last 2 decades acute recurrent pancreatitis and chronic pancreatitis (CP) have moved from diseases of alcohol abuse to disorders of complex interactions between environmental, metabolic, and genetic risk factors.1Whitcomb D.C. Genetic risk factors for pancreatic disorders.Gastroenterology. 2013; 144: 1292-1302Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 2Ravi Kanth V. Nageshwar Reddy D. Genetics of acute and chronic pancreatitis: an update.World J Gastrointest Pathophysiol. 2014; 5: 427-437Crossref PubMed Google Scholar The new era dawned in 1996 with the description of mutations in the gene encoding cationic trypsinogen (PRSS1) that cause hereditary pancreatitis.3Whitcomb D.C. Gorry M.C. Preston R.A. et al.Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.Nat Genet. 1996; 14: 141-145Crossref PubMed Scopus (1323) Google Scholar Shortly after that report, candidate gene and unbiased approaches revealed mutations in other genes that increased susceptibility to CP. Genetic factors seem to be particularly important in early onset cases because predisposing variants are found in ≥60% of children with acute recurrent pancreatitis or CP.4Schwarzenberg S.J. Bellin M. Husain S.Z. et al.Pediatric chronic pancreatitis is associated with genetic risk factors and substantial disease burden.J Pediatr. 2015; 166: 890-896Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar CP risk variants also tend to occur across multiple ethnic groups, and most of the CP-associated genes encode components of the protease–antiprotease system of the pancreatic acinar cell. A notable exception is CEL, which recently was identified as a pancreatitis gene by a European study.5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar Not only does CEL encode a lipase, its risk variant appears, as shown in the report by Zou et al in this issue of Gastroenterology,6Zou W.-B. Boulling A. Masamune A. et al.No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations.Gastroenterology. 2016; 150: 1558-1560Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar to be absent in large Asian populations. CEL gives rise to carboxyl-ester lipase, a digestive enzyme secreted by pancreatic acinar cells.7Hui D.Y. Howles P.N. Carboxyl ester lipase: structure-function relationship and physiological role in lipoprotein metabolism and atherosclerosis.J Lipid Res. 2002; 43: 2017-2030Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar In the duodenum, CEL is activated by bile salts, which is why the protein is known in the literature also as bile salt-stimulated or bile salt-dependent lipase.8Lombardo D. Bile salt-dependent lipase: its pathophysiological implications.Biochim Biophys Acta. 2001; 1533: 1-28Crossref PubMed Scopus (75) Google Scholar The enzyme has wide substrate specificity and is capable of hydrolyzing substrates such as cholesteryl esters, triacylglycerides, and phospholipids. As is often the case in human molecular genetics, a rare monogenic condition was the beacon that directed attention to CEL as a factor in a complex, common disorder. It all started in 2001 when a large family living on a Norwegian island was referred to genetic testing because of suspected maturity-onset diabetes of the young (MODY). Although the pedigree fulfilled well-established MODY criteria,9Molven A. Njølstad P.R. Role of molecular genetics in transforming diagnosis of diabetes mellitus.Expert Rev Mol Diagn. 2011; 11: 313-320Crossref PubMed Scopus (55) Google Scholar it soon became apparent that affected members also suffered from pancreatic exocrine disease, manifesting as fecal elastase deficiency, elevated pancreatic fat content, and recurrent abdominal pain relatively early in life,10Ræder H. Johansson S. Holm P.I. et al.Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.Nat Genet. 2006; 38: 54-62Crossref PubMed Scopus (252) Google Scholar followed by development of pancreatic cysts after the age of 40.11Ræder H. McAllister F.E. Tjora E. et al.Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid.Diabetes. 2014; 63: 259-269Crossref PubMed Scopus (32) Google Scholar By that age, all affected persons had also become diabetic. A genome-wide linkage analysis revealed that a CEL mutation co-segregated with the disease, which was denoted MODY8. The CEL gene consists of 11 exons, where the last exon contains a variable number of tandem repeats (VNTR) region that encodes a series of repetitive amino acid segments.10Ræder H. Johansson S. Holm P.I. et al.Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.Nat Genet. 2006; 38: 54-62Crossref PubMed Scopus (252) Google Scholar The number of repeats varies between 3 and 23, with 16 repeats being the most common in all populations studied so far.12Higuchi S. Nakamura Y. Saito S. Characterization of a VNTR polymorphism in the coding region of the CEL gene.J Hum Genet. 2002; 47: 213-215Crossref PubMed Scopus (23) Google Scholar, 13Lindquist S. Blackberg L. Hernell O. Human bile salt-stimulated lipase has a high frequency of size variation due to a hypervariable region in exon 11.Eur J Biochem. 2002; 269: 759-767Crossref PubMed Scopus (28) Google Scholar, 14Torsvik J. Johansson S. Johansen A. et al.Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.Hum Genet. 2010; 127: 55-64Crossref PubMed Scopus (49) Google Scholar In the original MODY8 family, a single-base pair deletion has arisen in the first VNTR repeat, causing an altered reading frame.10Ræder H. Johansson S. Holm P.I. et al.Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.Nat Genet. 2006; 38: 54-62Crossref PubMed Scopus (252) Google Scholar The resulting protein contains a new and truncated C-terminus with 11 repeats (Figure 1). The disease mechanism awaits full clarification, but studies in cell culture suggest that the mutant CEL protein forms intracellular and extracellular aggregates, which have led to the suggestion that MODY8 is a protein misfolding disease.15Johansson B.B. Torsvik J. Bjørkhaug L. et al.Diabetes and pancreatic exocrine dysfunction due to mutations in carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease.J Biol Chem. 2011; 286: 34593-34605Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Endocytic reuptake of the protein aggregates by pancreatic acinar and β-cells tends to reduce cellular viability.16Torsvik J. Johansson B.B. Dalva M. et al.Endocytosis of secreted carboxyl ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction.J Biol Chem. 2014; 289: 29097-29111Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar CEL is a very polymorphic gene. In addition to greatly varying VNTR lengths and several frameshift variants within that region,10Ræder H. Johansson S. Holm P.I. et al.Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.Nat Genet. 2006; 38: 54-62Crossref PubMed Scopus (252) Google Scholar copy number variants of CEL have been reported.14Torsvik J. Johansson S. Johansen A. et al.Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes.Hum Genet. 2010; 127: 55-64Crossref PubMed Scopus (49) Google Scholar Two such copy number variants have been characterized in depth: one duplication allele and one deletion allele.5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar These copy number variants have most probably arisen from nonallelic homologous recombination within the CEL locus, involving also an adjacent CEL pseudogene. Interestingly, the deletion allele was formed by a fusion between the proximal part of CEL and the distal part of the pseudogene, and the resulting “hybrid” allele (CEL-HYB) was found to be a novel risk factor for CP.5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar Compared with the general population, the carrier frequency of CEL-HYB was increased by >5-fold in patients with idiopathic CP from Germany and France. Like CEL-MODY, the CEL-HYB protein has a new and shorter C-terminus. In CEL-HYB, however, the VNTR originates from the pseudogene and contains only 3 repeats (Figure 1). When investigated in cellular models, the functional consequences are impaired protein secretion, reduced enzyme activity, and stimulation of autophagy.5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar Thus, CEL-MODY and CEL-HYB probably do not impose identical effects at the cellular level. This difference is reflected in their association with pancreatic disease: the presence of CEL-MODY in the acinar cells causes a dominantly inherited, high-penetrant syndrome of exocrine and endocrine pancreatic dysfunction. In contrast, the majority of CEL-HYB carriers in the general population are likely to stay healthy despite the allele serving as a significant risk factor for development of CP. Now Zou et al6Zou W.-B. Boulling A. Masamune A. et al.No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations.Gastroenterology. 2016; 150: 1558-1560Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar present a new twist on the CEL saga. Given that the discovery of CEL-HYB involved only Europeans subjects,5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar the authors asked whether this allele would be enriched also among CP patients from Asia. Their initial conclusion seemed to be somewhat disappointing: CEL-HYB carrier frequencies among cases and controls were identical (1.7%) in a combined material from China, Japan, and India.6Zou W.-B. Boulling A. Masamune A. et al.No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations.Gastroenterology. 2016; 150: 1558-1560Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar However, upon DNA sequencing Zou et al made the surprising discovery that every Asian CEL-HYB allele detected exhibited a premature stop codon in exon 10 (Figure 1). Accordingly, it became necessary to distinguish between the originally identified CEL-HYB allele in European populations5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar and the Asian variants, by designating them CEL-HYB1 and CEL-HYB2, respectively.6Zou W.-B. Boulling A. Masamune A. et al.No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations.Gastroenterology. 2016; 150: 1558-1560Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar In fact, Fjeld et al5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar did observe a few subjects carrying CEL-HYB2, but removed them from further analyses as the stop codon in exon 10 made translation of the VNTR region very unlikely. Instead, a truncated protein is predicted to be produced. Moreover, transcripts containing stop codons before the last exon tend to be degraded by a process called nonsense-mediated messenger RNA decay. Zou et al tested this possibility by transfecting a CEL-HYB2 construct into HEK293T cells. Their data do indeed indicate that the CEL-HYB2 transcript is less stable than that originating from CEL-HYB1.6Zou W.-B. Boulling A. Masamune A. et al.No association between CEL–HYB hybrid allele and chronic pancreatitis in Asian populations.Gastroenterology. 2016; 150: 1558-1560Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar How do these novel findings reconcile with our previous understanding of how CEL variants are involved in exocrine pancreatic disease? Quite nicely, actually (Figure 1). It is all in the protein ends! In MODY8, the frame-shift mutation in the VNTR leads to a new protein tail of considerable length and with a strong tendency to form aggregates. CEL-HYB1, too, contains a modified C-terminus, but this one is considerably shorter. A less severe influence on protein function and cellular processes might therefore be anticipated. It is to be noted that both the CEL-MODY and CEL-HYB1 allele associate with pancreatic disease in the heterozygous state5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar, 10Ræder H. Johansson S. Holm P.I. et al.Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.Nat Genet. 2006; 38: 54-62Crossref PubMed Scopus (252) Google Scholar and their modified tails are therefore likely to have a dominant-negative effect. For CEL-HYB2, the premature stop codon and unstable messenger RNA should cause less CEL protein to be produced. We assume that simply decreasing the amount of CEL within the acinar cell does not have detrimental effects, a view that is in line with the failure of detecting a pancreatic phenotype in CEL knock-out mice.17Vesterhus M. Ræder H. Kurpad A.J. et al.Pancreatic function in carboxyl-ester lipase knockout mice.Pancreatology. 2010; 10: 467-476Crossref PubMed Scopus (23) Google Scholar The lack of CEL-HYB1 in Asians suggests that it is an ethnic-specific risk allele for CP. Although this finding is quite new in the pancreatitis field, it is well-known from other areas, for example, from diabetes studies, that both risk and protective gene variants can be confined to certain populations.18Estrada K. Aukrust I. et al.SIGMA Type 2 Diabetes ConsortiumAssociation of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.JAMA. 2014; 311: 2305-2314Crossref PubMed Scopus (155) Google Scholar, 19Flannick J. Thorleifsson G. Beer N.L. et al.Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.Nat Genet. 2014; 46: 357-363Crossref PubMed Scopus (346) Google Scholar Straightforward genetic screenings should now be performed to determine the distribution of CEL-HYB1 in various ethnicities. Another natural question is which other factors, environmental or genetic, are needed to precipitate pancreatic exocrine disease in CEL-HYB1 carriers. There are clearly genetic interactions among the pancreatitis genes in that patients who carry risk variants in ≥2 genes are of increased disease risk.20Noone P.G. Zhou Z. Silverman L.M. et al.Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations.Gastroenterology. 2001; 121: 1310-1319Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 21Rosendahl J. Landt O. Bernadova J. et al.CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?.Gut. 2013; 62: 582-592Crossref PubMed Scopus (134) Google Scholar Intriguingly, mutations in the genes encoding chymotrypsinogen C (CTRC) and calcium sensing receptor (CASR), seem to influence pancreatitis risk only when expressed with heterozygous mutations in other genes known to increase susceptibility.1Whitcomb D.C. Genetic risk factors for pancreatic disorders.Gastroenterology. 2013; 144: 1292-1302Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar Interacting genes need to be examined also for CEL-HYB1, although the usual suspects, SPINK1 and PRSS1, do not seem to play a role as genetic cofactors here.5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar The most interesting conundrum raised by the recent developments in CEL molecular genetics may pertain to the role of the VNTR region. This sequence is not present in the otherwise relatively conserved CEL gene of lower vertebrates such as fish, amphibians, reptiles, and birds.22Holmes R.S. Cox L.A. Comparative structures and evolution of vertebrate carboxyl ester lipase (CEL) genes and proteins with a major role in reverse cholesterol transport.Cholesterol. 2011; : 781643PubMed Google Scholar It could therefore be a mammalian-specific evolutionary invention. In most mammals, the CEL VNTR is relatively short (3-4 repeats), whereas in primates it tends to contain ≥15 repeats.22Holmes R.S. Cox L.A. Comparative structures and evolution of vertebrate carboxyl ester lipase (CEL) genes and proteins with a major role in reverse cholesterol transport.Cholesterol. 2011; : 781643PubMed Google Scholar Why did this sequence expand despite the immanent mutational risk of replicating a very GC-rich, repetitive DNA region? Why is 16 the predominating repeat number in humans? Enzymatic activity is not markedly affected by the lack of the VNTR,5Fjeld K. Weiss F.U. Lasher D. et al.A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis.Nat Genet. 2015; 47: 518-522Crossref PubMed Scopus (126) Google Scholar and it has been suggested that the protein repeat region, which is highly glycosylated, protects CEL against proteolytic degradation by other digestive enzymes.23Loomes K.M. Senior H.E. West P.M. et al.Functional protective role for mucin glycosylated repetitive domains.Eur J Biochem. 1999; 266: 105-111Crossref PubMed Scopus (30) Google Scholar Although many questions about the physiology and biochemistry of the protein remain, the description of CEL genetic variants associated with pancreatic disease suggests there may be multiple pathways that result in CP. Based on the number of pancreatitis-associated genes with a biologic connection to trypsinogen activation or to trypsin inhibition/degradation, the trypsin molecule holds a central role in prevailing models for acute recurrent pancreatitis and CP.1Whitcomb D.C. Genetic risk factors for pancreatic disorders.Gastroenterology. 2013; 144: 1292-1302Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar Thus, inappropriate intracellular activation of trypsinogen or failure of intracellular trypsin inactivation dominates our current understanding of CP pathogenesis. The association of CEL variants with increased risk for pancreatic disease and the recent description of a mutation in the gene encoding pancreatic lipase (PNLIP) in 2 brothers with likely CP have important implications for the pathophysiology of pancreatitis.24Behar D.M. Basel-Vanagaite L. Glaser F. et al.Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency.J Lipid Res. 2014; 55: 307-312Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 25Szabo A. Xiao X. Haughney M. et al.A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding.Biochim Biophys Acta. 2015; 1852: 1372-1379Crossref PubMed Scopus (21) Google Scholar Because the CEL and PNLIP proteins have no apparent role in trypsinogen regulation and neither requires trypsin activation, their risk variants could cause disease through a trypsin-independent mechanism. Understanding the pathophysiology of pancreatitis associated with lipase mutants can, therefore, also provide insight into novel therapies for CP as well as for acute recurrent pancreatitis. No Association Between CEL–HYB Hybrid Allele and Chronic Pancreatitis in Asian PopulationsGastroenterologyVol. 150Issue 7PreviewA hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL–HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10′, was found to increase susceptibility to chronic pancreatitis in a case–control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL–HYB allele in any of these populations. The CEL–HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. Full-Text PDF" @default.
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• W2342592802 title "Lipase Genetic Variants in Chronic Pancreatitis: When the End Is Wrong, All’s Not Well" @default.
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