Institution
University of Groningen
Education•Groningen, Groningen, Netherlands•
About: University of Groningen is a education organization based out in Groningen, Groningen, Netherlands. It is known for research contribution in the topics: Population & Context (language use). The organization has 36346 authors who have published 69116 publications receiving 2940370 citations. The organization is also known as: Rijksuniversiteit Groningen & RUG.
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TL;DR: In this article, the first catalytic asymmetric 1,4-addition reactions of organometallic reagents with complete stereocontrol were shown to be possible with complete enantioselectivity.
Abstract: Although efficient catalysts for a number of asymmetric carbon carbon formations are known to date, a highly enantioselective catalytic version of the conjugate addition of organometallic reagents to enones is lacking. Recently chiral catalysts based on Cu, Ni, Zn, or Co complexes of a variety of ligands have shown enantioselectivities up to 90 % in 1,4additions of Grignard, organolithium, or dialkylzinc reagents. The results so far have not revealed, however, the key elements for realization of complete stereocontrol but do reveal the rather complex nature of some of these chiral catalytic systems. Previously we have demonstrated that copper complexes of chiral phosphorus amidites show relatively high ee values for the 1,4-adducts of R2Zn reagents and acyclic as well as cyclic enones. In this communication both the first catalytic asymmetric 1,4-addition reactions of organometallic reagents with complete
395 citations
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TL;DR: Evidence for linkage of the IgE phenotype to 5q was obtained by both sib-pair and lod score analysis with evidence for recessive inheritance of high IgE levels from segregation analysis, a major step in mapping genes important in the regulation of allergic responses and the pathogenesis of asthma.
395 citations
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TL;DR: Natural human genetic variation is relied upon to identify effects of variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial.
Abstract: For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the trans-acting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P<10(-16)). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes.
395 citations
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TL;DR: This work provides the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm, and predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN 5A mutations.
Abstract: Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening1,2,3; however, a chief function of the Na+ channel is to initiate cardiac impulse conduction. Here we provide the first functional characterization of an SCN5A mutation that causes a sustained, isolated conduction defect with pathological slowing of the cardiac rhythm. By analysing the SCN5A coding region, we have identified a single mutation in five affected family members; this mutation results in the substitution of cysteine 514 for glycine (G514C) in the channel protein. Biophysical characterization of the mutant channel shows that there are abnormalities in voltage-dependent ‘gating’ behaviour that can be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.
395 citations
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TL;DR: This article identified new regions showing association with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2.
Abstract: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
394 citations
Authors
Showing all 36692 results
Name | H-index | Papers | Citations |
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Ronald C. Kessler | 274 | 1332 | 328983 |
Nicholas J. Wareham | 212 | 1657 | 204896 |
André G. Uitterlinden | 199 | 1229 | 156747 |
Lei Jiang | 170 | 2244 | 135205 |
Brenda W.J.H. Penninx | 170 | 1139 | 119082 |
Richard H. Friend | 169 | 1182 | 140032 |
Panos Deloukas | 162 | 410 | 154018 |
Jerome I. Rotter | 156 | 1071 | 116296 |
Christopher M. Dobson | 150 | 1008 | 105475 |
Dirk Inzé | 149 | 647 | 74468 |
Scott T. Weiss | 147 | 1025 | 74742 |
Dieter Lutz | 139 | 671 | 67414 |
Wilmar B. Schaufeli | 137 | 513 | 95718 |
Cisca Wijmenga | 136 | 668 | 86572 |
Arnold B. Bakker | 135 | 506 | 103778 |