| 1. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 2. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 3. |
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| 4. |
- Dörr, N., et al.
(författare)
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Late Mesozoic-Cenozoic exhumation history of northern Svalbard and its regional significance : Constraints from apatite fission track analysis
- 2012
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Ingår i: Tectonophysics. - : Elsevier BV. - 0040-1951 .- 1879-3266. ; 514, s. 81-92
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Tidskriftsartikel (refereegranskat)abstract
- The late Mesozoic-Cenozoic was a time of profound tectonic activity in the Arctic, with incipient spreading in the Arctic Ocean, Baffin Bay-Labrador Sea and North Atlantic, as well as the northward movement of the Greenland microplate leading to collision and deformation in Greenland, Arctic Canada and Svalbard (Eurekan Orogeny). It is, however, still unclear, how northern Svalbard, situated at the northwestern edge of the Barents Shelf, was affected by these processes. Furthermore, northern Svalbard has been proposed to have been a Cretaceous-Cenozoic sediment source to surrounding regions because it lacks a post-Devonian sedimentary cover. When erosion took place and how that related to the tectonic history of the Arctic, is yet unresolved. In order to reconstruct the erosion history of northern Svalbard, we constrained its thermal evolution using apatite fission track (AFT) thermochronology. Our data reveal AFT ages between 62 +/- 5 and 214 +/- 10 Ma, recording late Mesozoic-early Paleogene exhumation. Our data show that northern Svalbard was emergent and experienced erosion from the Early Jurassic and presumably through the Cenozoic, although total exhumation was restricted to similar to 6 km. Pronounced exhumation took place during Jurassic-Cretaceous time, probably linked to the extensional tectonics during the opening of the Amerasian Basin (Arctic Ocean). In contrast, Cenozoic ocean basin formation and the Eurekan deformation did not cause significant erosion of northem Svalbard. Nonetheless, AFT data show that Late Cretaceous-Early Paleocene fault-related exhumation affected some parts of northern Svalbard. Fault zones were reactivated due to the reorganization of Arctic landmasses during an early phase of the Eurekan deformation, which implies that this episode commenced similar to 20 m.y. earlier in Svalbard than previously understood.
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| 5. |
- Dörr, Tobias, et al.
(författare)
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A novel peptidoglycan binding protein crucial for PBP1A-mediated cell wall biogenesis in Vibrio cholerae
- 2014
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Ingår i: PLOS Genetics. - : Public library science. - 1553-7390 .- 1553-7404. ; 10:6, s. e1004433-
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Tidskriftsartikel (refereegranskat)abstract
- The bacterial cell wall, which is comprised of a mesh of polysaccharide strands crosslinked via peptide bridges (peptidoglycan, PG), is critical for maintenance of cell shape and survival. PG assembly is mediated by a variety of Penicillin Binding Proteins (PBP) whose fundamental activities have been characterized in great detail; however, there is limited knowledge of the factors that modulate their activities in different environments or growth phases. In Vibrio cholerae, the cause of cholera, PG synthesis during the transition into stationary phase is primarily mediated by the bifunctional enzyme PBP1A. Here, we screened an ordered V. cholerae transposon library for mutants that are sensitive to growth inhibition by non-canonical D-amino acids (DAA), which prevent growth and maintenance of cell shape in PBP1A-deficient V. cholerae. In addition to PBP1A and its lipoprotein activator LpoA, we found that CsiV, a small periplasmic protein with no previously described function, is essential for growth in the presence of DAA. Deletion of csiV, like deletion of lpoA or the PBP1A-encoding gene mrcA, causes cells to lose their rod shape in the presence of DAA or the beta-lactam antibiotic cefsulodin, and all three mutations are synthetically lethal with deletion of mrcB, which encodes PBP1B, V. cholerae's second key bifunctional PBP. CsiV interacts with LpoA and PG but apparently not with PBP1A, supporting the hypothesis that CsiV promotes LpoA's role as an activator of PBP1A, and thereby modulates V. cholerae PG biogenesis. Finally, the requirement for CsiV in PBP1A-mediated growth of V. cholerae can be overcome either by augmenting PG synthesis or by reducing PG degradation, thereby highlighting the importance of balancing these two processes for bacterial survival.
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| 6. |
- Dörr, Tobias, et al.
(författare)
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Differential Requirement for PBP1a and PBP1b in In Vivo and In Vitro Fitness of Vibrio cholerae
- 2014
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 82:5, s. 2115-2124
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the roles of the Vibrio cholerae high-molecular-weight bifunctional penicillin binding proteins, PBP1a and PBP1b, in the fitness of this enteric pathogen. Using a screen for synthetic lethality, we found that the V. cholerae PBP1a and PBP1b proteins, like their Escherichia coli homologues, are each essential in the absence of the other and in the absence of the other's putative activator, the outer membrane lipoproteins LpoA and LpoB, respectively. Comparative analyses of V. cholerae mutants suggest that PBP1a/LpoA of V. cholerae play a more prominent role in generating and/or maintaining the pathogen's cell wall than PBP1b/LpoB.V. cholerae lacking PBP1b or LpoB exhibited wild-type growth under all conditions tested. In contrast, V. cholerae lacking PBP1a or LpoA exhibited growth deficiencies in minimal medium, in the presence of deoxycholate and bile, and in competition assays with wild-type cells both in vitro and in the infant mouse small intestine. PBP1a pathway mutants are particularly impaired in stationary phase, which renders them sensitive to a product(s) present in supernatants from stationary-phase wild-type cells. The marked competitive defect of the PBP1a pathway mutants in vivo was largely absent when exponential-phase cells rather than stationary-phase cells were used to inoculate suckling mice. Thus, at least for V. cholerae PBP1a pathway mutants, the growth phase of the inoculum is a key modulator of infectivity.
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| 7. |
- Dörr, Tobias, et al.
(författare)
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Substrate specificity of an elongation-specific peptidoglycan endopeptidase and its implications for cell wall architecture and growth of Vibrio cholerae
- 2013
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Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 89:5, s. 949-962
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Tidskriftsartikel (refereegranskat)abstract
- The bacterial cell wall consists of peptidoglycan (PG), a sturdy mesh of glycan strands cross-linked by short peptides. This rigid structure constrains cell shape and size, yet is sufficiently dynamic to accommodate insertion of newly synthesized PG, which was long hypothesized, and recently demonstrated, to require cleavage of the covalent peptide cross-links that couple previously inserted material. Here, we identify several genes in Vibrio cholerae that collectively are required for growth - particularly elongation - of this pathogen. V. cholerae encodes three putative periplasmic proteins, here denoted ShyA, ShyB, and ShyC, that contain both PG binding and M23 family peptidase domains. While none is essential individually, the absence of both ShyA and ShyC results in synthetic lethality, while the absence of ShyA and ShyB causes a significant growth deficiency. ShyA is a D,d-endopeptidase able to cleave most peptide chain cross-links in V. cholerae's PG. PG from a ∆shyA mutant has decreased average chain length, suggesting that ShyA may promote removal of short PG strands. Unexpectedly, ShyA has little activity against muropeptides containing pentapeptides, which typically characterize newly synthesized material. ShyA's substrate-dependent activity may contribute to selection of cleavage sites in PG, whose implications for the process of side-wall growth are discussed.
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