| 11. |
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| 12. |
- Teslovich, Tanya M., et al.
(author)
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Biological, clinical and population relevance of 95 loci for blood lipids
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
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Journal article (peer-reviewed)abstract
- Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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| 13. |
- Van Deerlin, Vivian M, et al.
(author)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Journal article (peer-reviewed)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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| 14. |
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| 15. |
- Richards, Stephen, et al.
(author)
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Genome Sequence of the Pea Aphid Acyrthosiphon pisum
- 2010
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In: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 8:2, s. e1000313-
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Journal article (peer-reviewed)abstract
- Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.
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| 16. |
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| 17. |
- de Louw, P. G. B., et al.
(author)
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Quantifying water and salt fluxes in a lowland polder catchment dominated by boil seepage : a probabilistic end-member mixing approach
- 2011
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In: Hydrology and Earth System Sciences. - : Copernicus GmbH. - 1027-5606 .- 1607-7938. ; 15, s. 2101-2117
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Journal article (peer-reviewed)abstract
- Upward saline groundwater seepage is leading to surface water salinization of deep lying polders in the Netherlands. Identifying measures to reduce the salt content requires a thorough understanding and quantification of the dominant sources of water and salt on a daily basis. However, as in most balance studies, there are large uncertainties in the contribution from groundwater seepage. Taking these into account, we applied a probabilistic (GLUE) end-member mixing approach to simulate two years of daily to weekly observations of discharge, salt loads and salt concentration of water pumped out of an artificially drained polder catchment area. We were then able to assess the contribution from the different sources to the water and salt balance of the polder and uncertainties in their quantification. Our modelling approach demonstrates the need to distinguish preferential from diffuse seepage. Preferential seepage via boils contributes, on average, 66% to the total salt load and only about 15% to the total water flux into the polder and therefore forms the main salinization pathway. With the model we were able to calculate the effect of future changes on surface water salinity and to assess the uncertainty in our predictions. Furthermore, we analyzed the parameter sensitivity and uncertainty to determine for which parameter the quality of field measurements should be improved to reduce model input and output uncertainty. High frequency measurements of polder water discharge and weighted concentration at the outlet of the catchment area appear to be essential for obtaining reliable simulations of water and salt fluxes and for allotting these to the different sources.
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| 18. |
- van der Velde, Ype, et al.
(author)
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Quantifying catchment-scale mixing and its effect on time-varying travel time distributions
- 2012
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In: Water resources research. - 0043-1397 .- 1944-7973. ; 48, s. W06536-
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Journal article (peer-reviewed)abstract
- Travel time distributions are often used to characterize catchment discharge behavior, catchment vulnerability to pollution and pollutant loads from catchments to downstream waters. However, these distributions vary with time because they are a function of rainfall and evapotranspiration. It is important to account for these variations when the time scale of interest is smaller than the typical time-scale over which average travel time distributions can be derived. Recent studies have suggested that subsurface mixing controls how rainfall and evapotranspiration affect the variability in travel time distributions of discharge. To quantify this relation between subsurface mixing and dynamics of travel time distributions, we propose a new transformation of travel time that yields transformed travel time distributions, which we call Storage Outflow Probability (STOP) functions. STOP functions quantify the probability for water parcels in storage to leave a catchment via discharge or evapotranspiration. We show that this is equal to quantifying mixing within a catchment. Compared to the similar Age function introduced by Botter et al. (2011), we show that STOP functions are more constant in time, have a clearer physical meaning and are easier to parameterize. Catchment-scale STOP functions can be approximated by a two-parameter beta distribution. One parameter quantifies the catchment preference for discharging young water; the other parameter quantifies the preference for discharging old water from storage. Because of this simple parameterization, the STOP function is an innovative tool to explore the effects of catchment mixing behavior, seasonality and climate change on travel time distributions and the related catchment vulnerability to pollution spreading.
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| 19. |
- van Dongen, Koen W, et al.
(author)
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European consensus on a competency-based virtual reality training program for basic endoscopic surgical psychomotor skills.
- 2010
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In: Surgical endoscopy. - : Springer Science and Business Media LLC. - 1432-2218 .- 0930-2794. ; 25:1, s. 166-171
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Journal article (peer-reviewed)abstract
- BACKGROUND: Virtual reality (VR) simulators have been demonstrated to improve basic psychomotor skills in endoscopic surgery. The exercise configuration settings used for validation in studies published so far are default settings or are based on the personal choice of the tutors. The purpose of this study was to establish consensus on exercise configurations and on a validated training program for a virtual reality simulator, based on the experience of international experts to set criterion levels to construct a proficiency-based training program. METHODS: A consensus meeting was held with eight European teams, all extensively experienced in using the VR simulator. Construct validity of the training program was tested by 20 experts and 60 novices. The data were analyzed by using the t test for equality of means. RESULTS: Consensus was achieved on training designs, exercise configuration, and examination. Almost all exercises (7/8) showed construct validity. In total, 50 of 94 parameters (53%) showed significant difference. CONCLUSIONS: A European, multicenter, validated, training program was constructed according to the general consensus of a large international team with extended experience in virtual reality simulation. Therefore, a proficiency-based training program can be offered to training centers that use this simulator for training in basic psychomotor skills in endoscopic surgery.
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| 20. |
- Shigenobu, S., et al.
(author)
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Comprehensive survey of developmental genes in the pea aphid, Acyrthosiphon pisum : frequent lineage-specific duplications and losses of developmental genes
- 2010
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In: Insect molecular biology (Print). - : Wiley. - 0962-1075 .- 1365-2583. ; 19:Supplements2, s. 47-62
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Journal article (peer-reviewed)abstract
- Aphids exhibit unique attributes, such as polyphenisms and specialized cells to house endosymbionts, that make them an interesting system for studies at the interface of ecology, evolution and development. Here we present a comprehensive characterization of the developmental genes in the pea aphid, Acyrthosiphon pisum, and compare our results to other sequenced insects. We investigated genes involved in fundamental developmental processes such as establishment of the body plan and organogenesis, focusing on transcription factors and components of signalling pathways. We found that most developmental genes were well conserved in the pea aphid, although many lineage-specific gene duplications and gene losses have occurred in several gene families. In particular, genetic components of transforming growth factor beta (TGF beta) Wnt, JAK/STAT (Janus kinase/signal transducer and activator of transcription) and EGF (Epidermal Growth Factor) pathways appear to have been significantly modified in the pea aphid.
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