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- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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- Arneth, A., et al.
(författare)
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Historical carbon dioxide emissions caused by land-use changes are possibly larger than assumed
- 2017
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 10:2, s. 79-84
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Forskningsöversikt (refereegranskat)abstract
- The terrestrial biosphere absorbs about 20% of fossil-fuel CO 2 emissions. The overall magnitude of this sink is constrained by the difference between emissions, the rate of increase in atmospheric CO 2 concentrations, and the ocean sink. However, the land sink is actually composed of two largely counteracting fluxes that are poorly quantified: fluxes from land-use change and CO 2 uptake by terrestrial ecosystems. Dynamic global vegetation model simulations suggest that CO 2 emissions from land-use change have been substantially underestimated because processes such as tree harvesting and land clearing from shifting cultivation have not been considered. As the overall terrestrial sink is constrained, a larger net flux as a result of land-use change implies that terrestrial uptake of CO 2 is also larger, and that terrestrial ecosystems might have greater potential to sequester carbon in the future. Consequently, reforestation projects and efforts to avoid further deforestation could represent important mitigation pathways, with co-benefits for biodiversity. It is unclear whether a larger land carbon sink can be reconciled with our current understanding of terrestrial carbon cycling. Our possible underestimation of the historical residual terrestrial carbon sink adds further uncertainty to our capacity to predict the future of terrestrial carbon uptake and losses.
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- Adam, J., et al.
(författare)
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Fumarate Hydratase Deletion in Pancreatic beta Cells Leads to Progressive Diabetes
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:13, s. 3135-3148
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Tidskriftsartikel (refereegranskat)abstract
- We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic beta cells (Fh1 beta KO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1 alpha or Nrf2. Progressive hyperglycemia in Fh1bKO mice led to dysregulated metabolism in b cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+](i) elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1bKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.
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- Pugh, T. A. M., et al.
(författare)
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Simulated carbon emissions from land-use change are substantially enhanced by accounting for agricultural management
- 2015
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- It is over three decades since a large terrestrial carbon sink (S-T) was first reported. The magnitude of the net sink is now relatively well known, and its importance for dampening atmospheric CO2 accumulation, and hence climate change, widely recognised. But the contributions of underlying processes are not well defined, particularly the role of emissions from land-use change (E-LUC) versus the biospheric carbon uptake (S-L; S-T. = S-L - E-LUC). One key aspect of the interplay of E-LUC and SL is the role of agricultural processes in land-use change emissions, which has not yet been clearly quantified at the global scale. Here we assess the effect of representing agricultural land management in a dynamic global vegetation model. Accounting for harvest, grazing and tillage resulted in cumulative E-LUC since 1850 ca. 70% larger than in simulations ignoring these processes, but also changed the timescale over which these emissions occurred and led to underestimations of the carbon sequestered by possible future reforestation actions. The vast majority of Earth system models in the recent IPCC Fifth Assessment Report omit these processes, suggesting either an overestimation in their present-day ST, or an underestimation of SL, of up to 1.0 Pg Ca-1. Management processes influencing crop productivity per se are important for food supply, but were found to have little influence on E-LUC.
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- Bodin, P., et al.
(författare)
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Accounting for interannual variability in agricultural intensification : The potential of crop selection in Sub-Saharan Africa
- 2016
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Ingår i: Agricultural Systems. - : Elsevier BV. - 0308-521X. ; 148, s. 159-168
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Tidskriftsartikel (refereegranskat)abstract
- Providing sufficient food for a growing global population is one of the fundamental global challenges today. Crop production needs not only to be increased, but also remain stable over the years, in order to limit the vulnerability of producers and consumers to inter-annual weather variability, especially in areas of the world where the food consumed is mainly produced locally (e.g. Sub Saharan Africa (SSA)). For subsistence agriculture, stable yields form a crucial contribution to food security. At a regional to global scale dynamical crop models can be used to study the impact of future changes in climate on food production. However, simulations of future crop production, for instance in response to climate change, often do not take into account either changes in the sown areas of crops or yield interannual variability. Here, we explore the response of simulated crop production to assumptions of crop selection, also taking into account interannual variability in yields and considering the response of agricultural productivity to climate change. We apply the dynamic global vegetation model LPJ-GUESS, which is designed to simulate yield over large regions under a changing environment. Model output provides the basis for selecting the relative fractions of sown areas of a range of crops, either by selecting the highest yielding crop, or by using an optimization approach in which crop production is maximized while the standard deviation in crop production is kept at below current levels. Maximizing simulated crop production for current climate while keeping interannual variability in crop production constant at today's level generates rather similar simulated geographical distributions of crops compared to observations. Even so, the optimization results suggest that it is possible to increase crop production regionally by adjusting crop selection, both for current and future climate, assuming the same cropland cover as today. For future climates modelled production increase is > 25% in more than 15% of the grid cells. For a small number of grid cells it is possible to both increase crop production while at the same time decreasing its interannual variability. Selecting the highest yielding crop for any location will lead to a large potential increase in mean food production, but at the cost of a very large increase in variability.
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