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- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Wightman, D. P., et al.
(author)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Journal article (peer-reviewed)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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| 3. |
- Spokes, L., et al.
(author)
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MEAD: An interdisciplinary study of the marine effects of atmospheric deposition in the Kattegat
- 2006
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In: Environmental Pollution. - : Elsevier BV. - 0269-7491. ; 140:3, s. 453-462
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Journal article (peer-reviewed)abstract
- This paper summarises the results of the EU funded MEAD project, an interdisciplinary study of the effects of atmospheric nitrogen deposition on the Kattegat Sea between Denmark and Sweden. The study considers emissions of reactive nitrogen gases, their transport, transformations, deposition and effects on algal growth together with management options to reduce these effects. We conclude that atmospheric deposition is an important source of fixed nitrogen to the region particularly in summer, when nitrogen is the limiting nutrient for phytoplankton growth, and contributes to the overall eutrophication pressures in this region. However, we also conclude that it is unlikely that atmospheric deposition can, on its own, induce algal blooms in this region. A reduction of atmospheric nitrogen loads to this region will require strategies to reduce emissions of ammonia from local agriculture and Europe wide reductions in nitrous oxide emissions. (c) 2005 Elsevier Ltd. All rights reserved.
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| 7. |
- Håkansson, H., et al.
(author)
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In vivo and in vitro toxicity of fractionated fish lipids, with particular regard to their content of chlorinated organic compounds
- 1991
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In: Pharmacology and Toxicology. - : Wiley. - 0901-9928 .- 1600-0773. ; 69:6, s. 459-471
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Journal article (peer-reviewed)abstract
- Six different lipid matrices (the intact lipid (IL), four lipid fractions with different polarity, and the free fatty acids (FFAs) obtained by hydrolysis of the triacylglycerol (TAG) containing fraction) were obtained from salmon (Salmo salar) and eel (Anguilla anguilla), each collected at a contaminated and a comparatively uncontaminated catch site along the coast of Scandinavia. The lipid matrices were studied in toxicological test systems representing various biological functions of different organ systems from several species and trophic levels. The results were evaluated with particular respect to the concentrations of extractable organically bound chlorine (EOCl) in the matrices tested. In some test systems, the specimens with a higher EOCl concentration appeared to be more toxic. For example, the TAG containing fraction (F2) from Idefjord eel, having a higher EOCl content than F2 from Oslofjord eel, reduced the number and hatchability of eggs laid by zebrafish. Both IL and F2 of Idefjord eel increased mortality and reduced the oxygen/nitrogen-ratio in blue mussels. Non-polar compounds (F1) from Bothnian Sea salmon induced 7-ethoxyresurofin O-deethylase (EROD) activity in rainbow trout hepatocytes, whereas F1 from Senja salmon did not. F1 from Bothnian Sea salmon also reduced the number of T-cells in foetal mouse thymus anlagen in vitro compared with the cell number in anlagen exposed to F1 from Senja salmon. A positive correlation between EOCl concentration and test response was found for EROD activity in rainbow trout hepatocytes and for ATP-leakage in Erlich ascites tumour cells when testing the phospolipid containing fraction (F4). However, in most test systems the fish oils, irrespective of EOCl content, were of low toxicity, and the observed effects need to be verified in future studies.
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| 9. |
- Vekic, T. T., et al.
(author)
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Effect of calcareous and siliceous amendments on N2O emissions of a grassland soil
- 2023
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In: Soil Use and Management. - 0266-0032. ; 39:3, s. 1082-1095
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Journal article (peer-reviewed)abstract
- Liming of acidic agricultural soils has been proposed as a strategy to mitigate nitrous oxide (N2O) emissions, as increased soil pH reduces the N2O/N-2 product ratio of denitrification. The capacity of different calcareous (calcite and dolomite) and siliceous minerals to increase soil pH and reduce N2O emissions was assessed in a 2-year grassland field experiment. An associated pot experiment was conducted using homogenized field soils for controlling spatial soil variability. Nitrous oxide emissions were highly episodic with emission peaks in response to freezing-thawing and application of NPK fertilizer. Liming with dolomite caused a pH increase from 5.1 to 6.2 and reduced N2O emissions by 30% and 60% after application of NPK fertilizer and freezing-thawing events, respectively. Over the course of the 2-year field trial, N2O emissions were significantly lower in dolomite-limed than non-limed soil (p < .05), although this effect was variable over time. Unexpectedly, no significant reduction of N2O emission was found in the calcite treatment, despite the largest pH increase in all tested minerals. We tentatively attribute this to increased N2O production by overall increase in nitrogen turnover rates (both nitrification and denitrification) following rapid pH increase in the first year after liming. Siliceous materials showed little pH effect and had no significant effect on N2O emissions probably because of their lower buffering capacity and lower cation content. In the pot experiment using soils taken from the field plots 3 years after liming and exposing them to natural freezing-thawing, both calcite (p < .01) and dolomite (p < .05) significantly reduced cumulative N2O emission by 50% and 30%, respectively, relative to the non-limed control. These results demonstrate that the overall effect of liming is to reduce N2O emission, although high lime doses may lead to a transiently enhanced emission.
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