| 1. |
- van der Lee, S. J., et al.
(författare)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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| 2. |
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| 3. |
- 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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| 4. |
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| 5. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 6. |
- Singh, T. P., et al.
(författare)
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Systematic review and meta-analysis of the association between intraluminal thrombus volume and abdominal aortic aneurysm rupture
- 2019
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Ingår i: Journal of Vascular Surgery. - : Mosby Inc.. - 0741-5214 .- 1097-6809. ; 70:6, s. 2065--2073.e10
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Forskningsöversikt (refereegranskat)abstract
- Background: Intraluminal thrombus (ILT) is present in most abdominal aortic aneurysms (AAAs), although its role in AAA progression is controversial. Methods: A literature search was performed to identify studies that investigated the association between ILT volume and AAA rupture. A study assessment tool was developed to assess the methodologic quality of included studies. A meta-analysis was conducted using an inverse variance-weighted random-effects model to compare the ILT volume in ruptured and asymptomatic intact AAAs. Leave-one-out sensitivity analyses were conducted to assess the robustness of the findings. A subanalysis was performed including studies in which patients with asymptomatic intact and ruptured AAAs were matched for aortic diameter. Interstudy heterogeneity was assessed using the I2 statistic. Results: Eight studies involving 672 patients were included in this systematic review. Meta-analysis of all studies found a greater ILT volume in patients with ruptured AAAs than in patients with asymptomatic intact AAAs (standardized mean difference, 0.56; 95% confidence interval, 0.17-0.96; P =.005; I2 = 79.8%). Sensitivity analyses suggested that the findings were robust; however, aortic diameter was significantly larger in ruptured than in asymptomatic intact AAAs (mean ± standard deviation, 78 ± 18 and 64 ± 15 mm, respectively; P <.001). In the subanalysis of studies that matched for diameter, no significant difference in ILT volume between groups was found (standardized mean difference, 0.03; 95% confidence interval, −0.27 to 0.33; P =.824; I2 = 0%). Conclusions: This meta-analysis suggests that ILT volume is greater in patients with ruptured AAAs than in patients with asymptomatic intact AAAs, although this is most likely due to the larger diameter of ruptured AAAs.
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| 8. |
- Cherubini, F., et al.
(författare)
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Bridging the gap between impact assessment methods and climate science
- 2016
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Ingår i: Environmental Science and Policy. - : Elsevier BV. - 1873-6416 .- 1462-9011. ; 64, s. 129-140
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Forskningsöversikt (refereegranskat)abstract
- Life-cycle assessment and carbon footprint studies are widely used by decision makers to identify climate change mitigation options and priorities at corporate and public levels. These applications, including the vast majority of emission accounting schemes and policy frameworks, traditionally quantify climate impacts of human activities by aggregating greenhouse gas emissions into the so-called CO2-equivalents using the 100-year Global Warming Potential (GWP100) as the default emission metric. The practice was established in the early nineties and has not been coupled with progresses in climate science, other than simply updating numerical values for GWP100. We review the key insights from the literature surrounding climate science that are at odds with existing climate impact methods and we identify possible improvement options. Issues with the existing approach lie in the use of a single metric that cannot represent the climate system complexity for all possible research and policy contexts, and in the default exclusion of near-term climate forcers such as aerosols or ozone precursors and changes in the Earth's energy balance associated with land cover changes. Failure to acknowledge the complexity of climate change drivers and the spatial and temporal heterogeneities of their climate system responses can lead to the deployment of suboptimal, and potentially even counterproductive, mitigation strategies. We argue for an active consideration of these aspects to bridge the gap between climate impact methods used in environmental impact analysis and climate science.
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| 9. |
- Comellas, E., et al.
(författare)
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A homeostatic-driven turnover remodelling constitutive model for healing in soft tissues
- 2016
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Ingår i: Journal of the Royal Society Interface. - : Royal Society of London. - 1742-5689 .- 1742-5662. ; 13:116
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Tidskriftsartikel (refereegranskat)abstract
- Remodelling of soft biological tissue is characterized by interacting biochemical and biomechanical events, which change the tissue's microstructure, and, consequently, its macroscopic mechanical properties. Remodelling is a well-defined stage of the healing process, and aims at recovering or repairing the injured extracellular matrix. Like other physiological processes, remodelling is thought to be driven by homeostasis, i.e. it tends to re-establish the properties of the uninjured tissue. However, homeostasis may never be reached, such that remodelling may also appear as a continuous pathological transformation of diseased tissues during aneurysm expansion, for example. A simple constitutive model for soft biological tissues that regards remodelling as homeostatic-driven turnover is developed. Specifically, the recoverable effective tissue damage, whose rate is the sum of a mechanical damage rate and a healing rate, serves as a scalar internal thermodynamic variable. In order to integrate the biochemical and biomechanical aspects of remodelling, the healing rate is, on the one hand, driven by mechanical stimuli, but, on the other hand, subjected to simple metabolic constraints. The proposed model is formulated in accordance with continuum damage mechanics within an open-system thermodynamics framework. The numerical implementation in an in-house finite-element code is described, particularized for Ogden hyperelasticity. Numerical examples illustrate the basic constitutive characteristics of the model and demonstrate its potential in representing aspects of remodelling of soft tissues. Simulation results are verified for their plausibility, but also validated against reported experimental data.
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| 10. |
- Erhart, P., et al.
(författare)
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Finite-Elemente-Analyse abdomineller Aortenaneurysmen : Aktuelle Wertigkeit als Ergänzung zur herkömmlichen Diagnostik
- 2015
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Ingår i: Gefässchirurgie. - : Springer Science and Business Media LLC. - 0948-7034 .- 1434-3932. ; 20:7, s. 503-507
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Tidskriftsartikel (refereegranskat)abstract
- Finite element analysis (FEA) of abdominal aortic aneurysms (AAA) could enable a more precise patient-specific risk assessment of AAA rupture. Further clinical studies are needed to validate this model as a clinical decision-making tool. The A4clinics™ software provides a simple and detailed FEA simulation. After implementation of a FEA workstation in a high volume university vascular center, relevant studies for further model validation are expected to be carried out.
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