| 1. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 2. |
- Furberg, Helena, et al.
(författare)
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Genome-wide meta-analyses identify multiple loci associated with smoking behavior
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441
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Tidskriftsartikel (refereegranskat)abstract
- Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
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| 3. |
- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 4. |
- De Kauwe, Martin G., et al.
(författare)
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Forest water use and water use efficiency at elevated CO2: a model-data intercomparison at two contrasting temperate forest FACE sites
- 2013
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 19:6, s. 1759-1779
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Tidskriftsartikel (refereegranskat)abstract
- Predicted responses of transpiration to elevated atmospheric CO2 concentration (eCO2) are highly variable amongst process-based models. To better understand and constrain this variability amongst models, we conducted an intercomparison of 11 ecosystem models applied to data from two forest free-air CO2 enrichment (FACE) experiments at Duke University and Oak Ridge National Laboratory. We analysed model structures to identify the key underlying assumptions causing differences in model predictions of transpiration and canopy water use efficiency. We then compared the models against data to identify model assumptions that are incorrect or are large sources of uncertainty. We found that model-to-model and model-to-observations differences resulted from four key sets of assumptions, namely (i) the nature of the stomatal response to elevated CO2 (coupling between photosynthesis and stomata was supported by the data); (ii) the roles of the leaf and atmospheric boundary layer (models which assumed multiple conductance terms in series predicted more decoupled fluxes than observed at the broadleaf site); (iii) the treatment of canopy interception (large intermodel variability, 215%); and (iv) the impact of soil moisture stress (process uncertainty in how models limit carbon and water fluxes during moisture stress). Overall, model predictions of the CO2 effect on WUE were reasonable (intermodel =approximately 28%+/- 10%) compared to the observations (=approximately 30%+/- 13%) at the well-coupled coniferous site (Duke), but poor (intermodel =approximately 24%+/- 6%; observations =approximately 38%+/- 7%) at the broadleaf site (Oak Ridge). The study yields a framework for analysing and interpreting model predictions of transpiration responses to eCO2, and highlights key improvements to these types of models.
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| 5. |
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| 6. |
- Högberg, Mona N, et al.
(författare)
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Quantification of effects of season and nitrogen supply on tree below-ground carbon transfer to ectomycorrhizal fungi and other soil organisms in a boreal pine forest
- 2010
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Ingår i: New Phytologist. - : Wiley. - 0028-646X .- 1469-8137. ; 187:2, s. 485-493
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Tidskriftsartikel (refereegranskat)abstract
- P>The flux of carbon from tree photosynthesis through roots to ectomycorrhizal (ECM) fungi and other soil organisms is assumed to vary with season and with edaphic factors such as nitrogen availability, but these effects have not been quantified directly in the field. To address this deficiency, we conducted high temporal-resolution tracing of 13C from canopy photosynthesis to different groups of soil organisms in a young boreal Pinus sylvestris forest. There was a 500% higher below-ground allocation of plant C in the late (August) season compared with the early season (June). Labelled C was primarily found in fungal fatty acid biomarkers (and rarely in bacterial biomarkers), and in Collembola, but not in Acari and Enchytraeidae. The production of sporocarps of ECM fungi was totally dependent on allocation of recent photosynthate in the late season. There was no short-term (2 wk) effect of additions of N to the soil, but after 1 yr, there was a 60% reduction of below-ground C allocation to soil biota. Thus, organisms in forest soils, and their roles in ecosystem functions, appear highly sensitive to plant physiological responses to two major aspects of global change: changes in seasonal weather patterns and N eutrophication.
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| 7. |
- Walker, Anthony P., et al.
(författare)
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Comprehensive ecosystem model-data synthesis using multiple data sets at two temperate forest free-air CO2 enrichment experiments: Model performance at ambient CO2 concentration
- 2014
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Ingår i: Journal of Geophysical Research - Biogeosciences. - 2169-8953 .- 2169-8961. ; 119:5, s. 937-964
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Tidskriftsartikel (refereegranskat)abstract
- Free-air CO2 enrichment (FACE) experiments provide a remarkable wealth of data which can be used to evaluate and improve terrestrial ecosystem models (TEMs). In the FACE model-data synthesis project, 11 TEMs were applied to two decadelong FACE experiments in temperate forests of the southeastern U.S.the evergreen Duke Forest and the deciduous Oak Ridge Forest. In this baseline paper, we demonstrate our approach to model-data synthesis by evaluating the models' ability to reproduce observed net primary productivity (NPP), transpiration, and leaf area index (LAI) in ambient CO2 treatments. Model outputs were compared against observations using a range of goodness-of-fit statistics. Many models simulated annual NPP and transpiration within observed uncertainty. We demonstrate, however, that high goodness-of-fit values do not necessarily indicate a successful model, because simulation accuracy may be achieved through compensating biases in component variables. For example, transpiration accuracy was sometimes achieved with compensating biases in leaf area index and transpiration per unit leaf area. Our approach to model-data synthesis therefore goes beyond goodness-of-fit to investigate the success of alternative representations of component processes. Here we demonstrate this approach by comparing competing model hypotheses determining peak LAI. Of three alternative hypotheses(1) optimization to maximize carbon export, (2) increasing specific leaf area with canopy depth, and (3) the pipe modelthe pipe model produced peak LAI closest to the observations. This example illustrates how data sets from intensive field experiments such as FACE can be used to reduce model uncertainty despite compensating biases by evaluating individual model assumptions.
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| 8. |
- Zaehle, Soenke, et al.
(författare)
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Evaluation of 11 terrestrial carbon-nitrogen cycle models against observations from two temperate Free-Air CO2 Enrichment studies
- 2014
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Ingår i: New Phytologist. - : Wiley. - 1469-8137 .- 0028-646X. ; 202:3, s. 803-822
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Tidskriftsartikel (refereegranskat)abstract
- We analysed the responses of 11 ecosystem models to elevated atmospheric [CO2] (eCO(2)) at two temperate forest ecosystems (Duke and Oak Ridge National Laboratory (ORNL) Free-Air CO2 Enrichment (FACE) experiments) to test alternative representations of carbon (C)-nitrogen (N) cycle processes. We decomposed the model responses into component processes affecting the response to eCO(2) and confronted these with observations from the FACE experiments. Most of the models reproduced the observed initial enhancement of net primary production (NPP) at both sites, but none was able to simulate both the sustained 10-yr enhancement at Duke and the declining response at ORNL: models generally showed signs of progressive N limitation as a result of lower than observed plant N uptake. Nonetheless, many models showed qualitative agreement with observed component processes. The results suggest that improved representation of above-ground-below-ground interactions and better constraints on plant stoichiometry are important for a predictive understanding of eCO(2) effects. Improved accuracy of soil organic matter inventories is pivotal to reduce uncertainty in the observed C-N budgets. The two FACE experiments are insufficient to fully constrain terrestrial responses to eCO(2), given the complexity of factors leading to the observed diverging trends, and the consequential inability of the models to explain these trends. Nevertheless, the ecosystem models were able to capture important features of the experiments, lending some support to their projections.
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