| 1. |
- Liu, Hui, et al.
(author)
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Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors
- 2022
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 92:2, s. 270-278
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.METHODS: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.RESULTS: A higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.INTERPRETATION: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.
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| 2. |
- Matthews, Evan O., et al.
(author)
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Athero-occlusive Disease Appears to be Associated with Slower Abdominal Aortic Aneurysm Growth : An Exploratory Analysis of the TEDY Trial
- 2022
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In: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 63:4, s. 632-640
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Journal article (peer-reviewed)abstract
- Objective: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). Methods: Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models; 131 of the 210 participants recruited to TEDY were included. Results: In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm(3) and 0.70 (0.19 - 1.22) mm slower than those without AOD, p = .008 and.007 respectively. The association between AOD and significantly slower AAA growth was maintained after adjusting for risk factors and medications, significantly unequally distributed between participants with and without an AOD diagnosis. Conclusion: In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.
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| 3. |
- Qiu, Chunjing, et al.
(author)
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A strong mitigation scenario maintains climate neutrality of northern peatlands
- 2022
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In: One Earth. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 5:1, s. 86-97
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Journal article (peer-reviewed)abstract
- Northern peatlands store 300–600 Pg C, of which approximately half are underlain by permafrost. Climate warming and, in some regions, soil drying from enhanced evaporation are progressively threatening this large carbon stock. Here, we assess future CO2 and CH4 fluxes from northern peatlands using five land surface models that explicitly include representation of peatland processes. Under Representative Concentration Pathways (RCP) 2.6, northern peatlands are projected to remain a net sink of CO2 and climate neutral for the next three centuries. A shift to a net CO2 source and a substantial increase in CH4 emissions are projected under RCP8.5, which could exacerbate global warming by 0.21°C (range, 0.09–0.49°C) by the year 2300. The true warming impact of peatlands might be higher owing to processes not simulated by the models and direct anthropogenic disturbance. Our study highlights the importance of understanding how future warming might trigger high carbon losses from northern peatlands.
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| 4. |
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| 5. |
- Grover, Sandeep, et al.
(author)
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Replication of a Novel Parkinson's Locus in a European Ancestry Population
- 2021
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In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:7, s. 1689-1695
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Journal article (peer-reviewed)abstract
- BACKGROUND: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.OBJECTIVES: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations.METHODS: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled.RESULTS: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ).CONCLUSIONS: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 6. |
- Roberts, Sean, et al.
(author)
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CHIELD: the causal hypotheses in evolutionary linguistics database
- 2020
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In: Journal of Language Evolution. - : Oxford University Press (OUP). - 2058-458X. ; 5:2, s. 101-120
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Journal article (peer-reviewed)abstract
- Language is one of the most complex of human traits. There are many hypotheses about how it originated, what factors shaped its diversity, and what ongoing processes drive how it changes. We present the Causal Hypotheses in Evolutionary Linguistics Database (CHIELD, https://chield.excd.org/), a tool for expressing, exploring, and evaluating hypotheses. It allows researchers to integrate multiple theories into a coherent narrative, helping to design future research. We present design goals, a formal specification, and an implementation for this database. Source code is freely available for other fields to take advantage of this tool. Some initial results are presented, including identifying conflicts in theories about gossip and ritual, comparing hypotheses relating population size and morphological complexity, and an author relation network.
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| 7. |
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| 8. |
- Lerche, Stefanie, et al.
(author)
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Parkinson's disease : Evolution of cognitive impairment and CSF Aβ1-42 profiles in a prospective longitudinal study
- 2019
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:2, s. 165-170
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Journal article (peer-reviewed)abstract
- Objective: To evaluate the evolution of cognitive impairment in relation to cerebrospinal fluid (CSF) profiles of amyloid-β (Aβ), total-Tau and phosphorylated-Tau in Parkinson's disease (PD). Methods: Prospective, longitudinal, observational study up to 10 years with follow-up every 2 years. We assessed CSF profiles in 415 patients with sporadic PD (median age 66; 63% men) and 142 healthy controls (median age 62; 43% men). Results: Patients with PD with low CSF Aβ1-42 levels at baseline were more often cognitively impaired than patients with intermediate and high Aβ1-42 levels. Sixty-seven per cent of the patients with low Aβ1-42 levels at baseline and normal cognition developed cognitive impairment during follow-up, compared with 41% and 37% of patients having intermediate and high CSF Aβ1-42 levels. Kaplan-Meier survival curves and Cox regression revealed that patients with low CSF Aβ1-42 levels at baseline developed cognitive impairment more frequently and earlier during follow-up. Conclusion: We conclude that in patients with sporadic PD, low levels of Aβ1-42 are associated with a higher risk of developing cognitive impairment earlier in the disease process at least in a subgroup of patients.
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| 9. |
- Lade, Steven J., et al.
(author)
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Analytically tractable climate-carbon cycle feedbacks under 21st century anthropogenic forcing
- 2018
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In: Earth System Dynamics. - : Copernicus GmbH. - 2190-4979 .- 2190-4987. ; 9:2, s. 507-523
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Journal article (peer-reviewed)abstract
- Changes to climate-carbon cycle feedbacks may significantly affect the Earth system's response to greenhouse gas emissions. These feedbacks are usually analysed from numerical output of complex and arguably opaque Earth system models. Here, we construct a stylised global climate-carbon cycle model, test its output against comprehensive Earth system models, and investigate the strengths of its climate-carbon cycle feedbacks analytically. The analytical expressions we obtain aid understanding of carbon cycle feedbacks and the operation of the carbon cycle. Specific results include that different feedback formalisms measure fundamentally the same climate-carbon cycle processes; temperature dependence of the solubility pump, biological pump, and CO2 solubility all contribute approximately equally to the ocean climate-carbon feedback; and concentration-carbon feedbacks may be more sensitive to future climate change than climate-carbon feedbacks. Simple models such as that developed here also provide workbenches for simple but mechanistically based explorations of Earth system processes, such as interactions and feedbacks between the planetary boundaries, that are currently too uncertain to be included in comprehensive Earth system models.
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| 10. |
- Man, V., et al.
(author)
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Impact of isotropic constitutive descriptions on the predicted peak wall stress in abdominal aortic aneurysms
- 2018
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In: Medical Engineering and Physics. - : Elsevier. - 1350-4533 .- 1873-4030. ; 53, s. 49-57
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Journal article (peer-reviewed)abstract
- Biomechanics-based assessment of Abdominal Aortic Aneurysm (AAA) rupture risk has gained considerable scientific and clinical momentum. However, computation of peak wall stress (PWS) using state-ofthe-art finite element models is time demanding. This study investigates which features of the constitutive description of AAA wall are decisive for achieving acceptable stress predictions in it. Influence of five different isotropic constitutive descriptions of AAA wall is tested; models reflect realistic non-linear, artificially stiff non-linear, or artificially stiff pseudo-linear constitutive descriptions of AAA wall. Influence of the AAA wall model is tested on idealized (n = 4) and patient-specific (n = 16) AAA geometries. Wall stress computations consider a (hypothetical) load-free configuration and include residual stresses homogenizing the stresses across the wall. Wall stress differences amongst the different descriptions were statistically analyzed. When the qualitatively similar non-linear response of the AAA wall with low initial stiffness and subsequent strain stiffening was taken into consideration, wall stress (and PWS) predictions did not change significantly. Keeping this non-linear feature when using an artificially stiff wall can save up to 30% of the computational time, without significant change in PWS. In contrast, a stiff pseudo-linear elastic model may underestimate the PWS and is not reliable for AAA wall stress computations.
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