| 1. |
- Nicolas, Aude, et al.
(author)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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In: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Journal article (peer-reviewed)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 2. |
- Gavin, Michael C., et al.
(author)
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Process-based modelling shows how climate and demography shape language diversity
- 2017
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In: Global Ecology and Biogeography. - : WILEY. - 1466-822X .- 1466-8238. ; 26:5, s. 584-591
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Journal article (peer-reviewed)abstract
- AimTwo fundamental questions about human language demand answers: why are so many languages spoken today and why is their geographical distribution so uneven? Although hypotheses have been proposed for centuries, the processes that determine patterns of linguistic and cultural diversity remain poorly understood. Previous studies, which relied on correlative, curve-fitting approaches, have produced contradictory results. Here we present the first application of process-based simulation modelling, derived from macroecology, to examine the distribution of human groups and their languages. LocationThe Australian continent is used as a case study to demonstrate the power of simulation modelling for identifying processes shaping the diversity and distribution of human languages. MethodsProcess-based simulation models allow investigators to hold certain factors constant in order to isolate and assess the impact of modelled processes. We tested the extent to which a minimal set of processes determines the number and spatial distribution of languages on the Australian continent. Our model made three basic assumptions based on previously proposed, but untested, hypotheses: groups fill unoccupied spaces, rainfall limits population density and groups divide after reaching a maximum population. ResultsRemarkably, this simple model accurately predicted the total number of languages (average estimate 406, observed 407), and explained 56% of spatial variation in language richness on the Australian continent. Main conclusionsOur results present strong evidence that current climatic conditions and limits to group size are important processes shaping language diversity patterns in Australia. Our study also demonstrates how simulation models from macroecology can be used to understand the processes that have shaped human cultural diversity across the globe.
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| 3. |
- Gavin, Michael C., et al.
(author)
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Toward a Mechanistic Understanding of Linguistic Diversity
- 2013
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In: BioScience. - : Oxford University Press (OUP). - 0006-3568 .- 1525-3244. ; 63:7, s. 524-535
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Journal article (peer-reviewed)abstract
- Our species displays remarkable linguistic diversity. Although the uneven distribution of this diversity demands explanation, the drivers of these patterns have not been conclusively determined. We address this issue in two steps: First, we review previous empirical studies whose authors have suggested environmental, geographical, and sociocultural drivers of linguistic diversification. However, contradictory results and methodological variation make it difficult to draw general conclusions. Second, we outline a program for future research. We suggest that future analyses should account for interactions among causal factors, the lack of spatial and phylogenetic independence of the data, and transitory patterns. Recent analytical advances in biogeography and evolutionary biology, such as simulation modeling of diversity patterns, hold promise for testing four key mechanisms of language diversification proposed here: neutral change, population movement, contact, and selection. Future modeling approaches should also evaluate how the outcomes of these processes are influenced by demography, environmental heterogeneity, and time.
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| 6. |
- Drake, TM, et al.
(author)
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Surgical site infection after gastrointestinal surgery in children: an international, multicentre, prospective cohort study
- 2020
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In: BMJ global health. - : BMJ. - 2059-7908. ; 5:12
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Journal article (peer-reviewed)abstract
- Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings.MethodsA multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI).ResultsOf 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI.ConclusionThe odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.
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| 8. |
- Etiene, Tiago, et al.
(author)
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Verifying Volume Rendering Using Discretization Error Analysis
- 2014
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In: IEEE Transactions on Visualization and Computer Graphics. - : Institute of Electrical and Electronics Engineers (IEEE). - 1077-2626 .- 1941-0506. ; 20:1, s. 140-154
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Journal article (peer-reviewed)abstract
- We propose an approach for verification of volume rendering correctness based on an analysis of the volume rendering integral, the basis of most DVR algorithms. With respect to the most common discretization of this continuous model (Riemann summation), we make assumptions about the impact of parameter changes on the rendered results and derive convergence curves describing the expected behavior. Specifically, we progressively refine the number of samples along the ray, the grid size, and the pixel size, and evaluate how the errors observed during refinement compare against the expected approximation errors. We derive the theoretical foundations of our verification approach, explain how to realize it in practice, and discuss its limitations. We also report the errors identified by our approach when applied to two publicly available volume rendering packages.
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| 9. |
- Fenner, Merle Friederike, et al.
(author)
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Effect of selective IK,ACh inhibition by XAF-1407 in an equine model of tachypacing-induced persistent atrial fibrillation
- 2020
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In: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 177:16, s. 3778-3794
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Journal article (peer-reviewed)abstract
- Background and Purpose: Inhibition of the G-protein gated ACh-activated inward rectifier potassium current, IK,ACh may be an effective atrial selective treatment strategy for atrial fibrillation (AF). Therefore, the anti-arrhythmic and electrophysiological properties of a novel putatively potent and highly specific IK,ACh inhibitor, XAF-1407 (3-methyl-1-[5-phenyl-4-[4-(2-pyrrolidin-1-ylethoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-6-yl]azetidin-3-ol), were characterised for the first time in vitro and investigated in horses with persistent AF. Experimental Approach: The pharmacological ion channel profile of XAF-1407 was investigated using cell lines expressing relevant ion channels. In addition, eleven horses were implanted with implantable cardioverter defibrillators enabling atrial tachypacing into self-sustained AF. The electrophysiological effects of XAF-1407 were investigated after serial cardioversions over a period of 1 month. Cardioversion success, drug-induced changes of atrial tissue refractoriness, and ventricular electrophysiology were assessed at baseline (day 0) and days 3, 5, 11, 17, and 29 after AF induction. Key Results: XAF-1407 potently and selectively inhibited Kir3.1/3.4 and Kir3.4/3.4, underlying the IK,ACh current. XAF-1407 treatment in horses prolonged atrial effective refractory period as well as decreased atrial fibrillatory rate significantly (~20%) and successfully cardioverted AF, although with a decreasing efficacy over time. XAF-1407 shortened atrioventricular-nodal refractoriness, without effect on QRS duration. QTc prolongation (4%) within 15 min of drug infusion was observed, however, without any evidence of ventricular arrhythmia. Conclusion and Implications: XAF-1407 efficiently cardioverted sustained tachypacing-induced AF of short duration in horses without notable side effects. This supports IK,ACh inhibition as a potentially safe treatment of paroxysmal AF in horses, suggesting potential clinical value for other species including humans.
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| 10. |
- Hudson, Lawrence N, et al.
(author)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Journal article (peer-reviewed)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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