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| 2. |
- Schmidt, Amand F., et al.
(author)
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study
- 2017
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In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:2, s. 97-105
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Journal article (peer-reviewed)abstract
- Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
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- Zuntini, Alexandre R., et al.
(author)
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Phylogenomics and the rise of the angiosperms
- 2024
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In: NATURE. - 0028-0836 .- 1476-4687. ; 629, s. 843-850
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Journal article (peer-reviewed)abstract
- Angiosperms are the cornerstone of most terrestrial ecosystems and human livelihoods(1,2). A robust understanding of angiosperm evolution is required to explain their rise to ecological dominance. So far, the angiosperm tree of life has been determined primarily by means of analyses of the plastid genome(3,4). Many studies have drawn on this foundational work, such as classification and first insights into angiosperm diversification since their Mesozoic origins(5-7). However, the limited and biased sampling of both taxa and genomes undermines confidence in the tree and its implications. Here, we build the tree of life for almost 8,000 (about 60%) angiosperm genera using a standardized set of 353 nuclear genes(8). This 15-fold increase in genus-level sampling relative to comparable nuclear studies(9) provides a critical test of earlier results and brings notable change to key groups, especially in rosids, while substantiating many previously predicted relationships. Scaling this tree to time using 200 fossils, we discovered that early angiosperm evolution was characterized by high gene tree conflict and explosive diversification, giving rise to more than 80% of extant angiosperm orders. Steady diversification ensued through the remaining Mesozoic Era until rates resurged in the Cenozoic Era, concurrent with decreasing global temperatures and tightly linked with gene tree conflict. Taken together, our extensive sampling combined with advanced phylogenomic methods shows the deep history and full complexity in the evolution of a megadiverse clade.
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| 4. |
- Brant, William, et al.
(author)
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Selective Control of Composition in Prussian White for Enhanced Material Properties
- 2019
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In: Chemistry of Materials. - : AMER CHEMICAL SOC. - 0897-4756 .- 1520-5002. ; 31:18, s. 7203-7211
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Journal article (peer-reviewed)abstract
- Sodium-ion batteries based on Prussian blue analogues (PBAs) are ideal for large-scale energy storage applications due to the ability to meet the huge volumes and low costs required. For Na2-xFe[Fe(CN)(6)](1-y)center dot zH(2)O, realizing its commercial potential means fine control of the concentration of sodium, Fe(CN)(6) vacancies, and water content. To date, there is a huge variation in the literature of composition leading to variable electrochemical performance. In this work, we break down the synthesis of PBAs into three steps for controlling the sodium, vacancy, and water content via an inexpensive, scalable synthesis method. We produce rhombohedral Prussian white Na1.88(5)Fe[Fe-(CN)(6)]center dot 0.18(9)H2O with an initial capacity of 158 mAh/g retaining 90% capacity after 50 cycles. Subsequent characterization revealed that the increased polarization on the 3 V plateau is coincident with a phase transition and reduced utilization of the high-spin Fe(III)/Fe(II) redox couple. This reveals a clear target for subsequent improvements of the material to boost long-term cycling stability. These results will be of great interest for the myriad of applications of PBAs, such as catalysis, magnetism, electrochromics, and gas sorption.
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| 5. |
- Burt, O, et al.
(author)
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Genetic Variation in the ASTN2 Locus in Cardiovascular, Metabolic and Psychiatric Traits: Evidence for Pleiotropy Rather Than Shared Biology
- 2021
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In: Genes. - : MDPI AG. - 2073-4425. ; 12:8
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Journal article (peer-reviewed)abstract
- Background: The link between cardiometabolic and psychiatric illness has long been attributed to human behaviour, however recent research highlights shared biological mechanisms. The ASTN2 locus has been previously implicated in psychiatric and cardiometabolic traits, therefore this study aimed to systematically investigate the genetic architecture of ASTN2 in relation to a wide range of relevant traits. Methods: Baseline questionnaire, assessment and genetic data of 402111 unrelated white British ancestry individuals from the UK Biobank was analysed. Genetic association analyses were conducted using PLINK 1.07, assuming an additive genetic model and adjusting for age, sex, genotyping chip, and population structure. Conditional analyses and linkage disequilibrium assessment were used to determine whether cardiometabolic and psychiatric signals were independent. Results: Associations between genetic variants in the ASTN2 locus and blood pressure, total and central obesity, neuroticism, anhedonia and mood instability were identified. All analyses support the independence of the cardiometabolic traits from the psychiatric traits. In silico analyses provide support for the central obesity signal acting through ASTN2, however most of the other signals are likely acting through other genes in the locus. Conclusions: Our systematic analysis demonstrates that ASTN2 has pleiotropic effects on cardiometabolic and psychiatric traits, rather than contributing to shared pathology.
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- Pnevmatikatos, Dionisios N., et al.
(author)
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Effective reconfigurable design: The FASTER approach
- 2014
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In: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - Cham : Springer International Publishing. - 1611-3349 .- 0302-9743. ; 8405, s. 318-323
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Conference paper (peer-reviewed)abstract
- While fine-grain, reconfigurable devices have been available for years, they are mostly used in a fixed functionality, "asic-replacement" manner. To exploit opportunities for flexible and adaptable run-time exploitation of fine grain reconfigurable resources (as implemented currently in dynamic, partial reconfiguration), better tool support is needed. The FASTER project aims to provide a methodology and a tool-chain that will enable designers to efficiently implement a reconfigurable system on a platform combining software and reconfigurable resources. Starting from a high-level application description and a target platform, our tools analyse the application, evaluate reconfiguration options, and implement the designer choices on underlying vendor tools. In addition, FASTER addresses micro-reconfiguration, verification, and the run-time management of system resources. We use industrial applications to demonstrate the effectiveness of the proposed framework and identify new opportunities for reconfigurable technologies.
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| 8. |
- Pnevmatikatos, Dionisios N., et al.
(author)
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FASTER: Facilitating Analysis and Synthesis Technologies for Effective Reconfiguration
- 2015
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In: Microprocessors and Microsystems. - : Elsevier BV. - 0141-9331. ; 39:4-5, s. 321-338
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Journal article (peer-reviewed)abstract
- The FASTER (Facilitating Analysis and Synthesis Technologies for Effective Reconfiguration) EU FP7 project, aims to ease the design and implementation of dynamically changing hardware systems. Our motivation stems from the promise reconfigurable systems hold for achieving high performance and extending product functionality and lifetime via the addition of new features that operate at hardware speed. However, designing a changing hardware system is both challenging and time-consuming. FASTER facilitates the use of reconfigurable technology by providing a complete methodology enabling designers to easily specify, analyze, implement and verify applications on platforms with general-purpose processors and acceleration modules implemented in the latest reconfigurable technology. Our tool-chain supports both coarse- and fine-grain FPGA reconfiguration, while during execution a flexible run-time system manages the reconfigurable resources. We target three applications from different domains. We explore the way each application benefits from reconfiguration, and then we asses them and the FASTER tools, in terms of performance, area consumption and accuracy of analysis.
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| 9. |
- Pnevmatikatos, Dionisios N., et al.
(author)
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FASTER: Facilitating analysis and synthesis technologies for effective reconfiguration
- 2012
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In: 15th Euromicro Conference on Digital System Design, DSD 2012; Cesme, Izmir; Turkey; 5 September 2012 through 8 September 2012. - 9780769547985 ; , s. 234-241
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Conference paper (peer-reviewed)abstract
- The FASTER project aims to ease the definition, implementation and use of dynamically changing hardware systems. Our motivation stems from the promise reconfigurable systems hold for achieving better performance and extending product functionality and lifetime via the addition of new features that work at hardware speed. This is a clear advantage over the more straightforward software component adaptivity. However, designing a changing hardware system is both challenging and time consuming. The FASTER project will facilitate the use of reconfigurable technology by providing a complete methodology that enables designers to easily specify, analyse, implement and verify applications on platforms with general-purpose processors and acceleration modules implemented in the latest reconfigurable technology. To better adapt to different application requirements, the tool-chain will support both region-based and micro-reconfiguration and provide a flexible run-time system that will efficiently manage the reconfigurable resources. We will use applications from the embedded, high performance computing, and desktop domains to demonstrate the potential benefits of the FASTER tools on metrics such as performance, power consumption and total ownership cost.
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| 10. |
- Schmidt, Amand F., et al.
(author)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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In: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Journal article (peer-reviewed)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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