| 1. |
- Baigent, Colin, et al.
(författare)
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The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection) : a randomised placebo-controlled trial
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 377:9784, s. 2181-2192
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Tidskriftsartikel (refereegranskat)abstract
- Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and I SRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0.85 mmol/L (SE 0.02; with about two-thirds compliance) during a median follow-up of 4.9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74-0.94; log-rank p=0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92,95% CI 0.76-1.11; p=0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75,95% CI 0.60-0.94; p=0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68-0.93; p=0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p=0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p=0.13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
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| 2. |
- Craig, Rory J., et al.
(författare)
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Natural selection beyond genes : Identification and analyses of evolutionarily conserved elements in the genome of the collared flycatcher (Ficedula albicollis)
- 2018
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Ingår i: Molecular Ecology. - : WILEY. - 0962-1083 .- 1365-294X. ; 27:2, s. 476-492
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Tidskriftsartikel (refereegranskat)abstract
- It is becoming increasingly clear that a significant proportion of the functional sequence within eukaryotic genomes is noncoding. However, since the identification of conserved elements (CEs) has been restricted to a limited number of model organisms, the dynamics and evolutionary character of the genomic landscape of conserved, and hence likely functional, sequence is poorly understood in most species. Moreover, identification and analysis of the full suite of functional sequence are particularly important for the understanding of the genetic basis of trait loci identified in genome scans or quantitative trait locus mapping efforts. We report that similar to 6.6% of the collared flycatcher genome (74.0Mb) is spanned by similar to 1.28 million CEs, a higher proportion of the genome but a lower total amount of conserved sequence than has been reported in mammals. We identified >200,000 CEs specific to either the archosaur, avian, neoavian or passeridan lineages, constituting candidates for lineage-specific adaptations. Importantly, no less than similar to 71% of CE sites were nonexonic (52.6Mb), and conserved nonexonic sequence density was negatively correlated with functional exonic density at local genomic scales. Additionally, nucleotide diversity was strongly reduced at nonexonic conserved sites (0.00153) relative to intergenic nonconserved sites (0.00427). By integrating deep transcriptome sequencing and additional genome annotation, we identified novel protein-coding genes, long noncoding RNA genes and transposon-derived (exapted) CEs. The approach taken here based on the use of a progressive cactus whole-genome alignment to identify CEs should be readily applicable to nonmodel organisms in general and help to reveal the rich repertoire of putatively functional noncoding sequence as targets for selection.
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| 3. |
- Goubert, Clement, et al.
(författare)
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A beginner's guide to manual curation of transposable elements
- 2022
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Ingår i: Mobile DNA. - : Springer Nature. - 1759-8753. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the study of transposable elements (TEs), the generation of a high confidence set of consensus sequences that represent the diversity of TEs found in a given genome is a key step in the path to investigate these fascinating genomic elements. Many algorithms and pipelines are available to automatically identify putative TE families present in a genome. Despite the availability of these valuable resources, producing a library of high-quality full-length TE consensus sequences largely remains a process of manual curation. This know-how is often passed on from mentor-to-mentee within research groups, making it difficult for those outside the field to access this highly specialised skill.Results: Our manuscript attempts to fill this gap by providing a set of detailed computer protocols, software recommendations and video tutorials for those aiming to manually curate TEs. Detailed step-by-step protocols, aimed at the complete beginner, are presented in the Supplementary Methods.Conclusions: The proposed set of programs and tools presented here will make the process of manual curation achievable and amenable to all researchers and in special to those new to the field of TEs.
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| 4. |
- Monterisi, Stefania, et al.
(författare)
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PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling.
- 2017
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Ingår i: eLife. - 2050-084X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- cAMP/PKA signalling is compartmentalised with tight spatial and temporal control of signal propagation underpinning specificity of response. The cAMP-degrading enzymes, phosphodiesterases (PDEs), localise to specific subcellular domains within which they control local cAMP levels and are key regulators of signal compartmentalisation. Several components of the cAMP/PKA cascade are located to different mitochondrial sub-compartments, suggesting the presence of multiple cAMP/PKA signalling domains within the organelle. The function and regulation of these domains remain largely unknown. Here, we describe a novel cAMP/PKA signalling domain localised at mitochondrial membranes and regulated by PDE2A2. Using pharmacological and genetic approaches combined with real-time FRET imaging and high resolution microscopy, we demonstrate that in rat cardiac myocytes and other cell types mitochondrial PDE2A2 regulates local cAMP levels and PKA-dependent phosphorylation of Drp1. We further demonstrate that inhibition of PDE2A, by enhancing the hormone-dependent cAMP response locally, affects mitochondria dynamics and protects from apoptotic cell death.
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| 5. |
- Riddell, Michael C, et al.
(författare)
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Exercise management in type 1 diabetes: a consensus statement.
- 2017
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Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595. ; 5:5, s. 377-390
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes is a challenging condition to manage for various physiological and behavioural reasons. Regular exercise is important, but management of different forms of physical activity is particularly difficult for both the individual with type 1 diabetes and the health-care provider. People with type 1 diabetes tend to be at least as inactive as the general population, with a large percentage of individuals not maintaining a healthy body mass nor achieving the minimum amount of moderate to vigorous aerobic activity per week. Regular exercise can improve health and wellbeing, and can help individuals to achieve their target lipid profile, body composition, and fitness and glycaemic goals. However, several additional barriers to exercise can exist for a person with diabetes, including fear of hypoglycaemia, loss of glycaemic control, and inadequate knowledge around exercise management. This Review provides an up-to-date consensus on exercise management for individuals with type 1 diabetes who exercise regularly, including glucose targets for safe and effective exercise, and nutritional and insulin dose adjustments to protect against exercise-related glucose excursions.
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