| 231. |
- Kohlhauer, M., et al.
(författare)
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Protection against cardiac ischemia-reperfusion injury by hypothermia and by inhibition of succinate accumulation and oxidation is additive
- 2019
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Ingår i: Basic Research in Cardiology. - : Springer Science and Business Media LLC. - 0300-8428 .- 1435-1803. ; 114:3
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Tidskriftsartikel (refereegranskat)abstract
- Hypothermia induced at the onset of ischemia is a potent experimental cardioprotective strategy for myocardial infarction. The aim of our study was to determine whether the beneficial effects of hypothermia may be due to decreasing mitochondria-mediated mechanisms of damage that contribute to the pathophysiology of ischemia/reperfusion injury. New Zealand male rabbits were submitted to 30min of myocardial ischemia with hypothermia (32 degrees C) induced by total liquid ventilation (TLV). Hypothermia was applied during ischemia alone (TLV group), during ischemia and reperfusion (TLV-IR group) and normothermia (Control group). In all the cases, ischemia was performed by surgical ligation of the left anterior descending coronary artery and was followed by 3h of reperfusion before assessment of infarct size. In a parallel study, male C57BL6/J mice underwent 30min myocardial ischemia followed by reperfusion under either normothermia (37 degrees C) or conventionally induced hypothermia (32 degrees C). In both the models, the levels of the citric acid cycle intermediate succinate, mitochondrial complex I activity were assessed at various times. The benefit of hypothermia during ischemia on infarct size was compared to inhibition of succinate accumulation and oxidation by the complex II inhibitor malonate, applied as the pro-drug dimethyl malonate under either normothermic or hypothermic conditions. Hypothermia during ischemia was cardioprotective, even when followed by normothermic reperfusion. Hypothermia during ischemia only, or during both, ischemia and reperfusion, significantly reduced infarct size (2.8 +/- 0.6%, 24.2 +/- 3.0% and 49.6 +/- 2.6% of the area at risk, for TLV-IR, TLV and Control groups, respectively). The significant reduction of infarct size by hypothermia was neither associated with a decrease in ischemic myocardial succinate accumulation, nor with a change in its rate of oxidation at reperfusion. Similarly, dimethyl malonate infusion and hypothermia during ischemia additively reduced infarct size (4.8 +/- 2.2% of risk zone) as compared to either strategy alone. Hypothermic cardioprotection is neither dependent on the inhibition of succinate accumulation during ischemia, nor of its rapid oxidation at reperfusion. The additive effect of hypothermia and dimethyl malonate on infarct size shows that they are protective by distinct mechanisms and also suggests that combining these different therapeutic approaches could further protect against ischemia/reperfusion injury during acute myocardial infarction.
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| 232. |
- Kraja, Aldi T., et al.
(författare)
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New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475000 Individuals
- 2017
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 1942-325X .- 1942-3268. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.Methods and Results - Here, we augment the sample with 140886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, approximate to 475000), and the other in the subset of individuals of European descent (approximate to 423000). Twenty-one SNVs were genome-wide significant (P<5x10(-8) ) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.
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| 233. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 234. |
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| 235. |
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| 236. |
- Li, Chen, et al.
(författare)
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Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length
- 2020
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Ingår i: American Journal of Human Genetics. - : CELL PRESS. - 0002-9297 .- 1537-6605. ; 106:3, s. 389-404
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Tidskriftsartikel (refereegranskat)abstract
- Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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| 237. |
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| 238. |
- Mahdavi, Ardeshir, et al.
(författare)
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The role of occupants in buildings’ energy performance gap: Myth or reality?
- 2021
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Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 13:6
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Forskningsöversikt (refereegranskat)abstract
- Buildings’ expected (projected, simulated) energy use frequently does not match actual observations. This is commonly referred to as the energy performance gap. As such, many factors can contribute to the disagreement between expectations and observations. These include, for in-stance, uncertainty about buildings’ geometry, construction, systems, and weather conditions. However, the role of occupants in the energy performance gap has recently attracted much atten-tion. It has even been suggested that occupants are the main cause of the energy performance gap. This, in turn, has led to suggestions that better models of occupant behavior can reduce the energy performance gap. The present effort aims at the review and evaluation of the evidence for such claims. To this end, a systematic literature search was conducted and relevant publications were identified and reviewed in detail. The review entailed the categorization of the studies according to the scope and strength of the evidence for occupants’ role in the energy performance gap. Moreover, deployed calculation and monitoring methods, normalization procedures, and reported causes and magnitudes of the energy performance gap were documented and evaluated. The results suggest that the role of occupants as significant or exclusive contributors to the energy performance gap is not sufficiently substantiated by evidence.
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| 239. |
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| 240. |
- McKay, C. P., et al.
(författare)
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Possible sources for methane and C 2-C 5 organics in the plume of Enceladus
- 2012
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Ingår i: Planetary and Space Science. - : Elsevier BV. - 0032-0633 .- 1873-5088. ; 71:1, s. 73-79
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Tidskriftsartikel (refereegranskat)abstract
- We consider six possible sources of CH 4 and other lowmass (C 2-C 5) organics in the plume of Enceladus: three of these sources represent initial endowments of organics: cometary organics, Titan-like tholin, and the Fisher-Tropsch type reactions in the gases from which Enceladus formed. The other three sources represent processes inside Enceladus: water-rock reactions, microbiology, and thermogenesis. We report on new laboratory results for C 2 hydrocarbons released by thermogenesis of laboratory tholin and the Fisher-Tropsch type synthesis. Thermal processing of Titan-like tholin produced ratios of CH 4/C 2H 4 and CH 4/C 2H 6 of about two for temperatures up to 450 °C and about six for a temperature of 650°C. The low pressure (∼1 atm) Fisher-Tropsch type experiments produced CH 4/C 2H 4 of ∼1.5, similar to previous results. C 2H 2 was not produced by either process. Tests of gas production by four strains of methanogens confirmed the absence of any detectable production of non-methane hydrocarbons. Cometary endowment, the Fisher-Tropsch type synthesis, and Titan-like tholin incorporation could be primary inputs of organics and subsequent thermal processing of any of these all are possible sources of low mass organics in the plume. Biological production and water-rock reactions are an alternative source of CH 4. Aqueous reactions with CO and H 2 can produce C 2-C 5 organics even at the low pressures of the interior of Enceladus. If there is a confirmed detection of CO and C 2H 2 in the plume of Enceladus, this provides an important constraint on sources, as we have identified no process, other than the initial volatile component of cometary organics, which can supply these gases. Precise determination of the relative concentrations of C 1-C 5 hydrocarbons may provide additional constraints on sources, but a detailed isotopic analysis of C and H in these organics and a search for amino acids constitute the next important steps in resolving the sources of the organics in Enceladus' plume.
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