| 11. |
- Willems, S. M., et al.
(författare)
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Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10-8) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality. © The Author(s) 2017.
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| 12. |
- Zheng, Hou-Feng, et al.
(författare)
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Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
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| 13. |
- Drlica-Wagner, A., et al.
(författare)
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SEARCH FOR GAMMA-RAY EMISSION FROM DES DWARF SPHEROIDAL GALAXY CANDIDATES WITH FERMI-LAT DATA
- 2015
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 809:1
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Tidskriftsartikel (refereegranskat)abstract
- Due to their proximity, high dark-matter (DM) content, and apparent absence of non-thermal processes, Milky Way dwarf spheroidal satellite galaxies (dSphs) are excellent targets for the indirect detection of DM. Recently, eight new dSph candidates were discovered using the first year of data from the Dark Energy Survey (DES). We searched for gamma-ray emission coincident with the positions of these new objects in six years of Fermi Large Area Telescope data. We found no significant excesses of gamma-ray emission. Under the assumption that the DES candidates are dSphs with DM halo properties similar to the known dSphs, we computed individual and combined limits on the velocity-averaged DM annihilation cross section for these new targets. If the estimated DM content of these dSph candidates is confirmed, they will constrain the annihilation cross section to lie below the thermal relic cross section for DM particles with masses less than or similar to 20 GeV annihilating via the b (b) over bar or pi(+)pi(-) channels.
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| 14. |
- Ershova, Victoria B., et al.
(författare)
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The De Long Islands : A missing link in unraveling the Paleozoic paleogeography of the Arctic
- 2016
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Ingår i: Gondwana Research. - : Elsevier BV. - 1342-937X .- 1878-0571. ; 35, s. 305-322
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Tidskriftsartikel (refereegranskat)abstract
- The vast Laptev and East Siberian shelves in the eastern Russian Arctic, largely covered by a shallow sea and buried beneath sea ice for 9 months of the year, remain one of the least studied parts of continental crust of the Earth and represent a big unknown when performing pre-Cenozoic geodynamic reconstructions of the Arctic. The De Long islands provide a vitally important window into the geology of this area and are a key for [1] understanding the Early Paleozoic history of the Amerasian Arctic. Four of them (Jeanette, Henrietta, Bennett and Zhokhov islands) were studied using structural data, petrographic and geochemical analyses and U-Pb zircon age dating to offer the following new constraints for the Early Paleozoic paleogeography of the Arctic realm. The basement beneath the De Long Islands is of Late Neoproterozoic to earliest Cambrian age, about 670-535 Ma. In the Early Paleozoic, the De Long Islands were located along the broad Timanian margin of Baltica, with a clastic sediment provenance from the Timanian, Grenville-Sveconorwegian, and Baltic Shield domains. The Cambro-Ordovician volcaniclastic successions on Jeannette and Henrietta islands formed part of a continental margin volcanic arc with a corresponding back-arc basin located to the south (in present co-ordinates). On the continent-ward side of the back-arc basin, shallow marine shelf clastic and carbonate rocks were deposited, which are exposed today on Bennett Island in the south-west of the archipelago (in modern coordinates). The De Long Islands together with other continental blocks, such as Severnaya Zemlya, Arctic Alaska-Chukotka, and the Alexander Terrane, formed the contiguous active continental margin of Baltica during the Early Paleozoic. Today however, these terranes are spread out over a distance of 5000 km across the Arctic and eastern Pacific margins due to the subsequent opening of a series of Late Paleozoic, Mesozoic and Cenozoic oceanic basins.
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| 15. |
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| 16. |
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| 17. |
- Rayon-Estrada, V, et al.
(författare)
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Epitranscriptomic profiling across cell types reveals associations between APOBEC1-mediated RNA editing, gene expression outcomes, and cellular function
- 2017
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 114:50, s. 13296-13301
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Tidskriftsartikel (refereegranskat)abstract
- RNA editing is an enzymatic modification that leads to single-nucleotide changes in mRNA. Editing is particularly robust within cells of the immune lineage. Here, we focus on the macrophage and demonstrate that genetic inactivation of the RNA-editing enzyme Apobec1 affects protein levels of genes that underlie macrophage-specific behaviors including phagocytosis and transendothelial migration. We further show that loss of Apobec1 leads to an overabundance of proinflammatory monocytes, a hallmark of many chronic diseases. These data provide the first view of the consequences of editing for gene expression and cellular function. Overall, epitranscriptomic changes catalyzed by RNA editing might be important biomarkers of diseases associated with inflammation (e.g., neurodegenerative diseases), for which an association with DNA mutation has been lacking.
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| 18. |
- Tovedal, Thomas, et al.
(författare)
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Blood Flow Quantitation by Positron Emission Tomography During Selective Antegrade Cerebral Perfusion
- 2017
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Ingår i: Annals of Thoracic Surgery. - : Elsevier BV. - 0003-4975 .- 1552-6259. ; 103:2, s. 610-616
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Perfusion strategies during aortic surgery usually comprise hypothermic circulatory arrest (HCA), often combined with selective antegrade cerebral perfusion (SACP) or retrograde cerebral perfusion. Cerebral blood flow (CBF) is a fundamental parameter for which the optimal level has not been clearly defined. We sought to determine the CBF at a pump flow level of 6 mL/kg/min, previously shown likely to provide adequate SACP at 20°C in pigs.METHODS: Repeated positron emission tomography (PET) scans were used to quantify the CBF and glucose metabolism throughout HCA and SACP including cooling and rewarming. Eight pigs on cardiopulmonary bypass were assigned to either HCA alone (n = 4) or HCA+SACP (n = 4). The CBF was measured by repeated [(15)O]water PET scans from baseline to rewarming. The cerebral glucose metabolism was examined by [(18)F]fluorodeoxyglucose PET scans after rewarming to 37°C.RESULTS: Cooling to 20°C decreased the cortical CBF from 0.31 ± 0.06 at baseline to 0.10 ± 0.02 mL/cm(3)/min (p = 0.008). The CBF was maintained stable by SACP of 6 mL/kg/min during 45 minutes. After rewarming to 37°C, the mean CBF increased to 0.24 ± 0.07 mL/cm(3)/min, without significant differences between the groups at any time-point exclusive of the HCA period. The net cortical uptake (Ki) of [(18)F]fluorodeoxyglucose after rewarming showed no significant difference between the groups.CONCLUSIONS: Cooling autoregulated the CBF to 0.10 mL/cm(3)/min, and 45 minutes of SACP at 6 mL/kg/min maintained the CBF in the present model. Cerebral glucose metabolism after rewarming was similar in the study groups.
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| 19. |
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