| 1. |
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| 2. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 3. |
- Murari, A., et al.
(författare)
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A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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| 4. |
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| 5. |
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| 6. |
- Joffrin, E., et al.
(författare)
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Overview of the JET preparation for deuterium-tritium operation with the ITER like-wall
- 2019
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 59:11
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Forskningsöversikt (refereegranskat)abstract
- For the past several years, the JET scientific programme (Pamela et al 2007 Fusion Eng. Des. 82 590) has been engaged in a multi-campaign effort, including experiments in D, H and T, leading up to 2020 and the first experiments with 50%/50% D-T mixtures since 1997 and the first ever D-T plasmas with the ITER mix of plasma-facing component materials. For this purpose, a concerted physics and technology programme was launched with a view to prepare the D-T campaign (DTE2). This paper addresses the key elements developed by the JET programme directly contributing to the D-T preparation. This intense preparation includes the review of the physics basis for the D-T operational scenarios, including the fusion power predictions through first principle and integrated modelling, and the impact of isotopes in the operation and physics of D-T plasmas (thermal and particle transport, high confinement mode (H-mode) access, Be and W erosion, fuel recovery, etc). This effort also requires improving several aspects of plasma operation for DTE2, such as real time control schemes, heat load control, disruption avoidance and a mitigation system (including the installation of a new shattered pellet injector), novel ion cyclotron resonance heating schemes (such as the three-ions scheme), new diagnostics (neutron camera and spectrometer, active Alfven eigenmode antennas, neutral gauges, radiation hard imaging systems...) and the calibration of the JET neutron diagnostics at 14 MeV for accurate fusion power measurement. The active preparation of JET for the 2020 D-T campaign provides an incomparable source of information and a basis for the future D-T operation of ITER, and it is also foreseen that a large number of key physics issues will be addressed in support of burning plasmas.
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| 7. |
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| 8. |
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| 9. |
- Zillikens, M. C., et al.
(författare)
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Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.
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| 10. |
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| 11. |
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| 12. |
- Palmer, Nicholette D, et al.
(författare)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
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Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
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Tidskriftsartikel (refereegranskat)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 13. |
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| 14. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 15. |
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| 16. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 17. |
- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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| 18. |
- Jenab, M., et al.
(författare)
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Dietary intakes of retinol, beta-carotene, vitamin D and vitamin E in the European Prospective Investigation into Cancer and Nutrition cohort
- 2009
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; 63:4s, s. 150-178
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To describe the intake of the fat-soluble nutrients retinol, beta-carotene, vitamin E and vitamin D and their food sources among 27 redefined centres in 10 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: Between 1995 and 2000, 36 034 subjects (age range: 35-74 years) completed a single standardized 24-h dietary recall using a computerized interview software program (EPIC-SOFT). Intakes of the fat-soluble nutrients were estimated using the standardized EPIC Nutrient Database. Results: For all the nutrients, in most centres, men had a higher level of intake than did women, even after adjustments for total energy intake and anthropometric confounders. Distinct regional gradients from northern to southern European countries were observed for all nutrients. The level intake of beta-carotene and vitamin E also showed some differences by level of education, smoking status and physical activity. No meaningful differences in the nutrient intake were observed by age range. Conclusions: These results show differences by study centre, gender, age and various lifestyle variables in the intake of retinol, beta-carotene, vitamin E and vitamin D between 10 European countries. European Journal of Clinical Nutrition (2009) 63, S150-S178; doi: 10.1038/ejcn.2009.79
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| 19. |
- Ferrari, P., et al.
(författare)
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A bivariate measurement error model for nitrogen and potassium intakes to evaluate the performance of regression calibration in the European Prospective Investigation into Cancer and Nutrition study
- 2009
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Ingår i: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; 63:4s, s. 179-187
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, the performance of 24-h dietary recall (24-HDR) measurements as reference measurements in a linear regression calibration model is evaluated critically at the individual (within-centre) and aggregate (between-centre) levels by using unbiased estimates of urinary measurements of nitrogen and potassium intakes. Methods: Between 1995 and 1999, 1072 study subjects (59% women) from 12 EPIC centres volunteered to collect 24-h urine samples. Log-transformed questionnaire, 24-HDR and urinary measurements of nitrogen and potassium intakes were analysed in a multivariate measurement error model to estimate the validity of coefficients and error correlations in self-reported dietary measurements. In parallel, correlations between means of 24-HDR and urinary measurements were computed. Linear regression calibration models were used to estimate the regression dilution (attenuation) factors. Results: After adjustment for sex, centre, age, body mass index and height, the validity coefficients for 24-HDRs were 0.285 (95% confidence interval: 0.194, 0.367) and 0.371 (0.291, 0.446) for nitrogen and potassium intakes, respectively. The attenuation factors estimated in a linear regression calibration model were 0.368 (0.228, 0.508) for nitrogen and 0.500 (0.361, 0.639) for potassium intakes; only the former was different from the estimate obtained using urinary measurements in the measurement error model. The aggregate-level correlation coefficients between means of urinary and 24-HDR measurements were 0.838 (0.637, 0.932) and 0.756 (0.481, 0.895) for nitrogen and potassium intakes, respectively. Conclusions: This study suggests that 24-HDRs can be used as reference measurements at the individual and aggregate levels for potassium intake, whereas, for nitrogen intake, good performance is observed for between-centre calibration, but some limitations are apparent at the individual level. European Journal of Clinical Nutrition (2009) 63, S179-S187; doi: 10.1038/ejcn.2009.80
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| 20. |
- Fretwell, P., et al.
(författare)
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Bedmap2 : improved ice bed, surface and thickness datasets for Antarctica
- 2013
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Ingår i: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 7:1, s. 375-393
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Tidskriftsartikel (refereegranskat)abstract
- We present Bedmap2, a new suite of gridded products describing surface elevation, ice-thickness and the seafloor and subglacial bed elevation of the Antarctic south of 60 degrees S. We derived these products using data from a variety of sources, including many substantial surveys completed since the original Bedmap compilation (Bedmap1) in 2001. In particular, the Bedmap2 ice thickness grid is made from 25 million measurements, over two orders of magnitude more than were used in Bedmap1. In most parts of Antarctica the subglacial landscape is visible in much greater detail than was previously available and the improved data-coverage has in many areas revealed the full scale of mountain ranges, valleys, basins and troughs, only fragments of which were previously indicated in local surveys. The derived statistics for Bedmap2 show that the volume of ice contained in the Antarctic ice sheet (27 million km(3)) and its potential contribution to sea-level rise (58 m) are similar to those of Bedmap1, but the mean thickness of the ice sheet is 4.6% greater, the mean depth of the bed beneath the grounded ice sheet is 72m lower and the area of ice sheet grounded on bed below sea level is increased by 10 %. The Bedmap2 compilation highlights several areas beneath the ice sheet where the bed elevation is substantially lower than the deepest bed indicated by Bedmap1. These products, along with grids of data coverage and uncertainty, provide new opportunities for detailed modelling of the past and future evolution of the Antarctic ice sheets.
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| 21. |
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| 22. |
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| 23. |
- Palmese, A., et al.
(författare)
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Stellar mass as a galaxy cluster mass proxy : application to the Dark Energy Survey redMaPPer clusters
- 2020
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Ingår i: \mnras. - : Oxford University Press (OUP). ; 493:4, s. 4591-4606
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Tidskriftsartikel (refereegranskat)abstract
- We introduce a galaxy cluster mass observable, μ⋆, based on the stellar masses of cluster members, and we present results for the Dark Energy Survey (DES) Year 1 (Y1) observations. Stellar masses are computed using a Bayesian model averaging method, and are validated for DES data using simulations and COSMOS data. We show that μ⋆ works as a promising mass proxy by comparing our predictions to X-ray measurements. We measure the X-ray temperature–μ⋆ relation for a total of 129 clusters matched between the wide-field DES Y1 redMaPPer catalogue and Chandra and XMM archival observations, spanning the redshift range 0.1 < z < 0.7. For a scaling relation that is linear in logarithmic space, we find a slope of α = 0.488 ± 0.043 and a scatter in the X-ray temperature at fixed μ⋆ of σlnTX|μ⋆=0.266+0.019−0.020 for the joint sample. By using the halo mass scaling relations of the X-ray temperature from the Weighing the Giants program, we further derive the μ⋆-conditioned scatter in mass, finding σlnM|μ⋆=0.26+0.15−0.10. These results are competitive with well-established cluster mass proxies used for cosmological analyses, showing that μ⋆ can be used as a reliable and physically motivated mass proxy to derive cosmological constraints.
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| 24. |
- Scott, Robert A., et al.
(författare)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Tidskriftsartikel (refereegranskat)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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| 25. |
- Sonnenwald, D.H., et al.
(författare)
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Illuminating collaboration in emergency health care situations : paramedic-physician collaboration and 3D telepresence technology
- 2014
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Ingår i: Information research. - : University of Sheffield: Department of Information Studies. - 1368-1613. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. This paper focuses on paramedics' perspectives regarding paramedic-physician collaboration today, and their perspectives regarding the potential of 3D telepresence technology in the future. Method. Interviews were conducted with forty practicing paramedics. Analysis. The interview data were analysed using open and axial coding. An agreement of 0.82 using Cohen's kappa inter-coder reliability measure was reached. After coding was completed themes and relationships among codes were synthesised using topic memos. Results. Paramedics expressed concern about the lack of respect and trust exhibited towards them by other medical professionals. They discussed how they paint the picture for physicians and the importance of the physician trusting the paramedic. They further reported 3D telepresence technology would make their work visible in ways not previously possible. They also reported the technology would require additional training, changes to existing financial models used in emergency health care, and increased access to physicians. Conclusions. Teaching collaboration skills and strategies to physicians and paramedics could benefit their collaboration today, and increase their readiness to effectively use collaboration technologies in the future.
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