| 1. |
- Wain, Louise V., et al.
(författare)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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Ingår i: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
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| 2. |
- Abel, I, et al.
(författare)
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Overview of the JET results with the ITER-like wall
- 2013
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
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Tidskriftsartikel (refereegranskat)abstract
- Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
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| 3. |
- Romanelli, F, et al.
(författare)
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Overview of the JET results
- 2011
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 51:9
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Tidskriftsartikel (refereegranskat)abstract
- Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower ρ*and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower ρ*and ν*and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2 MW m-2) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling. © 2011 IAEA, Vienna.
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| 4. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 5. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 6. |
- Stokes, Chris R., et al.
(författare)
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On the reconstruction of palaeo-ice sheets : Recent advances and future challenges
- 2015
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 125, s. 15-49
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Forskningsöversikt (refereegranskat)abstract
- Reconstructing the growth and decay of palaeo-ice sheets is critical to understanding mechanisms of global climate change and associated sea-level fluctuations in the past, present and future. The significance of palaeo-ice sheets is further underlined by the broad range of disciplines concerned with reconstructing their behaviour, many of which have undergone a rapid expansion since the 1980s. In particular, there has been a major increase in the size and qualitative diversity of empirical data used to reconstruct and date ice sheets, and major improvements in our ability to simulate their dynamics in numerical ice sheet models. These developments have made it increasingly necessary to forge interdisciplinary links between sub-disciplines and to link numerical modelling with observations and dating of proxy records. The aim of this paper is to evaluate recent developments in the methods used to reconstruct ice sheets and outline some key challenges that remain, with an emphasis on how future work might integrate terrestrial and marine evidence together with numerical modelling. Our focus is on pan-ice sheet reconstructions of the last deglaciation, but regional case studies are used to illustrate methodological achievements, challenges and opportunities. Whilst various disciplines have made important progress in our understanding of ice-sheet dynamics, it is clear that data-model integration remains under-used, and that uncertainties remain poorly quantified in both empirically-based and numerical ice-Sheet reconstructions. The representation of past climate will continue to be the largest source of uncertainty for numerical modelling. As such, palaeo-observations are critical to constrain and validate modelling. State-of-the-art numerical models will continue to improve both in model resolution and in the breadth of inclusion of relevant processes, thereby enabling more accurate and more direct comparison with the increasing range of palaeo-observations. Thus, the capability is developing to use all relevant palaeo-records to more strongly constrain deglacial (and to a lesser extent pre-LGM) ice sheet evolution. In working towards that goal, the accurate representation of uncertainties is required for both constraint data and model outputs. Close cooperation between modelling and data-gathering communities is essential to ensure this capability is realised and continues to progress.
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| 7. |
- van der Harst, Pim, et al.
(författare)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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| 8. |
- Rugenstein, Maria, et al.
(författare)
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LongRunMIP : Motivation and Design for a Large Collection of Millennial-Length AOGCM Simulations
- 2019
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 100:12, s. 2551-2570
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Tidskriftsartikel (refereegranskat)abstract
- We present a model intercomparison project, LongRunMIP, the first collection of millennial-length (1,000+ years) simulations of complex coupled climate models with a representation of ocean, atmosphere, sea ice, and land surface, and their interactions. Standard model simulations are generally only a few hundred years long. However, modeling the long-term equilibration in response to radiative forcing perturbation is important for understanding many climate phenomena, such as the evolution of ocean circulation, time- and temperature-dependent feedbacks, and the differentiation of forced signal and internal variability. The aim of LongRunMIP is to facilitate research into these questions by serving as an archive for simulations that capture as much of this equilibration as possible. The only requirement to participate in LongRunMIP is to contribute a simulation with elevated, constant CO2 forcing that lasts at least 1,000 years. LongRunMIP is an MIP of opportunity in that the simulations were mostly performed prior to the conception of the archive without an agreed-upon set of experiments. For most models, the archive contains a preindustrial control simulation and simulations with an idealized (typically abrupt) CO2 forcing. We collect 2D surface and top-of-atmosphere fields and 3D ocean temperature and salinity fields. Here, we document the collection of simulations and discuss initial results, including the evolution of surface and deep ocean temperature and cloud radiative effects. As of October 2019, the collection includes 50 simulations of 15 models by 10 modeling centers. The data of LongRunMIP are publicly available. We encourage submissions of more simulations in the future.
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| 9. |
- Depienne, Christel, et al.
(författare)
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Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU
- 2017
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 136:4, s. 463-479
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Tidskriftsartikel (refereegranskat)abstract
- Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.
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| 10. |
- Kwan, Johnny S H, et al.
(författare)
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Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels.
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6684-93
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Tidskriftsartikel (refereegranskat)abstract
- Osteoprotegerin (OPG) is involved in bone homeostasis and tumor cell survival. Circulating OPG levels are also important biomarkers of various clinical traits, such as cancers and atherosclerosis. OPG levels were measured in serum or in plasma. In a meta-analysis of genome-wide association studies in up to 10,336 individuals from European and Asian origin, we discovered that variants >100 Kb upstream of the TNFRSF11B gene encoding OPG and another new locus on chromosome 17q11.2 were significantly associated with OPG variation. We also identified a suggestive locus on chromosome 14q21.2 associated with the trait. Moreover, we estimated that over half of the heritability of OPG levels could be explained by all variants examined in our study. Our findings provide further insight into the genetic regulation of circulating OPG levels.
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