The Space Weather Modeling Framework (SWMF) provides a high‐performance flexible framework for physics‐based space weather simulations, as well as for various space physics applications. The SWMF ...integrates numerical models of the Solar Corona, Eruptive Event Generator, Inner Heliosphere, Solar Energetic Particles, Global Magnetosphere, Inner Magnetosphere, Radiation Belt, Ionosphere Electrodynamics, and Upper Atmosphere into a high‐performance coupled model. The components can be represented with alternative physics models, and any physically meaningful subset of the components can be used. The components are coupled to the control module via standardized interfaces, and an efficient parallel coupling toolkit is used for the pairwise coupling of the components. The execution and parallel layout of the components is controlled by the SWMF. Both sequential and concurrent execution models are supported. The SWMF enables simulations that were not possible with the individual physics models. Using reasonably high spatial and temporal resolutions in all of the coupled components, the SWMF runs significantly faster than real time on massively parallel supercomputers. This paper presents the design and implementation of the SWMF and some demonstrative tests. Future papers will describe validation (comparison of model results with measurements) and applications to challenging space weather events. The SWMF is publicly available to the scientific community for doing geophysical research. We also intend to expand the SWMF in collaboration with other model developers.
Aims
Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β‐cells. We hypothesized that single nucleotide polymorphisms in the ...DRD2/ANKK1 locus may affect susceptibility to Type 2 diabetes in humans.
Methods
Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for Type 2 diabetes susceptibility in up to 25 000 people (8148 with Type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2‐h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender‐stratified analysis.
Results
rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06–1.23); P = 4.1*10−4) but not in men (odds ratio 1.00 (95% CI 0.93–1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first‐phase glucose‐stimulated insulin secretion in women (P = 5.5*10−4) but again not in men (P = 0.34).
Conclusion
The present data identify DRD2/ANKK1 as a potential sex‐specific Type 2 diabetes susceptibility gene.
What's new?
The rs1800497 single nucleotide polymorphism at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women but not in men.
The rs6275 single nucleotide polymorphism in the DRD2 gene is associated with increased first‐phase glucose‐stimulated insulin secretion in women only.
Our data identify DRD2/ANKK1 as a potential sex‐specific Type 2 diabetes susceptibility gene.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used ...four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30-1.84, P = 6.87 × 10
). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Perfluorooctanesulfonate (PFOS) is a widely distributed, environmentally persistent acid found at low levels in human, wildlife, and environmental media samples. Neonatal mortality has been observed ...following PFOS exposure in a two-generation reproduction study in rats and after dosing pregnant rats and mice during gestation. Objectives of the current study were to better define the dose–response curve for neonatal mortality in rat pups born to PFOS-exposed dams and to investigate biochemical and pharmacokinetic parameters potentially related to the etiology of effects observed in neonatal rat pups. In the current study, additional doses of 0.8, 1.0, 1.2, and 2.0
mg/kg/day were included with original doses used in the two-generation study of 0.4 and 1.6
mg/kg/day in order to obtain data in the critical range of the dose–response curve. Biochemical parameters investigated in dams and litters included: (1) serum lipids, glucose, mevalonic acid, and thyroid hormones; (2) milk cholesterol; and (3) liver lipids. Pharmacokinetic parameters investigated included the interrelationship of administered oral dose of PFOS to maternal body burden of PFOS and the transfer of maternal body burden to the fetus in utero and pup during lactation, as these factors may affect neonatal toxicity. Dosing of dams occurred for 6 weeks prior to mating with untreated breeder males, through confirmed mating, gestation, and day four of lactation. Dose levels for the dose–response and etiological investigation were 0.0, 0.4, 0.8, 1.0, 1.2, 1.6, and 2.0
mg/kg/day PFOS. Statistically significant decreases in gestation length were observed in the 0.8
mg/kg and higher dose groups. Decreases in viability through lactation day 5 were observed in the 0.8
mg/kg and higher dose groups, becoming statistically significant in the 1.6 and 2.0
mg/kg dose groups. Reduced neonatal survival did not appear to be the result of reductions in lipids, glucose utilization, or thyroid hormones. The endpoints of gestation length and decreased viability were positively correlated, suggesting that late-stage fetal development may be affected in pups exposed to PFOS in utero and may contribute to the observed mortality. Benchmark dose (BMD) estimates for decreased gestation length, birth weight, pup weight on lactation day 5, pup weight gain through lactation day 5, and viability resulted in values ranging from 0.27 to 0.89
mg/kg/day for the lower 95% confidence limit of the BMD
5 (BMDL
5). Results of analyses for PFOS in biological matrices indicate a linear proportionality of mean serum PFOS concentration to maternal administered dose prior to mating and through the first two trimesters of gestation. However, at 21 days of gestation, mean serum PFOS concentrations were notably reduced from values measured earlier in gestation. Urinary and fecal elimination was low as expected from prior observations in adult rats. Significant transfer of PFOS from dam to fetus in utero was confirmed, and results suggest that dam and corresponding fetal body burdens, as indicated by serum and liver PFOS levels, correlate with neonatal survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Planck intermediate results Adam, R; Aghanim, N; Ashdown, M ...
Astronomy and astrophysics (Berlin),
12/2016, Volume:
596
Journal Article
Peer reviewed
Open access
We investigate constraints on cosmic reionization extracted from the Planck cosmic microwave background (CMB) data. We combine the Planck CMB anisotropy data in temperature with the low-multipole ...polarization data to fit LambdaCDM models with various parameterizations of the reionization history. We obtain a Thomson optical depth tau= 0.058 + or - 0.012 for the commonly adopted instantaneous reionization model. This confirms, with data solely from CMB anisotropies, the low value suggested by combining Planck 2015 results with other data sets, and also reduces the uncertainties. We reconstruct the history of the ionization fraction using either a symmetric or an asymmetric model for the transition between the neutral and ionized phases. To determine better constraints on the duration of the reionization process, we also make use of measurements of the amplitude of the kinetic Sunyaev-Zeldovich (kSZ) effect using additional information from the high-resolution Atacama Cosmology Telescope and South Pole Telescope experiments. The average redshift at which reionization occurs is found to lie between z= 7.8 and 8.8, depending on the model of reionization adopted. Using kSZ constraints and a redshift-symmetric reionization model, we find an upper limit to the width of the reionization period of Deltaz< 2.8. In all cases, we find that the Universe is ionized at less than the 10% level at redshifts above z = 10. This suggests that an early onset of reionization is strongly disfavoured by the Planck data. We show that this result also reduces the tension between CMB-based analyses and constraints from other astrophysical sources.
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FMFMET, NUK, UL, UM, UPUK
Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, ...and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.
Multiple healing cycles of a single crack in a brittle polymer coating are achieved by microvascular delivery of a two‐part, epoxy‐based self‐healing chemistry. Epoxy resin and amine‐based curing ...agents are transported to the crack plane through two sets of independent vascular networks embedded within a ductile polymer substrate beneath the coating. The two reactive components remain isolated and stable in the vascular networks until crack formation occurs in the coating under a mechanical load. Both healing components are wicked by capillary forces into the crack plane, where they react and effectively bond the crack faces closed. Healing efficiencies of over 60% are achieved for up to 16 intermittent healing cycles of a single crack, which represents a significant improvement over systems in which a single monomeric healing agent is delivered.
Multiple self‐healing networks supply a two‐part epoxy healing chemistry to cracks in a coating (see left of figure). The healing components react in the crack plane to repeatedly heal damage to the same location. After many healing cycles a significant amount of healed material builds up in the crack plane (see right of figure; scale bar = 20 mm).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Metazoan phylogeny remains one of evolutionary biology's major unsolved problems. Molecular and morphological data, as well as different analytical approaches, have produced highly conflicting ...results due to homoplasy resulting from more than 570 million years of evolution 1–4. To date, parsimony has been the only feasible combined approach but is highly sensitive to long-branch attraction 5–7. Recent development of stochastic models for discrete morphological characters and computationally efficient methods for Bayesian inference has enabled combined molecular and morphological data analysis with rigorous statistical approaches less prone to such inconsistencies 8–10. We present the first statistically founded analysis of a metazoan data set based on a combination of morphological and molecular data and compare the results with a traditional parsimony analysis. Interestingly, the Bayesian analyses demonstrate a high degree of congruence between morphological and molecular data, and both data sets contribute to the result of the combined analysis. Additionally, they resolve several irregularities obtained in previous studies and show high credibility values for controversial groups such as the ecdysozoans and lophotrochozoans. Parsimony, on the contrary, shows conflicting results, with morphology being congruent to the Bayesian results and the molecular data set producing peculiarities that are largely reflected in the combined analysis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence ...for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥ 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.
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