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OBJECTIVE: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.
RESEARCH DESIGN AND METHODS: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.
RESULTS: We identified 11 genomic regions associated with plasma vitamin C (P < 5 x 10(-8)), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).
CONCLUSIONS: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
The unidentified very-high-energy (VHE; E > 0.1 TeV) gamma -ray source, HESS J1826-130, was discovered with the High Energy Stereoscopic System (HESS) in the Galactic plane. The analysis of 215 h of HESS data has revealed a steady gamma -ray flux from HESS J1826-130, which appears extended with a half-width of 0.21 degrees +/- 0.02 <br /> (stat)degrees <br /> stat degrees +/- 0.05 <br /> (sys)degrees sys degrees . The source spectrum is best fit with either a power-law function with a spectral index Gamma = 1.78 +/- 0.10(stat) +/- 0.20(sys) and an exponential cut-off at 15.2 <br /> (+5.5)(-3.2) -3.2+5.5 TeV, or a broken power-law with Gamma (1) = 1.96 +/- 0.06(stat) +/- 0.20(sys), Gamma (2) = 3.59 +/- 0.69(stat) +/- 0.20(sys) for energies below and above E-br = 11.2 +/- 2.7 TeV, respectively. The VHE flux from HESS J1826-130 is contaminated by the extended emission of the bright, nearby pulsar wind nebula, HESS J1825-137, particularly at the low end of the energy spectrum. Leptonic scenarios for the origin of HESS J1826-130 VHE emission related to PSR J1826-1256 are confronted by our spectral and morphological analysis. In a hadronic framework, taking into account the properties of dense gas regions surrounding HESS J1826-130, the source spectrum would imply an astrophysical object capable of accelerating the parent particle population up to greater than or similar to 200 TeV. Our results are also discussed in a multiwavelength context, accounting for both the presence of nearby supernova remnants, molecular clouds, and counterparts detected in radio, X-rays, and TeV energies.
For hybrid organic-inorganic as well as all-inorganic lead halide perovskites a Rashba effect has been invoked to explain the high efficiency in energy conversion by prohibiting direct recombination. Both a bulk and surface Rashba effect have been predicted. In the valence band of methylammonium (MA) lead bromide a Rashba effect has been reported by angle-resolved photoemission and circular dichroism with giant values of 7-11 eV angstrom. We present band dispersion measurements of MAPbBr(3) and spin-resolved photoemission of CsPbBr3 to show that a large Rashba effect detectable by photoemission or circular dichroism does not exist and cannot be the origin of the high effciency.
X-ray free-electron lasers have, over the past decade, opened up the possibility of understanding the ultrafast response of matter to intense X-ray pulses. In earlier research on atoms and small molecules, new aspects of this response were uncovered, such as rapid sequences of inner-shell photoionization and Auger ionization. Here, we studied a larger molecule, buckminsterfullerene (C-60), exposed to 640 eV X-rays, and examined the role of chemical effects, such as chemical bonds and charge transfer, on the fragmentation following multiple ionization of the molecule. To provide time resolution, we performed femtosecond-resolved X-ray pump/X-ray probe measurements, which were accompanied by advanced simulations. The simulations and experiment reveal that despite substantial ionization induced by the ultrashort (20 fs) X-ray pump pulse, the fragmentation of C-60 is considerably delayed. This work uncovers the persistence of the molecular structure of C-60, which hinders fragmentation over a timescale of hundreds of femtoseconds. Furthermore, we demonstrate that a substantial fraction of the ejected fragments are neutral carbon atoms. These findings provide insights into X-ray free-electron laser-induced radiation damage in large molecules, including biomolecules.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
Background: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence.
Objective: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries.
Methods: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association.
Results: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea. Conclusions: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.
Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (>= 1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modem legacy of past equestrian civilisations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia. None of these contributed significantly to modern diversity. We show that the influence of Persian-related horse lineages increased following the Islamic conquests in Europe and Asia. Multiple alleles associated with elite-racing, including at the MSTN "speed gene," only rose in popularity within the last millennium. Finally, the development of modem breeding impacted genetic diversity more dramatically than the previous millennia of human management.
In this work we present spectra of all gamma-ray burst (GRB) afterglows that have been promptly observed with the X-shooter spectrograph until 31/03/2017. In total, we have obtained spectroscopic observations of 103 individual GRBs observed within 48 hours of the GRB trigger. Redshifts have been measured for 97 per cent of these, covering a redshift range from 0.059 to 7.84. Based on a set of observational selection criteria that minimise biases with regards to intrinsic properties of the GRBs, the follow-up effort has been focused on producing a homogeneously selected sample of 93 afterglow spectra for GRBs discovered by the Swift satellite. We here provide a public release of all the reduced spectra, including continuum estimates and telluric absorption corrections. For completeness, we also provide reductions for the 18 late-time observations of the underlying host galaxies. We provide an assessment of the degree of completeness with respect to the parent GRB population, in terms of the X-ray properties of the bursts in the sample and find that the sample presented here is representative of the full Swift sample. We have constrained the fraction of dark bursts to be <28 per cent and confirm previous results that higher optical darkness is correlated with increased X-ray absorption. For the 42 bursts for which it is possible, we have provided a measurement of the neutral hydrogen column density, increasing the total number of published HI column density measurements by similar to 33 per cent. This dataset provides a unique resource to study the ISM across cosmic time, from the local progenitor surroundings to the intervening Universe.
The flat spectrum radio quasar 3C 279 is known to exhibit pronounced variability in the high-energy (100MeV < E < 100 GeV) gamma-ray band, which is continuously monitored with Fermi-LAT. During two periods of high activity in April 2014 and June 2015 target-of-opportunity observations were undertaken with the High Energy Stereoscopic System (H.E.S.S.) in the very-high-energy (VHE, E > 100 GeV) gamma-ray domain. While the observation in 2014 provides an upper limit, the observation in 2015 results in a signal with 8 : 7 sigma significance above an energy threshold of 66 GeV. No VHE variability was detected during the 2015 observations. The VHE photon spectrum is soft and described by a power-law index of 4.2 +/- 0.3. The H.E.S.S. data along with a detailed and contemporaneous multiwavelength data set provide constraints on the physical parameters of the emission region. The minimum distance of the emission region from the central black hole was estimated using two plausible geometries of the broad-line region and three potential intrinsic spectra. The emission region is confidently placed at r greater than or similar to 1 : 7 X 1017 cm from the black hole, that is beyond the assumed distance of the broad-line region. Time-dependent leptonic and lepto-hadronic one-zone models were used to describe the evolution of the 2015 flare. Neither model can fully reproduce the observations, despite testing various parameter sets. Furthermore, the H.E.S.S. data were used to derive constraints on Lorentz invariance violation given the large redshift of 3C 279.