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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
A novel common variant in DCST2 is associated with length in early life and height in adulthood
(2015)
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 x 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; beta = 0.046, SE = 0.008, P = 2.46 x 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 x 10(-4)) and adult height (N = 127 513; P = 1.45 x 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Axionlike particles (ALPs) are hypothetical light (sub-eV) bosons predicted in some extensions of the Standard Model of particle physics. In astrophysical environments comprising high-energy gamma rays and turbulent magnetic fields, the existence of ALPs can modify the energy spectrum of the gamma rays for a sufficiently large coupling between ALPs and photons. This modification would take the form of an irregular behavior of the energy spectrum in a limited energy range. Data from the H. E. S. S. observations of the distant BL Lac object PKS 2155 - 304 (z = 0.116) are used to derive upper limits at the 95% C. L. on the strength of the ALP coupling to photons, g(gamma a) < 2.1 x 10(-11) GeV-1 for an ALP mass between 15 and 60 neV. The results depend on assumptions on the magnetic field around the source, which are chosen conservatively. The derived constraints apply to both light pseudoscalar and scalar bosons that couple to the electromagnetic field.
Ground-based gamma-ray astronomy has had a major breakthrough with the impressive results obtained using systems of imaging atmospheric Cherenkov telescopes. Ground-based gamma-ray astronomy has a huge potential in astrophysics, particle physics and cosmology. CTA is an international initiative to build the next generation instrument, with a factor of 5-10 improvement in sensitivity in the 100 GeV-10 TeV range and the extension to energies well below 100 GeV and above 100 TeV. CTA will consist of two arrays (one in the north, one in the south) for full sky coverage and will be operated as open observatory. The design of CTA is based on currently available technology. This document reports on the status and presents the major design concepts of CTA.
Discovery of high and very high-energy emission from the BL Lacertae object SHBL J001355.9-185406
(2013)
The detection of the high-frequency peaked BL Lac object (HBL) SHBL J001355.9-185406 (z = 0.095) at high (HE; 100 MeV < E < 300 GeV) and very high-energy (VHE; E > 100 GeV) with the Fermi Large Area Telescope (LAT) and the High Energy Stereoscopic System (H.E.S.S.) is reported. Dedicated observations were performed with the H. E. S. S. telescopes, leading to a detection at the 5.5 sigma significance level. The measured flux above 310 GeV is (8.3 +/- 1.7(stat) +/- 1.7(sys)) x 10(-13) photons cm(-2) s(-1) (about 0.6% of that of the Crab Nebula), and the power-law spectrum has a photon index of Gamma = 3.4 +/- 0.5(stat) +/- 0.2(sys). Using 3.5 years of publicly available Fermi-LAT data, a faint counterpart has been detected in the LAT data at the 5.5 sigma significance level, with an integrated flux above 300 MeV of (9.3 +/- 3.4(stat) +/- 0.8(sys)) x 10(-10) photons cm(-2) s(-1) and a photon index of Gamma = 1.96 +/- 0.20(stat) +/- 0.08(sys). X-ray observations with Swift-XRT allow the synchrotron peak energy in vF(v) representation to be located at similar to 1.0 keV. The broadband spectral energy distribution is modelled with a one-zone synchrotron self-Compton (SSC) model and the optical data by a black-body emission describing the thermal emission of the host galaxy. The derived parameters are typical of HBLs detected at VHE, with a particle-dominated jet.
Very high-energy gamma-ray emission from PKS 0447-439 was detected with the H. E. S. S. Cherenkov telescope array in December 2009. This blazar is one of the brightest extragalactic objects in the Fermi bright source list and has a hard spectrum in the MeV to GeV range. In the TeV range, a photon index of 3.89 +/- 0.37 (stat) +/- 0.22 (sys) and a flux normalisation at 1 TeV, phi(1) (TeV) = (3.5 +/- 1.1(stat) +/- 0.9(sys)) x 10(-13) cm(-2) s(-1) TeV-1 were found. The detection with H. E. S. S. triggered observations in the X-ray band with the Swift and RXTE telescopes. Simultaneous UV and optical data from Swift UVOT and data from the optical telescopes ATOM and ROTSE are also available. The spectrum and light curve measured with H. E. S. S. are presented and compared to the multi-wavelength data at lower energies. A rapid flare is seen in the Swift XRT and RXTE data, together with a flux variation in the UV band, at a time scale of the order of one day. A firm upper limit of z < 0.59 on the redshift of PKS 0447-439 is derived from the combined Fermi-LAT and H. E. S. S. data, given the assumptions that there is no upturn in the intrinsic spectrum above the Fermi-LAT energy range and that absorption on the extragalactic background light (EBL) is not weaker than the lower limit provided by current models. The spectral energy distribution is well described by a simple one-zone synchrotron self-Compton scenario, if the redshift of the source is less than z less than or similar to 0.4.
Discovery of very high energy gamma-ray emission from the BL Lacertae
object PKS0301-243 with HESS
(2013)
The active galactic nucleus PKS 0301-243 (z = 0.266) is a high-synchrotron-peaked BL Lac object that is detected at high energies (HE, 100 MeV < E < 100 GeV) by Fermi/LAT. This paper reports on the discovery of PKS 0301-243 at very high energies (E > 100 GeV) by the High Energy Stereoscopic System (H.E.S.S.) from observations between September 2009 and December 2011 for a total live time of 34.9 h. Gamma rays above 200 GeV are detected at a significance of 9.4 sigma. A hint of variability at the 2.5 sigma level is found. An integral flux I(E > 200GeV) = (3.3 +/- 1.1(stat) +/- 0.7(syst)) x 10(-12) ph cm(-2) s(-1) and a photon index Gamma = 4.6 +/- 0.7(stat) +/- 0.2(syst) are measured. Multi-wavelength light curves in HE, X-ray and optical bands show strong variability, and a minimal variability timescale of eight days is estimated from the optical light curve. A single-zone leptonic synchrotron self-Compton scenario satisfactorily reproduces the multi-wavelength data. In this model, the emitting region is out of equipartition and the jet is particle dominated. Because of its high redshift compared to other sources observed at TeV energies, the very high energy emission from PKS 0301-243 is attenuated by the extragalactic background light (EBL) and the measured spectrum is used to derive an upper limit on the opacity of the EBL.