Application of long-read sequencing to elucidate complex pharmacogenomic regions: a proof of principle

The use of pharmacogenomics in clinical practice is becoming standard of care. However, due to the complex genetic makeup of pharmacogenes, not all genetic variation is currently accounted for. Here, we show the utility of long-read sequencing to resolve complex pharmacogenes by analyzing a well-characterised sample. This data consists of long reads that were processed to resolve phased haploblocks. 73% of pharmacogenes were fully covered in one phased haploblock, including 9/15 genes that are 100% complex. Variant calling accuracy in the pharmacogenes was high, with 99.8% recall and 100% precision for SNVs and 98.7% precision and 98.0% recall for Indels. For the majority of gene-drug interactions in the DPWG and CPIC guidelines, the associated genes could be fully resolved (62% and 63% respectively). Together, these findings suggest that long-read sequencing data offers promising opportunities in elucidating complex pharmacogenes and haplotype phasing while maintaining accurate variant calling.Personalised Therapeutic

Discovery of the Binary Pulsar PSR B1259-63 in Very-High-Energy Gamma Rays around Periastron with H.E.S.S

We report the discovery of very-high-energy (VHE) gamma-ray emission of the binary system PSR B1259-63/SS 2883 of a radio pulsar orbiting a massive, luminous Be star in a highly eccentric orbit. The observations around the 2004 periastron passage of the pulsar were performed with the four 13 m Cherenkov telescopes of the H.E.S.S. experiment, recently installed in Namibia and in full operation since December 2003. Between February and June 2004, a gamma-ray signal from the binary system was detected with a total significance above 13 sigma. The flux was found to vary significantly on timescales of days which makes PSR B1259-63 the first variable galactic source of VHE gamma-rays observed so far. Strong emission signals were observed in pre- and post-periastron phases with a flux minimum around periastron, followed by a gradual flux decrease in the months after. The measured time-averaged energy spectrum above a mean threshold energy of 380 GeV can be fitted by a simple power law F_0(E/1 TeV)^-Gamma with a photon index Gamma = 2.7+-0.2_stat+-0.2_sys and flux normalisation F_0 = (1.3+-0.1_stat+-0.3_sys) 10^-12 TeV^-1 cm^-2 s^-1. This detection of VHE gamma-rays provides unambiguous evidence for particle acceleration to multi-TeV energies in the binary system. In combination with coeval observations of the X-ray synchrotron emission by the RXTE and INTEGRAL instruments, and assuming the VHE gamma-ray emission to be produced by the inverse Compton mechanism, the magnetic field strength can be directly estimated to be of the order of 1 G.Comment: 10 pages, 8 figures, accepted in Astronomy and Astrophysics on 2 June 2005, replace: document unchanged, replaced author field in astro-ph entry - authors are all members of the H.E.S.S. collaboration and three additional authors (99+3, see document

<i>Gaia</i> Data Release 1. Summary of the astrometric, photometric, and survey properties

Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues – a realisation of the Tycho-Gaia Astrometric Solution (TGAS) – and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of ∼3000 Cepheid and RR-Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr−1 for the proper motions. A systematic component of ∼0.3 mas should be added to the parallax uncertainties. For the subset of ∼94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr−1. For the secondary astrometric data set, the typical uncertainty of the positions is ∼10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to ∼0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data

The technical performance of the HEGRA system of imaging air Cherenkov telescopes

Between early 1997 and late 2002, the HEGRA collaboration operated a stereoscopic system of 4 (later 5) imaging atmospheric Cherenkov telescopes. In this paper we present the calibration schemes which were developed for the system, and report on the performance of the detector over the years. In general, the telescope system was very well understood, regarding both the absolute calibration and the slight changes in performance over the years. The system had an energy threshold of 500 GeV for observations at zenith and under optimum detector conditions. With the corresponding calibration schemes, a systematic accuracy of 15 percent on the absolute energy scale has been achieved. The continuous sensitivity monitoring provided a relative accuracy of a few percent, and showed that the threshold did not exceed 600 GeV throughout the entire operation time. The readout electronics and the imaging quality of the dishes were well monitored and stable. The absolute pointing had an accuracy of at least 25 arcsec; this number was guaranteed throughout the whole lifetime of the experiment.G. Puhlhofer ... G. P. Rowell.. and W. Wittek...et al., the HEGRA Collaboratio

A low level of extragalactic background light as revealed by big gamma-rays from blazars

The diffuse extragalactic background light consists of the sum of the starlight emitted by galaxies through the history of the Universe, and it could also have an important contribution from the 'first stars', which may have formed before galaxy formation began. Direct measurements are difficult and not yet conclusive, owing to the large uncertainties caused by the bright foreground emission associated with zodiacal light1. An alternative approach2, 3, 4, 5 is to study the absorption features imprinted on the -ray spectra of distant extragalactic objects by interactions of those photons with the background light photons6. Here we report the discovery of -ray emission from the blazars7 H 2356 - 309 and 1ES 1101 - 232, at redshifts z = 0.165 and z = 0.186, respectively. Their unexpectedly hard spectra provide an upper limit on the background light at optical/near-infrared wavelengths that appears to be very close to the lower limit given by the integrated light of resolved galaxies8. The background flux at these wavelengths accordingly seems to be strongly dominated by the direct starlight from galaxies, thus excluding a large contribution from other sources—in particular from the first stars formed9. This result also indicates that intergalactic space is more transparent to -rays than previously thought

Constraints on axionlike particles with H.E.S.S. from the irregularity of the PKS 2155-304 energy spectrum

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, ggammaa<2.1×10-11GeV-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 fieldFil: Medina, Maria Clementina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico La Plata. Instituto Argentino de Radioastronomia (i); ArgentinaFil: H.E.S. S. collaboration

Observation of a sudden cessation of a very-high-energy gamma-ray flare in PKS 1510-089 with H.E.S.S. and MAGIC in May 2016

The flat spectrum radio quasar (FSRQ) PKS 1510-089 is known for its complex multiwavelength behavior, and is one of only a few FSRQs detected at very high energy (VHE, E >100 GeV) -rays. VHE -ray observations with H.E.S.S. and MAGIC during late May and early June 2016 resulted in the detection of an unprecedented flare, which reveals for the first time VHE -ray intranight variability in this source. While a common variability timescale of 1.5 hr is found, there is a significant deviation near the end of the flare with a timescale of ∼ 20 min marking the cessation of the event. The peak flux is nearly two orders of magnitude above the low-level emission. For the first time, curvature is detected in the VHE -ray spectrum of PKS 1510-089, which is fully explained through absorption by the extragalactic background light. Optical R-band observations with ATOM reveal a counterpart of the -ray flare, even though the detailed flux evolution differs from the VHE lightcurve. Interestingly, a steep flux decrease is observed at the same time as the cessation of the VHE flare. In the high energy (HE, E >100 MeV) -ray band only a moderate flux increase is observed with Fermi-LAT, while the HE -ray spectrum significantly hardens up to a photon index of 1.6. A search for broad-line region (BLR) absorption features in the -ray spectrum indicates that the emission region is located outside of the BLR. Radio VLBI observations reveal a fast moving knot interacting with a standing jet feature around the time of the flare. As the standing feature is located ∼ 50 pc from the black hole, the emission region of the flare may have been located at a significant distance from the black hole. If this correlation is indeed true, VHE rays have been produced far down the jet where turbulent plasma crosses a standing shock.Accepted manuscrip