13 research outputs found
Diversity and impact of rare variants in genes encoding the platelet G protein-coupled receptors
Platelet responses to activating agonists are influenced by common
population variants within or near G protein-coupled receptor (GPCR)
genes that affect receptor activity. However, the impact of rare GPCR
gene variants is unknown. We describe the rare single nucleotide variants
(SNVs) in the coding and splice regions of 18 GPCR genes in
7,595 exomes from the 1,000-genomes and Exome Sequencing
Project databases and in 31 cases with inherited platelet function disorders
(IPFDs). In the population databases, the GPCR gene target
regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop
gain and 6 splice region) of which 70 % had global minor allele frequency
(MAF) < 0.05 %. Functional annotation using six computational
algorithms, experimental evidence and structural data identified
156/740 (21 %) SNVs as potentially damaging to GPCR function, most
commonly in regions encoding the transmembrane and C-terminal intracellular
receptor domains. In 31 index cases with IPFDs (Gi-pathway
defect n=15; secretion defect n=11; thromboxane pathway defect
n=3 and complex defect n=2) there were 256 SNVs in the target
regions of 15 stimulatory platelet GPCRs (34 unique; 12 with
MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting
R122H, P258T and V207A substitutions in the P2Y12 receptor
that were annotated as potentially damaging, but only partially explained
the platelet function defects in each case. Our data highlight
that potentially damaging variants in platelet GPCR genes have low
individual frequencies, but are collectively abundant in the population.
Potentially damaging variants are also present in pedigrees with IPFDs
and may contribute to complex laboratory phenotypes
Impaired thromboxane receptor dimerization reduces signaling efficiency: a potential mechanism for reduced platelet function in vivo
Thromboxane A2 is a potent mediator of inflammation and platelet aggregation exerting its effects through the activation of a G protein-coupled receptor (GPCR), termed TP. Although the existence of dimers/oligomers in Class A GPCRs is widely accepted, their functional significance still remains controversial. Recently, we have shown that TP\u3b1 and TP\u3b2 homo-/hetero-dimers interact through an interface of residues in transmembrane domain 1 (TM1) whose disruption impairs dimer formation. Here, biochemical and pharmacological characterization of this dimer deficient mutant (DDM) in living cells indicates a significant impairment in its response to agonists. Interestingly, two single loss-of-function TP\u3b1 variants, namely W29C and N42S recently identified in two heterozygous patients affected by bleeding disorders, match some of the residues mutated in our DDM. These two naturally occurring variants display a reduced potency to TP agonists and are characterized by impaired dimer formation in transfected HEK-293T cells. These findings provide proofs that lack of homo-dimer formation is a crucial process for reduced TP\u3b1 function in vivo, and might represent one molecular mechanism through which platelet TP\u3b1 receptor dysfunction affects the patient(s) carrying these mutations
Active Galactic Nuclei at the Crossroads of Astrophysics
Over the last five decades, AGN studies have produced a number of spectacular
examples of synergies and multifaceted approaches in astrophysics. The field of
AGN research now spans the entire spectral range and covers more than twelve
orders of magnitude in the spatial and temporal domains. The next generation of
astrophysical facilities will open up new possibilities for AGN studies,
especially in the areas of high-resolution and high-fidelity imaging and
spectroscopy of nuclear regions in the X-ray, optical, and radio bands. These
studies will address in detail a number of critical issues in AGN research such
as processes in the immediate vicinity of supermassive black holes, physical
conditions of broad-line and narrow-line regions, formation and evolution of
accretion disks and relativistic outflows, and the connection between nuclear
activity and galaxy evolution.Comment: 16 pages, 5 figures; review contribution; "Exploring the Cosmic
Frontier: Astrophysical Instruments for the 21st Century", ESO Astrophysical
Symposia Serie
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Gaia Early Data Release 3: Gaia photometric science alerts
Context. Since July 2014, the Gaia mission has been engaged in a high-spatial-resolution, time-resolved, precise, accurate astrometric, and photometric survey of the entire sky. Aims. We present the Gaia Science Alerts project, which has been in operation since 1 June 2016. We describe the system which has been developed to enable the discovery and publication of transient photometric events as seen by Gaia. Methods. We outline the data handling, timings, and performances, and we describe the transient detection algorithms and filtering procedures needed to manage the high false alarm rate. We identify two classes of events: (1) sources which are new to Gaia and (2) Gaia sources which have undergone a significant brightening or fading. Validation of the Gaia transit astrometry and photometry was performed, followed by testing of the source environment to minimise contamination from Solar System objects, bright stars, and fainter near-neighbours. Results. We show that the Gaia Science Alerts project suffers from very low contamination, that is there are very few false-positives. We find that the external completeness for supernovae, CE = 0.46, is dominated by the Gaia scanning law and the requirement of detections from both fields-of-view. Where we have two or more scans the internal completeness is CI = 0.79 at 3 arcsec or larger from the centres of galaxies, but it drops closer in, especially within 1 arcsec. Conclusions. The per-Transit photometry for Gaia transients is precise to 1% at G = 13, and 3% at G = 19. The per-Transit astrometry is accurate to 55 mas when compared to Gaia DR2. The Gaia Science Alerts project is one of the most homogeneous and productive transient surveys in operation, and it is the only survey which covers the whole sky at high spatial resolution (subarcsecond), including the Galactic plane and bulge. © S. T. Hodgkin et al. 2021
Choice of monetary policy instruments in a stochastic IS-LM model: Some empirical remarks for the Netherlands
Recent Progress of Adenosine Receptor Modulators in the Development of Anticancer Chemotherapeutic Agents
Monte Carlo studies for the optimisation of the Cherenkov Telescope Array layout
International audienceThe Cherenkov Telescope Array (CTA) is the major next-generation observatory for ground-based very-high-energy gamma-ray astronomy. It will improve the sensitivity of current ground-based instruments by a factor of five to twenty, depending on the energy, greatly improving both their angular and energy resolutions over four decades in energy (from 20 GeV to 300 TeV). This achievement will be possible by using tens of imaging Cherenkov telescopes of three successive sizes. They will be arranged into two arrays, one per hemisphere, located on the La Palma island (Spain) and in Paranal (Chile). We present here the optimised and final telescope arrays for both CTA sites, as well as their foreseen performance, resulting from the analysis of three different large-scale Monte Carlo productions
Sensitivity of the Cherenkov Telescope Array for probing cosmology and fundamental physics with gamma-ray propagation
The Cherenkov Telescope Array (CTA), the new-generation ground-based observatory for γ astronomy, provides unique capabilities to address significant open questions in astrophysics, cosmology, and fundamental physics. We study some of the salient areas of γ cosmology that can be explored as part of the Key Science Projects of CTA, through simulated observations of active galactic nuclei (AGN) and of their relativistic jets. Observations of AGN with CTA will enable a measurement of γ absorption on the extragalactic background light with a statistical uncertainty below 15% up to a redshift z=2 and to constrain or detect γ halos up to intergalactic-magnetic-field strengths of at least 0.3 pG . Extragalactic observations with CTA also show promising potential to probe physics beyond the Standard Model. The best limits on Lorentz invariance violation from γ astronomy will be improved by a factor of at least two to three. CTA will also probe the parameter space in which axion-like particles could constitute a significant fraction, if not all, of dark matter. We conclude on the synergies between CTA and other upcoming facilities that will foster the growth of γ cosmology