375 research outputs found
High precision astrometry mission for the detection and characterization of nearby habitable planetary systems with the Nearby Earth Astrometric Telescope (NEAT)
(abridged) A complete census of planetary systems around a volume-limited
sample of solar-type stars (FGK dwarfs) in the Solar neighborhood with uniform
sensitivity down to Earth-mass planets within their Habitable Zones out to
several AUs would be a major milestone in extrasolar planets astrophysics. This
fundamental goal can be achieved with a mission concept such as NEAT - the
Nearby Earth Astrometric Telescope. NEAT is designed to carry out space-borne
extremely-high-precision astrometric measurements sufficient to detect
dynamical effects due to orbiting planets of mass even lower than Earth's
around the nearest stars. Such a survey mission would provide the actual
planetary masses and the full orbital geometry for all the components of the
detected planetary systems down to the Earth-mass limit. The NEAT performance
limits can be achieved by carrying out differential astrometry between the
targets and a set of suitable reference stars in the field. The NEAT instrument
design consists of an off-axis parabola single-mirror telescope, a detector
with a large field of view made of small movable CCDs located around a fixed
central CCD, and an interferometric calibration system originating from
metrology fibers located at the primary mirror. The proposed mission
architecture relies on the use of two satellites operating at L2 for 5 years,
flying in formation and offering a capability of more than 20,000
reconfigurations (alternative option uses deployable boom). The NEAT primary
science program will encompass an astrometric survey of our 200 closest F-, G-
and K-type stellar neighbors, with an average of 50 visits. The remaining time
might be allocated to improve the characterization of the architecture of
selected planetary systems around nearby targets of specific interest (low-mass
stars, young stars, etc.) discovered by Gaia, ground-based high-precision
radial-velocity surveys.Comment: Accepted for publication in Experimental Astronomy. The full member
list of the NEAT proposal and the news about the project are available at
http://neat.obs.ujf-grenoble.fr. The final publication is available at
http://www.springerlink.co
Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.
BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options
A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007
We present the results of the first search for gravitational wave bursts
associated with high energy neutrinos. Together, these messengers could reveal
new, hidden sources that are not observed by conventional photon astronomy,
particularly at high energy. Our search uses neutrinos detected by the
underwater neutrino telescope ANTARES in its 5 line configuration during the
period January - September 2007, which coincided with the fifth and first
science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed
for candidate gravitational-wave signals coincident in time and direction with
the neutrino events. No significant coincident events were observed. We place
limits on the density of joint high energy neutrino - gravitational wave
emission events in the local universe, and compare them with densities of
merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at
http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access
area to figures, tables at
https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000
Hundreds of variants clustered in genomic loci and biological pathways affect human height
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML
Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets
The structure of the first representative of Pfam family PF06475 reveals a new fold with possible involvement in glycolipid metabolism
PA1994, a Pfam PF06475 (DUF1089) family homolog from P. aeruginosa, reveals remote similarities to lipoprotein localization factors and a conserved putative glycolipid-binding site
Structure of a tryptophanyl-tRNA synthetase containing an iron–sulfur cluster
The crystal structure of tryptophanyl-tRNA synthetase from T. maritima unexpectedly revealed an iron–sulfur cluster bound to the tRNA anticodon-binding region
Conformational changes associated with the binding of zinc acetate at the putative active site of XcTcmJ, a cupin from Xanthomonas campestris pv. campestris
The crystal structure of an RmlC-type cupin with zinc acetate bound at the putative active site reveals significant differences from a previous structure without any bound ligand. The functional implications of the ligand-induced conformational changes are discussed
The structure of Jann_2411 (DUF1470) from Jannaschia sp. at 1.45 Å resolution reveals a new fold (the ABATE domain) and suggests its possible role as a transcription regulator
The crystal structure of the first representative of the Pfam PF07336 (DUF1470) family reveals a two-domain organization that contains a new fold, termed the ABATE domain, at the N-terminus and a treble-clef zinc finger that is likely to bind DNA at the C-terminus
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