Discovery and SAR of a novel series of non-MPEP site mGlu(5) PAMs based on an aryl glycine sulfonammide scaffold

Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu(5)) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu(5) PAM chemotype.

The unexpected discovery of a novel low-oxygen-activated locus for the anoxic persistence of Burkholderia cenocepacia

Burkholderia cenocepacia is a Gram-negative aerobic bacterium that belongs to a group of opportunistic pathogens displaying diverse environmental and pathogenic lifestyles. B. cenocepacia is known for its ability to cause lung infections in people with cystic fibrosis and it possesses a large 8?Mb multireplicon genome encoding a wide array of pathogenicity and fitness genes. Transcriptomic profiling across nine growth conditions was performed to identify the global gene expression changes made when B. cenocepacia changes niches from an environmental lifestyle to infection. In comparison to exponential growth, the results demonstrated that B. cenocepacia changes expression of over one-quarter of its genome during conditions of growth arrest, stationary phase and surprisingly, under reduced oxygen concentrations (6% instead of 20.9% normal atmospheric conditions). Multiple virulence factors are upregulated during these growth arrest conditions. A unique discovery from the comparative expression analysis was the identification of a distinct, co-regulated 50-gene cluster that was significantly upregulated during growth under low oxygen conditions. This gene cluster was designated the low-oxygen-activated (lxa) locus and encodes six universal stress proteins and proteins predicted to be involved in metabolism, transport, electron transfer and regulation. Deletion of the lxa locus resulted in B. cenocepacia mutants with aerobic growth deficiencies in minimal medium and compromised viability after prolonged incubation in the absence of oxygen. In summary, transcriptomic profiling of B. cenocepacia revealed an unexpected ability of aerobic Burkholderia to persist in the absence of oxygen and identified the novel lxa locus as key determinant of this important ecophysiological trait.

Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase

A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a sub-genomic replication system for a series of non-nucleoside boron-containing HCV RNA-Dependent RNA Polymerase (NS5B) inhibitors are described. A summary of the discovery of GSK5852 (3), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included.

Discovery and Evidence in Transnational Antitrust Cases: Current Framework and the Way Forward

This paper identifies and analyses the means of accessing and collecting foreign-based evidence in transnational antitrust cases. It makes an original contribution to the existing scholarship by critically addressing the available mechanisms of judicial cooperation, the possibility of reliance on domestic discovery in transnational context, as well as the existing instruments allowing for cooperation between antitrust agencies. It identifies the shortcomings of the current regulatory framework and points out to the existing good practices in those jurisdictions which provide their antitrust agencies with more leeway in sharing confidential information with foreign counterparts.

Discovery of WASP-65b and WASP-75b: Two hot Jupiters without highly inflated radii

We report the discovery of two transiting hot Jupiters, WASP-65b (M_pl = 1.55 ± 0.16 M_J; R_pl = 1.11 ± 0.06 R_J), and WASP-75b (M_pl = 1.07 ± 0.05 M_J; R_pl = 1.27 ± 0.05 R_J). They orbit their host star every ∼2.311, and ∼2.484 days, respectively. The planet host WASP-65 is a G6 star (T_eff = 5600 K, [Fe/H] = −0.07 ± 0.07, age 8 Gyr); WASP-75 is an F9 star (T_eff = 6100 K, [Fe/H] = 0.07 ± 0.09, age ∼ 3 Gyr). WASP-65b is one of the densest known exoplanets in the mass range 0.1 and 2.0 MJ (ρpl = 1.13 ± 0.08 ρJ), a mass range where a large fraction of planets are found to be inflated with respect to theoretical planet models. WASP-65b is one of only a handful of planets with masses of ∼1.5 MJ, a mass regime surprisingly underrepresented among the currently known hot Jupiters. The radius of WASP-75b is slightly inflated (10%) as compared to theoretical planet models with no core, and has a density similar to that of Saturn (ρpl = 0.52 ± 0.06 ρJ). Key words. planetary systems – stars: individual:

Model selection for prognostic time-to-event gene signature discovery with applications in early breast cancer data

Model selection between competing models is a key consideration in the discovery of prognostic multigene signatures. The use of appropriate statistical performance measures as well as verification of biological significance of the signatures is imperative to maximise the chance of external validation of the generated signatures. Current approaches in time-to-event studies often use only a single measure of performance in model selection, such as logrank test p-values, or dichotomise the follow-up times at some phase of the study to facilitate signature discovery. In this study we improve the prognostic signature discovery process through the application of the multivariate partial Cox model combined with the concordance index, hazard ratio of predictions, independence from available clinical covariates and biological enrichment as measures of signature performance. The proposed framework was applied to discover prognostic multigene signatures from early breast cancer data. The partial Cox model combined with the multiple performance measures were used in both guiding the selection of the optimal panel of prognostic genes and prediction of risk within cross validation without dichotomising the follow-up times at any stage. The signatures were successfully externally cross validated in independent breast cancer datasets, yielding a hazard ratio of 2.55 [1.44, 4.51] for the top ranking signature.

EL CVn-type binaries - Discovery of 17 helium white dwarf precursors in bright eclipsing binary star systems

The star 1SWASP J024743.37-251549.2 was recently discovered to be a binary star in which an A-type dwarf star eclipses the remnant of a disrupted red giant star (WASP 0247-25 B). The remnant is in a rarely observed state evolving to higher effective temperatures at nearly constant luminosity prior to becoming a very low mass white dwarf composed almost entirely of helium, i.e. it is a pre-helium white dwarf (pre-He-WD). We have used the photometric database from theWide Angle Search for Planets (WASP) to find 17 eclipsing binary stars with orbital periods P = 0.7-2.2 d with similar light curves to 1SWASP J024743.37-251549.2. The only star in this group previously identified as a variable star is the brightest one, EL CVn, which we adopt as the prototype for this class of eclipsing binary star. The characteristic light curves of EL CVn-type stars show a total eclipse by an A-type dwarf star of a smaller, hotter star and a secondary eclipse of comparable depth to the primary eclipse. We have used new spectroscopic observations for six of these systems to confirm that the companions to the A-type stars in these binaries have very low masses (≈0.2M⊙). This includes the companion to EL CVn which was not previously known to be a pre-He-WD. EL CVn-type binary star systems will enable us to study the formation of very low mass white dwarfs in great detail, particularly in those cases where the pre-He-WD star shows non-radial pulsations similar to those recently discovered in WASP0247-25 B. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.