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.

Who was Andrea? Writing Oneself as a Feminist Icon

This article explores the construction of Andrea Dworkin as a public persona, or a ‘feminist icon’, revered by some and demonized by others. It argues that in both her fiction and non-fiction, Dworkin engaged in a process of writing herself as an exceptional woman, a ‘feminist militant’ as she describes herself in the subheading of her 2002 memoir, Heartbreak. The article illustrates Dworkin’s autobiographical logic of exceptionalism by comparing the story told in Heartbreak to the story of Dworkin’s major novel, Mercy, which features a heroine, Andrea, who shares Dworkin’s name and significant biographical details. While Dworkin has insisted that Mercy is not an autobiographical novel, the author undertakes a reading here of Mercy as the story of Dworkin if she had not become the feminist icon of her own and others’ construction. In Mercy, Andrea unsuccessfully attempts to escape the silent, victimized status that Dworkin has insistently argued is imposed upon women. In her repeated victimization, Andrea functions for Dworkin as an ‘everywoman’ who both embodies Dworkin’s world-view and highlights how Dworkin’s own biography exists in tension with some of her central assumptions about women, gender and contemporary society.