The Acknowledgement of Love in Sarah Ruhl’s Drama

How can the mourning of a parent have anything to do with romantic love? This question is at the heart of much of Sarah Ruhl’s wide-ranging drama. Ruhl, the popular and prolific thirty-nine-year-old American playwright, has written nine original plays that have been produced, not counting her versions of Virginia Woolf’s Orlando and Anton Chekhov’s Three Sisters. In recent years, her Passion Play and In the Next Room or the Vibrator Play have had runs in several cities and have received critical accolades. As these titles suggest, Ruhl’s interests have been so expansive and idiosyncratic that they include both the history of the passion play and the invention of the vibrator as a means of therapy for “hysterical” women. In much of her work, New Yorker theatre critic John Lahr perceives a certain “lightness”—an aesthetic term borrowed from Italo Calvino—that comes across, Lahr says, as “the distillation of things into a quick, terse, almost innocent directness.” Speaking to Lahr, Ruhl agrees: “Lightness isn’t stupidity. It’s actually a philosophical and aesthetic viewpoint, deeply serious, and has a kind of wisdom—stepping back to be able to laugh at horrible things even as you’re experiencing them.” Ruhl’s sensibility for lightness allows her works to explore without sentimentality characters’ concomitant emotions of grief and vitality

mode_hopping.avi

Visualisation 1 shows an animation of the experimentally measured real time laser dynamics of a swept source external cavity laser. The complex electric field of the laser is measured using an interferometric phase detection technique. The upper plot of the animation displays the instantaneous optical spectrum over the course of 500 ns calculated from the windowed E-field. The lower plots show the corresponding measured Intensity and instantaneous frequency of the laser over the same period. The windowing limits are shown with red, dashed lines. During this time period, the laser operates in several dynamic regimes, including CW operation, mode-hopping dynamics, multi-mode transient oscillations, and chirped mode-pulling

Discovery of the First <i>C</i>‑Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients

Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been <i>N</i>-nucleoside derivatives. Herein, we report the discovery of a <i>C</i>-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1′-cyano-2′-<i>C</i>-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability