Framing the Narrative: Female Fighters, External Audience Attitudes, and Transnational Support for Armed Rebellions

Female combatants play a central role in rebel efforts to cultivate and disseminate positive narratives regarding the movement and its political goals. Yet, the effectiveness of such strategies in shaping audience attitudes or generating tangible benefits for the group remains unclear. We propose and test a theory regarding the channels through which female fighters advance rebel goals. We argue that female fighters positively influence audience attitudes toward rebel groups by strengthening observers’ beliefs about their legitimacy and their decision to use armed tactics. We further contend that these effects directly help them secure support from transnational non-state actors and indirectly promote state support. We assess our arguments by combining a novel survey experiment in two countries with analyses of new cross-national data on female combatants and information about transnational support for rebels. The empirical results support our arguments and demonstrate the impact of gender framing on rebel efforts to secure support

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day

A Viral Dynamic Model for Treatment Regimens with Direct-acting Antivirals for Chronic Hepatitis C Infection

We propose an integrative, mechanistic model that integrates in vitro virology data, pharmacokinetics, and viral response to a combination regimen of a direct-acting antiviral (telaprevir, an HCV NS3-4A protease inhibitor) and peginterferon alfa-2a/ribavirin (PR) in patients with genotype 1 chronic hepatitis C (CHC). This model, which was parameterized with on-treatment data from early phase clinical studies in treatment-naïve patients, prospectively predicted sustained virologic response (SVR) rates that were comparable to observed rates in subsequent clinical trials of regimens with different treatment durations in treatment-naïve and treatment-experienced populations. The model explains the clinically-observed responses, taking into account the IC50, fitness, and prevalence prior to treatment of viral resistant variants and patient diversity in treatment responses, which result in different eradication times of each variant. The proposed model provides a framework to optimize treatment strategies and to integrate multifaceted mechanistic information and give insight into novel CHC treatments that include direct-acting antiviral agents

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Ionized gas kinematics in bipolar H ii regions

Stellar feedback plays a fundamental role in shaping the evolution of galaxies. Here, we explore the use of the ionized gas kinematics in young, bipolar H II regions as a probe of early feedback in these star-forming environments. We have undertaken a multiwavelength study of a young, bipolar H II region in the Galactic disc, G316.81–0.06, which lies at the centre of a massive (∼103 M⊙) infrared dark cloud filament. It is still accreting molecular gas as well as driving a ∼0.2 pc ionized gas outflow perpendicular to the filament. Intriguingly, we observe a large velocity gradient (47.81 ± 3.21  km s−1 pc−1) across the ionized gas in a direction perpendicular to the outflow. This kinematic signature of the ionized gas shows a reasonable correspondence with the simulations of young H II regions. Based on a qualitative comparison between our observations and these simulations, we put forward a possible explanation for the velocity gradients observed in G316.81−0.06. If the velocity gradient perpendicular to the outflow is caused by the rotation of the ionized gas, then we infer that this rotation is a direct result of the initial net angular momentum in the natal molecular cloud. If this explanation is correct, this kinematic signature should be common in other young (bipolar) H II regions. We suggest that further quantitative analysis of the ionized gas kinematics of young H II regions, combined with additional simulations, should improve our understanding of feedback at these early stages

Contribution of telaprevir and PR treatment to the antiviral blockage and infected-cell clearance rates in treatment-naïve patient population.

<p>Contribution of telaprevir and PR treatment to the antiviral blockage and infected-cell clearance rates in treatment-naïve patient population.</p

Predicted clinical outcome among treatment-naïve patients who completed T12PR24 treatment, with and without the eradication assumption.

<p><u>Notes</u>: The simulations are for a simulated treatment-naïve population, with HCV genotype 1a∶1b ratio of 1∶1. The analyses of sensitivities to the eradication assumption were performed as follows: “Yes”, if variants cannot replicate when their levels are below eradication limit; “No”, if variants can replicate when their levels are below eradication limit. The simulated clinical outcomes were defined as follows: Failure at Week 1–12, HCV RNA returns back to detectable levels in the first 12 weeks (during telaprevir treatment); Failure at Week 13–24, HCV RNA levels return back to detectable level during Weeks 13–24 of therapy (during PR treatment, after completion of 12 weeks of telaprevir treatment); Relapse, HCV RNA undetectable at the end of treatment, but did not reach eradication; SVR, eradicated prior to the end of treatment. Compared to the simulated outcomes without the eradication assumption, the simulated outcomes with the eradication assumption better matched the observed clinical outcomes.</p

Simulated viral dynamics in patients treated with TPR, by prior PR48 responses.

<p><u>Notes</u>: The simulations are for typical subtype 1a (top row) or subtype 1b (second row) patients treated with a combination regimen of 12 weeks of telaprevir and 48 weeks of peginterferon alfa-2a and ribavirin, with PR responsiveness of a typical simulated prior PR48-SVR, prior PR48-relapse, and prior PR48-null responders. The parameters were obtained from the median of parameter values in the respective category of simulated PR48 treatment. Parameters used in these simulated patients are provided in Supplementary <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002339#pcbi.1002339.s006" target="_blank">Table S4</a>.</p

Multi-variant, viral dynamic model of a combination regimen of telaprevir and PR treatment.

<p>Parameters are defined in Supplementary <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002339#pcbi.1002339.s004" target="_blank">Table S2</a> and Supplementary <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002339#pcbi.1002339.s005" target="_blank">Table S3</a>.</p