Key steps in the structure-based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034

Crystal structures of protease/inhibitor complexes guided optimization of the buried nonpolar surface area thereby maximizing hydrophobic binding. The resulting potent tripeptide inhibitor is in clinical trials

The LHS 1678 system : two earth-sized transiting planets and an astrometric companion orbiting an M dwarf near the convective boundary at 20 pc

Funding: The MEarth Team gratefully acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering (awarded to D.C.). This material is based upon work supported by the National Science Foundation under grants AST-0807690, AST-1109468, AST-1004488 (Alan T. Waterman Award), and AST-1616624, and upon work supported by the National Aeronautics and Space Administration under Grant No. 80NSSC18K0476 issued through the XRP Program. This work is made possible by a grant from the John Templeton Foundation. N. A.-D. acknowledges the support of FONDECYT project 3180063. TD acknowledges support from MIT’s Kavli Institute as a Kavli postdoctoral fellow. KH acknowledges support from STFC grant ST/R000824/1. E.A.G. thanks the LSSTC Data Science Fellowship Program, which is funded by LSSTC, NSF Cybertraining Grant #1829740, the Brinson Foundation, and the Moore Foundation; The material is based upon work supported by NASA under award number 80GSFC21M0002. This work was supported by the lead author’s appointment to the NASA Postdoctoral Program at the Goddard Space Flight Center, administered by Universities Space Research Association under contract with NASAWe present the Transiting Exoplanet Survey Satellite (TESS) discovery of the LHS 1678 (TOI-696) exoplanet system, comprised of two approximately Earth-sized transiting planets and a likely astrometric brown dwarf orbiting a bright (VJ = 12.5, Ks = 8.3) M2 dwarf at 19.9 pc. The two TESS-detected planets are of radius 0.70 ± 0.04 R⊕ and 0.98 ± 0.06 R⊕ in 0.86 day and 3.69 day orbits, respectively. Both planets are validated and characterized via ground-based follow-up observations. High Accuracy Radial Velocity Planet Searcher RV monitoring yields 97.7 percentile mass upper limits of 0.35 M⊕ and 1.4 M⊕ for planets b and c, respectively. The astrometric companion detected by the Cerro Tololo Inter-American Observatory/Small and Moderate Aperture Telescope System 0.9 m has an orbital period on the order of decades and is undetected by other means. Additional ground-based observations constrain the companion to being a high-mass brown dwarf or smaller. Each planet is of unique interest; the inner planet has an ultra-short period, and the outer planet is in the Venus zone. Both are promising targets for atmospheric characterization with the James Webb Space Telescope and mass measurements via extreme-precision radial velocity. A third planet candidate of radius 0.9 ± 0.1 R⊕ in a 4.97 day orbit is also identified in multicycle TESS data for validation in future work. The host star is associated with an observed gap in the lower main sequence of the Hertzsprung–Russell diagram. This gap is tied to the transition from partially to fully convective interiors in M dwarfs, and the effect of the associated stellar astrophysics on exoplanet evolution is currently unknown. The culmination of these system properties makes LHS 1678 a unique, compelling playground for comparative exoplanet science and understanding the formation and evolution of small, short-period exoplanets orbiting low-mass stars.Publisher PDFPeer reviewe

The LHS 1678 System: Two Earth-sized Transiting Planets and an Astrometric Companion Orbiting an M Dwarf Near the Convective Boundary at 20 pc

We present the Transiting Exoplanet Survey Satellite (TESS) discovery of the LHS 1678 (TOI-696) exoplanet system, comprised of two approximately Earth-sized transiting planets and a likely astrometric brown dwarf orbiting a bright (V J = 12.5, K s = 8.3) M2 dwarf at 19.9 pc. The two TESS-detected planets are of radius 0.70 ± 0.04 R ⊕ and 0.98 ± 0.06 R ⊕ in 0.86 day and 3.69 day orbits, respectively. Both planets are validated and characterized via ground-based follow-up observations. High Accuracy Radial Velocity Planet Searcher RV monitoring yields 97.7 percentile mass upper limits of 0.35 M ⊕ and 1.4 M ⊕ for planets b and c, respectively. The astrometric companion detected by the Cerro Tololo Inter-American Observatory/Small and Moderate Aperture Telescope System 0.9 m has an orbital period on the order of decades and is undetected by other means. Additional ground-based observations constrain the companion to being a high-mass brown dwarf or smaller. Each planet is of unique interest; the inner planet has an ultra-short period, and the outer planet is in the Venus zone. Both are promising targets for atmospheric characterization with the James Webb Space Telescope and mass measurements via extreme-precision radial velocity. A third planet candidate of radius 0.9 ± 0.1 R ⊕ in a 4.97 day orbit is also identified in multicycle TESS data for validation in future work. The host star is associated with an observed gap in the lower main sequence of the Hertzsprung-Russell diagram. This gap is tied to the transition from partially to fully convective interiors in M dwarfs, and the effect of the associated stellar astrophysics on exoplanet evolution is currently unknown. The culmination of these system properties makes LHS 1678 a unique, compelling playground for comparative exoplanet science and understanding the formation and evolution of small, short-period exoplanets orbiting low-mass stars

The requirement of p56Lck tyrosine kinase in the modulation of fas-mediated apoptosis by HIV-1 Nef protein /

The HIV-1 protein Nef is a critical factor in the viral pathogenesis and decline of CD4 T-cells during HIV infection. Nef has been implicated in modulating several cellular pathways, including apoptosis. This thesis herein describes our attempt to elucidate the mechanism by which Nef modulates apoptosis in T-cells. Using Jurkat cells inducibly expressing wild-type Nef, we observe that Nef renders cells more sensitive to apoptosis upon cross-linking with anti-Fas or TRAIL. Enhancement of Fas-mediated apoptosis required the presence of Lck, as apoptosis was abrogated in Nef expressing Lck-/- cells as compared to wild type Jurkat cells. Nef does not modulate expression of pro or anti-apoptotic proteins, or cell surface Fas receptor. Furthermore, Nef differentially mediates activation signaling pathways upon anti-CD3 stimulation. Enhancement of apoptosis by Nef may represent one of the mechanisms by which HIV depletes CD4 T-cells during infection

A Canadian Perspective on the Challenges for Delivery of Curative-Intent Therapy in Stage III Unresectable Non-Small Cell Lung Cancer

Stage III non-small cell lung cancer (NSCLC) comprises a highly heterogenous group of patients with regards to patient fitness and tumour size and distribution, resulting in a wide range of treatment goals and therapy options. Curative-intent multimodality treatment should be considered in all patients with stage III NSCLC. For patients with unresectable disease who are fit, have adequate lung function, and have a disease that can be encompassed within a radical radiation volume, concurrent chemoradiation therapy (cCRT) is the standard of care and can produce cure rates of 20–30%. Recently, consolidation immunotherapy with durvalumab has been recognized as the standard of care following cCRT based on significant improvement rates in overall survival at 4 years. The large heterogeneity of the stage III NSCLC population, along with the need for extensive staging procedures, multidisciplinary care, intensive cCRT, and now consolidation therapy makes the delivery of timely and optimal treatment for these patients complex. Several logistical, communication, and education factors hinder the delivery of guideline-recommended care to patients with stage III unresectable NSCLC. This commentary discusses the potential challenges patients may encounter at different points along their care pathway that can interfere with delivery of curative-intent therapy and suggests strategies for improving care delivery

Microstructural Changes in Absence Seizure Children: A Diffusion Tensor Magnetic Resonance Imaging Study

Absence seizures are a subtype of epileptic seizures clinically characterized by transient alterations in states of consciousness and by electroencephalography indicating diffuse spike-wave discharges (SWD). Conventional brain magnetic resonance imaging (MRI) is not routinely used to establish the diagnosis, but rather to rule out other diseases. The present study investigated tissue integrity in children with SWD epilepsy using diffusion tensor imaging (DTI). Methods: Magnetic resonance imaging (MRI)-DTI was conducted in 18 patients with absence seizures and 10 control participants. Brain areas were evaluated using diffusion maps, and fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ||), and perpendicular diffusivity (λ⊥) values were extracted and analyzed. Tractography at the regions of abnormal diffusion indices was then reconstructed in each group, and tract symmetry was evaluated by an index of asymmetry (AI). Statistical analyses were performed using nonparametric Mann–Whitney U tests, with p values < 0.05 indicating statistical significance. Results: Compared to the control group, patients with SWD epilepsy had lower FA values and higher MD values at the genu of the corpus callosum. There was also a stronger negative correlation between MD and FA values at the genu of the corpus callosum in patients than in control participants. The AI for the fiber tracts through the genu of the corpus callosum in the SWD group was significantly higher than that of the control group, indicating that tract distribution was more asymmetric in patients with epilepsy. There were no significant differences between groups in diffusion indices for other brain areas. Conclusion: We observed microstructural changes in the genu of the corpus callosum, as well as reduced FA values, increased λ⊥ values, increased MD values, and asymmetric distribution of fiber tracts, indicating that DTI is more sensitive than conventional MRI to detect brain abnormalities in children with absence seizures