Activity

Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.Cs2AgBiBr6 is a promising metal halide double perovskite offering the possibility of efficient photovoltaic devices based on lead-free materials. Here, we report on the evolution of photoexcited charge carriers in Cs2AgBiBr6 using a combination of temperature-dependent photoluminescence, absorption and optical pump-terahertz probe spectroscopy. We observe rapid decays in terahertz photoconductivity transients that reveal an ultrafast, barrier-free localization of free carriers on the time scale of 1.0 ps to an intrinsic small polaronic state. While the initially photogenerated delocalized charge carriers show bandlike transport, the self-trapped, small polaronic state exhibits temperature-activated mobilities, allowing the mobilities of both to still exceed 1 cm2 V-1 s-1 at room temperature. Self-trapped charge carriers subsequently diffuse to color centers, causing broad emission that is strongly red-shifted from a direct band edge whose band gap and associated exciton binding energy shrink with increasing temperature in a correlated manner. Overall, our observations suggest that strong electron-phonon coupling in this material induces rapid charge-carrier localization.Drug resistance threatens many critical therapeutics through mutations in the drug target. The molecular mechanisms by which combinations of mutations, especially those remote from the active site, alter drug binding to confer resistance are poorly understood and thus difficult to counteract. buy MSU-42011 A machine learning strategy was developed that coupled parallel molecular dynamics simulations with experimental potency to identify specific conserved mechanisms underlying resistance. Physical features were extracted from the simulations, analyzed, and integrated into one consistent and interpretable elastic network model. To rigorously test this strategy, HIV-1 protease variants with diverse mutations were used, with potencies ranging from picomolar to micromolar to the drug darunavir. Feature reduction resulted in a model with four specific features that predicts for both the training and test sets inhibitor binding free energy within 1 kcal/mol of the experimental value over this entire range of potency. These predictive features are physically interpretable, as they vary specifically with affinity and diagonally transverse across the protease homodimer. This physics-based strategy of parallel molecular dynamics and machine learning captures mechanisms by which complex combinations of mutations confer resistance and identify critical features that serve as bellwethers of affinity, which will be critical in future drug design.Classical density functional theory (DFT) has proven to be a sophisticated and efficient approach for investigating charge systems. In DFT, the excess free energy functional for inhomogeneous charged hard-sphere fluids consists of hard-core interactions and charge-charge electrostatic interactions. The former component can be precisely described by well-established fundamental measure theory (FMT). The latter component is usually computed using the Poisson equation combined with the mean spherical approximation (MSA). In order to predict accurate density profiles of ions and satisfy some thermodynamics sum rules, Roth and Gillespie [J. Phys. Condens. Matter 2016, 28, 244006] proposed a DFT combining a functional-based version of MSA and an approximated charged shell model. Here, we rebuild the DFT based on the exact charged shell model, and the analytic expressions for the shell interaction potential and the corresponding thermodynamic quantities are provided. The structural and thermodynamic properties of both bulk and inhomogeneous electrolyte systems are analyzed. Moreover, the software named Atif (an advanced theoretical tool for inhomogeneous fluids) is released to the public via this work.Quantum chemistry and statistical reaction rate theory calculations have been performed to investigate the products and kinetics of indenyl radical decomposition. Three competitive product sets are identified, including formation of a cyclopentadienyl radical (c-C5H5) and diacetylene (C4H2), which has not been included in prior theoretical kinetics investigations. Rate coefficients for indenyl decomposition are determined from master equation simulations at 1800-2400 K and 0.01-100 atm, and temperature- and pressure-dependent rate coefficient expressions are incorporated into a detailed chemical kinetic model for indene pyrolysis. Indenyl is found to predominantly decompose to o-benzyne (o-C6H4) + propargyl (C3H3), with lesser amounts of fulvenallenyl (C7H5) + C2H2 and c-C5H5 + C4H2.Aqueous rechargeable zinc ion batteries are promising candidates for grid-scale applications owing to their low cost and high safety. However, they are plagued by the lack of suitable cathode and anode materials. Herein, we report on potassium vanadate (KVO) nanobelts as a promising cathode for an aqueous zinc ion battery, which shows a high discharge capacity of 461 mA h g-1 at 0.2 A g-1 and exhibits a capacity retention of 96.2% over 4000 cycles at 10 A g-1. Furthermore, to enhance the energy efficiency in an aqueous zinc ion battery, a facile and effective method on the anode is demonstrated. The energy efficiency increases from 47.5% for Zn//KVO coupled with the zinc foil anode to 66.5% for AB-Zn//KVO coupled with an acetylene black film improved zinc foil anode at 10 A g-1. The remarkable electrochemical performance makes AB-Zn//KVO a strong candidate for a high-performance aqueous zinc ion battery.