VX Hydrolysis by Human Serum Paraoxonase 1: A Comparison of Experimental and Computational Results

Human Serum paraoxonase 1 (HuPON1) is an enzyme that has been shown to hydrolyze a variety of chemicals including the nerve agent VX. While wildtype HuPON1 does not exhibit sufficient activity against VX to be used as an in vivo countermeasure, it has been suggested that increasing HuPON1's organophosphorous hydrolase activity by one or two orders of magnitude would make the enzyme suitable for this purpose. The binding interaction between HuPON1 and VX has recently been modeled, but the mechanism for VX hydrolysis is still unknown. In this study, we created a transition state model for VX hydrolysis (VXts) in water using quantum mechanical/molecular mechanical simulations, and docked the transition state model to 22 experimentally characterized HuPON1 variants using AutoDock Vina. The HuPON1-VXts complexes were grouped by reaction mechanism using a novel clustering procedure. The average Vina interaction energies for different clusters were compared to the experimentally determined activities of HuPON1 variants to determine which computational procedures best predict how well HuPON1 variants will hydrolyze VX. The analysis showed that only conformations which have the attacking hydroxyl group of VXts coordinated by the sidechain oxygen of D269 have a significant correlation with experimental results. The results from this study can be used for further characterization of how HuPON1 hydrolyzes VX and design of HuPON1 variants with increased activity against VX.United States. Defense Threat Reduction Agenc

Timescales of chemical equilibrium between the convecting solid mantle and over- and underlying magma oceans

After accretion and formation, terrestrial planets go through at least one magma ocean episode. As the magma ocean crystallises, it creates the first layer of solid rocky mantle. Two different scenarios of magma ocean crystallisation involve that the solid mantle either (1) first appears at the core–mantle boundary and grows upwards or (2) appears at mid-mantle depth and grows in both directions. Regardless of the magma ocean freezing scenario, the composition of the solid mantle and liquid reservoirs continuously change due to fractional crystallisation. This chemical fractionation has important implications for the long-term thermo-chemical evolution of the mantle as well as its present-day dynamics and composition. In this work, we use numerical models to study convection in a solid mantle bounded at one or both boundaries by magma ocean(s) and, in particular, the related consequences for large-scale chemical fractionation. We use a parameterisation of fractional crystallisation of the magma ocean(s) and (re)melting of solid material at the interface between these reservoirs. When these crystallisation and remelting processes are taken into account, convection in the solid mantle occurs readily and is dominated by large wavelengths. Related material transfer across the mantle–magma ocean boundaries promotes chemical equilibrium and prevents extreme enrichment of the last-stage magma ocean (as would otherwise occur due to pure fractional crystallisation). The timescale of equilibration depends on the convective vigour of mantle convection and on the efficiency of material transfer between the solid mantle and magma ocean(s). For Earth, this timescale is comparable to that of magma ocean crystallisation suggested in previous studies (Lebrun et al., 2013), which may explain why the Earth's mantle is rather homogeneous in composition, as supported by geophysical constraints

Design, fabrication and control of soft robots

Conventionally, engineers have employed rigid materials to fabricate precise, predictable robotic systems, which are easily modelled as rigid members connected at discrete joints. Natural systems, however, often match or exceed the performance of robotic systems with deformable bodies. Cephalopods, for example, achieve amazing feats of manipulation and locomotion without a skeleton; even vertebrates such as humans achieve dynamic gaits by storing elastic energy in their compliant bones and soft tissues. Inspired by nature, engineers have begun to explore the design and control of soft-bodied robots composed of compliant materials. This Review discusses recent developments in the emerging field of soft robotics.National Science Foundation (U.S.) (Grant IIS-1226883

Tumor Treating Fields Increases Blood-Brain Barrier Permeability and Relative Cerebral Blood Volume in Patients With Glioblastoma

BACKGROUND AND OBJECTIVE: 200 kHz tumor treating fields (TTFields) is clinically approved for newly-diagnosed glioblastoma (nGBM). Because its effects on conventional surveillance MRI brain scans are equivocal, we investigated its effects on perfusion MRI (pMRI) brain scans. METHODS: Each patient underwent institutional standard pMRI: dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast (DSC) pMRI at three time points: baseline, 2-, and 6-months on-adjuvant therapy. At each timepoint, the difference between T1 pre- versus post-contrast tumor volume (ΔT1) and these pMRI metrics were evaluated: normalized and standardized relative cerebral blood volume (nRCBV, sRCBV); fractional plasma volume (V RESULTS: Among 13 pMRI datasets (11 nGBM, 2 recurrent GBM), therapies included temozolomide-only ( CONCLUSION: Using pMRI, we provide initial in-human validation of pre-clinical studies regarding the effects of TTFields on tumor blood volume and BBB permeability in GBM

PETSc Users Manual

The Portable, Extensible Toolkit for Scientific Computation (PETSc), is a suite of data structures and routines for the scalable (parallel) solution of scientific applications modeled by partial differential equations. It supports MPI, and GPUs through CUDA or OpenCL, as well as hybrid MPI-GPU parallelism. PETSc (sometimes called PETSc/Tao) also contains the Tao optimization software library

Enhancement of stress tolerance in transgenic tobacco plants constitutively expressing AtIpk2β, an inositol polyphosphate 6-/3-kinase from Arabidopsis thaliana

Inositol phosphates (IPs) and their turnover products have been implicated to play important roles in stress signaling in eukaryotic cells. In higher plants genes encoding inositol polyphosphate kinases have been identified previously, but their physiological functions have not been fully resolved. Here we expressed Arabidopsis inositol polyphosphate 6-/3-kinase (AtIpk2β) in two heterologous systems, i.e. the yeast Saccharomycescerevisiae and in tobacco (Nicotiana tabacum), and tested the effect on abiotic stress tolerance. Expression of AtIpk2β rescued the salt-, osmotic- and temperature-sensitive growth defects of a yeast mutant strain (arg82Δ) that lacks inositol polyphosphate multikinase activity encoded by the ARG82/IPK2 gene. Transgenic tobacco plants constitutively expressing AtIpk2β under the control of the Cauliflower Mosaic Virus 35S promoter were generated and found to exhibit improved tolerance to diverse abiotic stresses when compared to wild type plants. Expression patterns of various stress responsive genes were enhanced, and the activities of anti-oxidative enzymes were elevated in transgenic plants, suggesting a possible involvement of AtIpk2β in plant stress responses