Analysis and Monte Carlo modelling of radio-opaque personal protective fabrics

The composition of a second generation radio-opaque fabric and its performance relative to established characterised materials are described. The protection offered by this fabric has been examined using a wide range of discrete gamma photon energies. Data indicate improved attenuation in the range 50–300 keV relative to earlier lightweight personal protective materials and conventional personal protection fabrics. Statistically significant improvements were not observed for gamma photons possessing energies > 300 keV. Experimentally benchmarked models represent powerful tools for the investigation and optimisation of radio-opaque fabrics. In the present work, Monte Carlo simulations using the Monte Carlo N-Particle Transport Code, Version 5 software produced single layer fabric attenuation results for first and second generation fabrics within the uncertainties associated with the experimental data. This model was then used to assess secondary X-ray production and consider the attenuation performance of alternative fabric compositions.     

The potential of 19F NMR spectroscopy for rapid screening of cell cultures for models of mammalian drug metabolism

The use of microbial cultures as a complementary model for mammalian drug metabolism has been well established previously. Here is a preliminary investigation into the potential of 19F NMR spectroscopy as a rapid screening tool to quantify the biotransformations of fluorine-containing model drugs. Biotransformations of three model drugs in 48 taxonomically diverse organisms were measured by acquiring 19F NMR spectra at 376 MHz. The presence of fluorine in the molecules allowed rapid, simultaneous detection of over 20 biotransformation products without sample pretreatment, chromatography, mass spectrometric techniques or the use of radiolabelled substrates. The detection limit at 376 MHz using 5 mm NMR tubes was ca. 0.3 microg ml(-1) using a typical analysis time of 20 min per sample. With the recent advent of flow injection NMR technology, analysis time of 5 min could be achieved with less sample. This approach may be used to develop fast small-scale microbial screens for the biosynthesis of metabolite standards and production of novel drug analogues, whilst also having a role in reducing animal experiments needed to identify animal and human metabolites of fluorinated xenobiotics.     

Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3. RESULTS: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase. CONCLUSIONS: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.     

Analyzing power in the reaction pp→dπ for beam momenta from 1.17 to 1.96 GeV/c

The analyzing power A_y0 in the reaction p↑p→dπ⁺ has been measured using the polarized proton beam at Argonne National Laboratory's zero gradient synchrotron. Data were taken at beam momenta of 1.17, 1.47, 1.70, and 1.96 GeV/c and for pion center of mass angles from 8° to 163°.