99 research outputs found

    Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?

    Get PDF
    The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects

    Icing: Supporting Fast-Math Style Optimizations in a Verified Compiler

    Get PDF
    Verified compilers like CompCert and CakeML offer increasingly sophisticated optimizations. However, their deterministic source semantics and strict IEEE 754 compliance prevent the verification of ``fast-math'' style floating-point optimizations. Developers often selectively use these optimizations in mainstream compilers like GCC and LLVM to improve the performance of computations over noisy inputs or for heuristics by allowing the compiler to perform intuitive but IEEE 754-unsound rewrites

    The effects of milling conditions on the subsequent oxidation behaviour of mechanically alloyed Fe3_{\bf 3}Al-based powders

    No full text
    Mechanically alloyed, Fe3_{3}Al-based, oxide dispersion strengthened alloys form a surface oxide scale during powder processing. This scale becomes entrained in the consolidated alloy, and may have a significant effect on subsequent recrystallisation behaviour. The high oxidation rates found in these alloys are mainly due to the bulk alloy composition. However, batch-to-batch differences in oxidation mass gain occur in powders with ostensibly identical compositions. Batches PMWY2 and PMWY3 were studied and parameters such as alloy composition and homogeneity, powder surface area to volume ratios and scale thickening rates considered. Batch PMWY2 showed 20-90% faster weight gain than PMWY3 and reached the onset of breakaway oxidation approximately twice as quickly. PMWY2 was found to contain aluminium-depleted regions, whereas PMWY3 is much more homogeneous. The surface area to volume ratio for PMWY2 was 44% higher than that of PMWY3, and batch PMWY2 was found to contain extremely fine powder particles. The scale on batch PMWY2 thickened more quickly than that on batch PMWY3, with rates 20-40% higher at different stages in the oxidation. The major contributory factor to the difference in oxidation mass gain between the two alloy batches is scale thickening rate and factors influencing thickening rates are discussed

    FEG-SEM investigation of α\alpha-alumina scales formed on FeCrAlY alloys oxidised at 1200^{\circ}C

    No full text
    This work is part of an ongoing European funded project, “SMILER”, with the aim of improving the performance of alumina forming Fe-20Cr-5Al-Y alloys for high temperature industrial applications. One aspect of the project is to investigate the influence of additives on the oxidation behaviour of these alloys. During this study a LEO 1550 FESEM (field emission scanning electron microscope), equipped with INCA X-ray microanalysis facilities was used. Ultra-high-purity model alloys, where the levels of additives (Hf, Zr, Ti, Si, La and Y) were carefully controlled, and two commercial Aluchrom YHfAl and Kanthal AMPT alloys were oxidised at 1200^{\circ}C for up to 3100h (100h/cycle).
The YHfAl, (Y+Ti+Zr)- and (Y+Zr+Hf)-containing alloys showed the highest oxidation rates when oxidised, whereas the La-containing alloy showed the lowest oxidation rate. However, the La-containing alloy spalled the most, while the (Y+Zr+Hf)-containing and YHfAl alloys showed little spallation, and the additives appeared to have a major influence on the spallation of the α\alpha -alumina scale formed. On the alloys with La and Si respectively, the scale spalled at the scale/metal interface (adhesively), whereas on alloys containing (Y+Hf+Ti) and (Y+Hf+Zr) and the YHfAl alloy, the scale spalled mainly in a cohesive manner (within the scale). Also, the added elements affected the scale topography. In general the scale had a columnar structure at the scale/metal interface, whereas the grains were equiaxed at the scale/gas interface. However, in the case of YHfAl and (Y+Zr+Hf)-containing alloys, a sunflower type structure was observed in both fractured samples, in the regions where the scale spalled cohesively. Preliminary EDX analyses revealed that, in the case of YHfAl, for example, the center of the sunflower structure was rich in Mg. This suggests that there may be inhomogeneities in the metal substrate, prior to oxidation, where high concentrations of Mg increase the local oxide growth rate
    corecore