Design, synthesis and analysis of inhibitors of bacterial aspartate semialdehyde dehydrogenase

Unsaturated and fluorinated analogues of aspartyl-beta-phosphate were synthesised as potential inhibitors of the bacterial enzyme aspartate semialdehyde dehydrogenase (ASA-DH). Acetylenic and Z-olefinic analogues showed competitive inhibition, but an E-olefinic analogue was inactive. A monofluoromethylene phosphonate competed poorly, but showed time-dependent inhibition of ASA-DH in the absence of phosphate. Simulated docking procedures were used to rationalise the results. These studies showed that substrate and inhibitor binding are mediated by interaction with two active-site arginine residues, and for likely covalent attachment to the active-site thiol group, electrophilic carbon atoms should be located 4.5 A, or less, from the thiol.     

An assessment of various crack tip displacement based elastic-plastic fracture parameters to characterise ductile crack growth resistance

There is continuing interest in defining a fracture parameter which is capable of characterising the ductile crack growth resistance of a material under conditions of large scale plasticity. The aim of this study is to assess the capability of a number of elastic-plastic fracture parameters for the case of a C-Mn steel. The fracture parameters considered are: the crack opening displacement at the original crack tip (CTOD); the crack opening angle at the growing crack tip (CTOA); and the crack opening displacement at the growing crack tip (_a). The parameters were assessed by determining experimentally whether they were affected by changes in test specimen size and geometry in cases where there was no change in the crack tip constraint. Changes in the latter were assessed from changes in the CTOD at crack initiation (CTOD_i). Only _a was capable of characterising the crack growth resistance, as unlike both CTOD_i and _a, dCTOD/da and CTOA were dependent on specimen geometry.

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Résumé L'intérêt persiste à définir un paramètre de rupture capable de caractériser la résistance d'un matériau à la propagation ductile d'une fissure, dans des conditions de plastification à grande échelle. L'étude a pour objet d'établir la pertinence d'un certain nombre de paramètres élasto-plastiques relatifs à la rupture d'un acier CMn. On considère en particulier le déplacement d'ouverture de l'extrémité de la fissure initiale (CTOB), l'angle d'ouverture en cours de croissance de la fissure à son extrémité (CTOA) et le déplacement d'ouverture en cours de croissance de l'extrémité de la fissure (_a).L'analyse à porté sur la réaction expérimentale de ces paramètres à des changements de taille ou de géométrie d'éprouvettes, dans des cas où il ne se produisait pas de modifications des contraintes d'environnement à l'extrémité de la fissure. Lorsque celles-ci survenaient, le CTOD correspondant à l'amorçage (CTOD_i) y était sensible.II est apparu que seul _a pouvait caractériser la résistance à la croissance d'une fissure, dans la mesure où, á l'inverse du CTOD_i et du _a, le CTOA et la variation du CTOD en fonction de la longueur de la fissure sont dépendants de la géométrie de l'éprouvette.

     

The hydrostatic extrusion of polymethylmethacrylate

The hydrostatic extrusion behaviour of two grades of polymethylmethacrylate (PMMA) is reported and an analysis of the mechanics of the extrusion process is presented. Although the maximum degree of deformation achieved is considerably lower than that obtained for crystalline polymers, the process mechanics are controlled by the same factors (i.e. the billet-die friction, and the effects of strain rate and pressure on the material flow stress). A method for equating the effects of pressure and friction is described, following the work of Tabor on the adhesive mechanism of friction in polymers. This method gives a friction coefficient in the range 0.1 to 0.2 for the hydrostatic extrusion of PMMA, compared to values in the region 0.03 to 0.08 for crystalline polymers, suggesting conditions of boundary lubrication. The relatively high values of friction for PMMA are consistent with the requirement for careful preparation of the billet surface prior to extrusion, and the observation of the stick-slip phenomenon during extrusion. The differences between the grades of PMMA in both extrusion behaviour and tensile drawing behaviour are explicable in terms of their different glass transition temperatures.     

Policy and Legislation Relevant to the Conservation of Freshwater SSSIs Subject to Eutrophication

Although no legislation in England and Wales directly addresses the causes and effects of eutrophication of surface freshwaters, a wide range of laws may be applied to the reduction of nutrient inputs. Nature conservation laws are applicable, in that rivers, lakes, reservoirs and canals designated as 'sites of special scientific interest'(SSSIs) are theoretically safeguarded from degradation. However, the SSSI system is not designed to protect water quality at the catchment level. Since intensive agricultural practices are responsible for significant nutrient losses, legislation aimed at extensification is also relevant. Increasingly, laws related to extensification of agriculture include environmental imperatives - a trend which will inevitably extend to nutrient conservation. Basically, enrichment is a water-quality issue, but policy and legislation in this area are not yet sufficiently developed to address the problem comprehensively. Existing regulatory systems for water quality carry the potential to work comparatively well for point sources, but appear ineffective in dealing with diffuse losses.     

Partial acetylation of lysine residues improves intraprotein cross-linking

Intramolecular cross-linking coupled with mass spectrometric identification of cross-linked amino acids is a rapid method for elucidating low-resolution protein tertiary structures or fold families. However, previous cross-linking studies on model proteins, such as cytochrome c and ribonuclease A, identified a limited number of peptide cross-links that are biased toward only a few of the potentially reactive lysine residues. Here, we report an approach to improve the diversity of intramolecular protein cross-linking starting with a systematic quantitation of the reactivity of lysine residues of a model protein, bovine cytochrome c. Relative lysine reactivities among the 18 lysine residues of cytochrome c were determined by the ratio of d0 and acetyl-d3 groups at each lysine after partial acetylation with sulfosuccinimidyl acetate followed by denaturation and quantitative acetylation of remaining unmodified lysines with acetic-d6 anhydride. These lysine reactivities were then compared with theoretically derived pKa and relative solvent accessibility surface values. To ascertain if partial N-acetylation of the most reactive lysine residues prior to cross-linking can redirect and increase the observable Lys-Lys cross-links, partially acetylated bovine cytochrome c was cross-linked with the amine-specific, bis-functional reagent, bis(sulfosuccinimidyl)suberate. After proteolysis and mass spectrometry analysis, partial acetylation was shown to significantly increase the number of observable peptides containing Lys-Lys cross-links, shifting the pattern from the most reactive lysine residues to less reactive ones. More importantly, these additional cross-linked peptides contained novel Lys-Lys cross-link information not seen in the non-acetylated protein and provided additional distance constraints that were consistent with the crystal structure and facilitated the identification of the proper protein fold.     

Posttraumatic stress disorder and anxious and fearful reactivity to bodily arousal: A test of the mediating role of nicotine withdrawal severity among daily smokers in 12-hr nicotine deprivation.

Posttraumatic stress disorder (PTSD) is associated with high rates of smoking and fear of bodily perturbation. The current study examined the role of nicotine withdrawal in the association between PTSD and responding to bodily arousal among 52 participants (27 women; Mage = 30.50 years). Compared to participants without current axis I psychopathology, persons with current PTSD responded to a 3-min voluntary hyperventilation procedure with greater increases in anxiety and more intense cognitive and physical panic symptoms, despite no group differences in physiological arousal. Nicotine withdrawal demonstrated significant mediational effects in the relations between diagnostic group and panic symptoms elicited by the hyperventilation procedure. Findings suggest nicotine withdrawal is an important factor to consider in terms of better understanding the nature of fear responding to bodily sensations among persons with PTSD. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Energy Absorption Characteristics of Web-Core Sandwich Composite Panels Subjected to Drop-Weight Impact

The objective of the study was to characterise the energy absorption of composite panels with tied cores, subjected to a drop weight impact test. Numerical simulations based on explicit finite element analysis have successfully modelled low velocity impact tests carried out on sandwich panels with web-core structure and plastic foam. The numerical model has been validated in terms of the failure behaviour of the panel and the variation of the contact force after the initial peak load corresponding to flexural failure. The numerical model is used for a better interpretation of the test results and of the failure mechanisms within the structure. The contribution to the overall energy absorption of the different parts composing the panels has been studied, with the aim of evaluating the feasibility of using low density foam in combination with web-core reinforcement in structural applications.     

Linear and nonlinear reconstruction for optical tomography of phantoms with nonscattering regions

Most research in optical imaging incorrectly assumes that light transport in nonscattering regions in the head may be modeled by use of the diffusion approximation. The effect of this assumption is examined in a series of experiments on tissue-equivalent phantoms. Images from cylindrical and head-shaped phantoms with and without clear regions [simulating the cerebrospinal fluid (CSF) filled ventricles] and a clear layer (simulating the CSF layer surrounding the brain) are reconstructed with linear and nonlinear reconstruction techniques. The results suggest that absorbing and scattering perturbations can be identified reliably with nonlinear reconstruction methods when the clear regions are also present in the reference data but that the quality of the image degrades considerably if the reference data does not contain these features. Linear reconstruction performs similarly to nonlinear reconstruction, provided the clear regions are present in the reference data, but otherwise linear reconstruction fails. This study supports the use of linear reconstruction for dynamic imaging but suggests that, in all cases, image quality is likely to improve if the clear regions are modeled correctly.     

Color-Matching Functions: A Set of Transformations with Essentially Single Maximums

A set of essentially single-maximum, minimal-overlap color-matching fnctions without negative portions has been developed. Transformation matrices defining conversion from the CIE standard 2° and supplementary standard 10° observers are proposed. The merits of various conversions are discussed.