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

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Sex and character: an investigation of fundamental principles

No description supplie

The School Psychologist as a Chameleon

No abstract availabl

Play and the Hospitalized Child

Play is the way that children are able to come to terms with reality. Throughplay children are not only able to revise their ideas and actions, but are also able toformulate ways in which they can put these ideas into use. Children who are separated from parents by reason of hospitalization experience severe anxiety and have very limited ways of coping with this painful experience. Play offers a medium through which the child may be able to express and then cope with some of these feelings. Play offers, as well, a window to the examiner, to observe the fright andpain and then, hopefully, provide some relief.Le jeu est la manière dont les enfants sont capables de concevoir la réalité .Par le jeu, les enfants sont non seulement capables de réviser leurs idées et leursactions, mais ils peuvent aussi trouver des moyens de mettre en oeuvre ces idées .Les enfants séparés de leurs parents à cause d'une hospitalisation ressentent une anxiété sévère et ont des moyens très limités de venir à bout de cette expérience douloureuse. Le jeu constitue un moyen par lequel l'enfant peut s'exprimer et ensuite composer avec quelques-uns de ces sentiments. Pour l'observateur, le jeu seprésente aussi comme une occasion d'examiner la peur et la douleur, et ensuite,il faut l'espérer, de pouvoir leur trouver un soulagement