The Heme Biosynthetic Pathway of the Obligate Wolbachia Endosymbiont of Brugia malayi as a Potential Anti-filarial Drug Target

Human filarial nematodes are causative agents of elephantiasis and African river blindness, which are among the most debilitating tropical diseases. Currently used drugs mainly affect microfilariae (mf) and have less effect on adult filarial nematodes, which can live in the human host for more than a decade. Filariasis drug control strategy relies on recurrent mass drug administration for many years. Development of novel drugs is also urgently needed due to the threat of drug resistance occurrence. Most filarial worms harbor an obligate endosymbiotic bacterium, Wolbachia, whose presence has been identified as a potential drug target. Comparative genomics had suggested Wolbachia heme biosynthesis as a potential drug target, and we present an analysis of selected enzymes alongside their human homologues from several different aspects—gene phylogenetic analyses, in vitro enzyme kinetic and inhibition assays and heme-deficient E. coli complementation assays. We also conducted ex vivo Brugia malayi viability assays using heme pathway inhibitors. These experiments demonstrate that heme biosynthesis could be critical for filarial worm survival and thus is a potential anti-filarial drug target set

Task Models and System Models as a Bridge between HCI and Sofware Engineering

International audienceThis chapter claims that task models per se do not contain sufficient and necessary information to permit automatic generation of interactive systems. Beyond this, we claim that they must not contain sufficient and necessary information otherwise they could no longer be considered as task models. On the contrary we propose a way of exploiting in a synergistic way task models with other models to be built during the development process. This chapter presents a set of tools supporting the development of interactive systems using two different notations. One of these notations called ConcurTaskTree (CTT) is used for task modeling. The other notation called Interactive Cooperative Objects (ICO) is used for system modeling. Even though these two kinds of models represent two different views of the same world (a user interacting with an interactive system), they are built by different people (human factors specialist for the task models and software engineer for the system models) and are used independently. The aim of this chapter is to propose the use of scenarios as a bridge between these two views. On the task modeling side, scenarios are seen as a possible trace of user’s activity. On the system side, scenarios are seen as a trace of user’s actions. This generic approach is presented on a case study in the domain of Air Traffic Control. As both CTT and ICO notations are tool supported (environments are respectively CTTE and PetShop) an integration tool based on this notion of scenarios is presented. Its use on the selected case study is also presented in detail

Noninvasive measurement of diameter changes in the distal abdominal aorta in man

An ultrasound phase-locked, echo-tracking system was used to determine the dynamic properties of the distal abdominal aorta in 10 Caucasian male subjects (mean age, 25 years). Recordings were made at rest and during the blood pressure increase resulting from isometric exercise. The pressure diameter curve was nonlinear with an inflection at about 90-110 mmHg. Above this pressure range, the vessel was stiffer (less compliant), but the pressure diameter relationship was roughly linear above as well as below the inflection. Individual pressure diameter curves showed hysteresis, i.e., the aorta had a smaller diameter during expansion than during retraction at corresponding pressures. The pressure strain elastic modulus (Ep) and stiffness (beta) were at rest [Mean Arterial Pressure (MAP), 81 mmHg] 0.70 10(5) N/m2 and 6.0, respectively. During isometric exercise (MAP, 122 mmHg), Ep increased significantly by 91% and stiffness (beta) nonsignificantly by 27%. The variability of the compliance determinations was 5% when the ultrasonic system was combined with intra-arterial blood pressure measurements and less than 7% when combined with auscultatory blood pressure measurements. It is concluded that the phase-locked, echo-tracking system fulfills clinical requirements for routine measurements of vascular compliance

Metal Ion Selectivity and Substrate Inhibition in the Metal Ion Chelation Catalyzed by Human Ferrochelatase*

Protoporphyrin IX ferrochelatase (EC 4.99.1.1) catalyzes the terminal step in the heme biosynthetic pathway, the insertion of ferrous iron into protoporphyrin IX. Ferrochelatase shows specificity, in vitro, for multiple metal ion substrates and exhibits substrate inhibition in the case of zinc, copper, cobalt, and nickel. Zinc is the most biologically significant of these; when iron is depleted, zinc porphyrins are formed physiologically. Examining the kcat/Kmapp ratios for zinc and iron reveals that, in vitro, zinc is the preferred substrate at all concentrations of porphyrin. This is not the observed biological specificity, where zinc porphyrins are abnormal; these data argue for the existence of a specific iron delivery mechanism in vivo. We demonstrate that zinc acts as an uncompetitive substrate inhibitor, suggesting that ferrochelatase acts via an ordered pathway. Steady-state characterization demonstrates that the apparent kcat depends on zinc and shows substrate inhibition. Although porphyrin substrate is not inhibitory, zinc inhibition is enhanced by increasing porphyrin concentration. This indicates that zinc inhibits by binding to an enzyme-product complex (EZnDIX) and is likely to be the second substrate in an ordered mechanism. Our analysis shows that substrate inhibition by zinc is not a mechanism that can promote specificity for iron over zinc, but is instead one that will reduce the production of all metalloporphyrins in the presence of high concentrations of zinc

Empirical usability testing in a component-based environment : improving test efficiency with component-specific usability measures

This paper addresses the issue of usability testing in a component-based software engineering environment, specifically measuring the usability of different versions of a component in a more powerful manner than other, more holistic, usability methods. Three component-specific usability measures are presented: an objective performance measure, a perceived ease-of-use measure, and a satisfaction measure. The objective performance measure is derived from the message exchange between components recorded in a log file, whereas the other measures are obtained through a questionnaire. The power of the measures was studied in an experimental setting. Eight different prototypes of a mobile telephone were subjected to usability tests, in which 80 subjects participated. Analyses of the statistical power of these measures show that the component-specific performance measure can be more powerful than overall usability measures, which means fewer users are needed in a test