Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID50 of 25 mu mol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 mu M). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G*) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1: 1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

Model-based life cycle cost and assessment tool for sustainable building design decision

There is a growing concern in reducing greenhouse gas emissions all over the world. The U.K. has set 34% target reduction of emission before 2020 and 80% before 2050 compared to 1990 recently in Post Copenhagen Report on Climate Change. In practise, Life Cycle Cost (LCC) and Life Cycle Assessment (LCA) tools have been introduced to construction industry in order to achieve this such as. However, there is clear a disconnection between costs and environmental impacts over the life cycle of a built asset when using these two tools. Besides, the changes in Information and Communication Technologies (ICTs) lead to a change in the way information is represented, in particular, information is being fed more easily and distributed more quickly to different stakeholders by the use of tool such as the Building Information Modelling (BIM), with little consideration on incorporating LCC and LCA and their maximised usage within the BIM environment. The aim of this paper is to propose the development of a model-based LCC and LCA tool in order to provide sustainable building design decisions for clients, architects and quantity surveyors, by then an optimal investment decision can be made by studying the trade-off between costs and environmental impacts. An application framework is also proposed finally as the future work that shows how the proposed model can be incorporated into the BIM environment in practise.

An economic decision support tool for simulating paratuberculosis control strategies in a UK suckler beef herd

A dynamic, deterministic, economic simulation model was developed to estimate the costs and benefits of controlling Mycobacterium avium subsp. paratuberculosis (Johne's disease) in a suckler beef herd. The model is intended as a demonstration tool for veterinarians to use with farmers. The model design process involved user consultation and participation and the model is freely accessible on a dedicated website. The 'user-friendly' model interface allows the input of key assumptions and farm specific parameters enabling model simulations to be tailored to individual farm circumstances. The model simulates the effect of Johne's disease and various measures for its control in terms of herd prevalence and the shedding states of animals within the herd, the financial costs of the disease and of any control measures and the likely benefits of control of Johne's disease for the beef suckler herd over a 10-year period. The model thus helps to make more transparent the 'hidden costs' of Johne's in a herd and the likely benefits to be gained from controlling the disease. The control strategies considered within the model are 'no control', 'testing and culling of diagnosed animals', 'improving management measures' or a dual strategy of 'testing and culling in association with improving management measures'. An example 'run' of the model shows that the strategy 'improving management measures', which reduces infection routes during the early stages, results in a marked fall in herd prevalence and total costs. Testing and culling does little to reduce prevalence and does not reduce total costs over the 10-year period.

A tool for mapping research skills in undergraduate curricula

There has been considerable interest recently in the teaching of skills to undergraduate students. However, existing methods for collating data on how much, where and when students are taught and assessed skills have often been shown to be time-consuming and ineffective. Here, we outline an electronic research skills audit tool that has been developed to map both transferable and discipline-specific skills teaching and assessment within individual modules, the results of which can be collated and analysed across entire degree programmes. The design and use of the audit tool is described in detail and a bioscience case study is presented to illustrate the types of data that can be collected. The audit tool has been designed as a time-effective way of collecting information on skills teaching and assessment, but also actively encourages staff to reflect on their teaching and learning practices. Conclusions are drawn about the practicalities of using the audit tool and its importance in both curriculum design and as a resource to encourage dialogue with graduate employers.

The potential for high performance design adoption in retail property portfolios

Growing legislative pressures and increasing stakeholder awareness of environmental issues are pushing the property market to consider high-performance, low-impact retail buildings. The office sector is relatively advanced in its apparent appreciation of such buildings; however, the retail sector is slow to recognize these benefits. In exploring the business case for high-performance design adoption in the retail sector, this paper examines the overlaps between office and retail sector benefits and considers the potential benefits peculiar to retailers. Barriers to high-performance design adoption are then addressed through case research, interviews with key representatives from the retail property market and a questionnaire survey of FTSE listed retail company property departments. The paper concludes that information gaps are a significant hindrance to high-performance property development and that they can be reduced, to some extent, by the forthcoming introduction of the BREEAM Retail environmental assessment tool. Copyright © 2003 John Wiley & Sons, Ltd and ERP Environment.

A novel Bayesian approach to drug design with simple and complex enzymes: Use with lens aldehyde dehydrogenase and the glyoxalase pathway

Purpose: Acquiring details of kinetic parameters of enzymes is crucial to biochemical understanding, drug development, and clinical diagnosis in ocular diseases. The correct design of an experiment is critical to collecting data suitable for analysis, modelling and deriving the correct information. As classical design methods are not targeted to the more complex kinetics being frequently studied, attention is needed to estimate parameters of such models with low variance. Methods: We have developed Bayesian utility functions to minimise kinetic parameter variance involving differentiation of model expressions and matrix inversion. These have been applied to the simple kinetics of the enzymes in the glyoxalase pathway (of importance in posttranslational modification of proteins in cataract), and the complex kinetics of lens aldehyde dehydrogenase (also of relevance to cataract). Results: Our successful application of Bayesian statistics has allowed us to identify a set of rules for designing optimum kinetic experiments iteratively. Most importantly, the distribution of points in the range is critical; it is not simply a matter of even or multiple increases. At least 60 % must be below the KM (or plural if more than one dissociation constant) and 40% above. This choice halves the variance found using a simple even spread across the range.With both the glyoxalase system and lens aldehyde dehydrogenase we have significantly improved the variance of kinetic parameter estimation while reducing the number and costs of experiments. Conclusions: We have developed an optimal and iterative method for selecting features of design such as substrate range, number of measurements and choice of intermediate points. Our novel approach minimises parameter error and costs, and maximises experimental efficiency. It is applicable to many areas of ocular drug design, including receptor-ligand binding and immunoglobulin binding, and should be an important tool in ocular drug discovery.

Quantitative comparison between the use of 3D vs 2D visualization tools to present building design proposals to non-spatial skilled end users

Information technology in construction (ITC) has been gaining wide acceptance and is being implemented in the construction research domains as a tool to assist decision makers. Most of the research into visualization technologies (VT) has been on the wide range of 3D and simulation applications suitable for construction processes. Despite its development with interoperability and standardization of products, VT usage has remained very low when it comes to communicating and addressing the needs of building end-users (BEU). This paper argues that building end users are a source of experience and expertise that can be brought into the briefing stage for the evaluation of design proposals. It also suggests that the end user is a source of new ideas promoting innovation. In this research a positivistic methodology that includes the comparison of 3D models and the traditional 2D methods is proposed. It will help to identify "how much", if anything, a non-spatial specialist can gain in terms Of "understanding" of a particular design proposal presented, using both methods.