Neglected tropical diseases in the genomics era: re-evaluating the impact of new drugs and mass drug administration.

Simon Croft answers Genome Biology's questions on ways to approach neglected tropical diseases in the genomics era, including re-evaluating the impact of new drugs and mass drug administration

Leishmania and other intracellular pathogens: selectivity, drug distribution and PK-PD.

New drugs and treatments for diseases caused by intracellular pathogens, such as leishmaniasis and the Leishmania species, have proved to be some of the most difficult to discover and develop. The focus of discovery research has been on the identification of potent and selective compounds that inhibit target enzymes (or other essential molecules) or are active against the causative pathogen in phenotypic in vitro assays. Although these discovery paradigms remain an essential part of the early stages of the drug R & D pathway, over the past two decades additional emphasis has been given to the challenges needed to ensure that the potential anti-infective drugs distribute to infected tissues, reach the target pathogen within the host cell and exert the appropriate pharmacodynamic effect at these sites. This review will focus on how these challenges are being met in relation to Leishmania and the leishmaniases with lessons learned from drug R & D for other intracellular pathogens

Stochastic models of plant growth and competition

Plants have been observed to show a range of plastic responses to environmental conditions. For example, the abundance and distribution of nutrients, as well as the presence and proximity of local competition, have been seen to result in changes in root proliferation and architecture. However, whilst some species have been witnessed displaying certain responses under given circumstances, experimental evidence suggests that responses to environmental factors can be far from simple, and sometimes counter-intuitive. Plant responses to components of the environment, and the benefit of such responses, are highly context sensitive. This thesis explores some of the real world complexities that result in the observed responses to hierarchical sets of environmental factors, and presents a theoretical model that seeks to elucidate the interplay between different factors and their effects on “optimal” behaviour by both individuals and populations. Starting with a simple one-dimensional model comprising a linearised approximation of a Gompertz growth function with nutrient patch dependent growth, the individual and combined effects of stochasticity in resource and competitor distribution are investigated. Complexity and functionality are progressively built up, with a resource dependent proliferation response, a scaling up into two-dimensions, and finally different intrinsic plant growth strategies trading growth rate against root system efficiency all introduced and investigated. Throughout the work presented in this thesis, complex and subtle behavioural responses and patterns emerge from seemingly simple models. The importance of stochasticity on individual and population level performance is also highlighted, and the results demonstrate the inability for mean-field approximations and expected results to capture the emergent behaviour

Leishmaniasis: new approaches to disease control.

The leishmaniases afflict the world's poorest populations. Among the two million new cases each year in the 88 countries where the disease is endemic (fig 1), it is estimated that 80% earn less than $2 a day. Human infections with Leishmania protozoan parasites, transmitted via the bite of a sandfly, cause visceral, cutaneous, or mucocutaneous leishmaniasis. The global burden of leishmaniasis has remained stable for some years, causing 2.4 million disability adjusted life years (DALYs) lost and 59 000 deaths in 2001. Neglected by researchers and funding agencies, leishmaniasis control strategies have varied little for decades, but in recent years there have been exciting advances in diagnosis, treatment, and prevention. These include an immunochromatographic dipstick for diagnosing visceral leishmaniasis; the licensing of miltefosine, the first oral drug for visceral leishmaniasis; and evidence that the incidence of zoonotic visceral leishmaniasis in children can be reduced by providing dogs with deltamethrin collars. There is also hope that the first leishmaniasis vaccine will become available within a decade. Here we review these developments and identify priorities for research

Noncovalent complexation of amphotericin-B with Poly(α-glutamic acid).

A noncovalent complex of amphotericin B (AmB) and poly(α-glutamic acid) (PGA) was prepared to develop a safe and stable formulation for the treatment of leishmaniasis. The loading of AmB in the complex was in the range of ∼20-50%. AmB was in a highly aggregated state with an aggregation ratio often above 2.0. This complex (AmB-PGA) was shown to be stable and to have reduced toxicity to human red blood cells and KB cells compared to the parent compound; cell viability was not affected at an AmB concentration as high as 50 and 200 μg/mL respectively. This AmB-PGA complex retained AmB activity against intracellular Leishmania major amastigotes in the differentiated THP-1 cells with an EC50 of 0.07 ± 0.03-0.08 ± 0.01 μg/mL, which is similar to Fungizone (EC50 of 0.06 ± 0.01 μg/mL). The in vitro antileishmanial activity of the complex against Leishmania donovani was retained after storage at 37 °C for 7 days in the form of a solution (EC50 of 0.27 ± 0.03 to 0.35 ± 0.04 μg/mL) and for 30 days as a solid (EC50 of 0.41 ± 0.07 to 0.63 ± 0.25 μg/mL). These encouraging results indicate that the AmB-PGA complex has the potential for further development

Modelling collective motion and obstacle avoidance to assess avian collision risk with wind turbines

Hazardous obstacles are a prominent feature of all natural environments and moving animals must demonstrate a robust avoidance response in order to prevent collisions. Whilst the study of collective motion has yielded many models for simulating animal movements, comparatively few have considered interactions with such obstacles. This thesis outlines a framework for incorporating obstacles into existing models of collective motion and uses these models to explore the impact of social interactions on collision risk. The findings presented show that in the case of obstacle avoidance, where navigational information can be contradictory, the collective decisions of homogeneous groups often results in increased collision risk due to contradictory information between individuals. The introduction of heterogeneous social networks, which gives preference to particular individuals, acts as a natural mechanism by which these conflicted decisions may be averted, thereby facilitating coherent avoidance manoeuvres. However, this comes at the cost of cohesion, and groups must balance staying together against the benefits of more effective decision making. The insights provided by models are applied to assess avian collision risk with wind turbines. This is an increasingly important ecological problem and has received wide attention. The difficulties in obtaining accurate empirical data at the individual level require that accurate and robust modelling solutions are developed. The models presented in this thesis provide a powerful tool in which collision risk can be assessed taking into account site- and species-specific factors. The key observation is that both social factors such as flock size, and spatial factors such as array design, significantly affect avoidance rates and consequently collision risk. Therefore the established methods of risk assessment, which assume a general avoidance rate and apply this to each individual independently, are argued to be inadequate

Antiprotozoal glutathione derivatives with flagellar membrane binding activity against T. brucei rhodesiense.

A new series of N-substituted S-(2,4-dinitrophenyl)glutathione dibutyl diesters were synthesized to improve in vitro anti-protozoal activity against the pathogenic parasites Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania donovani. The results obtained indicate that N-substituents enhance the inhibitory properties of glutathione diesters whilst showing reduced toxicity against KB cells as in the cases of compounds 5, 9, 10, 16, 18 and 19. We suggest that the interaction of N-substituted S-(2,4-dinitrophenyl) glutathione dibutyl diesters with T. b. brucei occurs mainly by weak hydrophobic interactions such as London and van der Waals forces. A QSAR study indicated that the inhibitory activity of the peptide is associated negatively with the average number of C atoms, NC and positively to SZX, the ZX shadow a geometric descriptor related to molecular size and orientation of the compound. HPLC-UV studies in conjunction with optical microscopy indicate that the observed selectivity of inhibition of these compounds against bloodstream form T. b. brucei parasites in comparison to L. donovani under the same conditions is due to intracellular uptake via endocytosis in the flagellar pocket