Trypanosoma brucei Glycogen Synthase Kinase-3, A Target for Anti-Trypanosomal Drug Development: A Public-Private Partnership to Identify Novel Leads

Over 60 million people in sub-Saharan Africa are at risk of infection with the parasite Trypanosoma brucei which causes Human African Trypanosomiasis (HAT), also known as sleeping sickness. The disease results in systemic and neurological disability to its victims. At present, only four drugs are available for treatment of HAT. However, these drugs are expensive, limited in efficacy and are severely toxic, hence the need to develop new therapies. Previously, the short TbruGSK-3 short has been validated as a potential target for developing new drugs against HAT. Because this enzyme has also been pursued as a drug target for other diseases, several inhibitors are available for screening against the parasite enzyme. Here we present the results of screening over 16,000 inhibitors of human GSK-3β (HsGSK-3) from the Pfizer compound collection against TbruGSK-3 short. The resulting active compounds were tested for selectivity versus HsGSK-3β and a panel of human kinases, as well as their ability to inhibit proliferation of the parasite in vitro. We have identified attractive compounds that now form potential starting points for drug discovery against HAT. This is an example of how a tripartite partnership involving pharmaceutical industries, academic institutions and non-government organisations such as WHO TDR, can stimulate research for neglected diseases

Research Challenges Involving Coupled Flows in Geotechnical Engineering

Coupled fluid, chemical, heat, and electrical flows are common phenomena that arc relevant to a wide variety of applications in Geotechnical Engineering, including the use of engineered clay barriers for waste containment, electro-osmosis for soil consolidation, highly compacted bentonite buffers for high-level radioactive nuclear waste disposal, and electrokinetics for soil contaminant removal. among others. For all of these applications, a fundamental understanding of coupled flow phenomena is required, including the basis of the various phenomena. the potential effect of the phenomena on fundamental soil behavior, and the applicability of the phenomena in both natural and built environments. This chapter highlights some of the advances over the past approximate three decades, including the effects of osmotic phenomena (chemico-osmosis, electro-osmosis, and thermo-osmosis) on the mechanical behavior of clays, the formulations and measurement of coupled flow phenomena, the distinction between phenomenological and microscopic (physical-based) formalisms, and considerations with respect to both saturated and unsaturated soil conditions. Based on the description of these advances, research challenges pertaining lo the study of coupled flow phenomena for Geotechnical Engineering applications are identified