The Mechanism of Inhibition of Botulinum Neurotoxin Type A by Two Quinolinol Compounds

Quinolinol-based compounds are a promising starting point for discovery o f effective inhibitors o f the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism o f inhibition by quinolinol compounds facilitate interpretation o f docking data and inhibitor optimization. In this study, a fluorogenic substrate o f BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 uM and 5.8 uM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors o f BoNT/A LC with inhibition constants (KI) 3.2 uM and 6.2 uM for MSU58 and MSU84, respectively. The kinetic rate constant for substrate and inhibitor binding and release were also determined. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding o f the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis

Purine and Pyrimidine Pathways as Antimalarial Targets

Malaria continues to plague the endemic regions of sub-Saharan Africa and Southeast Asia. With the current development of artemisinin resistance and a risk of failure of the current first line therapies, there is a growing need for novel antimalarials. Purine and pyrimidine metabolism in Plasmodium is distinctly different from the human host, making these pathways valid targets for the development of novel antimalarials. Targeting key enzymes in these pathways with transition state analogs has provided high affinity inhibitors. Transition state mimicry can also provide selectivity for the parasite enzymes over the homologous enzymes of the human host. Resistance of Plasmodium parasites to current antimalarials will be compared to resistance development induced by transition state analogs inhibitors, a feature that may contribute to decreased resistance development. Tight binding and specificity of transition state analog inhibitors provide important features for novel antimalaria therapy with low toxicity and prevention of antibiotic resistance

MSFC/EV44 Natural Environment Capabilities

The Natural Environments Branch at Marshall Space Flight Center is an integral part of many NASA satellite and launch vehicle programs, providing analyses of the space and terrestrial environments that are used for program development efforts, operational support, and anomaly investigations. These capabilities include model development, instrument build and testing, analysis of space and terrestrial related data, spacecraft charging anomaly investigations, surface and internal charging modeling, space environment definition, and radiation assessments for electronic parts. All aspects of space and terrestrial design are implemented with the goal of devising missions that are successful from launch to operations in the space environment of LEO, polar, GEO, and interplanetary orbits

Forces Sauces and Eggs for Soldiers: food, nostalgia, and the rehabilitation of the British military

This article identifies, and considers the political implications of, the association of the contemporary British military and British soldiers with nostalgia. This aspect of the discursive project of rehabilitating the British military post-Iraq has not hitherto been theorized. The article analyses a set of exemplifying texts, four military charity food brands (Eggs for Soldiers, Forces Sauces, Red Lion Foods, and Rare Tea Company Battle of Britain Tea) to ask how nostalgic rehabilitation of the British military unfolds at the intersections of militarization, commemoration, and post-2008 “conscience capitalism”. I outline how military charity food brands are a form of “conscience capitalism” through which the perpetuation of militarized logics are produced as a notionally apolitical social “cause”, rendered intelligible within the terms of existing commoditized discourses of post-2008 vintage nostalgia. I then ask what understandings of British soldiers and the British military are constituted within the discourse of nostalgic rehabilitation, and secondly what forms of commemoration are entailed. I argue that a nostalgic generalization of soldiers and the military nullifies the potential unruliness of individual soldiers and obscures the specifics of recent, controversial, wars. Secondly nostalgic civil–military engagement entails a commemorative logic in which forms of quasi-military service are brought into the most banal spaces of everyday civilian life

Discourse and religion in educational practice

Despite the existence of long-held binaries between secular and sacred, private and public spaces, school and religious literacies in many contemporary societies, the significance of religion and its relationship to education and society more broadly has become increasingly topical. Yet, it is only recently that the investigation of the nexus of discourse and religion in educational practice has started to receive some scholarly attention. In this chapter, religion is understood as a cultural practice, historically situated and embedded in specific local and global contexts. This view of religion stresses the social alongside the subjective or experiential dimensions. It explores how through active participation and apprenticeship in culturally appropriate practices and behaviors often mediated intergenerationally and the mobilisation of linguistic and other semiotic resources but also affective, social and material resources, membership in religious communities is constructed and affirmed. The chapter reviews research strands that have explored different aspects of discourse and religion in educational practice as a growing interdisciplinary field. Research strands have examined the place and purpose of religion in general and evangelical Christianity in particular in English Language Teaching (ELT) programmes and the interplay of religion and teaching and learning in a wide range of religious and increasingly secular educational contexts. They provide useful insights for scholars of discourse studies to issues of identity, socialisation, pedagogy and language policy

Contributions of viral and cellular gene products to the pathogenesis and prognosis of aggressive lymphomas

A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of PhilosophyHigh grade aggressive lymphomas have high mortality. By their nature, more than 40% of patients die from these diseases even with the improved treatment strategies currently available for oncology patients. The characteristic feature is that they are functionally heterogeneous and therefore have different biological and molecular signatures which make it difficult for all groups to respond to same line of treatment. Based on the above, I set out to look at the impact of viral and cellular gene products on these groups of diseases: In chapter 3 I developed monoclonal antibodies against HERV‐K10. I subsequently investigated their expressions in aggressive lymphomas including Diffuse Large B‐cell lymphoma, Hodgkin’s lymphoma and Primary CNS lymphomas. I showed HERV‐K10 is expressed in cell lines of aggressive lymphomas, but not in paraffin‐embedded tissues. In chapter 4 I showed that the expression of ATM using immune‐histochemistry techniques in aggressive lymphomas does offer a guide to prognosis and treatment. Nearly 30% of Diffuse Large B‐cell lymphomas express ATM, 55% of Hodgkin’s lymphomas and more than 80% of Primary CNS lymphomas. I also showed there is a correlation of ATM expression and EBV‐driven aggressive lymphomas and that this has a poor prognostic significance. Chapter 5 analysed the results obtained by generating, validating and evaluating data base of DLBCL and PCNSL from a retrospective cohort over a 17‐year period. The results confirmed that prognostic indicators including ATM, S1PR2, Autotaxin and EBV using immuno‐histochemistry techniques help with categorising aggressive lymphomas into different prognostic groups and does influence future management. In summary, my results showed there is a critical place for immuno‐histochemistry techniques in convincingly helping understand the expressions of viral and cellular gene products in aggressive lymphomas and in contributing positively to their management.Cancer Studies, University of Birmingha

Benchmark of countries’ performance in logistics : an approach based on world bank open data

Logistics which can be considered as the science of planning, implementing and controlling the physical flow of materials and goods from point of origin to point of use to meet customer`s need at a profit has become very important in recent times that it now plays a vital role in companies’ performance as well as the economies of nations. One of the attempts to measure logistics performance at national level is the Logistics Performance Index (LPI) published by the World Bank Group. In fact this study dubbed ”Benchmark of countries’ performance in Logistics – an approach based on World Bank Open Data” argues that there is a close relationship between global competitiveness level of a country and its logistics performance level. It discusses some types of Logistics and also aims to analyze the logistics competitiveness of some countries from a national competitiveness perspective using World Bank Open Data. This work sought to compare Logistics Performance Index (LPI) of Ghana and its region as well as Hungary and its region. Finally, the work made use of international score card where six key dimensions (thus Customs, Infrastructure, International shipments, logistics competitiveness, Tracking & tracing and Timeliness) are applied to benchmark countries' performance and also display their derived overall LPI index to discuss Logistic Performance of Hungary together with that of Ghana