Throwing a chemical spanner in the malaria invasion motor: Interaction and dynamics of the Plasmodium MTIP/MyoA complex

Malaria kills over one million people per year and has devastating social and economic effects on endemic countries. It is caused by the Plasmodium parasite which has a history of developing resistance to anti-malarial drugs, meaning new therapeutics are urgently required. A key event in the Plasmodium life cycle is the invasion of human erythrocytes. The force for this invasion is derived from an actomyosin motor located inside the parasite plasma membrane. This molecular motor consists of a type XIV myosin, Myosin A (MyoA), bound to myosin tail interacting protein (MTIP). The MTIP/MyoA protein-protein interaction is a potential anti-malarial drug target; disruption of this complex should stall erythrocyte invasion and kill the parasite. In the work discussed in this thesis the MyoA tail was mimicked using short chain peptides for the study of MTIP/MyoA binding in vitro. Development of fluorescence assays for the analysis of MyoA peptide binding to MTIP and the screening of potential inhibitors of this complex is described, together with the application of these assays to identify novel binding motifs at the MTIP/MyoA interface. In combination with peptide arrays, these fluorescence assays were also used to investigate MTIP binding to Myosin B (MyoB), another Plasmodium myosin of unknown function. No binding partners of MyoB have yet been identified in vivo, but results reported here show that MTIP can bind MyoB peptides in vitro. CD spectroscopy and protein NMR experiments were used to investigate the structures of MTIP/MyoA and MTIP/MyoB peptide complexes in solution, and indicate that MTIP undergoes a large conformational change upon myosin peptide binding. These structural techniques together with the fluorescence assays provide a platform for future drug discovery efforts targeting MTIP/MyoA. Finally, the information obtained concerning the MTIP/MyoA interaction was used to design and synthesise α-helix mimetic compounds of MyoA. These compounds were examined for inhibition activity against MTIP/MyoA using fluorescence assays, and appear to be able to disrupt MTIP/MyoA complex formation in vitro. This provides a starting point for future anti-malarial drug development and is a further step towards the chemical validation of MTIP/MyoA as a drug target

Synthetic studies directed towards hunanamycin, teixobactin and telomycin antibiotic natural products and their analogues

The emergence of bacteria resistant to all clinically approved antibiotics has led to a worldwide search for new drugs. Without new antibiotics many aspects of modern medicine would become nearly impossible. One possible solution is to use natural products which show antibacterial activity as the starting point for new antibiotics. Sometimes new natural products act upon well-known targets. However, sometimes they will show previously unknown modes of action. One natural product which acts upon a new target is hunanamycin A, a small molecule inhibitor of the riboflavin synthase enzyme, an enzyme not found in mammalian cells. A new synthesis of hunanamycin A has been achieved, using ribose as a starting material. The synthesis can easily be adapted to make new analogues to improve the activity of hunanamycin A. Teixobactin is a macrocyclic lariat depsipeptide showing excellent activity against Gram-positive bacteria, by targeting lipid II and III to prevent cell wall biosynthesis. Teixobactin is made up from a 13 membered depsipeptide macrocycle containing the non-proteinogenic amino acid enduracididine and a seven amino acid linear tail. Arginine was substituted for enduracididine in this research. A combination of solid phase and solution phase synthesis were then used in research towards teixobactin analogues for testing in order to improve the pharmacological properties and understand the structure-activity relationship. Another macrocyclic depsipeptide showing antibacterial activity is telomycin. A combination of solid and solution phase synthesis may also be used to make analogues of telomycin for structure-activity relationship. In summary, synthetic studies based on natural products showing antibacterial activity has been carried out in order to work towards the development of new antibiotics

E-mail archiving for records management

The business of universities is increasingly transacted by email, and the management and preservation of stored email is an important part of an institution’s records management process. Until recently at Loughborough University email was mostly sent from, and received into, email accounts assigned to individuals, and was stored and deleted by these individuals as they saw fit. Stored email was deleted when staff left. It was backed up for business continuity, but backups were kept for a short time, and not for archive purposes. In 2002 the University successfully bid for funding from JISC (Joint Information Systems Committee) under the programme “Study of the Records Lifecycle, specialist electronic studies” for a project to examine institutional email. An overview of the findings of this project is given, along with results of surveys of UK universities in 2003, 2004 and 2006 into their practice in archiving email. In 2006 the University embarked on the process of replacing the staff email system, the intention being to implement email archiving as part of the rollout, drawing on the work of the earlier project which had produced a draft email retention policy for the University. The design of the archiving facility was determined by user consultation and by involving the University senior management in consideration of the risks to being covered. Technical issues to do with the choice of server and supported client platforms also heavily influenced the choice of solution that is now being provided. The University is currently in the early stages of rollout of the email upgrade, and we describe the method we are using to implement the archiving facility

E-mail archiving: all things to all people

Need to preserve selected records in accordance with your retention schedule, remove "old" e-mail from fast storage media, or keep a tamper-proof copy of all e-mail for legal compliance? How do you implement a workable solution that balances risks, is underpinned by policy, and responds to legal, user, and technical pressures

Changing the support model for students’ hardware

In September 2009 Loughborough University launched a PC Clinic service supporting students' own computer hardware. Employing University students for a small number of hours each week to fit around their study commitments, and working in partnership with a local company co-located within the department, the PC Clinic provides initial diagnosis, and either a fix or referral to the hardware support partner which provides a chargeable repair service. The paper will describe the background to the service introduction, practicalities of setting up the PC Clinic, and lessons learnt

Reconstruction of the 1974 flash flood in Sóller (Mallorca) using a hydraulic 1D/2D model

Flash flood events are common in the Mediterranean basin, because of a combination of rugged coastal topography and climatological characteristics. The Balearic Islands are a flood-prone region with the research area, Sóller (Mallorca) being no exception. Between 1900 and 2000, Sóller experienced 48 flash floods with 17 categorised as catastrophic. In Sóller, the local surface water network comprises ephemeral streams. These are natural water networks that only carry water during periods of intense rainfall. Using the available evidence from the 1974 flash flood, this research used Flood Modeller to simulate the event. The research developed a one-dimensional (1D) and a one-dimensional two-dimensional (1D-2D) model that assisted in the understanding of the behaviour of the ephemeral stream during the flood. Analysis of hydraulic parameters such as water flow, depth and velocity provided an appreciation of the interaction between the channel and floodplain. Model development aims to forecast the impending impacts of climate change and urbanisation. The results suggest that the characteristics of Sóller’s catchment area naturally encourage flash flooding and hence can be deemed a flashy catchment. The model demonstrates that the interaction between the channel and floodplain relies heavily on surface roughness of both areas. The model proves that if flood intensity increases with climate change, the extent of flooding and consequently the damage will become more severe

A Lungfish survivor of the end-Devonian extinction and an Early Carboniferous dipnoan radiation.

Until recently the immediate aftermath of the Hangenberg event of the Famennian Stage (Upper Devonian) was considered to have decimated sarcopterygian groups, including lungfish, with only two taxa, Occludus romeri and Sagenodus spp., being unequivocally recorded from rocks of Tournaisian age (Mississippian, Early Carboniferous). Recent discoveries of numerous morphologically diverse lungfish tooth plates from southern Scotland and northern England indicate that at least ten dipnoan taxa existed during the earliest Carboniferous. Of these taxa, only two, Xylognathus and Ballgadus, preserve cranial and post-cranial skeletal elements and are yet to be described. Here we present a description of the skull of a new genus and species of lungfish, Limanichthys fraseri gen. et sp. nov. that hails from the very lowest Tournaisian from the Ballagan Formation of Burnmouth, southern Scotland. The new specimen represents the earliest definitive Tournaisian lungfish skull material thus providing valuable insight into the response of this group, and indeed, the Sarcopterygii as a whole, immediately following the Upper Devonian Hangenberg event. Phylogenetic analysis places Limanichthys fraseri within the Devonian ‘phaneropleurid-fleurantiid’ grade of lungfish and that the Carboniferous lungfish represent forms that have their origins deep in the Mid and Late Devonian as well as those from a unique Carboniferous radiation.This work was carried out with the aid of NERC consortium grants NE/J022713/1 (Cambridge), NE/J020729/1 (Leicester) and NE/J021091/1 (Southampton)

Self-efficacy and work engagement: Test of a chain model

Purpose – This study investigates the mediating roles of work and family demands and work–life balance on the relationship between self-efficacy (to regulate work and life) and work engagement. Specifically, it seeks to explain how self-efficacy influences employees’ thought patterns and emotional reactions, which in turn enable them to cope with work and family demands, and ultimately achieve work–life balance and work engagement. Design/methodology/approach – Structural equation modelling (SEM) of survey data obtained from a heterogeneous sample of 1,010 Australian employees is used to test the hypothesised chain mediation model. Findings – The SEM results support the hypothesised model. Self-efficacy was significantly and negatively related to work and family demands, which in turn were negatively associated with work–life balance. Work–life balance, in turn, enabled employees to be engaged in their work. Research limitations/implications – The findings support the key tenets of social cognitive theory and conservation of resources (COR) theory and demonstrate how self-efficacy can lead to work–life balance and engagement despite the presence of role demands. Study limitations (e.g., cross-sectional research design) and future research directions are discussed. Originality/value – This study incorporates COR theory with social cognitive theory to improve understanding of how self-efficacy enhances work–life balance and work engagement through a self-fulfilling cycle in which employees achieve what they believe they can accomplish, and in the process, build other skills and personal resources to manage work and family challenges.Data collection for this research was supported by the Australian Research Council Discovery Project under Grant DP0770109

Towards Better Sharing of Cultural Heritage -- An Agenda for Copyright Reform

This paper is intended to act as a pillar and reference point for CC's advocacy work in copyright reform in the cultural heritage context, with a focus on issues arising in the digital environment. It may serve to support members of the CC community in their own advocacy efforts, guide policymakers in their legislative processes, and inform anyone interested in the policy issues gravitating around access and reuse of culture and cultural heritage. It will likely be adapted into a GLAM Guide for Policymakers and will be augmented with real-life examples, case studies and practical advice.It starts with an overview of copyright challenges to the legitimate activities of GLAMs, notably preservation (largely through digitization) and sharing of digital and digitized content images and data for access, use and reuse. It also notes copyright's chilling effects in the face of the GLAM sector's general risk aversion. The paper then offers insights towards effective copyright reform addressing those challenges, with a focus on the opportunities related to the digital environment. The proposals for reform aim to create legal certainty and international harmonization as well as to facilitate cross-border transactions.The paper encourages policymakers to recognize and support the pivotal roles of GLAMs in preserving and providing access to knowledge and culture to all members of society. It urges policymakers to engage with stakeholders to ensure there are clear, simple, and effective policies in place to support better sharing of cultural heritage in the public interest.The paper provides a high-level overview of the policy issues and, as a whole, it does not necessarily reflect the current situation in any specific jurisdiction.