Generating a homology model of the human M1 muscarinic receptor and the design of cognate modulators at this locus for the management of Alzheimer’s disease

The link between Alzheimer’s disease and the M1 muscarinic receptor subtypes makes the latter a viable target for modulating the pathogenesis involved in the development of the disease. The aim of this project was to create a novel drug to modulate an in silico-created homology model of the M1 receptor to manage Alzheimer’s disease. The preliminary part of this study involved creation of a homology model of the M1 receptor. This was followed by analysis of the ligandbinding pocket and in silico design of novel molecules capable of modulating this proposed structure. SYBYL-X®, X-SCORE®, LigBuilder®, Visual Molecular Dynamics (VMD), Accelrys® Draw, Accelrys® Discovery Studio 3.5 and the Protein Data Bank were used to generate the results. A homology model for the M1 receptor was created. Analysis of the ligand binding pocket resulted in 12 varying conformers; that with optimal binding affinity was chosen to create a seed. This generated 200 molecules, classified into 12 chemical families, 124 of which were retained due to conformity to Lipinski’s Rules. Highest & lowest-ranked molecules in each chemical family were structurally-analysed, which yielded chemical moieties responsible for optimal chemical binding to the proposed ligand binding pocket. The de novo molecules created and optimized present viable leads for high-throughput screening in subsequent drug-design studies, potentially leading to identification of novel M1 muscarinic receptor subtype modulators for the use in managing Alzheimer’s disease.peer-reviewe

Growing intimate privatepublics: Everyday utopia in the naturecultures of a young lesbian and bisexual women’s allotment

The Young Women’s Group in Manchester is a ‘young women’s peer health project, run by and for young lesbian and bisexual women’, which runs an allotment as one of its activities. At a time when interest in allotments and gardening appears to be on the increase, the existence of yet another community allotment may seem unremarkable. Yet we suggest that this queer allotment poses challenges for conventional theorisations of allotments, as well as for understandings of public and private. In this article we explore how the allotment project might be understood to be intensely engaged in ‘growing intimate publics’, or what we term ‘privatepublics’. These are paradoxical intimacies, privatepublic spaces which are not necessarily made possible in the usual private sphere of domestic homes. Here we focus on the work involved in materialising the allotment, which we understand as a queer privatepublic ‘natureculture’ (Haraway, 2008) which appears as an ‘everyday utopia’ (Cooper, 2014)

Blind Admission? The ability of NSC maths to signal competence in university commerce courses as compared to the former SC Higher Grade maths

Mathematics is an important signal used for admission into commerce courses in South African universities. In 2008 the new National Senior Certificate replaced the former Senior Certificate. This new exam no longer had different grades and thus created a structural break in the ability of the mathematics mark to signal preparedness for university. Although the Department of Education provided a “translation” key between the two Certificates, the University of the Witwatersrand (and other universities) admitted many more students in 2009 that met the entry requirements than previously. However, this cohort has lower average test and exam scores than previous years. This suggests that marks obtained for mathematics in the new National Senior Certificate are inflated when compared to the former Senior Certificate. This paper uses similar tests, for two commerce subjects, written by students in 2008 and 2009 to create a comparison between the mathematics marks under the two different certificates. The results suggest that marks in the range of 40-100% for Higher Grade mathematics for the Senior Certificate are now compressed into the 70-95% range for the new National Senior Certificate. This significantly weakens the ability of the school-leaving mathematics mark to signal the ability of students to cope with first year commerce courses.Mathematics, National Senior Certificate, Economics 1, first year, Commerce courses, South Africa

Climate change mitigation and the age of tourism accommodation buildings: a UK perspective.

notes: Accepted 03/03/2015publication-status: Acceptedtypes: Article"This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Sustainable Tourism on 3 March 2015, available online: http://wwww.tandfonline.com/10.1080/09669582.2015.1027213.”Recent research on climate change mitigation has emphasized decision-making within tourism businesses is vital for sustainable futures. However, there has been little consideration of how the age of buildings and (historic) property frames, modifies or constrains the sector’s response to climate change. Through surveys of accommodation providers in South-West England, this paper explores relationships between property age, energy performance and pro-environmental innovations requiring adjustment to the fabric of buildings. Findings are presented from empirical research with small- and medium-sized tourism enterprises (SMTEs) occupying properties often well over a century old. This paper’s large-scale dataset and series of intensive case-histories demonstrates that property age does not play a straightforward role in encouraging or hindering efforts among accommodation providers to tackle climate change. Some (but not all) businesses with the oldest buildings performed and responded strongest, successfully introducing the latest renewable energy technologies, although adapting older buildings was not without complications and cost implications. Conceptually, this research points to the limits of calls for greater pro-environmental behaviour change without clearer understanding of the contexts and settings in which such behaviour takes place. Its findings are important to heritage based destinations worldwide: accommodation in heritage buildings can be a unique selling point

The influence of alloy composition on the as-cast grain structure in near net shape low-density steels

Low-density steels are considered an attractive potential replacement for conventional steel in industries such as the automotive sector. However, there are several issues that need to be overcome before they become commercially useful grades. A significant constraint is in their processability, for example, a large as-cast grain size means these steels are prone to hot cracking. This paper explores how compositional variations affect the as-cast grain size in 12 low-density steels cast at solidification rates representative of near net shape casting. It is shown that while mushy zone width is a good indicator of the cast grain size, using a mushy zone width from liquidus to 85% solidified fraction gives a better correlation. It was found that the as-cast grain size of a 7 wt-% Al steel can be reduced from 736 to 244 µm through the addition of 1.5 wt-% Si which acts to increase the mushy zone width by 19°C

Energy practices among small- and medium-sized tourism enterprises: a case of misdirected effort?

notes: Published online 18/09/2014publication-status: Publishedtypes: ArticleNOTICE: this is the author’s version of a work that was accepted for publication in Journal of Cleaner Production. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Cleaner Production. doi:10.1016/j.jclepro.2014.09.028Discussion of sustainable tourism has become dominated by the issue of climate change. As a major source of emissions, the tourism sector has a vital role to play in efforts to mitigate the effects of climate change. Within the current body of knowledge and among major policy discourses, the prevailing paradigm has been to encourage action: reduced emissions will follow innovations in managerial practices and the uptake of the latest, most resource-efficient technologies. This paper examines energy practices among small- and medium-sized tourism enterprises (SMTEs), reporting empirical research conducted as part of a five-year programme. Although energy was a significant cost of production, it did not feature prominently in the business administration of most SMTEs. A major knowledge gap was exposed regarding how energy was consumed and administered by individual businesses. The paper argues for a major shift in thinking away from the number of actions as the key success criterion. Action alone is no guarantee of emissions reductions in a sector where growth is the dominant imperative. Instead, a crucial reorientation towards stimulating higher levels of energy literacy among SMTEs is necessary in parallel to rebalancing of attention towards energy generation

Carbon villains? Climate change responses among accommodation providers in historic premises

Copyright © 2016 Taylor & Francis This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Heritage Tourism on 25 September 2015 available online: http://www.tandfonline.com/10.1080/1743873X.2015.1082569Building stock is a major anthropogenic source of emissions contributing to global warming. Older buildings are conventionally portrayed as performing worse environmentally than more recent buildings. For a sector like tourism, which relies heavily on historic building stock, this raises questions about its ability to contribute to emissions reductions moving forward. This paper explores the relationship between the age and environmental performance of historic premises for small accommodation businesses in South West England, first by correlation analysis and then three extensive case-studies. It argues that the failure to integrate heritage buildings in tourism scholarship on climate change is a major lacuna. Empirically, no statistically significant relationship is found between environmental performance and the date when the original premises were first built. Far from being carbon villains, several ccommodation providers in older premises perform very well against environmental benchmarking schemes. Three types of heritage accommodation providers are identified on the basis of their perceived and actual levels of environmental performance. The paper concludes that heritage building stock of itself is no impediment to action on climate change. Guidance to tourism businesses in such properties should make them aware of this, and provide tailored advice to help them realise potential opportunities.Economic and Social Research CouncilEuropean Regional Development Fund (2007-13

Applying a new concept for strategic performance indicators

Performance measurement provides critical information for strategic decision-making about the future of national infrastructure provision. The process of developing appropriate performance indicators must be based on an understanding of the high-level desired outcomes that infrastructure systems are intended to facilitate. These outcomes may be complex and dynamic and vary across the spectrum of infrastructure stakeholders. This paper demonstrates a conceptual process for developing outcome-related performance indicators by using case studies from the UK rail and water sectors. The case studies show that the process can provide an industry-specific picture of desired outcomes across the main stakeholders, together with their dimensions and associated performance indicators (so-called partial indicators). The work highlights potential shortfalls of a sector-by-sector approach to outcome-oriented strategic performance indicators and suggests that further work is required to integrate partial indicators to provide a holistic picture that recognises the contributions often made by a variety of infrastructures to a given high-level desired outcome