The heteromeric 5-HT3A/B receptor:the effect of 5-HT3B subunits on receptor structure and ligand recognition

The 5-HT3 receptors are members of the cys-loop family of ligand-gated ion channels. Two functional subtypes are known, the homomeric 5HT3A and the heteromeric 5HT3A/B receptors, which exhibit distinct biophysical characteristics but are difficult to differentiate pharmacologically. Atomic force microscopy has been used to determine the stoichiometry and architecture of the heteromeric 5HT3A/B receptor. Each subunit was engineered to express a unique C-terminal epitope tag, together with six sequential histidine residues to facilitate nickel affinity purification. The 5-HT3 receptors, ectopically expressed in HEK293 cells, were solubilised, purified and decorated with antibodies to the subunit specific epitope tags. Imaging of individual receptors by atomic force microscopy revealed a pentameric arrangement of subunits in the order BBABA, reading anti-clockwise when viewed from the extracellular face. Homology models for the heteromeric receptor were then constructed using both the electron microscopic structure of the nicotinic acetylcholine receptor, from Torpedo marmorata, and the X-ray crystallographic structure of the soluble acetylcholine binding protein, from Lymnaea stagnalis, as templates. These homology models were used, together with equivalent models constructed for the homomeric receptor, to interpret mutagenesis experiments designed to explore the minimal recognition differences of both the natural agonist, 5-HT, and the competitive antagonist, granisetron, for the two human receptor subtypes. The results of this work revealed that the 5-HT3B subunit residues within the ligand binding site, for both the agonist and antagonist, are accommodating to conservative mutations. They are consistent with the view that the 5-HT3A subunit provides the principal and the 5-HT38 subunit the complementary recognition interactions at the binding interface.

Design and function of trilobite exoskeletons

The fossil arthropod Class Trilobita is characterised by the possession of a highly mineralised dorsal exoskeleton with an incurved marginal flange (doublure). This cuticle is usually the only part of the organism to be preserved. Despite the common occurrence of trilobites in Palaeozoic sediments, the original exoskeletal mineralogy has not been determined previously. Petrographic data involving over seventy trilobite species, ranging in age from Cambrian to Devonian, together with atomic absorption and stable isotope analyses, indicate a primary low-magnesian calcite composition. Trilobite cuticles exhibit a variety of preservational textures which are related to the different diagenetic realms through which they have passed. A greater knowledge of post-depositional processes and the specific features they produce, has enabled post-mortem artefacts to be distinguished from primary cuticular microstructures. Alterations of the cuticle can either enhance or destroy primary features, and their effects are best observed in thin-sections, both under transmitted light and cathodoluminescence. Well-preserved trilobites often retain primary microstructures such as laminations, canals, and tubercles. These have been examined in stained thin-sections and by scanning electron microscopy, from as wide a range of trilobites as possible. Construction of sensory field maps has shown that although the basic organisation of the exoskeleton is the same in all trilobites, the types of microstructures found, and their distribution is species-specific. The composition, microstructure, and architecture of the trilobite exoskeleton have also been studied from a biomechanical viewpoint. Total cuticle thickness, and the relative proportions of the different layers, together with the overall architecture all affected the mechanical properties of the exoskeleton.

Creating innovation in small and medium-sized enterprises:evaluating the short-term effects of the creative credits pilot

This working paper looks at the short-term impact of the Creative Credits pilot scheme which operated in the Manchester City Region in the North West of England from September 2009 to September 2010, and was funded by NESTA, Manchester City Council, the North West Development Agency, the Economic and Social Research Council (ESRC) and the Arts and Humanities Research Council (AHRC). Creative Credits is a business-to-business (B2B) voucher mechanism designed to encourage small and medium-sized enterprises (SMEs) to work innovatively with creative companies. Businesses receive credits worth £4,000, which they must match with at least £1,000, to spend with creative firms on a variety of creative services.

Managing the threat of terrorism in British travel and leisure organizations

Purpose - To study how the threats of terrorism are being handled by a variety of UK companies in the travel and leisure sector in the UK in the post 9/11 era. Design/methodology/approach - A review of the literature of risk management in a world that is perceived to be more risky as a result of the terrorist attacks on the US on 11 September 2001 (9/11) is presented. Describes the application of theories of organizational resilience and institutions to frame an understanding of how managers make sense of terrorism risk and comprehend uncertainty. Reports a qualitative analysis of themes in interviews conducted with 25 managers from 6 unnamed organizations in the aviation industry (3 organizations) and the UK travel and leisure industry (3 organizations), representing a catering supplier, an airport, an airline, a tour company, a convention centre, and an arts and entertainment centre. Findings - The results indicated that the three organizations in the aviation industry prioritize threats from terrorism, whilst the three organizations in the leisure and travel sector do not, suggesting that the managers in the travel and leisure industry apply a probabilistic type of thinking and believe the likelihood of terrorism to be low. Reports that they give precedence to economic concerns and numerous other threats to the industry. Concludes that managers fall prey to the 'ludic fallacy', which conceives all odds as being calculable and hence managers conceive the terrorism risk as low while also expecting institutional factors to pre-empt and control terrorism threats, a reaction which the authors believe to be rather complacent and dangerous. Originality/value - Contributes to the research literature on risk management by revealing the gap in the ability of existing management tools and methodologies to deal with current and uncertain threats facing organizations due to terrorism.

The role of transport and mobility in the health of older people

The world's population is ageing. Older people are healthier and more active than previous generations. Living in a hypermobile world, people want to stay connected to dispersed communities as they age. Staying connected to communities and social networks enables older people to contribute and connect with society and is associated with positive mental and physical health, facilitating independence and physical activity while reducing social isolation. Changes in physiology and cognition associated with later life mean longer journeys may have to be curtailed. A shift in focus is needed to fully explore older people, transport and health; a need to be multidisciplinary in approach and to embrace social sciences and arts and humanities. A need to embrace different types of mobilities is needed for a full understanding of ageing, transport and health, moving from literal or corporeal through virtual and potential to imaginative mobility, taking into account aspirations and emotions. Mobility in later life is more than a means of getting to destinations and includes more affective or emotive associations. Cycling and walking are facilitated not just by improving safety but through social and cultural norms. Car driving can be continued safely in later life if people make appropriate and informed decisions about when and how to stop driving; stringent testing of driver ability and skill has as yet had little effect on safety. Bus use facilitates physical activity and keeps people connected but there are concerns for the future viability of buses. The future of transport may be more community led and involve more sharing of transport modes.