The structure and function of the human ghrelin receptor

The peptide hormone, ghrelin, exerts its physiological effects through a G-protein-coupled receptor called the ghrelin-R. The ghrelin-R displays a high degree of constitutive activity, signalling through the inositol phosphate pathway in the absence of bound agonist. TMs III and VI have been reported to be central to the activation of Family A GPCRs, with interactions between the two helices stabilising the ground state. During activation conformational rearrangements result in these interactions being broken, with new contacts forming and stabilising the active state. Investigation of the ghrelin-R constitutive activity gives an insight into the mechanisms involved in receptor activation. In this study the role of specific individual residues in the ghrelin-R has been investigated and the effect of disrupting or introducing intramolecular interactions was addressed. Site-directed mutagenesis and functional assays revealed that ghrelin-R constitutive activity can be increased and decreased with mutation of residues within the TM domains, specifically TMs III, VI and VII. The extracellular loops have been found to be involved in ligand binding and activation in a number of Family A GPCRs. The residues within ECL2 of the ghrelin-R were systematically mutated to alanine to determine their role. In particular, one residue, Asn196, was identified as being critical in ghrelin-R function and may be forming stabilising interactions which maintain ghrelin-R constitutive activity. The data presented in this thesis provide an insight into the structure and function of the ghrelin-R and the underlying molecular mechanisms of ghrelin-R constitutive activity.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Exploring illustration styles for materials used in visual resources for people with aphasia

Images are often used in cueing therapy and other kinds of rehabilitation activities for people with an acquired brain injury. This paper presents a small-scale pilot study, which explores the appropriateness of different styles of illustration applied to visual resources used in combination with assistive technologies for people with aphasia. The study is part of a larger multidisciplinary project exploring how assistive technologies can be used to facilitate maximal engagement with rehabilitation and to facilitate communication and reengagement with hobbies and leisure activities. The study explored participants’ preferences and impressions of the materials with a view to informing design choices made for resources developed for the larger project. Three participants with aphasia participated in a focus group in which they were shown examples of materials developed as resources for cueing therapy and lifestyle activities. Four sets of illustrations varying in visual complexity – from icons with no context to illustrations with developed backgrounds – were shown at two sizes (A3 and A4). Participants shared their impressions of ease of use and their preferences for different levels of visual complexity in the illustrations, as well as changes in format and layout (combinations of six, nine and 12 images per board). Based on previous research and existing guidelines for good practice, we had anticipated that participants would find the contextualised examples more meaningful. However, our findings highlighted that participants preferred simple, icon-style illustrations rather than those with contextual detail. Participants’ comments suggested that familiarity with this style of illustration – based on their everyday engagement with mobile interfaces – was a likely explanation for this

Effectiveness of a community group and home based exercise intervention on the maintenance of vertebral body height and prevention of vertebral compression fractures in older adults: The ProAct65+bone study [Abstract]

Effectiveness of a community group and home based exercise intervention on the maintenance of vertebral body height and prevention of vertebral compression fractures in older adults: The ProAct65+bone study [Abstract

Does adherence to falls prevention exercise programmes benefit bone mineral density in older people? The ProAct65+ bone study [abstract]

Does adherence to falls prevention exercise programmes benefit bone mineral density in older people? The ProAct65+ bone study [abstract

Can exercise protect against vertebral deformity? The proact65+bone study [Abstract]

Can exercise protect against vertebral deformity? The proact65+bone study [Abstract

Limits on the ultra-bright Fast Radio Burst population from the CHIME Pathfinder

We present results from a new incoherent-beam Fast Radio Burst (FRB) search on the Canadian Hydrogen Intensity Mapping Experiment (CHIME) Pathfinder. Its large instantaneous field of view (FoV) and relative thermal insensitivity allow us to probe the ultra-bright tail of the FRB distribution, and to test a recent claim that this distribution's slope, $\alpha\equiv-\frac{\partial \log N}{\partial \log S}$, is quite small. A 256-input incoherent beamformer was deployed on the CHIME Pathfinder for this purpose. If the FRB distribution were described by a single power-law with $\alpha=0.7$, we would expect an FRB detection every few days, making this the fastest survey on sky at present. We collected 1268 hours of data, amounting to one of the largest exposures of any FRB survey, with over 2.4\,$\times$\,10$^5$\,deg$^2$\,hrs. Having seen no bursts, we have constrained the rate of extremely bright events to $<\!13$\,sky$^{-1}$\,day$^{-1}$ above $\sim$\,220$\sqrt{(\tau/\rm ms)}$ Jy\,ms for $\tau$ between 1.3 and 100\,ms, at 400--800\,MHz. The non-detection also allows us to rule out $\alpha\lesssim0.9$ with 95$\%$ confidence, after marginalizing over uncertainties in the GBT rate at 700--900\,MHz, though we show that for a cosmological population and a large dynamic range in flux density, $\alpha$ is brightness-dependent. Since FRBs now extend to large enough distances that non-Euclidean effects are significant, there is still expected to be a dearth of faint events and relative excess of bright events. Nevertheless we have constrained the allowed number of ultra-intense FRBs. While this does not have significant implications for deeper, large-FoV surveys like full CHIME and APERTIF, it does have important consequences for other wide-field, small dish experiments

Barriers and facilitators to discontinuing antidepressant use: A systematic review and thematic synthesis.

OBJECTIVE: To explore patient and health professional views and experiences of antidepressant treatment with particular focus on barriers and facilitators to discontinuing use. DESIGN: Systematic review with thematic synthesis DATA SOURCES: MEDLINE, PubMed, Embase, PsycINFO, CINAHL, AMED, Health Management Information Consortium, OpenGrey, and the Networked Digital Library of Theses and Dissertations from inception until February 2017. Updated searches were carried out in July 2018. ELIGIBILITY CRITERIA: Primary studies, published in English, that used qualitative data collection and analysis, and had data on attitudes, beliefs, feelings, perceptions on continuing or discontinuing antidepressant use, of patients (aged 18 or above, who received treatment with antidepressants for at least 6 months) or any health professionals. DATA EXTRACTION: One reviewer extracted data and assessed study quality, which was checked by a second reviewer. FINDINGS: Twenty two papers were included in the review. A thematic synthesis was performed for patient perspectives only, due to insufficient data from a health professional perspective. The thematic synthesis yielded nine themes: (1) psychological and physical capabilities; (2) perception of antidepressants; (3) fears; (4) intrinsic motivators and goals; (5) the Doctor as a navigator to maintenance or discontinuation; (6) perceived cause of depression; (7) aspects of information that support decision-making; (8) significant others - a help or a hindrance; and (9) support from other health professionals. LIMITATIONS: Coding and development of subthemes and themes was performed by one researcher and further developed through discussion between two researchers. CONCLUSIONS: Barriers and facilitators to discontinuing antidepressant use are numerous and complex, and likely to require detailed conversations between patients and their general practitioners (GPs). These conversations are more likely to happen if GPs raise the issue of discontinuation. Further research from a health professional perspective including, but not limited to GPs, is needed

Effectiveness of systematically delivered evidence-based home safety promotion to improve child home safety practices: a controlled before-and-after study

Objective Evaluate the effectiveness of systematically delivered evidence-based home safety promotion for improving child home safety practices.Design Controlled before-and-after study.Setting Nine electoral wards in Nottingham, UK.Participants 361 families with children aged 2–7 months at recruitment living in four intervention wards with high health, education and social need; and 401 in five matched control wards.Intervention Evidence-based home safety promotion delivered by health visiting teams, family mentors and children’s centres including 24 monthly safety messages; home safety activity sessions; quarterly ‘safety weeks’; home safety checklists.Outcomes Primary: composite measure comprising having a working smoke alarm, storing poisons out of reach and having a stairgate. Secondary: other home safety practices; medically attended injuries. Parents completed questionnaires at 12 and 24 months after recruitment plus optional three monthly injury questionnaires.Results At 24 months there was no significant difference between groups in the primary outcome (55.8% vs 48.8%; OR 1.58, 95% CI 0.98 to 2.55) or medically attended injury rates (incidence rate ratio 0.89, 95% CI 0.51 to 1.56), but intervention families were more likely to store poisons safely (OR 1.81, 95% CI 1.06 to 3.07), have a fire escape plan (OR 1.81, 95% CI 1.06 to 3.08), use a fireguard or have no fire (OR 3.17, 95% CI 1.63 to 6.16) and perform more safety practices (β 0.46, 95% CI 0.13 to 0.79).Conclusions Systematic evidence-based home safety promotion in areas with substantial need increases adoption of some safety practices. Funders should consider commissioning evidence-based multicomponent child home safety interventions