GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014

G-protein coupled receptors (GPCRs) are the targets of over half of all prescribed drugs today. The UniProt database has records for about 800 proteins classified as GPCRs, but drugs have only been developed against 50 of these. Thus, there is huge potential in terms of the number of targets for new therapies to be designed. Several breakthroughs in GPCRs biased pharmacology, structural biology, modelling and scoring have resulted in a resurgence of interest in GPCRs as drug targets. Therefore, an international conference, sponsored by the Royal Society, with world-renowned researchers from industry and academia was recently held to discuss recent progress and highlight key areas of future research needed to accelerate GPCR drug discovery. Several key points emerged. Firstly, structures for all three major classes of GPCRs have now been solved and there is increasing coverage across the GPCR phylogenetic tree. This is likely to be substantially enhanced with data from x-ray free electron sources as they move beyond proof of concept. Secondly, the concept of biased signalling or functional selectivity is likely to be prevalent in many GPCRs, and this presents exciting new opportunities for selectivity and the control of side effects, especially when combined with increasing data regarding allosteric modulation. Thirdly, there will almost certainly be some GPCRs that will remain difficult targets because they exhibit complex ligand dependencies and have many metastable states rendering them difficult to resolve by crystallographic methods. Subtle effects within the packing of the transmembrane helices are likely to mask and contribute to this aspect, which may play a role in species dependent behaviour. This is particularly important because it has ramifications for how we interpret pre-clinical data. In summary, collaborative efforts between industry and academia have delivered significant progress in terms of structure and understanding of GPCRs and will be essential for resolving problems associated with the more difficult targets in the future.

Untargeted Metabolomic Analysis of Human Plasma Indicates Differentially Affected Polyamine and L-Arginine Metabolism in Mild Cognitive Impairment Subjects Converting to Alzheimer’s Disease

This study combined high resolution mass spectrometry (HRMS), advanced chemometrics and pathway enrichment analysis to analyse the blood metabolome of patients attending the memory clinic: cases of mild cognitive impairment (MCI; n = 16), cases of MCI who upon subsequent follow-up developed Alzheimer's disease (MCI_AD; n = 19), and healthy age-matched controls (Ctrl; n = 37). Plasma was extracted in acetonitrile and applied to an Acquity UPLC HILIC (1.7μm x 2.1 x 100 mm) column coupled to a Xevo G2 QTof mass spectrometer using a previously optimised method. Data comprising 6751 spectral features were used to build an OPLS-DA statistical model capable of accurately distinguishing Ctrl, MCI and MCI_AD. The model accurately distinguished (R2 = 99.1%; Q2 = 97%) those MCI patients who later went on to develop AD. S-plots were used to shortlist ions of interest which were responsible for explaining the maximum amount of variation between patient groups. Metabolite database searching and pathway enrichment analysis indicated disturbances in 22 biochemical pathways, and excitingly it discovered two interlinked areas of metabolism (polyamine metabolism and L-Arginine metabolism) were differentially disrupted in this well-defined clinical cohort. The optimised untargeted HRMS methods described herein not only demonstrate that it is possible to distinguish these pathologies in human blood but also that MCI patients 'at risk' from AD could be predicted up to 2 years earlier than conventional clinical diagnosis. Blood-based metabolite profiling of plasma from memory clinic patients is a novel and feasible approach in improving MCI and AD diagnosis and, refining clinical trials through better patient stratification.

British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus

These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia.

Haptic Aurality: Listening in a Digital World

I will question modes of listening in network music performance environments, drawing on my experience as a performer listening in these scenarios. I will situate network listening, which I have previously examined as ‘haptic aurality’ (Schroeder, 2009, 2012, 2013) within the context of current music making, and will refer to changes in compositional practices that draw specific attention to listening. I will show that some of these compositional developments play a determining role in articulating a new discourse of listening. French composer Eric Satie’s concept of Furniture Music (in Duckworth, 2005), Pierre Schaeffer’s ideas on reduced listening (1966), Pauline Oliveros’ deep listening practices (2005) as well as digital music platforms all serve to show a development towards a proliferation in listening experiences. I expand this narrative to listening practices in network performance environments, and identify a specific bodily fragility in listening in and to the network. This fragile state of listening and de-centered kind of performative being allow me to draw parallels to the Japanese art form Butoh (Kasai, 1999, 2000; Kasai and Parsons, 2003) and Elaine Scarry’s metaphor of beauty (Scarry, 2001). My own performance experiences, set within the context of several critical texts, allow me to understand network[ed] listening as an ideal corporeal state, which offers a rethinking of linear conceptions of the other and a subject’s own relation with her world. Ultimately, network[ed] listening posits listening as a corporeal and multi-dimensional experience that is continuously being re-shaped by technological, socio-political and cultural concerns.

A cross-sectional study demonstrating increased serum amyloid A-related inflammation in high density lipoproteins from subjects with type 1 diabetes mellitus and how this association was augmented by poor glycaemic control

Inflammatory atherosclerosis is increased in subjects with type 1 diabetes mellitus (T1DM). Normally high-density lipoproteins(HDL) protect against atherosclerosis; however, in the presence of serum amyloid-A- (SAA-) related inflammation this propertymay be reduced. Fasting blood was obtained from fifty subjects with T1DM, together with fifty age, gender and BMI matchedcontrol subjects. HDL was subfractionated into HDL2 and HDL3 by rapid ultracentrifugation. Serum-hsCRP and serum-, HDL2-,and HDL3-SAA were measured by ELISAs. Compared to control subjects, SAA was increased in T1DM subjects, nonsignificantly inserum (P = 0.088), and significantly in HDL2 (P  = 0.003) and HDL3 (P  = 0.005). When the T1DM group were separated accordingto mean HbA1c (8.34%), serum-SAA and HDL3-SAA levels were higher in the T1DM subjects with HbA1c ≥ 8.34%, compared towhen HbA1c was <8.34% (P  < 0.05). Furthermore, regression analysis illustrated, that for every 1%-unit increase in HbA1c, SAAincreased by 20% and 23% in HDL2 and HDL3, respectively, independent of BMI. HsCRP did not differ between groups (P  > 0.05).This cross-sectional study demonstrated increased SAA-related inflammation in subjects with T1DM that was augmented by poorglycaemic control. We suggest that SAA is a useful inflammatory biomarker in T1DM, which may contribute to their increasedatherosclerosis risk.

Northern Ireland: Religion, Religiosity and Politics in a Changing Society

The Handbook of Global Contemporary Christianity: Themes and Developments in Culture, Politics, and Society maps the transformations, as well as the continuities, of the largest of the major religions - engaging with the critical global issues which relate to the faith in a fast changing world. International experts in the area offer contributions focusing on global movements; regional trends and developments; Christianity, the state, politics and polity; and Christianity and social diversity. Collectively the contributors provide a comprehensive treatment of health of the religion as Christianity enters its third millennium in existence and details the challenges and dilemmas facing its various expressions, both old and new. The volume is a companion to the Handbook of Contemporary Global Christianity: Movements, Institutions, and Allegiance.

Cystic Fibrosis Foundation and European Cystic Fibrosis Society Survey of cystic fibrosis mental health care delivery

Background: Psychological morbidity in individuals with cystic fibrosis (CF) and their caregivers is common. The Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) Guidelines Committee on Mental Health sought the views of CF health care professionals concerning mental health care delivery. Methods: An online survey which focused on the current provision and barriers to mental health care was distributed to CF health care professionals. Results: Of the 1454 respondents, many did not have a colleague trained in mental health issues and 20% had no one on their team whose primary role was focused on assessing or treating these issues. Insufficient resources and a lack of competency were reported in relation to mental health referrals. Seventy-three percent of respondents had no experience with mental health screening. Of those who did, they utilized 48 different, validated scales. Conclusions: These data have informed the decision-making, dissemination and implementation strategies of the Mental Health Guidelines Committee sponsored by the CFF and ECFS.

European Cystic Fibrosis Society Standards of Care: Quality Management in cystic fibrosis

Since the earliest days of cystic fibrosis (CF) treatment, patient data have been recorded and reviewed in order to identify the factors that lead to more favourable outcomes. Large data repositories, such as the US Cystic Fibrosis Registry, which was established in the 1960s, enabled successful treatments and patient outcomes to be recognized and improvement programmes to be implemented in specialist CF centres. Over the past decades, the greater volumes of data becoming available through Centre databases and patient registries led to the possibility of making comparisons between different therapies, approaches to care and indeed data recording. The quality of care for individuals with CF has become a focus at several levels: patient, centre, regional, national and international. This paper reviews the quality management and improvement issues at each of these levels with particular reference to indicators of health, the role of CF Centres, regional networks, national health policy, and international data registration and comparisons.