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.

Instrumental Parasites: Interfacing the Fragile and the Robust

The parasitical relationship between the grand piano and the myriad objects used in its preparation as pioneered by John Cage in the late 1940’s is here discussed from a perspective of free improvisation practice. Preparations can be defined as the use of a “non-instrument” object (screws, bolts, rubbers etc…) to alter or modify the behaviour of an instrument or part of an instrument. Although also present in instrumental practices based on the electric guitar or the drum kit, the piano provides a privileged space of exploration given its large‐scale resonant body. It also highlights the transgressive aspect of preparation (the piano to be prepared often belongs to a venue rather than to the pianist herself, hence highlighting relationships of trust, care and respect). Since 2007 I have used a guitar-object (a small wooden board with strings and pick ups) connected to a small amplifier to prepare the grand piano in my free improvisation practice. This paper addresses the different relationships afforded by this type preparation which is characterised by the fact that the object for preparation is in itself an instrument (albeit a simplified one), and the preparation is ephemeral and intrinsic to the performance. The paper also reflects on the process of designing an interface from and for a particular practice and in collaboration with a guitar luthier.

Melt Processing and Properties of Polyamide 6/Graphene Nanoplatelet Composites

Graphene, due to its outstanding properties, has become the topic of much research activity in recent years. Much of that work has been on a laboratory scale however, if we are to introduce graphene into real product applications it is necessary to examine how the material behaves under industrial processing conditions. In this paper the melt processing of polyamide 6/graphene nanoplatelet composites via twin screw extrusion is investigated and structure–property relationships are examined for mechanical and electrical properties. Graphene nanoplatelets (GNPs) with two aspect ratios (700 and 1000) were used in order to examine the influence of particle dimensions on composite properties. It was found that the introduction of GNPs had a nucleating effect on polyamide 6 (PA6) crystallization and substantially increased crystallinity by up to 120% for a 20% loading in PA6. A small increase in crystallinity was observed when extruder screw speed increased from 50 rpm to 200 rpm which could be attributed to better dispersion and more nucleation sites for crystallization. A maximum enhancement of 412% in Young's modulus was achieved at 20 wt% loading of GNPs. This is the highest reported enhancement in modulus achieved to date for a melt mixed thermoplastic/GNPs composite. A further result of importance here is that the modulus continued to increase as the loading of GNPs increased even at 20 wt% loading and results are in excellent agreement with theoretical predictions for modulus enhancement. Electrical percolation was achieved between 10–15 wt% loading for both aspect ratios of GNPs with an increase in conductivity of approximately 6 orders of magnitude compared to the unfilled PA6.

Predictors of numeracy performance in undergraduate psychology, nursing and medical students

Psychology, nursing and medicine are undergraduate degrees that require students to attain a level of numerical competence for graduation. Yet, the numeracy aspect of these courses is often actively disliked and poorly performed. This study's aim was to identify what factors most strongly predict performance in such courses. Three hundred and twenty-five undergraduate students from these three disciplines were given measures of numeracy performance, maths anxiety, maths attitudes and various demographic and educational variables. From these data three separate path analysis models were formed, showing the predictive effects of affective, demographic and educational variables on numeracy performance. Maths anxiety was the strongest affective predictor for psychology and nursing students, with motivation being more important for medical students. Across participant groups, pre-university maths qualifications were the strongest demographic/educational predictor of performance. The results can be used to suggest ways to improve performance in students having difficulty with numeracy-based modules.

Accessory minerals and potentially toxic elements in Tanzanian vermiculites with respect to agricultural applications

The study assessed accessory minerals and metals in Tanzanian vermiculites with respect to their potential suitability for agricultural applications. Mineral and chemical analyses were involved. Pot experiments were also conducted to assess plant uptake of metals from soil with vermiculites. Fibrous sepiolite and amphiboles were minerals of health concern found in some samples. The sepiolite fibers had aspect ratios similar to those of asbestos minerals, which cause respiratory disorders and lung cancer when inhaled and thus pose a potential health risk to animals and humans. The amphibole fibers were thicker than 10 μm and are unlikely to be inhaled. Chromium (Cr) and nickel (Ni) concentrations in some samples were greater than the limits permitted in agricultural soils, but the elements are not highly plant available and do not inhibit the uptake of essential macronutrients. Heating vermiculites at 400-600° C enhanced extractability of Cr and Ni and should preferably be avoided. © Taylor & Francis Group, LLC.

Learning, fatigue and preference formation in discrete choice experiments

While the repeated nature of Discrete Choice Experiments is advantageous from a sampling efficiency perspective, patterns of choice may differ across the tasks, due, in part, to learning and fatigue. Using probabilistic decision process models, we find in a field study that learning and fatigue behavior may only be exhibited by a small subset of respondents. Most respondents in our sample show preference and variance stability consistent with rational pre-existent and
well formed preferences. Nearly all of the remainder exhibit both learning and fatigue effects. An important aspect of our approach is that it enables learning and fatigue effects to be explored, even though they were not envisaged during survey design or data collection.

A Numerical and Experimental Assessment of the Use of a Turbine Utilizing Splitter Blades for an Automotive Variable Geometry Turbocharger

Automotive manufacturers require improved part load engine performance to further improve fuel economy. For a swing vane VGS (Variable Geometry Stator) turbine this means a more closed stator vane, to deal with the low MFRs (Mass Flow Rates), high PRs (Pressure Ratios) and low rotor rotational speeds. During these conditions the turbine is operating at low velocity ratios. As more energy is available at high pressure ratios and during lower turbocharger rotational speeds, a turbine which is efficient at these conditions is desirable. Another key aspect for automotive manufacturers is engine responsiveness. High inertia designs result in “turbo lag” which means an increased time before the target boost pressure is reached. Therefore, designs with improved performance at low velocity ratios, reduced inertia or an increased swallowing capacity are the current targets for turbocharger manufacturers.

To try to meet these design targets a CFD (Computational Fluid Dynamics) study was performed on a turbine wheel using splitter blades. A number of parameters were investigated. These included splitter blade merdional length, blade number and blade angle distribution.

The numerical study was performed on a scaled automotive VGS. Three different stator vane positions have been analysed. A single passage CFD model was developed and used to provide information on the flow features affecting performance in both the stator vanes and turbine.

Following the CFD investigation the design with the best compromise in terms of performance, inertia and increased MFP (Mass Flow Parameter) was selected for manufacture and testing. Tests were performed on a scaled, low temperature turbine test rig. The aerodynamic flow path of the gas stand was the same as that investigated during the CFD. The test results revealed a design which had similar performance at the closed stator vane positions when compared to the baseline wheel. At the maximum MFR stator vane condition a drop of −0.6% pts in efficiency was seen. However, 5.5% increase in MFP was obtained with the additional benefit of a drop in rotor inertia of 3.7%, compared to the baseline wheel.

Still Unequal at Birth: Birth Weight, Socioeconomic Status and Outcomes at Age 9

The prevalence of low birth weight is an important aspect of public health which has been linked to increased risk of infant death, increased cost of care, and a range of later life outcomes. Using data from a new Irish cohort study, I document the relationship between birth weight and socio-economic status. The association of maternal education with birth weight does not appear to be due to the timing of birth or complications during pregnancy, even controlling for a wide range of background characteristics. However, results do suggest intergenerational persistence in the transmission of poor early life conditions. Birth weight predicts a number of outcomes at age 9, including test scores, hospital stays and health. An advantage of the data is that I am able to control for a number of typically unmeasured variables. I determine whether parental investments (as measured by the quality of interaction with the child, parenting style, or school quality) mediate the association between birth weight and later indicators. For test scores, there is evidence of non-linearity, and boys are more adversely affected than girls. I also consider whether there are heterogeneous effects by ability using quantile regression. These results are consistent with a literature which finds that there is a causal relationship between early life conditions and later outcomes.

Empathy in UK pharmacy students: assessing differences by gender, level in the degree programme, part-time employment and medical status

Background: Empathy is an important aspect of patient–healthcare professional interactions.Aims: To investigate whether gender, level in the degree programme, employment and health status affected empathy scores of undergraduate pharmacy students.Method: All undergraduate pharmacy students (n=529) at Queen’s University Belfast were invited via email to completean online validated empathy questionnaire. Empathy scores were calculated and non-parametric tests used to determine associations between factors.Results: Response rate was 60.1% (318/529) and the mean empathy score was 106.19. Scores can range from 20 to 140,with higher scores representing a greater degree of empathy. There was no significant difference between genders (p=0.211). There was a significant difference in scores across the four levels of the programme (p<0.001); scores were lowest at Level 1 and greatest at Level 4 (final year). There were no significant differences in scores for respondents who had a part-time job, a chronic condition, or took regular medication in comparison to those who did not (p=0.028,p=0.880, p=0.456, respectively).Conclusion: A reasonable level of empathy was found relative to other studies; this could be further enhanced at lower levels of the degree pathway.

Organo-mineral complexation alters carbon and nitrogen cycling in stream microbial assemblages

Inland waters are of global biogeochemical importance receiving carbon inputs of ~ 4.8 Pg C y^-1. Of this 12 % is buried, 18 % transported to the oceans, and 70 % supports aquatic secondary production. However, the mechanisms that determine the fate of organic matter (OM) in these systems are poorly defined. One important aspect is the formation of organo-mineral complexes in aquatic systems and their potential as a route for OM transport and burial vs. their use potential as organic carbon (C) and nitrogen (N) sources. Organo-mineral particles form by sorption of dissolved OM to freshly eroded mineral surfaces and may contribute to ecosystem-scale particulate OM fluxes. We tested the availability of mineral-sorbed OM as a C & N source for streamwater microbial assemblages and streambed biofilms. Organo-mineral particles were constructed in vitro by sorption of ¹³C:¹⁵N-labelled amino acids to hydrated kaolin particles, and microbial degradation of these particles compared with equivalent doses of ¹³C:¹⁵N-labelled free amino acids. Experiments were conducted in 120 ml mesocosms over 7 days using biofilms and streamwater sampled from the Oberer Seebach stream (Austria), tracing assimilation and mineralization of ¹³C and ¹⁵N labels from mineral-sorbed and dissolved amino acids.Here we present data on the effects of organo-mineral sorption upon amino acid mineralization and its C:N stoichiometry. Organo-mineral sorption had a significant effect upon microbial activity, restricting C and N mineralization by both the biofilm and streamwater treatments. Distinct differences in community response were observed, with both dissolved and mineral-stabilized amino acids playing an enhanced role in the metabolism of the streamwater microbial community. Mineral-sorption of amino acids differentially affected C & N mineralization and reduced the C:N ratio of the dissolved amino acid pool. The present study demonstrates that organo-mineral complexes restrict microbial degradation of OM and may, consequently, alter the carbon and nitrogen cycling dynamics within aquatic ecosystems.

The interplay between clathrin-coated vesicles and cell signalling

Internalization of cargo proteins and lipids at the cell surface occurs in both a constitutive and signal-regulated manner through clathrin-mediated and other endocytic pathways. Clathrin-coated vesicle formation is a principal uptake route in response to signalling events. Protein-lipid and protein-protein interactions control both the targeting of signalling molecules and their binding partners to membrane compartments and the assembly of clathrin coats. An emerging aspect of membrane trafficking research is now addressing how signalling cascades and vesicle coat assembly and subsequently disassembly are integrated.

Glacial cirques as palaeoenvironmental indicators: their potential and limitations

Glacial cirques are armchair-shaped erosional hollows, typified by steep headwalls and, often, overdeepened floors. They reflect former regions of glacier initiation, and their distribution is, therefore, linked to palaeoclimate. Because of this association, cirques can be analysed for the information they provide about past environments, an approach that has a strong heritage, and has seen resurgence over recent years. This paper provides a critical assessment of what cirques can tell us about past environments, and considers their reliability as palaeoenvironmental proxies. Specific focus is placed on information that can be obtained from consideration of cirque distribution, aspect, altitude, and morphometry. The paper highlights the fact that cirques potentially provide information about the style, duration and intensity of former glaciation, as well as information about past temperatures, precipitation gradients, cloud-cover and wind directions. In all, cirques are considered a valuable source of palaeoenvironmental information (if used judiciously), particularly as they are ubiquitous within formerly glaciated mountain ranges globally, thus making regional or even global scale studies possible. Furthermore, cirques often occupy remote and inaccessible regions where other palaeoenvironmental proxies may be limited or lacking.

An evaluation of palliative care services for cancer patients in the Southern Health and Social Services Board of Northern Ireland.

An interview study of 55 lay carers of people who died from cancer in the Southern Board of Northern Ireland was undertaken using a combination of closed-format and open-ended questions. The aim of the study was to evaluate palliative care services delivered in the last six months of their lives to cancer patients who died either at home or in hospital. Two-thirds of the deaths (36) occurred in the domestic home, 45 of the deceased were admitted as hospital inpatients, and the great majority were in receipt of community nursing (53) and general practitioner (54) services. Open-ended questions were used to allow respondents to give their views about services in some detail and their views about good and bad aspects of services were sought. While they were generally satisfied with services specific areas of difficulty were identified in each aspect of care addressed by the study. The most favourable assessments were made of community nursing with the greatest number of negative comments being made about inpatient hospital care. Differing interests between some of those who were dying and their lay carers were found in two areas: the receipt of help from nonfamily members and the information that the deceased received about their terminal status.

Factors that impact on the use of mechanical ventilation weaning protocols in critically ill adults and children: a qualitative-evidence synthesis

Background:
Prolonged mechanical ventilation is associated with a longer intensive care unit (ICU) length of stay and higher mortality. Consequently, methods to improve ventilator weaning processes have been sought. Two recent Cochrane systematic reviews in ICU adult and paediatric populations concluded that protocols can be effective in reducing the duration of mechanical ventilation, but there was significant heterogeneity in study findings. Growing awareness of the benefits of understanding the contextual factors impacting on effectiveness has encouraged the integration of qualitative evidence syntheses with effectiveness reviews, which has delivered important insights into the reasons underpinning (differential) effectiveness of healthcare interventions.

Objectives:
1. To locate, appraise and synthesize qualitative evidence concerning the barriers and facilitators of the use of protocols for weaning critically-ill adults and children from mechanical ventilation;

2. To integrate this synthesis with two Cochrane effectiveness reviews of protocolized weaning to help explain observed heterogeneity by identifying contextual factors that impact on the use of protocols for weaning critically-ill adults and children from mechanical ventilation;

3. To use the integrated body of evidence to suggest the circumstances in which weaning protocols are most likely to be used.

Search methods:
We used a range of search terms identified with the help of the SPICE (Setting, Perspective, Intervention, Comparison, Evaluation) mnemonic. Where available, we used appropriate methodological filters for specific databases. We searched the following databases: Ovid MEDLINE, Embase, OVID, PsycINFO, CINAHL Plus, EBSCOHost, Web of Science Core Collection, ASSIA, IBSS, Sociological Abstracts, ProQuest and LILACS on the 26th February 2015. In addition, we searched: the grey literature; the websites of professional associations for relevant publications; and the reference lists of all publications reviewed. We also contacted authors of the trials included in the effectiveness reviews as well as of studies (potentially) included in the qualitative synthesis, conducted citation searches of the publications reporting these studies, and contacted content experts.

We reran the search on 3rd July 2016 and found three studies, which are awaiting classification.

Selection criteria:
We included qualitative studies that described: the circumstances in which protocols are designed, implemented or used, or both, and the views and experiences of healthcare professionals either involved in the design, implementation or use of weaning protocols or involved in the weaning of critically-ill adults and children from mechanical ventilation not using protocols. We included studies that: reflected on any aspect of the use of protocols, explored contextual factors relevant to the development, implementation or use of weaning protocols, and reported contextual phenomena and outcomes identified as relevant to the effectiveness of protocolized weaning from mechanical ventilation.

Data collection and analysis:
At each stage, two review authors undertook designated tasks, with the results shared amongst the wider team for discussion and final development. We independently reviewed all retrieved titles, abstracts and full papers for inclusion, and independently extracted selected data from included studies. We used the findings of the included studies to develop a new set of analytic themes focused on the barriers and facilitators to the use of protocols, and further refined them to produce a set of summary statements. We used the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) framework to arrive at a final assessment of the overall confidence of the evidence used in the synthesis. We included all studies but undertook two sensitivity analyses to determine how the removal of certain bodies of evidence impacted on the content and confidence of the synthesis. We deployed a logic model to integrate the findings of the qualitative evidence synthesis with those of the Cochrane effectiveness reviews.

Main results:
We included 11 studies in our synthesis, involving 267 participants (one study did not report the number of participants). Five more studies are awaiting classification and will be dealt with when we update the review.

The quality of the evidence was mixed; of the 35 summary statements, we assessed 17 as ‘low’, 13 as ‘moderate’ and five as ‘high’ confidence. Our synthesis produced nine analytical themes, which report potential barriers and facilitators to the use of protocols. The themes are: the need for continual staff training and development; clinical experience as this promotes felt and perceived competence and confidence to wean; the vulnerability of weaning to disparate interprofessional working; an understanding of protocols as militating against a necessary proactivity in clinical practice; perceived nursing scope of practice and professional risk; ICU structure and processes of care; the ability of protocols to act as a prompt for shared care and consistency in weaning practice; maximizing the use of protocols through visibility and ease of implementation; and the ability of protocols to act as a framework for communication with parents.

Authors' conclusions:
There is a clear need for weaning protocols to take account of the social and cultural environment in which they are to be implemented. Irrespective of its inherent strengths, a protocol will not be used if it does not accommodate these complexities. In terms of protocol development, comprehensive interprofessional input will help to ensure broad-based understanding and a sense of ‘ownership’. In terms of implementation, all relevant ICU staff will benefit from general weaning as well as protocol-specific training; not only will this help secure a relevant clinical knowledge base and operational understanding, but will also demonstrate to others that this knowledge and understanding is in place. In order to maximize relevance and acceptability, protocols should be designed with the patient profile and requirements of the target ICU in mind. Predictably, an under-resourced ICU will impact adversely on protocol implementation, as staff will prioritize management of acutely deteriorating and critically-ill patients.

Integrating personality research and animal contest theory:Aggressiveness in the green swordtail xiphophorus helleri

Aggression occurs when individuals compete over limiting resources. While theoretical studies have long placed a strong emphasis on context-specificity of aggression, there is increasing recognition that consistent behavioural differences exist among individuals, and that aggressiveness may be an important component of individual personality. Though empirical studies tend to focus on one aspect or the other, we suggest there is merit in modelling both within- and among-individual variation in agonistic behaviour simultaneously. Here, we demonstrate how this can be achieved using multivariate linear mixed effect models. Using data from repeated mirror trials and dyadic interactions of male green swordtails, Xiphophorus helleri, we show repeatable components of (co)variation in a suite of agonistic behaviour that is broadly consistent with a major axis of variation in aggressiveness. We also show that observed focal behaviour is dependent on opponent effects, which can themselves be repeatable but were more generally found to be context specific. In particular, our models show that within-individual variation in agonistic behaviour is explained, at least in part, by the relative size of a live opponent as predicted by contest theory. Finally, we suggest several additional applications of the multivariate models demonstrated here. These include testing the recently queried functional equivalence of alternative experimental approaches, (e.g., mirror trials, dyadic interaction tests) for assaying individual aggressiveness. © 2011 Wilson et al.