Selective Orthosteric Free Fatty Acid Receptor 2 (FFA2) Agonists IDENTIFICATION OF THE STRUCTURAL AND CHEMICAL REQUIREMENTS FOR SELECTIVE ACTIVATION OF FFA2 VERSUS FFA3

Free fatty acid receptor 2 (FFA2; GPR43) is a G protein-coupled seven-transmembrane receptor for short-chain fatty acids (SCFAs) that is implicated in inflammatory and metabolic disorders. The SCFA propionate has close to optimal ligand efficiency for FFA2 and can hence be considered as highly potent given its size. Propionate, however, does not discriminate between FFA2 and the closely related receptor FFA3 (GPR41). To identify FFA2-selective ligands and understand the molecular basis for FFA2 selectivity, a targeted library of small carboxylic acids was examined using holistic, label-free dynamic mass redistribution technology for primary screening and the receptor-proximal G protein [S-35] guanosine 5'-(3-O-thio) triphosphate activation, inositol phosphate, and cAMP accumulation assays for hit confirmation. Structure-activity relationship analysis allowed formulation of a general rule to predict selectivity for small carboxylic acids at the orthosteric binding site where ligands with substituted sp(3)-hybridized alpha-carbons preferentially activate FFA3, whereas ligands with sp(2)- or sp-hybridized alpha-carbons prefer FFA2. The orthosteric binding mode was verified by site-directed mutagenesis: replacement of orthosteric site arginine residues by alanine in FFA2 prevented ligand binding, and molecular modeling predicted the detailed mode of binding. Based on this, selective mutation of three residues to their non-conserved counterparts in FFA3 was sufficient to transfer FFA3 selectivity to FFA2. Thus, selective activation of FFA2 via the orthosteric site is achievable with rather small ligands, a finding with significant implications for the rational design of therapeutic compounds selectively targeting the SCFA receptors.

Evolutionary Requirements for Next-Generation Dataflow-Based FPGA System Design

The use of dataflow digital signal processing system modelling
and synthesis techniques has been a fruitful research theme for many years and has yielded many powerful rapid system synthesis and optimisation capabilities. However, recent years have seen the spectrum of languages and techniques splinter in an application specific manner, resulting in an ad-hoc design process which is increasingly dependent on the particular application under development. This poses a major problem for automated toolflows attempting to provide rapid system synthesis for a wide ranges of applications. By analysing a number of dataflow FPGA implementation case studies, this paper shows that despit ethis common traits may be found in current techniques, which fall largely into three classes. Further, it exposes limitations pertaining to their ability to adapt algorith models to implementations for different operating environments and target platforms.

Stereoselective disposition of fluoxetine and norfluoxetine during pregnancy and breast-feeding

To compare the disposition of fluoxetine and norfluoxetine enantiomers in the mother, foetus and infant.

Conversion Ratios, Efficiency and Obfuscation: A Study of the Impact of Changed UK Charity Accounting Requirements on External Stakeholders

Key stakeholders in the UK charity sector have, in recent years, advocated greater accountability for charity performance. Part of that debate has focussed on the use of conversion ratios as indicators of efficiency, with importance to stakeholders being contrasted with charities’ apparent reluctance to report such measures. Whilst, before 2005, conversion ratios could have been computed from financial statements, changes in the UK charity SORP have radically altered the ability of users to do this. This article explores the impact on the visibility of such information through an analysis of the financial statements of large UK charities before and after the 2005 changes. Overall, the findings suggest that, despite the stated intention of increasing transparency in respect of charity costs, the application of the changes has resulted in charities ‘managing’ the numbers and limiting their disclosures, possibly to the detriment of external stakeholders.

Identifying optimal feeding habitat and proposed Marine Protected Areas (pMPAs) for the black-legged kittiwake (Rissa tridactyla) suggests a need for complementary management approaches

Marine Protected Areas (MPAs) are an important conservation tool. For marine predators, recent research has focused on the use of Species Distribution Models (SDMs) to identify proposed sites. We used a maximum entropy modelling approach based on static and dynamic oceanographic parameters to determine optimal feeding habitat for black-legged kittiwakes (Rissa tridactyla) at two colonies during two consecutive breeding seasons (2009 and 2010). A combination of Geographic Positioning System (GPS) loggers and Time-Depth Recorders (TDRs) attributed feeding activity to specific locations. Feeding areas were <30 km from the colony, <40 km from land, in productive waters, 25–175m deep. The predicted extent of optimal habitat declined at both colonies between 2009 and 2010 coincident with declines in reproductive success. Whilst the area of predicted optimal habitat changed, its location was spatially stable between years. There was a close match between observed feeding locations and habitat predicted as optimal at one colony (Lambay Island, Republic of Ireland), but a notable mismatch at the other (Rathlin Island, Northern Ireland). Designation of an MPA at Rathlin may, therefore, be less effective than a similar designation at Lambay perhaps due to the inherent variability in currents and sea state in the North Channel compared to the comparatively stable conditions in the central Irish Sea. Current strategies for designating MPAs do not accommodate likely future redistribution of resources due to climate change. We advocate the development of new approaches including dynamic MPAs that track changes in optimal habitat and non-colony specific ecosystem management.

Diet of Black-legged Kittiwakes (Rissa tridactyla) feeding chicks at two Irish colonies highlights the importance of clupeids

We examined regurgitates from Black-legged Kittiwakes during the early chick-rearing period over two breeding seasons at two colonies in Ireland where diet has not been studied previously. Clupeids were the dominant food source at both colonies, which contrasts with other studies throughout the British Isles that suggest Kittiwakes feed mainly on sandeels during this period. Our study is limited
by sample size and restricted to the early breeding season, but suggests a link between reproductive success and dietary composition which should be investigated further.

Meeting the Requirements of the CDM Regulations: Identification of Critical Success Factors of Small to Medium Sized Contractor’ Compliance in the UK Construction Industry

The Construction Design and Management (CDM) Regulations (2007) is one of the most important set of health and safety regulations in the construction industry today. The aim of this research is to examine critical success factors for CDM compliance in small to medium size contractors in the UK construction industry. The objectives of the research include the identification of critical barriers in doing so along with the identification of success factors where CDM is incorporated. A mixed method approach is adopted in the identification and categorisation of the various factors encompassing a literature review, interviews and questionnaire survey. The key finding which emerge is the lack of knowledge and understanding with regards the CDM regulations with the recommendation to encourage small and medium contractor compliance through illustrating the benefits attainable. The practicality of the research is evident based on the significant uptake in the CDM by larger contractors, yet the research indicates that further insight and guidance is required to educate and inform those working within small to medium sized contractors in the UK. Where such acknowledgement and compliance is adopted, it is envisaged that this sector will benefit from reduced incidents and accidents, increased productivity while ultimately leading to a safer and more productive industry as a whole.

Stock-recruitment relations controlled by feeding interactions alone

Stock-recruitment (S-R) relationships are the centrepiece of fisheries management aimed at achieving maximum sustainable yield (MSY). Here we consider the possibility that the density dependence evident in S-R relations is controlled by feeding interactions alone. We simulate a food-web model with dynamic representations of intra- and interspecific size structure and a linear relation between food intake and hatchling production of adults. Population sizes of individual stocks are modified by imposing additional mortality. The predominant functional forms and the steepness of resulting S-R relationships agree well with observations. We conclude that recruitment is plausibly regulated by feeding interactions alone.

Relationship between genome and epigenome - challenges and requirements for future research

Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level.

Supplementary feeding increases Common Buzzard Buteo buteo productivity but only in poor-quality habitat

Temporal heterogeneity in the effects of food supply during the breeding season on the productivity of the Common Buzzard Buteo buteo was investigated in a supplementary feeding experiment. Pairs were fed artificially (1) before egg-laying, (2) after chicks hatched and (3) continuously throughout the season, and compared with (4) unfed controls. Pairs fed before egg-laying had marginally larger clutches than those not fed, but lay date, egg volume and weight, brood size and hatching success were unaffected. Territorial quality had far greater effects, with pairs nesting in low-quality habitats (bog, scrub and semi-natural grassland) laying later and having lower hatching success, smaller broods and fewer fledglings than those in more productive agricultural landscapes. Supplementary feeding after egg hatching neutralized the negative effect of poor habitat, resulting in fed birds having significantly more fledglings. This study emphasizes the importance of food availability when provisioning chicks in suboptimal habitats and has implications for the success of diversionary feeding in reducing game losses to Buzzards.