G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target

The orientation of the standard six pupil transferring from primary to secondary schooling

Pupils entering High School for the first time experience many problems of orientation and adjustment. This study arose from the conviction that something could be done to alleviate this time of stress to the benefit of both pupil and school alike. A brief review of literature showed that despite a fair amount of research having been done in Britain and the United States, there is still a dearth of information relating directly to the South African situation. Most transition studies differentiate between factors affecting academic adjustment, those relating to personal adjustment after transfer, and those which involve adjustment to environmental factors. In general studies approached orientation pogrammes from two perspectives - those that handled orientation as an event with its concomitant administrative and practical advantages, and those that saw it to be a process which has more person-focussed advantages. Most researchers agree that each school has its own needs and that the orientation programme should reflect those needs. Many favour a problem-solving approach to the design of any programme and emphasize the need for constant evaluation of the programme to maintain relevance and effectiveness. A low-key investigation into adjustment problems faced by new pupils in the High School was conducted by means of a questionnaire. Three main areas of information were investigated: attitude to school; personal adjustment as indicated by the self-concept; and general impression of Secondary School. The results confirmed that problems of orientation and adjustment are experienced by pupils in the South African Education System and revealed a framework upon which an orientation programme could be based. An overview of existing orientation programme objectives stresses the fact that orientation must be concerned with the total adjustment of the child - personal, academic and environmental - and that, of necessity, it involves the whole family. An orientation programme is outlined and expanded upon in order to provide a framework upon which other programmes could be designed, specific to the particular needs of the schools involved. Finally, certain observations are offered which may lead to a better understanding of the demands of the orientation proces

"The Land Belongs To Those Who Work It": A Critical Evaluation of Land Redistribution Policy in South Africa, 1994-2012

Land ownership in post-apartheid South Africa carries a powerful symbolic charge for both black and white citizens. Under apartheid, state legislation denied black South Africans access to landownership rights, and confined them to 13 per cent of the available agricultural land. The election of the ANC government in 1994 marked the formal end of this process. Policies to provide access to land ownership to black South Africans were developed, raising widespread expectations for radical agrarian reform. The land reform policies of successive post-apartheid governments have, however, been unsuccessful in achieving any significant change to the overall proportions of land owned by black and white farmers, and the small amounts of land that have been transferred have failed to improve the lives of beneficiaries. In fact, the land ownership regime created under apartheid continues unchallenged in the post-apartheid era. This thesis seeks to investigate why successive democratically-elected governments with a mandate for reform have done so little to redress the entrenched inequality in land ownership. Informed by an anti-foundationalist ontology and an interpretive epistemology, this study focuses on processes of institutionalisation as they relate to both patterns of land ownership and the wider institutions of government inherited from the apartheid era that have continued to frame the policy process in South Africa. More specifically, the study adopts a ‘constructivist institutionalist’ approach to capture the way these institutions have been driven by a dominant discourse informed by apartheid-era values. It undertakes a multi-level institutional analysis, seeking to clarify the ideas underpinning the institutions and the discourses influencing the actors at the constitutional, national policy and provincial levels. The research involved examining key constitutional and policy documents and analysing interviews with key policy actors in the Eastern Cape and KwaZulu-Natal provinces. The analysis identifies the international discourses on development and land reform that constructed what South African policymakers understood as ‘possible’ and ‘impossible’ after 1994, and it traces how these discourses went on to inform the development of the property clause in the post-apartheid Constitution. The analysis also reveals how the shifting assumptions, silences and focuses of policymakers implicitly constructed the beneficiaries of such policies – the black landless – as incapable and undeserving. Finally, this study reveals a tacit agreement among the majority of the most powerful stakeholders that land redistribution policy cannot be allowed to fundamentally disturb the agrarian system created by apartheid policies. The research extends understanding of the South African land reform programme by identifying the discourses that inform contemporary policy and practice, with specific focus on the Settlement/Land Acquisition Grant (SLAG) policy, the Land Redistribution for Agricultural Development (LRAD) policy, and the recently adopted Proactive Land Acquisition Strategy (PLAS). There has been little scholarly analysis of PLAS, which seeks to provide leasehold access to approved beneficiaries who have the potential to purchase land at some point in the future. This research deepens scholarly understanding of PLAS, and the way the dominant land reform discourses continue to support the position of white large-scale commercial farmers and the emerging black bourgeoisie, at the expense of the interests and aspirations of the rural landless. It demonstrates why land reform has thus far failed to make meaningful changes to the agrarian system created by apartheid policies, and therefore failed to improve the lives of the rural landless

Non-equivalence of key positively charged residues of the free fatty acid 2 receptor in the recognition and function of agonist versus antagonist ligands

Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled Free Fatty Acid 2 (FFA2) receptor and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabelled FFA2 antagonist in order to probe ligand binding to FFA2 and in combination with mutagenesis and molecular modelling studies define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, while agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor

Strategic learning and teaching enhancement through funded teaching interventions

A case study of the Learning and Teaching Development Fund at University of Glasgow. In order to maintain the pace of learning and teaching development in line with recent changes in the student population (such as demographics, numbers, technological skill level and expectations) it is important for institutions such as Glasgow to support excellent and innovative learning and teaching at strategic levels. Strategic initiatives must be meaningful to encourage the appropriate changes in learning and teaching practices. The University of Glasgow has, since 2000-01, implemented several initiatives to specifically enhance learning and teaching. One of the longest-standing of these is the Learning and Teaching Development Fund (the LTDF). Annual bids are invited from members of staff for projects that aim to enhance learning and teaching and that align with key strategic aims

Mortality and quality of life in the five years after severe sepsis

Peer reviewedPublisher PD

Preparation of zein-based nanoparticles : nanoprecipitation versus microfluidic-assisted manufacture, effects of PEGylation on nanoparticle characteristics and cellular uptake by melanoma cells

Background: The manufacture of nanoparticles using manual methods is hampered by its challenging scaleup and poor reproducibility. To overcome this issue, the production of zein nanoparticles entrapping a lipophilic drug model, coumarin-6, by using a microfluidic system was assessed in this study. The influence of PEG density and chain length on zein nanoparticle characteristics, as well as their uptake efficacy in melanoma cancer cells, was also evaluated. Methods: Zein nanoparticles were prepared by both manual and microfluidic approaches to allow comparison between the two processes. PEGylated zein nanoparticles with various PEG densities and chain lengths were produced by nanoprecipitation and characterized. Their cellular uptake was evaluated on B16F10 melanoma cancer cells in vitro. Results: Zein nanoparticles have successfully been produced by both manual and microfluidic approaches. Parameters such as total flow rate and flow rate ratio of the aqueous and organic phases in microfluidic process, as well as the method preparation and aqueous to organic phase volume ratio during nanoprecipitation, have been shown to strongly influence the characteristics of the resulting nanoparticles. Continuous microfluidics led to the production of nanoparticles with low yield and drug entrapment, unlike nanoprecipitation, which resulted in zein nanoparticles with an appropriate size and an optimal drug entrapment efficiency of 64%. The surface modification of the nanoparticles produced by nanoprecipitation, with lower PEG density and shorter PEG chain length made mPEG5K-zein (0.5:1) the most favorable formulation in our study, resulting in enhanced stability and higher coumarin-6 uptake by melanoma cancer cells. Conclusion: mPEG5K-zein (0.5:1) nanoparticles prepared by nanoprecipitation were the most promising formulation in our study, exhibiting increased stability and enhancing coumarin-6 uptake by melanoma cancer cells

Improving arteriovenous fistula patency : transdermal delivery of diclofenac reduces cannulation-dependent neointimal hyperplasia via AMPK activation

Creation of an autologous arteriovenous fistula (AVF) for vascular access in haemodialysis is the modality of choice. However neointimal hyperplasia and loss of the luminal compartment result in AVF patency rates of ~60% at 12months. The exact cause of neointimal hyperplasia in the AVF is poorly understood. Vascular trauma has long been associated with hyperplasia. With this in mind in our rabbit model of AVF we simulated cannulation autologous to that undertaken in vascular access procedures and observed significant neointimal hyperplasia as a direct consequence of cannulation. The neointimal hyperplasia was completely inhibited by topical transdermal delivery of the non-steroidal anti-inflammatory (NSAID) diclofenac. In addition to the well documented anti-inflammatory properties we have identified novel anti-proliferative mechanisms demonstrating diclofenac increases AMPK-dependent signalling and reduced expression of the cell cycle protein cyclin D1. In summary prophylactic transdermal delivery of diclofenac to the sight of AVF cannulation prevents adverse neointimal hyperplasic remodelling and potentially offers a novel treatment option that may help prolong AVF patency and flow rates