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

Tartan entrepreneurs : exploring scottish overrepresentation through entrepreneurship in colonial Victoria 1851-1890

This thesis addresses a recurring theme in Scottish historiography – a perceived ‘overrepresentation’ of high achieving Scots throughout the Anglosphere – by means of case studies of selected Scottish-born migrants to colonial Australia. Alternative narratives about socioeconomic entrepreneurship under unfamiliar colonial conditions are developed through an innovative research paradigm, grounded in the radical constructivist theory of Ernst von Glasersfeld. This argues human agency is conditioned by knowledge, constructed from subjective experience of the external world, as a survival mechanism. The overrepresentation claims in the extant literature are conceptualised as cognitive constructs and critiqued as such through this paradigm. Key features of the early nineteenth century zeitgeist are identified to understand influences that shaped the constructed worlds of Scots in that era. These are used in two case studies to interpret the socioeconomic agency of two cohorts of Scottish migrants; the first is a sample of those born in Scotland between 1815 and 1830 and active in colonial Victoria between 1851 and 1890; and the second is a more detailed study of the entrepreneurial activities of five such migrants. The study finds that some specific knowledge and experience domains in which the Scots were prominent in their homeland appear to have remained viable in the Victorian colonial setting. A case is also made that differences between the constructed ‘worldviews’ of the Scots, as an ethnic and cultural minority, from those of the English majority, could be a significant factor in understanding the Scottish overrepresentation phenomenon. In particular, the inherently dissenting nature of Calvinism, and its pre-disposition for ‘improvement’, may have produced a greater appetite for the change and uncertainty inherent in modernity than did conformity with more conservative outlooks, including Anglicanism. Implications are drawn about the viability of the research paradigm as a means of understanding wider socioeconomic phenomenon and potential avenues for further research are identified.Doctor of Philosoph

Njinga

This piece is based upon my experiences over the course of 18 months in Lusaka, Zambia with the Cen- ter for Infectious Disease Research in Zambia (CIDRZ). I worked with patients in HIV/AIDS clinics across the country, coordinating community health initiatives and assisting in small business develop- ment for HIV support groups. In this setting, the limits and discrepancies in access to health care, nutri- tion, employment and education were stark and sobering, but it wasn’t necessary to venture into the heart of a compound to witness the risk factors faced by most Zambians. A simple commute to work was enough to see the effects of poverty and the threat of disease. My work and time in Zambia has im- pressed upon me the importance of understanding a patient’s life and context outside of the clinic, in order to treat them effectively within the clinic

The Court of Justice of the European Communities: The Scope of its Jurisidction and the Evolution of its Case Law under the EEC Treaty

The European Court of Justice, as the sole judicial institution of the European Communities, has evolved into a vigorous body asserting a strong cohesive influence upon the Member States through application of the principles asserted in the Communities\u27 Treaties. In this article, Lord Mackenzie Stuart examines the jurisdiction of the Court in light of recent case law. In particular, Judge MacKenzie Stuart discusses doctrines of jurisdiction adopted by the Court and the application of these doctrines to recent developments involving free movement of goods and of persons within the Communities and other Treaty principles such as equal pay for men and women

The Court of Justice of the European Communities: The Scope of its Jurisidction and the Evolution of its Case Law under the EEC Treaty

The European Court of Justice, as the sole judicial institution of the European Communities, has evolved into a vigorous body asserting a strong cohesive influence upon the Member States through application of the principles asserted in the Communities\u27 Treaties. In this article, Lord Mackenzie Stuart examines the jurisdiction of the Court in light of recent case law. In particular, Judge MacKenzie Stuart discusses doctrines of jurisdiction adopted by the Court and the application of these doctrines to recent developments involving free movement of goods and of persons within the Communities and other Treaty principles such as equal pay for men and women

Communication: Imaging wavefunctions in dissociative photoionization

The dissociative ionization dynamics of excited electronic states of the xenon dimer, Xe2, have been studied using velocity map ion imaging (VMI). A one-colour, (2+1) resonant excitation scheme was employed to first excite and then ionize selected vibrational levels of the Xe2 6p 2[1/2]0 0+g Rydberg state. Cationic fragments were then detected by the VMI. The data provide an outstanding example of the reflection principle in photodissociation with the full nodal structure of the Rydberg state wavefunctions clearly observed in the final Xe+ kinetic energy distributions without the need for scanning the excitation energy. Fitting of the observed distributions provides detailed and precise information on the form of the Xe2+ I(1/2g) potential energy curve involved which is in excellent agreement with the results of photoelectron imaging studies [Shubert and Pratt, J. Chem. Phys. 134, 044315 (2011) ]. Furthermore, the anisotropy of the product angular distributions yields information on the evolution of the electronic character of the ionic state with internuclear separation, R. The combination of the nature of dissociative ionization and the extent of the bound state wavefunctions provide information over an unusually wide range of internuclear separation R (ΔR > 0.75 Å). This would normally require scanning over a considerable energy region but is obtained in these studies at a fixed excitation energy

Species-Specific Activity of HIV-1 Vpu and Positive Selection of Tetherin Transmembrane Domain Variants

Tetherin/BST-2/CD317 is a recently identified antiviral protein that blocks the release of nascent retrovirus, and other virus, particles from infected cells. An HIV-1 accessory protein, Vpu, acts as an antagonist of tetherin. Here, we show that positive selection is evident in primate tetherin sequences and that HIV-1 Vpu appears to have specifically adapted to antagonize variants of tetherin found in humans and chimpanzees. Tetherin variants found in rhesus macaques (rh), African green monkeys (agm) and mice were able to inhibit HIV-1 particle release, but were resistant to antagonism by HIV-1 Vpu. Notably, reciprocal exchange of transmembrane domains between human and monkey tetherins conferred sensitivity and resistance to Vpu, identifying this protein domain as a critical determinant of Vpu function. Indeed, differences between hu-tetherin and rh-tetherin at several positions in the transmembrane domain affected sensitivity to antagonism by Vpu. Two alterations in the hu-tetherin transmembrane domain, that correspond to differences found in rh- and agm-tetherin proteins, were sufficient to render hu-tetherin completely resistant to HIV-1 Vpu. Interestingly, transmembrane and cytoplasmic domain sequences in primate tetherins exhibit variation at numerous codons that is likely the result of positive selection, and some of these changes coincide with determinants of HIV-1 Vpu sensitivity. Overall, these data indicate that tetherin could impose a barrier to viral zoonosis as a consequence of positive selection that has been driven by ancient viral antagonists, and that the HIV-1 Vpu protein has specialized to target the transmembrane domains found in human/chimpanzee tetherin proteins

Benjamin Franklin in Scotland

Benjamin Franklin in Scotlan