Pharmacogenomic Research in South Africa: Lessons Learned and Future Opportunities in the Rainbow Nation

South Africa, like many other developing countries, stands to benefit from novel diagnostics and drugs developed by pharmacogenomics guidance due to high prevalence of disease burden in the region. This includes both communicable (e.g., HIV/AIDS and tuberculosis) and non-communicable (e.g., diabetes and cardiovascular) diseases. For example, although only 0.7% of the world’s population lives in South Africa, the country carries 17% of the global HIV/AIDS burden and 5% of the global tuberculosis burden. Nobel Peace Prize Laureate Archbishop Emeritus Desmond Tutu has coined the term Rainbow Nation, referring to a land of wealth in its many diverse peoples and cultures. It is now timely and necessary to reflect on how best to approach new genomics biotechnologies in a manner that carefully considers the public health needs and extant disease burden in the region. The aim of this paper is to document and review the advances in pharmacogenomics in South Africa and importantly, to evaluate the direction that future research should take. Previous research has shown that the populations in South Africa exhibit unique allele frequencies and novel genetic variation in pharmacogenetically relevant genes, often differing from other African and global populations. The high level of genetic diversity, low linkage disequilibrium and the presence of rare variants in these populations question the feasibility of the use of current commercially available genotyping platforms, and may partially account for genotype-phenotype discordance observed in past studies. However, the employment of high throughput technologies for genomic research, within the context of large clinical trials, combined with interdisciplinary studies and appropriate regulatory guidelines, should aid in acceleration of pharmacogenomic discoveries in high priority therapeutic areas in South Africa. Finally, we suggest that projects such as the H3Africa Initiative, the SAHGP and PGENI should play an integral role in the coordination of genomic research in South Africa, but also other African countries, by providing infrastructure and capital to local researchers, as well as providing aid in addressing the computational and statistical bottlenecks encountered at present

Charge Accumulation at a Threading Edge Dislocation in GaN

We have performed Monte Carlo calculations to determine the charge accumulation on threading edge dislocations in GaN as a function of the dislocation density and background dopant density. Four possible core structures have been examined, each of which produces defect levels in the gap and may therefore act as electron or hole traps. Our results indicate that charge accumulation, and the resulting electrostatic interactions, can change the relative stabilities of the different core structures. Structures having Ga and N vacancies at the dislocation core are predicted to be stable under nitrogen-rich and gallium-rich growth conditions, respectively. Due to dopant depletion at high dislocation density and the multitude of charge states, the line charge exhibits complex crossover behavior as the dopant and dislocation densities vary

Displaying desire and distinction in housing

The article discusses the significance of cultural capital for the understanding of the field of housing in contemporary Britain. It explores the relationship between housing and the position of individuals in social space mapped out by means of a multiple correspondence analysis. It considers the material aspects of housing and the changing contexts that are linked to the creation and display of desire for social position and distinction expressed in talk about home decoration as personal expression and individuals' ideas of a `dream house'. It is based on an empirical investigation of taste and lifestyle using nationally representative survey data and qualitative interviews. The article shows both that personal resources and the imagination of home are linked to levels of cultural capital, and that rich methods of investigation are required to grasp the significance of these normally invisible assets to broaden the academic understanding of the field of housing in contemporary culture

Spinal motor neurite outgrowth over glial scar inhibitors is enhanced by coculture with bone marrow stromal cells

Background context Transplantation of bone marrow cells into spinal cord lesions promotes functional recovery in animal models, and recent clinical trials suggest possible recovery also in humans. The mechanisms responsible for these improvements are still unclear. Purpose To characterize spinal cord motor neurite interactions with human bone marrow stromal cells (MSCs) in an in vitro model of spinal cord injury (SCI). Study design/setting Previously, we have reported that human MSCs promote the growth of extending sensory neurites from dorsal root ganglia (DRG), in the presence of some of the molecules present in the glial scar, which are attributed with inhibiting axonal regeneration after SCI. We have adapted and optimized this system replacing the DRG with a spinal cord culture to produce a central nervous system (CNS) model, which is more relevant to the SCI situation. Methods We have developed and characterized a novel spinal cord culture system. Human MSCs were cocultured with spinal motor neurites in substrate choice assays containing glial scar-associated inhibitors of nerve growth. In separate experiments, MSC-conditioned media were analyzed and added to spinal motor neurites in substrate choice assays. Results As has been reported previously with DRG, substrate-bound neurocan and Nogo-A repelled spinal neuronal adhesion and neurite outgrowth, but these inhibitory effects were abrogated in MSC/spinal cord cocultures. However, unlike DRG, spinal neuronal bodies and neurites showed no inhibition to substrates of myelin-associated glycoprotein. In addition, the MSC secretome contained numerous neurotrophic factors that stimulated spinal neurite outgrowth, but these were not sufficient stimuli to promote spinal neurite extension over inhibitory concentrations of neurocan or Nogo-A. Conclusions These findings provide novel insight into how MSC transplantation may promote regeneration and functional recovery in animal models of SCI and in the clinic, especially in the chronic situation in which glial scars (and associated neural inhibitors) are well established. In addition, we have confirmed that this CNS model predominantly comprises motor neurons via immunocytochemical characterization. We hope that this model may be used in future research to test various other potential interventions for spinal injury or disease states

Human mesenchymal stem cells stimulate EaHy926 endothelial cell migration:combined proteomic and in vitro analysis of the influence of donor-donor variability

Mesenchymal stem cells (MSCs) stimulate angiogenesis within a wound environment and this effect is mediated through paracrine interactions with the endothelial cells present. Here we report that human MSC-conditioned medium (n=3 donors) significantly increased EaHy-926 endothelial cell adhesion and cell migration, but that this stimulatory effect was markedly donor-dependent. MALDI-TOF/TOF mass spectrometry demonstrated that whilst collagen type I and fibronectin were secreted by all of the MSC cultures, the small leucine rich proteoglycan, decorin was secreted only by the MSC culture that was least effective upon EaHy-926 cells. These individual extracellular matrix components were then tested as culture substrata. EaHy-926 cell adherence was greatest on fibronectin-coated surfaces with least adherence on decorin-coated surfaces. Scratch wound assays were used to examine cell migration. EaHy-926 cell scratch wound closure was quickest on substrates of fibronectin and slowest on decorin. However, EaHy-926 cell migration was stimulated by the addition of MSC-conditioned medium irrespective of the types of culture substrates. These data suggest that whilst the MSC secretome may generally be considered angiogenic, the composition of the secretome is variable and this variation probably contributes to donor-donor differences in activity. Hence, screening and optimizing MSC secretomes will improve the clinical effectiveness of pro-angiogenic MSC-based therapies

Interference of a Tonks-Girardeau Gas on a Ring

We study the quantum dynamics of a one-dimensional gas of impenetrable bosons on a ring, and investigate the interference that results when an initially trapped gas localized on one side of the ring is released, split via an optical-dipole grating, and recombined on the other side of the ring. Large visibility interference fringes arise when the wavevector of the optical dipole grating is larger than the effective Fermi wavevector of the initial gas.Comment: 7 pages, 3 figure

Adsorption Materials and Processes for Carbon Capture from Gas-Fired Power Plants- AMPGas

Financial support from the EPSRC AMPGas project EP/J0277X/1 is gratefully acknowledgedThe key challenge in postcombustion capture from gas-fired power plants is related to the low CO2 concentration in the flue gas (4–8% by volume). This means that conventional amine processes will result in a relatively high energy penalty, whereas novel adsorbents and adsorption processes have the potential to improve the efficiency of separation. High-selectivity adsorbents are required to achieve relatively high CO2 uptake at low partial pressures, which means that the separation process should be based on either very strong physisorption or chemisorption with thermal regeneration. From the process point of view, the main challenge is to develop efficient separation processes with rapid thermal cycles. In this report we present a detailed overview of the methodology behind the development of novel materials and processes as part of the “Adsorption Materials and Processes for Gas-fired power plants” (AMPGas) project. Examples from a wide variety of materials tested are presented, and the design of an innovative bench-scale 12-column rotary wheel adsorber system is discussed. The strategy to design, characterize, and test novel materials (zeolites, amine-containing MOFs, amine-based silicas, amine-based activated carbons, and carbon nanotubes), specifically designed for CO2 capture from dilute streams is presented.Publisher PDFPeer reviewe

Arctic shipping and polar seaways

Climate change in the Arctic triggered a series of discourses about the opening-up of a previously unreachable region. Navigation remains however difficult in the Arctic, transits are still very limited, as sea-ice still is a major constraint. How did the development policies of both the North West Passage and the Northern Sea Route unfold ? What are the recent trends in Arctic shipping ?

Evaluation of predictive CYP2C19 genotyping assays relative to measured phenotype in a South African cohort

AIM : To align predicted and measured CYP2C19 phenotype in a South African cohort. MATERIALS AND METHODS : Genotyping of CYP2C19*2, *3, *9, *15, *17, *27 and *28 was performed using PCR-RFLP, and an Activity Score (AS) system was used to predict phenotype.True phenotype was measured using plasma concentrations of omeprazole and its metabolite 5’-hydroxyomperazole. RESULTS : Partial genotype-phenotype discrepancies were reported, and an adapted AS system was developed, which showed a marked improvement in phenotype prediction. Results highlight the need for a more comprehensive CYP2C19 genotyping approach to improve prediction of omeprazole metabolism. CONCLUSION : Evidence for the utility of a CYP2C19 AS system is provided, for which the accuracy can be further improved by means of comprehensive genotyping and substrate specific modification.Departments of Pharmacology and Immunology, University of Pretoria; the National Research Foundation of South Africa (NRF) grant numbers FA2006032700005 and TK2006051500005; the National Health Laboratory Services of South Africa (NHLS); the South African Medical Research Council (SAMRC) Extramural Unit for Inflammation and Immunity, and Ampath Laboratories, South Africa.http://www.futuremedicine.com/loi/pgs2016-08-31hb201

Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10-5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use