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This master thesis discusses alternative debt management instruments - GDP-linked bonds. It provides concise characterization of sovereign debt management. Additionally, it discusses traditional derivatives, such as futures, swaps and bonds, from the government's point of view. The main goal of the thesis is to verify whether GDP-linked bonds are suitable for the Czech and Slovak debt management. Ergo, the bonds could smooth the cost of serving the debt. Furthermore, it describes the development of the sovereign debt and risk premium of the government bonds of the Czech and Slovak republics. It tries to find out whether the risk premium of Slovak bonds differed after introduction of euro. Additionally, the thesis analyzes the effect of various country specific variables on the development of the risk premium. The last but not least goal is to support or reject the hypothesis whether the GDP-linked bonds should be appealing to European economic and monetary union as the members has to satisfied Stability and Growth Pact requirements. The conclusion of the thesis is that the hypothesis of positive effect of the GDP-linked bonds on the cost of serving debt is partly rejected in case of the Czech and Slovak republics as well as in the case of European economic and monetary union. Furthermore, the risk...

The thesis describes several means of processing statistical data in the ambience of Linked Data and is in particular focused on the utilization of Data Cube Vocabulary metaformat. Its content offers a description of tools related to analysis and visualization of RDF data not only from the statistical view. An indivisible part of this work is the depiction of the Payola tool on whose development is the author still working on. The outcome of this thesis is mainly proposal and consequential implementation of the system that enables a conversion of RDF data in compliance with the DCV vocabularies. The designed system was implemented and integrated to the Payola application. Several other extensions of the system were also implemented by the author. Within the scope of the implementation process there are mentioned also limitations arising from the integration with Payola. In the conclusion the writer describes a few experiments where some of the chosen datasets were applied to the implemented system. Powered by TCPDF (www.tcpdf.org)

In this deliberately provocative position paper, we claim that ten years into Linked Data there are still (too?) many unresolved challenges towards arriving at a truly machine-readable and decentralized Web of data. We take a deeper look at the biomedical domain - currently, one of the most promising "adopters" of Linked Data - if we believe the ever-present "LOD cloud" diagram. Herein, we try to highlight and exemplify key technical and non-technical challenges to the success of LOD, and we outline potential solution strategies. We hope that this paper will serve as a discussion basis for a fresh start towards more actionable, truly decentralized Linked Data, and as a call to the community to join forces. / Series: Working Papers on Information Systems, Information Business and Operations

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand / Mental retardation (MR) is estimated to affect ~2-3% of the general population and may result from genetic causes and/or environmental causes. X-linked mental retardation (XLMR) is a heterogeneous group of disorders with a broad range of phenotypes and can be classified into syndromic XLMR (S-XLMR) and nonsyndromic XLMR (NS-XLMR) types. A number of X-linked genes have been identified that are associated with the different forms of XLMR. In an attempt to refine the diagnostic service to patients with XLMR, the Division of Human Genetics, Molecular Laboratory at the National Health Laboratory Service (NHLS) has investigated a number of associated X-linked genes. The main objective of this project was to investigate three genes, FMR2, XNP and ARX, associated with NS-XLMR and their contribution to XLMR in the South African (SA) population of MR males. Patients from different ethnic groups, referred to the Division of Human Genetics for fragile X MR syndrome that tested negative for the FMR1 expansion mutation were investigated for mutations in these genes. In addition, a cohort of Black institutionalized males was also investigated. The FMR2 expansion mutation responsible for fragile X E syndrome was not identified in 1194 FMR1 expansion negative MR male patients. FMR2 allele distribution analysis showed that a GCC repeat size of 15 was common in the MR cohort, accounting for 42% of alleles identified. From a total of 210 FMR1 expansion negative MR male subjects screened for mutations in a hotspot region (exons 7, 8 and 9) of the XNP gene, none was found to have a mutation in this region. Two patients from a cohort of 868 FMR1 expansion negative MR males were found to have a mutation in the ARX gene – one patient tested positive for the common 24 bp duplication mutation and a second patient appeared to have a deletion in the region amplified. These results indicate that the FMR2, XNP and ARX genes do not contribute significantly to MR in the SA population. As a result of this study, routine DNA testing for the FMR2 expansion, mutation screening in the hotspot region of the XNP gene and screening for the common 24 bp duplication mutation in the ARX gene in FMR1 expansion negative MR male subjects will not be implemented. A retrospective analysis was also done on 1862 probands referred to the Molecular Genetics Diagnostic service from 1992 to 2009 for fragile X MR syndrome testing. The FMR1 full expansion mutation was detected in 6.2% of probands, higher than reported worldwide figures. FMR1 allele distribution analysis in a cohort of 1184 FMR1 expansion negative MR males showed that 29 CGG repeats was the most frequent repeat size observed, accounting for 32.6% of all alleles in the cohort. The analysis of FMR1 alleles in MR males shows a similar distribution between different ethnic groups and compares well with other reported studies. This study reinforces the presence of fragile X MR syndrome in the SA Black population. Molecular investigations were also undertaken on 3 patients clinically suspected to have X-linked -thalassaemia mental retardation syndrome (ATR-X) and extended family members. Mutations were identified in each of the patients – two patients were found to have a novel mutation in the XNP gene and the third patient had a common XNP mutation. As a result, carrier testing and prenatal diagnosis was made possible in these families. A large family positive for the FMR1 expansion causing fragile X A MR syndrome was investigated. As an incidental finding, 2 females were found to be compound heterozygotes for 2 FMR1 alleles. Extended family members were tested and their FMR1 status was determined. Haplotype analysis was used to track the high-risk X chromosome in the family. As a result of this investigation, females at risk for premature ovarian failure and fragile X tremor ataxia syndrome have been identified. The approach to testing genes implicated in NS-XLMR has to be refined to allow for a cheaper and more efficient alternative. The use of newer techniques such as CGH microarray and MLPA has allowed for better detection of mutations. Delineating the causes of MR and their molecular and cellular consequences will assist families but also provide insight into the mechanisms that are required for the normal development of cognitive functions in humans.

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand / The hepatitis B virus remains a major public health problem even after decades of its discovery. Horizontal transmission during early childhood is the predominant mode of transmission in highly endemic regions such as sub-Saharan Africa. Infection exhibits a wide spectrum of clinical manifestations, from an asymptomatic stage to severe liver disease which may result in hepatocellular carcinoma (HCC). The HBV X protein (HBx) has been implicated in carcinogenesis, which often has a poor prognosis, consequently the use of highly specific monoclonal antibodies (mAbs) directed against HBx in an enzyme-linked immunosorbent assay (ELISA) could lead to early identification of HBV carriers at risk of developing liver cancer. A variety of mixed hybridoma cell cultures secreting anti-HBx antibodies were cloned and sub-cloned by “limiting dilution”. Clonal supernatants were assessed for anti-HBx antibody production by Indirect ELISA and Western/Immunoblotting. Monoclonal antibodies were then characterized according to their relative binding affinity (Indirect ELISA) and relative epitope specificity (Competitive ELISA). One of our monoclonal antibodies was found to bind to the same epitope on HBx as the commercial anti-HBx antibody and with the same high affinity. In the developed Sandwich ELISA, our monoclonal antibody proved effective as the „detecting‟ antibody when the commercial anti-HBx antibody was deployed as the „capture‟ antibody. This Sandwich ELISA will be further developed in our laboratory with the object of applying it to patient sera.

Genus Danio includes zebrafish (Danio rerio) and several other phenotypically diverse species. To understand the history of these species and how they acquired the genetic differences underlying their diverse phenotypes, I performed two phylogenomic studies using Restriction-Site Associated DNA Sequencing and DNA hybridization-based exome enrichment. The results of these studies highlight important methodological considerations applicable to future experiments across taxa. Furthermore, these studies provide detailed understanding of the relationships within Danio including extensive introgression between lineages. The extent of introgression varies across the genome with regions of high recombination at the ends of chromosomes having the most evidence for introgression. Together, this work gives vital insight into the history of a model organism and the evolutionary processes that give rise to phenotypic diversity.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder that results from a mutation of one of two key signaling receptors for the transforming growth factor beta (TGFβ) superfamily: endoglin and activin receptor-like kinase 1 (ALK1). These mutations result in development of HHT Type 1 and HHT Type 2, respectively. Patients suffering from HHT experience spontaneous blood vessel growth that can lead to telangiectasia, arteriovenous malformation (AVM) development, and other related health problems. ALK1 is a serine/threonine kinase receptor found on the cell membrane of endothelial cells. ALK1 and its co-receptor endoglin, are activated by binding to the circulating BMP9 ligand. The ALK1-endoglin-BMP9 complex will then regulate endothelial proliferation by activating the SMAD pathway by phosphorylation. Mutations in the ACVRL1 gene can form a modified ALK1 protein that has a high potential to inhibit this function, causing the hyperproliferation of endothelial cells and the development of AVMs, and ultimately HHT Type 2. It is believed, however unproven, that ALK1 is heavily glycosylated in the extracellular domain. My thesis research was aimed at studying the glycosylation of ALK1 and at exploring the relevance of this glycosylation to the development of HHT. The glycosylation of ALK1 was investigated by using: (i) a computational prediction approach (NetNGlyc 1.0 bioinformatics server), (ii) a glycosylation inhibiting drug (tunicamycin), (iii) an in vitro enzymatic approach of glycosylation breakdown, and (iv) site-directed mutagenesis to identify the ASP residue glycosylated on ALK1. The bioinformatics software NetNGlyc predicted a N-linked glycosylation site on an asparagine (ASN) residue located at position 98 in the extracellular domain of ALK1. I further found that, based on western blot analysis, ALK1 proteins shifted to a lighter molecular weight (5-8 kDa) when treated with tunicamycin, as well as endo H and PNGase F enzymes, which represent two glycosidases able to remove N-linked oligosaccharides on proteins. Western blot analysis also revealed an identical shift in protein size (5-8 kDa) when comparing wild type ALK1 to an asparagine98-to-alanine (N98A) mutant ALK1 construct. The 5-8 kDa shift observed in the drug and enzymatic experiments indicate the removal of a bulky oligosaccharide from the wild type ALK1 protein. This 5-8 kDa shift observed in the mutagenesis experiment indicated that the same oligosaccharide addition could not occur on ALK1 when ASP98 was missing. Thus proving that the asparagine at the 98th position of ALK1 is involved in N-linked glycosylation. These important findings on ALK1 modification offer a greater understanding of the mechanisms behind ALK1 regulation and function, especially its role in controlling angiogenesis. Furthermore, this data provides grounds for further research into the importance of ALK1 glycosylation in the pathogenesis of HHT, as well as the investigation into new treatment regiments.