No description available.

Despite the widely hailed success of South Africa’s transition from apartheid to democracy it was apparent by the mid-2000s that beneath the veneer of stability lay a country facing serious social and economic challenges. The employment and labour market participation rates were uniquely low among emerging markets. Protest action against the state had reached levels last encountered in the volatile 1980s and early 1990s. The budget and current account deficits had reached unsustainable levels. By its own admission the government realised that the country was not recording GDP growth rates necessary to make dramatic inroads into poverty, unemployment and inequality levels. A number of analysts and commentators therefore came to question the future stability of South Africa’s political system. Trade unions and some Cabinet ministers routinely described unemployment as a “ticking time bomb”. The Chairman of the Institute of International Affairs wrote in Business Day that he could predict when South Africa’s “Tunisia Day” would arrive. The respected Economist newspaper ran a front page feature on what it called South Africa’s “downhill slide”. Former President FW de Klerk warned that South Africa was approaching a precipice. Clem Sunter, South Africa’s most renowned scenario planner, upped his prospects that South Africa may become a failed state. Global ratings agencies downgraded South Africa citing the fear that government policy could not meet popular demands. Amidst such speculation it is vitally important that the prospects for instability be investigated and determined, not via opinion or speculation, but rather against a sound body of theory. This task is complicated by the fact that the feared instability may only occur at a point in the future. The theory must therefore be applied via a methodology capable of overcoming the weak track record of political science in accurately anticipating major shifts in political systems. This problem statement will be addressed by showing that complex systems theory holds the key to a series of units of analysis via which the stability or instability of any political system can be objectively determined, compared to any other political system, and tracked over time. Secondly that there are scenario planning methodologies that can overcome the uncertainty inherent in the futures of all complex systems and thereby the poor track record that political scientists have in anticipating dramatic future changes in the systems they study. When combined into a single complex systems/scenario model, these theoretical and methodological points of departure will allow the long term prospects for stability or instability of any political system to be accurately and objectively determined. / PhD (Development and Management) North-West University, Potchefstroom Campus, 2013

The global financial crisis has proved to have had a significant impact on countries worldwide and South Africa was not spared of this global phenomenon. The ecological systems theory, family systems theory and gestalt field theory accentuate the impact a change within the environment can have on interconnected systems and it is therefore argued that the global unstable economy can have a significant impact on families and children. Literature indicates a vast amount of confirmation on the impact of the financial crisis on already poverty stricken areas. On the contrary, less focus is offered on the impact of the financial crisis on families within middle to upper class communities. Preliminary research confirms that although the basic needs of these families (such as food and shelter) have not been affected, significant change with regards to luxuries and expenditure patterns is present. Due to the fact that parents within families are also faced with financial difficulties, these changes are not facilitated and discussed with children and adolescents, causing unresolved emotions and uncertainties. This research was therefore aimed at the development of web based assistance for parents. In addition to the set aim of this research, the study arrived at findings that indicate and emphasise the important contribution of this study. Intervention research as research method was used in the conducting of the study. The developed web based assistance proved to serve as a functional tool for parents in addressing financial issues with their children and adolescents. It also raised parents’ awareness of the impact that a change in finances in the family can have which empowered the parents as well. It was also significantly noted that the website can be utilised within an educational setting which enhances the applicability of this study. The developed assistance contributes to society as it serves as a cost effective, accessible means of providing parents with practical guidelines and activities to help their children and adolescents deal with the effects of economic instability within the family. / PhD (Psychology), North-West University, Potchefstroom Campus, 2014

Despite the widely hailed success of South Africa’s transition from apartheid to democracy it was apparent by the mid-2000s that beneath the veneer of stability lay a country facing serious social and economic challenges. The employment and labour market participation rates were uniquely low among emerging markets. Protest action against the state had reached levels last encountered in the volatile 1980s and early 1990s. The budget and current account deficits had reached unsustainable levels. By its own admission the government realised that the country was not recording GDP growth rates necessary to make dramatic inroads into poverty, unemployment and inequality levels. A number of analysts and commentators therefore came to question the future stability of South Africa’s political system. Trade unions and some Cabinet ministers routinely described unemployment as a “ticking time bomb”. The Chairman of the Institute of International Affairs wrote in Business Day that he could predict when South Africa’s “Tunisia Day” would arrive. The respected Economist newspaper ran a front page feature on what it called South Africa’s “downhill slide”. Former President FW de Klerk warned that South Africa was approaching a precipice. Clem Sunter, South Africa’s most renowned scenario planner, upped his prospects that South Africa may become a failed state. Global ratings agencies downgraded South Africa citing the fear that government policy could not meet popular demands. Amidst such speculation it is vitally important that the prospects for instability be investigated and determined, not via opinion or speculation, but rather against a sound body of theory. This task is complicated by the fact that the feared instability may only occur at a point in the future. The theory must therefore be applied via a methodology capable of overcoming the weak track record of political science in accurately anticipating major shifts in political systems. This problem statement will be addressed by showing that complex systems theory holds the key to a series of units of analysis via which the stability or instability of any political system can be objectively determined, compared to any other political system, and tracked over time. Secondly that there are scenario planning methodologies that can overcome the uncertainty inherent in the futures of all complex systems and thereby the poor track record that political scientists have in anticipating dramatic future changes in the systems they study. When combined into a single complex systems/scenario model, these theoretical and methodological points of departure will allow the long term prospects for stability or instability of any political system to be accurately and objectively determined. / PhD (Development and Management) North-West University, Potchefstroom Campus, 2013

Over 80% of colorectal cancers (CRCs) are sporadic/randomly arising tumors. Interval CRCs represent a subset of sporadic tumors that develop within 6-36 months after a negative colonoscopy. Interval CRCs are suggested to exhibit altered biological properties that contribute to rapid growth and proliferation. We hypothesize that chromosomal instability (CIN), or aberrant chromosome numbers, contributes to the etiology of Interval CRCs. We have assembled a Manitoban cohort of Interval and sporadic (control) CRC tumor samples, and established a fluorescence in situ hybridization approach to characterize CIN by enumerating specific chromosomes. The results of this study indicate that 75% of Interval CRCs exhibit a CIN phenotype, making CIN the most prevalent contributor to genomic instability in Interval CRCs. Only once we grasp a better understanding of the tumorigenic pathways through which Interval CRCs develop, can we tailor screening strategies and treatment options to specifically identify and combat this subset of sporadic CRC.

No description available.

Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder of the tyrosine degradation pathway. The defective fumarylacetoacetate hydrolase enzyme causes the accumulation of upstream metabolites such as fumarylacetoacetate (FAA), maleylacetoacetate (MAA), succinylacetone (SA) and p-hydroxyphenylpyruvic acid (pHPPA). In vitro and in vivo studies showed that the accumulation of these metabolites are detrimental to cell homeostasis, by inducing cell cycle arrest, apoptosis, and endoplasmic reticulum stress, depleting GSH, inhibiting DNA ligase, causing chromosomal instability, etc. For in vivo studies different models of HT1 were developed. Most notably was the fah deficient mouse, whose neonatally lethal phenotype is rescued by the administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Although, this model most closely resembles the human phenotype with elevated tyrosine levels and the development of hepatocellular carcinoma (HCC), the model is not human genome based. Both the in vitro and in vivo studies suggested that DNA repair is affected in HT1. However, it is not yet clear which DNA repair mechanisms are affected and if only protein functionality is affected, or if expression of DNA repair proteins are also affected. Characteristic of HT1 is the high prevalence of HCC and the presence of liver mosaicism. The liver mosaicism observed in HT1 patients are the result of reversion of the inherited mutation to wild-type. The general consensus is that the reversion is the result of a true back mutation. However, the mechanism underlying the back mutation is still unresolved. It was suggested that cancer develops either through a chromosomal instability mutator phenotype, a microsatellite instability mutator phenotype, or a point mutation instability mutator phenotype. In HT1 only chromosomal instability was reported. The aims of this study were to contribute to the understanding of the molecular basis of the genetic mosaicism in hereditary tyrosinemia type 1. More specifically, determine whether baseand nucleotide DNA repair mechanisms are affected and to what extent, and to determine if microsatellite instability is found in HT1. To achieve these aims, a parallel approach was followed: i.e. to develop a HT1 hepatic cell model and to use HT1 related models and HT1 patient material. To assess the molecular basis of the genetic mosaicism in HT1, the comet assay, gene expression assays, microsatellite instability assays, high resolution melting and dideoxy sequencing techniques were employed. Results from the comet assay showed that the HT1 accumulating metabolites, SA and pHPPA, decreased the capacity of cells for base- and nucleotide excision repair. Gene expression assays showed that short term exposure to SA and/or pHPPA do not affect expression of hOGG1 or ERCC1. The expression of these genes were, however, low in HT1 patient samples. Microsatellite instability assays showed allelic imbalance on chromosome 7 of the mouse genome, and microsatellite instability in the lymphocytes of HT1 patients. Although high resolution melt and sequencing results did not reveal any de novo mutations in fah or hprt1, the appearance of de novo mutations on other parts of the genome can not be ruled out. To conclude, results presented in this thesis, for the first time show that in HT1 the initiating proteins of the base- and nucleotide repair mechanisms are affected, the gene expression of DNA repair proteins are low, and microsatellite instability is found in HT1. By contributing to the elucidation of the mechanism underlying the development of HT1-associated HCC, and providing evidence for the development of a mutator phenotype, the results presented in this thesis contributes to the understanding of the molecular mechanisms underlying the genetic mosaicism in HT1. In addition to these contributions, a hypothesis is posited, which suggests that a point mutation instability (PIN) mutator phenotype is the mechanism underlying the mutation reversions seen in HT1. / Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2012

Element test results reported in the literature under both triaxial and plane strain conditions indicate that loose saturated granular specimens can experience softening instability at stress ratios lower than what might otherwise be expected given the critical state friction angle of the soil. The region of potential softening instability in stress-space is often explained using the framework of the instability line. This phenomenon is particularly relevant to shallow slopes of 1 to 2 m depth. However, the practical realities of sample preparation for triaxial testing make performing tests below 20 to 30 kPa of confining stress exceptionally difficult. In this thesis, the development of a centrifuge tilt-table test device is described which aims to test the behaviour of loose granular slopes under stress paths of increasing slope inclination or increasing pore water pressure. A system of instrumentation including pore pressure transducers, inclinometers, displacement transducers, and high-resolution cameras was designed to monitor the behaviour of the slope model. The development of a system to provide a controlled groundwater level within the slope model proved to be particularly challenging. The results of two competing design concepts are presented for the water boundary condition and discussed. The centrifuge tilt-table is used to compare the physical response of a slope to the behaviour predicted by the infinite slope and softening instability models using scale model centrifuge testing. If softening instability is a rigorous concept, it should be the primary observed failure mechanism as it will occur at a stress state below the failure line. Tests were performed on loose Ottawa F110 sand at 1g, 20g and 40g and 60g. Deviatoric strain-softening was observed in loose dry sand. The softening instability event resulted in a rapid increase in shear strain at constant shear stress while the soil was at a stress state below the failure envelope. Any soil that can experience softening instability (i.e. granular, loose, saturated, and behaves undrained) will undergo two failures: one caused by deviatoric strain-softening (softening instability) and a second caused by shear failure at a larger slope angle. / Thesis (Master, Civil Engineering) -- Queen's University, 2014-04-29 22:01:36.786

The current study addresses the stability of shock waves propagating through dissipative media, analogous to both granular media and molecular gases undergoing endothermic reactions. In order to investigate the stability, a simple molecular dynamics model was developed to observe shock waves and their structures with the inclusion of energy dissipation. For this, an Event Driven Molecular Dynamics model was implemented in a 2D environment, where a molecule is represented by a disk. The simulations addressed the formation of a shock wave in a gas by the sudden acceleration of a piston. Inelastic collisions were assumed to occur only if an impact velocity threshold is surpassed, representing the activation energy of the dissipative reactions. Parametric studies were conducted for this molecular model, by varying the strength of the shock wave, the activation threshold and the degree of inelasticity in the collisions. The resulting simulations showed that a shock structure does indeed become unstable with the presence of dissipative collisions. This instability manifests itself in the form of distinctive high density non-uniformities behind the shock wave, which take the form of convective rolls. The spacing and size of this ``finger-like" unstable pattern was shown to be dependent on the degree of inelasticity, the activation energy, and the strength of the driving piston. The mechanism responsible for the instability was addressed by studying the time evolution of the material undergoing the shock wave compression and further relaxation. It is found that the gas develops the instability on the same time scales as the clustering instability in homogeneous gases, first observed by Goldhirsch and Zanetti in granular gases. This confirmed that the clustering instability is the dominant mechanism.

Ovarian cancer (OCa) remains the leading cause of death due to a gynecologic malignancy in North American women, and the pathogenesis of this disease is a consequence of the interplay between DNA, RNA and proteins. The genomes of these cancers are characterized by numerical and structural aberrations, resulting in copy number changes of the affected regions. The serine protease, Kallikrein 6 (KLK6), is a promising biomarker and is over-expressed in OCa. However, the mechanisms leading to the observed KLK6 overexpression are poorly understood; and to date, no study examining the chromosomal contributions to the overexpression have been conducted. Utilization of multi-colour Fluorescence in situ Hybridization (FISH)-based technologies to untreated primary serous OCa samples and cancer cell lines, showed that the KLK locus, on 19q13.3/4, is involved in both numerical and structural aberrations; was subject to high-level copy-number heterogeneity (p<0.001); and structural rearrangements of 19q were significantly co-related to grade (p<0.001). Patients with a loss of the KLK locus, or no structural rearrangement on 19q, experienced a trend towards longer disease free survival (DFS and better overall survival (OS), over those with a gain or amplification, or with breakage events on 19q. KLK6-specific immunohistochemistry (IHC) showed weak correlation with KLK6 copy-number, suggesting other mechanisms together with copy-number, drives its over-expression. Among these mechanisms are microRNA (miRNAs), also shown to be affected by the copynumber changes in OCas. Therefore, we investigated the role of miRNAs in OCa and their role in KLK6 regulation. Specifically, we examined the copy-number status and miRNA expression in a representative OCa cell line, OVCAR-3. miRNA expression profiling of OCa cell lines and primary tumours showed their differential expression, including the decrease in expression of the let-7 family members, which are predicted to target KLK6. Indeed, when hsa-let-7a was transiently transfected into OVCAR-3, a reduction of secreted KLK6 protein was detected. Thus, the contribution of numerical and structural aberrations of the OCa genome can directly affect the expression KLK6 through copy-number, but is also aided post-transcriptionally by miRNAs.