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The paracrine effect of normoxic and hypoxic cancer secretions on blood-brain barrier endothelial cells
(University of the Western Cape, 2022) Rado, Mariam Abobaker M
Cancer is the most common leading cause of death worldwide. Glioblastoma and breast cancer are the most aggressive solid tumour. The survival rate of these tumours depends on their ability to progress and spread. These cancers use their high proliferative capabilities for survival, increasing their malignancies. Glioblastoma is considered the most aggressive tumour initiated in the brain, whereas breast cancer is the most common metastatic cancer in the brain, both types of cancer are known as high infiltrated cancer and their invasiveness due to their capability to release factors that can alter the neighbouring cells to facilitate their progression. On the other hand, the brain remains a vital organ where the blood-brain barrier (BBB) plays a protective and homeostasis role, thus ensuring optimum brain function. The endothelial cells are the functional site of the BBB; these cells, with assistance from other brain cells such as astrocytes and pericytes, maintain the BBB protective function. The literature revealed perturbations and disruption in the BBB integrity in glioblastoma and metastatic breast cancer. The endothelial cells and other components of the BBB have been morphologically altered, resulting in impacting the BBB integrity. The interaction between cancer cells and brain endothelial cells is a complex scenario that is not entirely illustrated; however, a vital role in the crosstalk between cancer cells and endothelial cells is played by signalling mediated by soluble factors that can further promote cancer progression. This study aimed to investigate whether the secretions from glioblastoma and breast cancer cells could influence the brain endothelial cells. Brain endothelial cells (bEnd.3) were cocultured with glioblastoma (U-87) or breast cancer (MCF7) cells or subjected to their conditioned media. To mimic the heterogeneous physiological conditions of the solid tumour such as glioblastoma and breast cancer, U87 and MCF7 cells were cultured under normoxia (to reflect cancer cells exposed to oxygen levels in the perivascular regions of the tumour) or hypoxia (to reflect the hypoxic tumour area where invasive cancer cells are detached and invade the surrounding tissue forward to the blood vessels). Our findings underlined the involvement of paracrine secretion of cancer cells in modulating brain endothelial cells’ properties. Our data suggested that both cancer secretions derived from normoxia and hypoxia rendered changes in the brain endothelial cells at the level of mitochondrial activity. To investigate whether the exerted effects were associated with the acquisition of the brain endothelial resistance, we screened the transelectrical endothelial resistance (TEER) of brain endothelial cells after exposure to cancer secretions. Our findings revealed a decrease in TEER of the exposed brain endothelial cells. Moreover, gene expression of the tight junction (Claudin-5 and Occludin) were quantified in brain endothelial cells (bEnd.3) after exposure to normoxic and hypoxic cancer secretion using real-time qPCR; results showed upregulation of Claudin-5 after exposure to normoxic and hypoxic cancer secretion. Occludin gene expression was also upregulated after exposure to normoxic cancer secretion; however, the exposure to hypoxic cancer secretion decreased Occludin gene expression. In addition, the proliferation of endothelial cells (bEnd.3) exposed to cancer secretion was measured by cell counting, followed by analyzing the cell cycle; results showed that long term exposure to cancer secretion suppressed the proliferation of brain endothelial cells (bEnd.3), mostly after exposure to hypoxic cancer secretion. Cells were accumulated in the G1 phase. Overall, data suggest that factors secreted from normoxic and hypoxic cancer cells modulate brain endothelial cells, affecting their function.
The role of visualization in the teaching and learning of multivariate calculus and systems of ordinary differential equations
(University of the Western Cape, 2015) Sheikh, T.O
The purpose of this study was to investigate the role of visualization in the conceptualisation and solution of problems in multivariate calculus and dynamical systems. The theoretical basis, and the visual and analytical aspects of evaluating multiple integrals, and the stability analysis of dynamical systems, were established. To address the research questions, a teaching experiment with activities to facilitate visualization of 3D objects and phase portraits of non-linear dynamic systems was conducted with an experimental class (n = 24) which received six activity sessions in the computer Laboratory in addition to traditional lectures. The control class (n = 26) received traditional lectures and tutorial instruction. Both groups were lectured by the researcher using the same set of class notes, assignments, worksheets and tutorials. Additional support materials were posted on the Blackboard on Web-City. The activities included tasks in the computer laboratory that reinforced visualization and spatial ability factors such as surface features, nets, projections, cross-sections and rotation of 3D objects as well as phase portraits of systems of differential equations. The students were tested at several time points, and over both the short and long term to assess the impact on their visual and analytical solutions to problems in the two study domains. The pre-test on prior knowledge indicated no significant differences between the means of the experimental and control groups. Results indicate that there were no significant differences between the achievement of the two groups in Test 1 and Test 2 while the activities were ongoing, but towards the end of the semester significant differences in favour of the experimental group were recorded. A multiple linear regression analysis confirmed that in addition to prior knowledge as measured by the pretest, two of the spatial factors were significant predictors of achievement for the domains under investigation. Students had difficulties in visualising 3D regions of integration and in switching the order of triple integrals. Very few (18%) recognised the need for split integrals to span the required area or volume. While students could find analytical solutions to systems of differential equations and describe the stability of individual equilibrium points using eigenvalues, they struggled with translating rates of change into slopes on the phase portraits, with the interpretation of the solutions and in describing the global behaviour of the system. Students had difficulties in visualizing the region of integration in R³, the stability of equilibrium points in the phase portraits, and in coordinating the treatments and conversions between the geometric, numerical, symbolic and algebraic registers. The tendency to work in the algebraic register to determine the limits of the integral was noted, and students opted to use analytic methods in conducting a stability analysis of the given dynamic system rather than the geometric method. This study adds to research on visualization in mathematics by examining how exposure to technologically enhanced representations complement and promote the conceptualisation of solutions to problems involving multiple integrals and systems of differential equations.
A retrospective analysis of semen samples and reproductive hormones in Africa and the middle east
(University of the Western Cape, 2021) Moungala, Lionel Wildy
Semen analysis is the cornerstone for the investigation of male infertility. Semen quality can be influenced by geographical location, age, ejaculatory abstinence, and season. In 2010, the WHO published criteria for human semen characteristics that were markedly lower than those previously reported. Many reports have discussed the methodology used by the WHO to set the 2010 reference values. Some of the limitations of the WHO (2010) study included an undefined ejaculatory abstinence period, the limited representation of different age groups, and a limitation in geographical representation as the study did not include any data from Africa and Middle East. Therefore, the current cohort study was designed to provide retrospective data on semen quality (Africa and Middle East) and reproductive hormones (Middle East) in patients who underwent semen analysis and endocrine investigation at Andrology Laboratories in South Africa and Qatar. The effects of geographical location, age, ejaculatory abstinence and seasonal changes were evaluated. Furthermore, data from Africa (from the current cohort study) was compared to data from America, Asia, Australia and Europe obtained from global data from Cooper et al. (2010) and Campbell et al. (2021). Semen analysis reports (n = 70,765) for Africa and Middle East were obtained from Ampath Andrology Laboratory (n = 35,516), Lancet Andrology Laboratory (n = 24 967), Androcryos Andrology Laboratory (n = 7 450) and Hamad Medical Center (n = 2,832). Basic semen parameters such as semen volume, sperm concentration, total sperm count, progressive motility, total progressively motile count, sperm morphology, total normal sperm count, and functional sperm count such as DNA fragmentation, sperm viability and oxidation-reduction potential (ORP) were collected for the purpose of the study. Furthermore, reproductive hormones (estradiol, follicle stimulating hormone, luteinizing hormone, prolactin and testosterone), as well as seminal epithelial and red blood cells were investigated. All statistical analysis was done using the MedCalc® statistical software 19.5 with P-value of < 0.05 considered statistically significant. Men residing in Africa and Middle East had median ejaculate volume, sperm concentration, total sperm count, progressive motility and normal morphology within the normal thresholds recommended by WHO (2010). A prevalence of 20.3% for oligozoospermia and 3.6% for azoospermia were found in men residing in Africa and the Middle East. Men residing in the MENA region had sperm vitality below the recommended threshold and a median SDF higher than current recommended thresholds. Compared to Southern and Eastern Africa, the MENA region had generally worse semen parameters, most notably in the Middle East region. In Southern Africa, the highest semen parameters were found in men residing in Mozambique and Zimbabwe while the lowest were observed in patients residing in Zambia. In South Africa, the Free-State and Mpumalanga provinces had the lowest median sperm concentration. Age was found to negatively influence semen parameters in Africa and the Middle East. In the MENA region, an age-related decline in testosterone and prolactin, and increase in FSH was found, with no significant changes for LH and estradiol with age. The duration of abstinence had a statistically significant positive influence on semen volume, sperm concentration and progressive motility, while SDF worsened with the increased duration of abstinence. Furthermore, the results show a temporal decline in semen parameters between 2005 and 2019 among men from sub-Sahara Africa. A seasonal change in semen parameters of men residing in sub-Sahara Africa below the equator was found, with sperm concentration and total sperm count higher in winter compared to summer and autumn. The lowest sperm concentration was found in summer. Lastly, the results indicated a reduced semen quality in men residing in Africa compared to those living in America, Asia, Australia and Europe when comparing to global data from Cooper et al. (2010) and Campbell et al. (2021). The differences observed in semen quality and hormones in this study may indicate different environmental exposures and lifestyle changes in the investigated regions which requires further investigation.
Optimal asset allocation and capital adequacy management strategies for Basel III compliant banks
(University of the Western Cape, 2015) Muller, Grant Envar
In this thesis we study a range of related commercial banking problems in discrete and continuous time settings. The ﬁrst problem is about a capital allocation strategy that optimizes the expected future value of a commercial bank’s total non-risk-weighted assets (TNRWAs) in terms of terminal time utility maximization. This entails ﬁnding optimal amounts of Total capital for investment in different bank assets. Based on the optimal capital allocation strategy derived for the ﬁrst problem, we derive stochastic models for respectively the bank’s capital adequacy and liquidity ratios in the second and third problems. The Basel Committee on Banking Supervision (BCBS) introduced these ratios in an attempt to improve the regulation of the international banking industry in terms of capital adequacy and liquidity management. As a fourth problem we derive a multi-period deposit insurance pricing model which incorporates the optimal capital allocation strategy, the BCBS’ latest capital standard, capital forbearance and moral hazard. In the ﬁfth and ﬁnal problem we show how the values of LIBOR-in-arrears and vanilla interest rate swaps, typically used by commercial banks and other ﬁnancial institutions to reduce risk, can be derived under a specialized version of the affine interest rate model originally considered by the bank in question. More speciﬁcally, in the ﬁrst problem we assume that the bank invests its Total capital in a stochastic interest rate ﬁnancial market consisting of three assets, viz., a treasury security, a marketable security and a loan. We assume that the interest rate in the market is described by an affine model, and that the value of the loan follows a jump-diffusion process. We wish to ﬁnd the optimal capital allocation strategy that maximizes an expected logarithmic utility of the bank’s TNRWAs at a future date. Generally, analytical solutions to stochastic optimal control problems in the jump setting are very difficult to obtain. We propose an approximation method that exploits a similarity between the forms of the control problems of the jump-diffusion model and the diffusion model obtained by removing the jump. With the jump assumed sufficiently small, the analytical solution of the diffusion model then serves as a proxy to the solution of the control problem with the jump. In the second problem we construct models for the bank’s capital adequacy ratios in terms of the proxy. We present numerical simulations to characterize the behaviour of the capital adequacy ratios. Furthermore, in this chapter, we consider the approximate optimal capital allocation strategy subject to a constant Leverage Ratio, which is a speciﬁc non-risk-based capital adequacy ratio, at the minimum prescribed level. We derive a formula for the bank’s TNRWAs at constant (minimum) Leverage Ratio value and present numerical simulations based on the modiﬁed TNRWAs formula. In the third problem we model the bank’s liquidity ratios and we monitor the levels of the liquidity ratios under the proxy numerically. In the fourth problem we derive a multi-period deposit insurance pricing model, the latest capital standard a la Basel III, capital forbearance and moral hazard behaviour. The deposit insurance pricing method utilizes an asset value reset rule comparable to the typical practice of insolvency resolution by insuring agencies. We perform numerical computations with our model to study its implications. In the ﬁnal problem, we specialize the affine interest rate model considered previously to the Cox-Ingersoll-Ross (CIR) interest rate dynamic. We consider ﬁxed-for-ﬂoating interest rate swaps under the CIR model. We show how analytical expressions for the values of both a LIBOR-in-arrears swap and a vanilla swap can be derived using a Green’s function approach. We employ Monte Carlo simulation methods to compute the values of the swaps for different scenarios. We wish to make explicit the contributions of this project to the literature. A research article titled “An Optimal Portfolio and Capital Management Strategy for Basel III Compliant Commercial Banks” by Grant E. Muller and Peter J. Witbooi [1] has been published in an accredited scientiﬁc journal. In the aforementioned paper we solve an optimal capital allocation problem for diffusion banking models. We propose using the solution of the Brownian motions control problem of [1] as the proxy in problems two to four of this thesis. Furthermore, we wish to note that the methodology employed on the ﬁnal problem of this study is actually from the paper [2] of Mallier and Alobaidi. In the paper [2] the authors did not present simulation studies to characterize their pricing models. We contribute a simulation study in which the values of the swaps are computed via Monte Carlo simulation methods.
The in vitro effects of heavy metals and nanoparticles on the immune system
(University of the Western Cape, 2017) Lategan, Kim Leigh
Heavy metals and nanoparticles may be released into the environment due to their use and applications. Sources of high, toxic metal concentrations may result from leachates from hazardous waste sites, discharge from industrial plants, and effluents from wastewater treatment plants being released into the environment. Nanoparticles may be found in a number of consumer products, and are used in medical applications such as drug delivery, bioimaging and biosensing. The release of heavy metals and nanoparticles to the environment may directly or indirectly impact abiotic and biotic systems. Three heavy metals and three nanoparticles were selected for this study. The heavy metals selected include cadmium (Cd), silver (Ag) and copper (Cu). The nanoparticles (NPs) chosen were silver nanoparicles (AgNPs), graphene oxide nanoparticles (GONPs) and carbon dots (CDs). These compounds were selected to evaluate the potential effects these compound may have on the immune system. The murine macrophage cell line RAW 264.7 and human whole blood cell cultures (WBCs) were selected as immune system representatives to assess the effects of heavy metals and nanoparticles on the immune system. The effects of heavy metals and NPs on RAW cells were monitored either in the absence or presence of the mitogen, lipopolysaccharide (LPS). The effects of heavy metals and NPs on WBCs were evaluated under basal conditions or in the presence of LPS or phytohaemmagglutinin (PHA). A number of parameters were monitored. These parameters included cytotoxicity, inflammatory biomarkers, cytokines of the acquired immune system and a proteome profile analysis. The first objective of this study was to assess the effects Cd, Ag and Cu on immune system biomarkers. No effects on were seen on cultures not stimulated by LPS. Cd was more cytotoxic than Ag, with Cu having no effect on cell viability of the RAW cells. The same trend was seen when evaluating the inflammatory biomarkers, nitric oxide (NO) and interleukin 6 (IL-6). Evaluating the effects of the metals on WBCs and the cytokines representing the innate (IL-6), humoral (IL-10) and cell mediated immunity (IFNγ) found that all the cytokines were reduced by the metals. The results show IL-6 was inhibited by Cu at lower concentrations than Cd, while Ag upregulated its synthesis. IL-10 was inhibited by Cd at lower concentrations than Cu, and Ag inhibited the production of this cytokine the least. IFNγ was reduced by higher concentrations of Ag, followed by Cu, and then Cd. The second objective of this study was to evaluate the effects AgNPs had on the immune system biomarkers. AgNP concentrations had no negative effect on RAW cell viability at concentrations used. However, AgNP cytotoxicity of WBCs was evident. Under basal conditions, AgNPs induced inflammation in RAW cells and WBCs respectively. Under a simulated inflammatory response, AgNPs inhibited the inflammatory response for both RAW and WBCs. The acquired immune cytokines IL-10 and IFNγ were both induced by AgNPs in the absence of PHA. IL-10 was partially inhibited by AgNPs when evaluated in the presence of PHA. Proteome profiles of RAW cell supernatants show that AgNPs do in fact modulate specific protein synthesis. Upregulated proteins due to AgNP exposure indicate induction of specific proteins indicative of inflammatory responses and wound healing. WBC supernatant proteome analysis indicates modulation of anti-inflammatory properties by AgNPs. The third objective was to monitor the effects of GONPs on the immune system biomarkers. GONPs were cytotoxic to both RAW and WBCs. In the absence of mitogens, GONPs elicited an inflammatory response from RAW and WBCs respectively. This activation was further corroborated by proteome profile analysis of both experimental cultures. GONPs inhibited LPS induced IL-6 synthesis and PHA induced IFNγ synthesis by WBCs in a dose dependent manner. In the absence of mitogens, GONPs stimulated IL-10 synthesis by WBCs. GONPs modulate immune system biomarkers and these may pose a health risk to individuals exposed to this type of nanoparticle. The last objective of this study was to evaluate the effects of CDs on the immune system. CDs were cytotoxic to RAW and WBCs respectively. Biomarkers associated with inflammation was induced by CDs under basal conditions for both RAW and WBCs respectively. The humoral immune system regulating cytokine IL-10 was increased by CDs under both basal and PHA activated WBCs. Proteome analysis supported the inflammatory data as proteins identified are associated with inflammation and provide potential biomarkers to be assessed upon CD exposure. The heavy metals and NPs assessed in this study can potentially be detrimental to human health as they are cytotoxic and induce immunomodulatory cytokines. This could potentially result in immunosuppression or immunostimulation in individuals exposed to these compounds.