Faculty of Science (ETDs)

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    The effect of cholesterol depletion on TGF-ß-induced epithelial-mesenchymal transition in pancreatic cancer cells
    (University of the Witwatersrand, Johannesburg, 2024-06) Breytenbach, Andrea; Kaur, Mandeep
    Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic cancer that relies on the epithelial to mesenchymal transition (EMT) program for its spread. EMT is a cell plasticity program that involves the reorganization of cell structure as cells transition from an epithelial to a mesenchymal phenotype. The dysregulated cholesterol metabolism resulting from metabolic reprogramming in PDAC is thought to play a role in EMT by affecting EMT-related signalling pathways. However, no publication has yet investigated the impact of EMT on cholesterol content in PDAC. To shed light on these dynamics, EMT was induced in PANC-1 cells using TGF-β1, thereafter the effect of cholesterol-depleting agents (KS-01 and methyl-β-cyclodextrin) alone or in combination with chemotherapeutic agents (Gemcitabine (GEM) and 5-Fluorouracil (5-FU)) on cholesterol content, EMT state, drug resistance, and invasion were investigated. Our results showed that mesenchymal cells rely on reduced membrane cholesterol levels, synthesis, and uptake, while storing more cholesterol and promoting efflux. EMT also promoted drug resistance via upregulation of ABCB1 expression and reduced hENT1 expression. Targeting cholesterol using cyclodextrins promoted a cholesterol compensatory mechanism, leading to a hybrid EMT state, drug resistance, and metastatic potential. Treating mesenchymal PANC-1 cells with GEM or 5-FU monotherapies were seen to promote EMT-transcription factors, as well as promote cholesterol efflux, synthesis, and import, an unexpected result as these chemotherapeutic agents are not known to affect cholesterol. When GEM was combined with KS-01, drug resistance, invasion, EMT-transcription factors, vimentin, and E-cadherin was promoted indicating the promotion of a hybrid EMT state. Interestingly however, combining KS-01 with 5-FU resulted in an interplay that was seen to mitigate the EMT-promoting effects typically associated with cholesterol depletion alone. The exact mechanism linking the cholesterol compensatory mechanism to EMT remains complex and unknown. Based on work presented in this dissertation, it is proposed that targeting cellular cholesterol should be continued to be investigated, particularly in understanding the repercussions of the use of cholesterol depleting agents for the treatment of other disorders in patients with PDAC.
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    Modelling and analysis of COVID-19 outspread at micro-levels using spatial autocorrelation: Case of eThekwini
    (University of the Witwatersrand, Johannesburg, 2024-09) Ngubane, Samukelisiwe; Chimhamhiwa, Dorman; Adam, Elhadi
    The alarming effects of the COVID-19 pandemic on different socio-economic spheres have been felt across the globe. These destructive effects have prompted plenty of research to understand and control the coronavirus pandemic. Notably, one strategic method of mitigating the effects of the coronavirus epidemic has been the utilisation of spatial and geostatistical models to gain insights into the potential predictors of the prevalence of the coronavirus. Considering the above, it was the aim of this study to explore the use of advanced geospatial modelling and analysis techniques, including Moran’s I, spatial error models, spatial lag models, MGWR, and GWR for analysing and modelling the settlement level determining factors of COVID-19 incidence within the eThekwini Metro to inform effectual micro-level planning. Notably, the lack of micro-level modelling of COVID-19 prevalence predictors also motivated the undertaking of this study. To the above aim, the objectives of the research were to utilise spatial autocorrelation to map the granular level COVID-19 spatial distribution over the 3rd wave in the eThekwini Metro, compare the applicability of global and local models in analysing and modelling micro-level COVID-19 incidence, analyse the spatial dependence of the occurrence of COVID-19 on local level variables through Moran’s I and to spatially model the effects of significant local-level determinants on COVID-19. The incidence of COVID-19 cases for the 3rd wave, which was from the 2nd of May 2021 to the 11th of September 2021, was analysed and modelled. The Moran’s I result illustrated that COVID-19 incidence within the eThekwini settlement places had a positive spatial autocorrelation, with a Moran’s I value of 0.14 and a p-value of 0.00. Also, the MGWR model's local R2 value was greater (72.5%) as compared to the other models. Moreover, economic wellness score, the sum of TB cases and population density came out as the significant determining factors of settlement level incidence of COVID-19. This research report offers a great foundation for gaining insights into the applicability of advanced geospatial models in guiding targeted COVID-19 interventions at lower levels.
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    Nutrient and Salinity Loading Based On The Temporal And Spatial Water Quality Data In The Upper Crocodile River Basin
    (University of the Witwatersrand, Johannesburg, 2024-03) Mistry, Nikhil Jayant; Ali, K. Adam; Abiye, Tamiru
    The Upper Crocodile River Basin has undergone a drastic change through anthropogenic factors such as rapid urban growth, industrial activities, agriculture and mining in the past thirty-eight years. This has led to an increase in nutrient and salinity loads with decreasing water quality. The Upper Crocodile River Basin wastewater treatment works struggle to maintain loading rates, causing partially treated wastewater to enter the river systems that increased the salinity loads. Water chemistry and discharge data from the DWS were collected, cleaned and processed; data were summated across the necessary river channels in which they are located to determine the nutrient and salinity loads in all rivers in the Upper Crocodile River Basin. The results indicated that the Hennops, Jukskei and Crocodile Rivers are responsible for the largest nutrient and salinity loading rates. Changes in land use activities and climate over the past thirty-eight years, since 1980, have drastically impacted the rate at which nutrient and salinity loads enter into the UCRB. During the early 1980s to 1990s a significant drop was observed in nutrient and salinity loading rates, spiking in the late 1990s and early 2000s, influenced by changes in water management and climatic events like the La Niña and the El Niño phenomena. The inter-basin transfer in the early 2000s and subsequent two decades have led to an overall rise in nutrient and salinity loading rates, posing serious water quality and health risks to people in the UCRB area. Mining activities, poor landfill management and leaking tailing storage facilities have resulted in increased sulphate loading rates into the UCRB. Nitrogen loading has risen due to uncontrolled waste disposal from informal settlements, industrial activities and sewage spills in the Johannesburg region. Phosphorus loading rates have risen due to agricultural fertiliser runoff, with the Jukskei River being the largest contributor to these loads in the Upper Crocodile River Basin. The loads entering the Hartbeespoort dam during summer and winter seasons in the 2016-2018 period for sulphate is 6819.24 kg/hr, 4873.62kg/hr; for nitrogen 4179.24 kg/hr, 4021.55 kg/hr and for phosphorus 40.08 kg/hr, 34.724 kg/hr, respectively. Salinity loads entering the Hartbeespoort dam during summer and winter are 42952.87 kg/hr and 27548.39 kg/hr, respectively. According to the findings, water resource management must act quickly to improve the overall quality of the water; in the upcoming ten years, as loading rates are expected to rise exponentially as a result of increased demand and stressed water use, which will lead to poor water quality. This will pose serious health and economic risks to the people of the Upper Crocodile River Basin and the populace of South Africa.
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    Envisioning the Future of Fashion: The Creation And Application Of Diverse Body Pose Datasets for Real-World Virtual Try-On
    (University of the Witwatersrand, Johannesburg, 2024-08) Molefe, Molefe Reabetsoe-Phenyo; Klein, Richard
    Fashion presents an opportunity for research methods to unite machine learning concepts with e-commerce to meet the growing demands of consumers. A recent development in intelligent fashion research envisions how individuals might appear in different clothes based on their selection, a process known as “virtual try-on”. Our research introduces a novel dataset that ensures multi-view consistency, facilitating the effective warping and synthesis of clothing onto individuals from any given perspective or pose. This addresses a significant shortfall in existing datasets, which struggle to recognise various views, thus limiting the versatility of virtual try-on. By fine-tuning state-of-the-art architectures on our dataset, we expand the utility of virtual try-on, making them more adaptable and robust across a diverse range of scenarios. A noteworthy additional advantage of our dataset is its capacity to facilitate 3D scene reconstruction. This capability arises from utilising a sparse collection of images captured from multiple angles, which, while primarily aimed at enriching 2D virtual try-on, inadvertently supports the simulation of 3D environments. This enhancement not only broadens the practical applications of virtual try-on in the real-world but also advances the field by demonstrating a novel application of deep learning within the fashion industry, enabling more realistic and comprehensive virtual try-on experiences. Therefore, our work heralds a novel dataset and approach for virtually synthesising clothing in an accessible way for real-world scenarios.
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    Investigating the DNA methylation status of the PXDN and PXDNL promoter regions in OSCC cell lines
    (University of the Witwatersrand, Johannesburg, 2024-06) Sebastian, Mistral; Mavri-Damelin, Demetra
    Background: Oesophageal squamous cell carcinoma (OSCC) is the most prevalent form of oesophageal cancer in South Africa. Aberrant DNA methylation is a well-established epigenetic mechanism involved in various cancers, including OSCC. This study focuses on the DNA methylation status of the peroxidasin (PXDN) and perodixasin like (PXDNL) promoter regions and the expression of PXDN and PXDNL in OSCC cell lines. PXDN consolidates the basement membrane through collagen IV unit oligomerization, influences epithelial-mesenchymal transition and correlates with poor prognosis in various cancers. PXDNL modulates the extracellular matrix (ECM) by antagonising PXDN. Since PXDNL shares domains with PXDN, that allow PXDN to interact with the ECM, it is speculated that PXDNL may possess other ECM modulation roles that require further elucidation. Dysregulated PXDNL expression also correlates with poor cancer prognosis. To date, within the context of South African derived OSCC cell lines, no studies pertaining to the DNA methylation status of the PXDN and PXDNL promoter regions and the expression of PXDN and PXDNL have been carried out. Aim: The aim of this project was to investigate the DNA methylation status of the PXDN and PXDNL promoter regions and observe PXDN and PXDNL expression in the SNO and WHCO5 OSCC cell lines. Methods: PXDN and PXDNL localisation was observed using immunofluorescence microscopy; expression of PXDN and PXDNL was quantified using western blotting and the DNA methylation status of the PXDN and PXDNL promoters was assessed using methylation specific PCR and bisulfite sequencing, respectively. Results: Immunofluorescence microscopy results indicated that both cell lines show varying degrees of PXDN and PXDNL expression. In addition, these results also showed that PXDN and PXDNL localise in the ECM. The western blotting results established that these cell lines express the canonical version of PXDN and possibly a PXDNL isoform (146kDa). Methylation specific PCR has shown that the promoter region of PXDN is differentially methylated across both cell lines. The sequencing results of the bisulfite converted PXDNL promoter region were unsuccessful. Hence, bisulfite sequencing requires further optimisation before the DNA methylation status of the PXDNL promoter region can be determined. Conclusion: This study is the first to show the novel finding that PXDN and PXDNL are expressed in South African derived OSCC cell lines. Within the context of OSCC, further investigation is warranted in order to elucidate the underlying mechanisms that these proteins play a role in. In addition, further study may determine whether a correlation exists between PXDN and PXDNL promoter methylation, protein expression as well as prognosis and whether these aspects should serve as novel markers for diagnosis and therapy. This may subsequently lead to increased OSCC patient survival rates by contributing to early diagnosis of OSCC and efficacious targeted therapeutic intervention.
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    High entropy spinel oxides and iron-cobalt based electrocatalysts for rechargeable zinc-air batteries
    (University of the Witwatersrand, Johannesburg, 2024-08) Mongwe, Agnes Monosi; Ozoemena, Kenneth Ikechukwu; Haruna, Aderemi B.
    The development of effective and stable rechargeable zinc-air batteries (RZABs) using noble-metal free bifunctional electrocatalysts for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) has been a key challenge to its practical applications. This MSc research work strategically investigated some synthetic methods aimed at tuning the physicochemistry and electrochemical properties of two electrocatalysts (i.e., noble-metal free high entropy spinel oxide (HESOx) ((CoCuFeMnNi)3O4) and spinel Fe2CoO4 for rechargeable zinc-air batteries). For HESOx, a simple and reproducible Pechini method was used to synthesize a homogeneous nanosized electrocatalyst HESOx-550. The HESOx-550 was thereafter supported on onion-like carbon (OLC) in (1) an acidic environment to produce HESOx-550/OLCAT (where AT stands for acid-treated) and (2) a nonacidic environment to produce HESOx-550/OLC. The effects of the different synthesis environments on these three samples were thoroughly investigated using different analytical techniques, including X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Raman spectroscopy, thermogravimetric analysis (TGA) and Nitrogen Gas Adsorption analysis. The Nitrogen Gas Adsorption analysis results show that the HESOx-550/OLCAT has the largest surface area and more volume. The electron paramagnetic resonance (EPR) and O1s XPS data consistently proved that HESOx-550/OLCAT has improved oxygen vacancies which are essential in improving conductivity and offering abundant reaction sites. The HESOx-550/OLCAT shows the best bifunctional ORR and OER electrocatalytic performance with a bifunctionality index (ΔE) of 0.70 V in 1 M KOH. In addition, the RZAB air electrode with HESOx 550/OLCAT exhibits high areal capacity (60 mAh cm-2) and areal energy density (73.2 mWh cm-2) with a long-term cycle stability over 112 h in 6.0 M KOH and 0.2 M zinc acetate. The HESOx-550/OLCAT RZAB shows better electrochemical performance than 10wt.% Pt/C- IrO2 when cycled over 315 h under 27% depth of discharge condition. For Fe2CoO4, iron cobalt-based electrocatalysts on Vulcan carbon support were synthesized using a simple reduction method to produce two composites (FeCo-Fe2CoO4/CAnnealed), and (FeCo Fe2CoO4/CMicrowave). The physicochemical analytical methods such as XRD, XPS, Raman, TGA and Nitrogen Gas Adsorption analysis were used to investigate the samples. The electrochemical analysis showed that the FeCo-Fe2CoO4/CAnn had a very low “bifunctionality index” (ΔE) of 0.76 V and the FeCo-Fe2CoO4/CAnn air cathode RZAB demonstrated good stability for over 50 h under harsh DOD conditions (35.2%). The assembled RZABs have areal energy densities of 48.4 mWhcm-2 and 60.5 mWhcm-2 which are higher than the minimum recommended areal energy density of 35 mWhcm-2 (and better than most electrocatalysts reported in the literature). This study has significant contributions to the progress of practical applications of RZABs.
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    Exploring the 95 GeV Excess with Extended Scalar Models
    (University of the Witwatersrand, Johannesburg, 2024-10) Mulaudzi, Anza-Tshilidzi; Mellado, Bruce; Kumar, Mukesh
    This thesis focuses on three interconnected studies investigating the presence of an additional scalar particle, S, of mass around mS ≈ 95 GeV. In the initial study, we explore the notion that an SU(2)L triplet scalar, characterised by a hypercharge Y = 0, could be the origin of the observed 95 GeV di-photon (γγ) excesses seen at ATLAS and CMS. By thoroughly examining its properties, particularly the neutral component, and considering a small mixing angle with the Standard Model Higgs boson, we uncover that this scalar naturally exhibits a substantial branching ratio to γγ. Additionally, we find that its Drell-Yan production via pp → W∗ → HH± adequately accounts for the observed excess. The second study examines how recent measurements of the W bosons’s mass by experiments such as ATLAS and CDF affect the theoretical predictions of the Two Higgs Doublet Model augmented with a Singlet Scalar (2HDM+S) model. It addresses how this model’s parameter space is further constrained by the inclusion of vector-like leptons, focusing on their impact on the muon g − 2 measurements. The third study involves exploring the potential discovery of the aforementioned scalar at future electron-positron colliders. Employing several methodologies, including the recoil mass method in e + e − collisions (e + e − → ZS, where Z → µ + µ − and S → b ¯ b), we leverage a Deep Neural Network to refine the differentiation between the Standard Model background and the targeted signal. The outcomes not only reinforce the potential for detecting the proposed scalar, but also enhance the scientific argument for the establishment of future electron-positron colliders like CEPC, FCC-ee or ILC. Together, these studies contribute valuable insights into the evolving landscape of particle physics.
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    The Gene Catalogue and Functional Analysis of the Gut Microbiome of Lions in Etosha National Park
    (University of the Witwatersrand, Johannesburg, 2024-09) Belger, Carl Warner; Hetem, Robyn; Hazelhurst, Scott
    Characterising the microbiomes of free-living mammals may aid conservation efforts, yet the gut microbiome of carnivores is underrepresented. This study represents the first description of the gut microbiome of free-living African lions (Panthera leo melanochaita). Faecal samples from 20 lions were collected in Etosha National Park, Namibia and microbial DNA was extracted. Samples were then whole genome sequenced, and classified using MetaPhlAn and Genome Taxonomy Database toolkit. The two most abundant bacterial genera in the lions’ gut microbiomes were Bacteroides (16.9%) and Phocaeicola (16.6%). Microbiome diversity was similar between the sexes and across seasons as assessed through Bray-Curtis dissimilarity and Shannon diversity index. The genus Clostridium_AH was more abundant in male lions (P = 0.007; d.f. = 22), while Aphodousia (P = 0.003; d.f. = 22) was more abundant in females. Lions captured in winter had a high abundance of Plesiomonas relative to those captured in summer (P = 0.008), whereas lions captured in summer a high abundance of Dysosmobacter (P = 0.038; d.f. = 22), Pelethomonas (P = 0.021; d.f. = 22), Metalachnospira (P = 0.033; d.f. = 22) and Clostridium Q (P = 0.012; d.f. = 22) compared to those captured in winter. Following various taxonomic classification approaches, a third of the reads (33.6%) present in the lion gut microbiome remained unclassified. We constructed 272 metagenome assembled genomes, from seven bacterial phyla, representing mostly new species which will contribute to understanding of the carnivore gut microbiome.
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    Baseline Hydrogeology of Dolerite Dykes in Lesotho, Mafeteng District as a Case Study
    (University of the Witwatersrand, Johannesburg, 2024-06-10) Monyane, Napo Shadrack; Shakhane, Teboho; Abiye, Tamiru
    Groundwater is a vital alternative resource due to the increasing demand for water supply in Lesotho’s rural and urban areas as surface water faces threats from population growth and climate variability. For instance, groundwater serves the demands of Lesotho's growing textile industry and agricultural sectors. The 3D form of the dolerite dykes widespread throughout the Karoo rocks in Lesotho may have an impact on the groundwater occurrence, flow, and yield characteristics of the region. However, specific research on their hydrogeology has not been extensively undertaken. This study aimed at characterising the hydrogeology of the dolerite dykes in the lowlands of Lesotho using selected places namely, Boluma-Tau, Ha Lumisi, Ha Mofota, Ha Maoela, Ha Mofo, Malumeng, Qalabane, Matlapaneng, Thabana Mohlomi, Ha Mohlehli, Malimong, Tsoeneng and Ha Lenonyane as case studies for the research. This research adopted the desktop and walkover survey in developing information on the region’s broad geological and hydrogeological setting within the Karoo lithologies. Included also was the use of ground magnetics in ascertaining the existence and determining the geometry of the dykes, using the D-8 algorithm for flow directions, and drilling and pumping tests for aquifer analysis. The dykes dominating the focal area in the Mafeteng District generally trend NE-SW, NNE-SSW and NW-SE. The magnetic results outlined negative anomalies along the dyke’s contact with the country rocks as surveyed from Qalabane, Mafeteng Lesotho, these magnetic lows imply fracture gaps along the strike of the dyke. A generalised dip, width, and depth could not be easily inferred due to inconsistent magnetic anomaly shapes, but forward modelling indicated a thin (10 m wide) shallow (10°) dyke trending NE-SW intruding both the Burgersdorp and Molteno Formations at Qalabane, Mafeteng. As per the D-8 results, the dolerite dykes in Mafeteng are distributed in the intermediate basin flow values due to a gentle hydraulic gradient. Certain dyke sites exhibit a groundwater flow direction towards the north, whilst others display a radial groundwater flow direction. The derivative analysis revealed the boreholes were drilled in a fractured dyke system, also the dominant radial flow regime and double porosity dip at different pumping durations, and the possible recharge boundary were revealed in some drilled dyke sites. Further analysis from the drawdown versus time curves resulted in average yields of 0.1 – 1.25 l/s with transmissivities ranging from 1 – 14 m2/day, insinuating that a limited extraction of the local water supply is suggested from the dolerite dyke lithologies in the lowlands of Mafeteng Lesotho, given the groundwater yielding capacity and magnitude of the transmissivities. Even though the drilled boreholes from the dyke sites indicated a fractured dyke setting, estimated transmissivity values are variable and low, this is indicative of the inconsistent apertures and lack of interconnectivity of the available secondary hydrogeological features in the lowlands of Lesotho.
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    The Taxonomy and Phylogeny of Varanopidae from the Middle Permian of outh Africa
    (University of the Witwatersrand, Johannesburg, 2024-08) Sibiya, Zoleka; Rubidge, Bruce; Benoit, Julien
    Varanopidae are the only pelycosaur-grade tetrapods from the Abrahamskraal Formation of the Beaufort Group. Although four varanopid species are described from the middle Permian of South Africa (SA), their validity has been questionable. Moreover, Ford and Benson recently proposed that varanopids belong to the Diapsida rather than Synapsida. Given this taxonomic and phylogenetic turmoil, this study i) describes two newly discovered and well-preserved varanopid specimens from the middle Permian of SA using CT scanning and ii) re-assesses the validity of the four species from the Karoo Basin in the light of new data from these specimens. The phylogeny of the group is addressed by updating two pre-existing cladistics matrices. The two new specimens exhibit a mosaic of features that overlap the diagnoses of several species of SA varanopids. In addition, some diagnostic traits of the four SA varanopid genera and species are found to be variable across ontogeny. For instance, dorsal osteoderms and the extent of ornamentation on the angular bone co-vary with size. It is therefore proposed that all varanopid specimens currently described from the middle Permian of South Africa belong to a single valid species, Heleosaurus scholtzi, with differences between specimens being accounted for by ontogenetic changes. The phylogenetic analysis supports Ford and Benson’s hypothesis but contra the prediction of this hypothesis, no differences in cranial fenestration during ontogeny are observed. Morphological characters preserved in the manus of the newly discovered specimen BP/1/8499 suggest that Heleosaurus was arboreal.