Faculty of Science (ETDs)

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End date: 2019

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    Investigating 2-hydroxypropyl-β-cyclodextrin (HPβCD) as a novel therapeutic agent for breast cancer
    (University of the Witwatersrand, Johannesburg, 2019) Saha, Sourav Taru; Kaur, Mandeep
    Cancer cells have an increased need for cholesterol, which is required for cell membrane integrity. Cholesterol accumulation has been described in various malignancies including breast cancer. Cholesterol has also been known to be the precursor of estrogen and vitamin D, both of which play a key role in the histology of breast cancer. Elevated cholesterol levels have been linked to breast cancer therefore depleting cholesterol levels in cancer cells can be a viable strategy for treatment. 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a cholesterol depleting compound which is a cyclic amylose oligomer composed of glucose units. It solubilizes cholesterol and is proven to be toxicologically benign in humans. This led us to hypothesise that it might deplete cholesterol from cancer cells and may prove to be a clinically useful compound. Our work provides experimental evidences to support this hypothesis. We identified the potency of HPβCD in vitro against two breast cancer cell lines: MCF7 (Estrogen positive, ER+), MDA-MB-231 [Triple negative breast cancer (TNBC)], and compared the results against two normal cell lines: MRC-5 (Normal Human Lung Fibroblasts) and HEK-293 (Human embryonic kidney) using cytotoxic, apoptosis and cholesterol based assays. HPβCD treatment reduced intracellular cholesterol resulting in significant breast cancer cell growth inhibition through apoptosis. The results hold true for both ER+ and TNBC. We have also tested HPβCD in vivo in MF-1 mice xenograft model and obtained 73.9%, 94% and 100% reduction in tumour size for late, intermediate and early stage TNBC. These data suggest that HPβCD can prevent cholesterol accumulation in breast cancer cells and is a promising anti- cancer agent
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    Characterisation of a geothermal resource at Kwako Hills in Zambia using magnetic and natural source audio magnetotelluric methods
    (University of the Witwatersrand, Johannesburg, 2019) Chinamora, Blessing; Dr Jones, Mike; Prof Webb, Susan
    The announcement by the Zambian government that geothermal energy will be recognized as an energy source in the 2013 national budget drew a lot of attention to investors and scientists. Since the 1950s reconnaissance geoscientific surveys have been carried out on geothermal targets in Zambia by the Geological Survey of Zambia (GSZ). The GSZ, together with an Italian company (DAL, SpA), studied various hot springs (Legg, 1974) and as a result, various prospects have been considered for development or exploration. In this research, the Kwako Hills prospect which is located near Mumbwa district, about 150 km northwest of Lusaka, hosts two hot springs which are good surface manifestations for geothermal energy potential was investigated for its geothermal energy reservoir potential using magnetic and natural source audio-magnetotelluric (NSAMT) geophysical methods. The focus of these surveys was on examining the structural controls that govern the occurrence of the hot springs and the outcropping Hook Batholith just to the north of the east-west trending alluvium filled valley. The northern branch of the alluvium valley has a northwest–southeast trend which is the same as the minor fault controlling the two hot springs. These structural controls increase the vertical permeability in the area causing the thermal waters to circulate to depths where they acquire their heat. Permeability is high at intersections of faults and fracture zones, intersection of major and minor faults or intersection of faults and sedimentary aquifers. Major ENE and NE trending faults were mapped along the Mwembeshi Shear Zone and the boundary between the Hook Batholith and the Katanga sediments respectively. The area is underlain by foliated basement granitic gneiss, Hook Batholith granites and Katanga metasediments that are broken into fractures along the foliation trends that control the occurrence and flow of rivers and streams. Overlying the basement rocks are the recent Karoo and Kundelungu sediments which are also permeable along the bedding or cleavage planes. The vegetation pattern, flow and occurrence of rivers or streams reflect trends of zones of weakness in the basement. Fractured zones developed along these foliations and were mapped at outcropping scale using Google Earth, aeromagnetic and ground magnetic data interpretation. Interpretation of aeromagnetic data confirmed the foliation trends that were suggested by Abell (1970) and Naydenov et al. (2014). One dimensional (1D) and two dimensional (2D) magnetotelluric (MT) resistivity models were created on the basis of a 120 MT sounding data set. A dimensionality and distortion analysis of the NSAMT data was carried out based on the approach of Groom and Bailey (1989) and it was concluded that the data were collected almost perpendicular to strike, which is also supported by the geological mapping. MT smooth inversion models showed the lateral and vertical extent of the potential geothermal reservoir. Different 2D MT inversion approaches were applied to investigate the lateral continuity of the conductive sedimentary layer of the Kundelungu unit (slate, siltstone and shale). In order to map the subsurface structure of the area, a magnetic model was then produced using the acquired ground magnetic data and constrained using magnetic susceptibility measurements, MT data and geology mapped on the surface. Magnetic data interpretation confirmed an NW-SE fault controlling the hot springs, which was mapped using the NSAMT inversion results. The research shows that there is a lateral conductive, water saturated zone (reservoir) present between 150 m and 550 m depth and deeply seated faults in the basin. Along the deeply seated faults the conductive zones are vertical and continue with depth. The information shows that the thermal waters of the hot springs appear to circulate to depths more than 2.5 km along deep seated faults and foliation fractures penetrating the foliated rocks of the Hook Batholith and basement rocks. This water is heated by the regional geothermal gradient of 23ºC/km. Further exploration can be carried out on the study area to prove its potential for a geothermal resource.
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    A comparative analysis of classic Geometrical methods and sparse regression methods for linearly unmixing hyperspectral image data
    (2019) Nicolae, Aurel
    This research report presents an across-the-board comparative analysis on algorithms for linearly unmixing hyperspectral image data cubes. Convex geometry based endmember extraction algorithms (EEAs) such as the pixel purity index (PPI) algorithm and N-FINDR have been commonly used to derive the material spectral signatures called endmembers from the hyperspectral images. The estimation of their corresponding fractional abundances is done by solving the related inverse problem in a least squares sense. Semi-supervised sparse regression algorithms such as orthogonal matching pursuit (OMP) and sparse unmixing algorithm via variable splitting and augmented Lagrangian (SUnSAL) bypass the endmember extraction process by employing widely available spectral libraries a priori, automatically returning the fractional abundances and sparsity estimates. The main contribution of this work is to serve as a rich resource on hyperspectral image unmixing, providing end-to-end evaluation of a wide variety of algorithms using di erent arti cial data sets.
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    Synthesis and characterization of novel short antimicrobial peptides with wound healing properties
    (University of the Witwatersrand, Johannesburg, 2019) Machumele, Khanani Peggy; Makatini, Maya Mellisa
    In recent years, there has been an increasing health crisis due to multidrug-resistant microbes. These pathogens are strains of bacteria that have become resistant to antibiotic drugs. In the year 2016, the World Health Organisation (WHO) had appealed to the members of states in the USA to create a priority list of other bacteria that are resistant to antibiotics in order to support research and development of effective drugs. According to literature, antimicrobial peptides have the potential to be potent agents against pathogens that have multidrug-resistant properties. Despite these studies, there are still substantial limitations (toxicity and susceptibility to proteases) that have affected their clinical and commercial development. In this study, the focus was on bacteria that infect wounds. The lack of potent chronic wound treatment has resulted in an enormous financial and physical burden on patients and the health care system. The stress of multi-resistant microbes heighten the challenges plagued on a patient due to untreatable infected wounds. Peptides which are able to kill bacteria and promote the wound healing process would greatly benefit patients. For example, patients with diabetic foot ulcers are prone to chronic wounds because of their condition, which may lead to amputation. Wound healing antimicrobial peptides are able to kill bacteria in the wound and induce the formation of collagen which will result in fewer amputations. The aim of this proposed research is to develop novel wound healing and antimicrobial compounds by derivatizing bioactive peptides into selective and protease-stable peptidomimetics. Tigerinin RC1 is an antimicrobial peptide with wound healing properties. It was chosen as a starting point for the design of analogues with drug-like properties and it was also conjugated to silver nanoparticle (AgNPs) to improve its bactericidal activity. In this study, 16 Tigerinin RC1 peptide analogues were successfully synthesized using the solid phase peptide synthesis strategy. Peptides were purified using the semi prep-HPLC however, the desired purity of > 90% was only achieved after two or more purification runs. Thus only 4 of the peptide analogues had a purity great than 90% which were KM-PEP-carb, KM-PEP-cyc-amide, KM-PEP-ada and KM-PEP-CT. These peptides were tested for antimicrobial activity and KM-PEP-cyc-amide peptide showed promising results with the minimum inhibitory concentration of 128 μg/ml against P. aeruginosa. Cytotoxicity studies also revealed that conjugation of KM-PEP-carb to AgNPs improved cytotoxicity because when 25 μg/ml of KM-PEP-carb was tested against human T cells the cell viability was -1.48% and when conjugated to AgNPs the cell viability increased to 35.17.
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    Control of serine dehydratase activity in rat liver
    (University of the Witwatersrand, Johannesburg, 2015-02-24) Abed, Suliman; Manchester, K.L.
    Gluconeogenesis from amino acids in the liver is enhanced when the utilisation of glucose is limited under various hormonal and dietary conditions, such as diabetes, starvation or administration of a carbohydrate free diet. Pyruvate is of great importance as a carbon source for gluconeogenesis, since the sequence of gluconeogenic reaction is initiated by carboxylation of pyruvate to oxaloacetate. From this point of view, an important physiological role is suggested for serine dehydratase, which catalyses the degradation of serine to pyruvate and ammonia. The relationship of serine dehydratase levels to gluconeogenic activities, however, is poorly understood, A study of the hormonal and dietary control of serine dehydratase activity was carried out in vivo and in vitro in rat liver. Serine dehydratase was assayed by the colorimetric method of Suda and Nakagawa (1971) and the enzymatic method of Wimhurst and Manchester (1973). Both these methods have been found to be suitable since they are in agreement with each other and also give results which compare favourably with other published values. Activities of serine dehydratase from fresh liver and in slices of liver cultured for various periods have been compared. Also a study of the activity of another soluble enzyme, lactic dehydrogenase, was undertaken and the in vivo and in vitro levels were compared.
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    Sex and age related distinctions in the feeding ecology of the African elephant
    (2010-01-29T08:19:33Z) Greyling, Michelle Deborah