Faculty of Science (ETDs)

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    A Clot to Uncover: FOXP3 and SARS-CoV-2 Nucleocapsid Interactions and Their Effect on DNA Binding
    (University of the Witwatersrand, Johannesburg, 2024) Mcinnes, Keiran; Fanucchi, Sylvia
    During COVID-19, systemic coagulopathy, which can lead to strokes and embolisms, is often observed in COVID-19 patients and may also contribute to long COVID. This coagulopathy is the result of overactivated platelets in circulation that leads to inappropriate clot formation. FOXP3 is a transcription factor involved in platelet development and loss of FOXP3 function leads to platelets that resemble those seen during COVID-19. Thus, FOXP3 may be dysregulated in COVID-19. The SARS-CoV- 2 nucleocapsid (NC) is a multifunctional protein typically associated with viral genome packaging and virion assembly. However, it is also capable of binding DNA and is potentially able to alter regulation of host protein expression. Here, potential interactions between the DNA-binding forkhead domain (FHD) of FOXP3 and the SARS-CoV-2 NC were investigated. Identification of a novel interaction between FOXP3 and SARS CoV-2 NC may provide new clues as to the pathophysiology of COVID-19. To address this aim, both proteins were overexpressed in T7 E. coli, purified via immobilised metal affinity chromatography, and monitored for potential interactions in the absence and presence of DNA using pull-down assays and fluorescence anisotropy. A direct interaction was identified between the two proteins in the absence of DNA. Additionally, it was found that both proteins are capable of binding to DNA at the same time, but excess NC was found to cause FHD dissociation from the FHD- NC-DNA complex. This result implicates NC in FOXP3 dysfunction which may be associated with the coagulopathy and other symptoms seen during COVID-19. Additionally, NC DNA binding does not appear to be driven by the FOXP3 consensus sequence, indicating that FOXP3 may not be the only transcription factor potentially dysregulated by NC
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    Federated learning in the detection of Covid -19 in patient Ct-Scans: A practical evaluation of external generalisation
    (University of the Witwatersrand, Johannesburg, 2023-08) Wapenaar, Korstiaan; Ranchod, Pravesh
    This research explores the practical utility of using convolutional neural networks in a federated learning architecture for COVID-19 diagnostics using chest CT-scans, and whether federated learning models can generalise to data from healthcare facilities that did not participate in training. A model that can generalise to these healthcare facilities could provide lower-resourced or over-utilised facilities with access to supplementary diagnostic services. Eleven models are trained using a modified VGG-16. The models are trained using data from five ‘sites’: four sites are single healthcare facilities and the fifth site is a composite of data from a variety of healthcare facilities. Eleven models are trained, evaluated and compared: five ‘independent models’ are each trained with data from a single site; three ‘global models’ are trained using centrally pooled data from a variety of sites; three ‘federated models’ are trained using a federated averaging approach. The site with composite data is held-out and never included in training the federated and global models. With the exception of this composite site, all models achieve a test accuracy of at least 0.93 when evaluated using test data from the sites used in training these models. All models are then evaluated using data from the composite site. The global and federated models achieve a 0.5 to 0.6 accuracy for the composite site, indicating that the model and training regime is unable to achieve useful accuracies for sites non-participant in training. The federated models are therefore not accurate enough to motivate a healthcare facility decision maker to use the federated models as an alternative or supplementary diagnostic tool to radiographers, or to developing their own independent model. Evaluation of the results suggests that high-quality and consistent image pre-processing may be a necessary precondition for the task.
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    Metal Pincers as Antiviral Agents Targeting SARS-CoV-2 Spike Protein
    (University of the Witwatersrand, Johannesburg, 2023-08) Bracken, Matthew Lee; Munro, Orde Q.
    The purpose of this work was to prove the concept that complexes of bioavailable metal ions may be designed to target specific solvent-exposed amino acid residues on therapeutic protein targets. The complexes synthesized and studied were novel Zn(II) and Cu(II) NNN amide pincers. The chelates were designed by in silico methods to target solvent-exposed tyrosine residues on the receptor binding domain of SARS-CoV-2. These tyrosine residues are crucial for binding host cell receptors and by targeting these groups, the metal pincers may potentially act as antiviral fusion inhibitors for the treatment of COVID-19. Biophysical studies were carried out to determine the binding affinity between the chelate and phenolic residues. These studies identified the most likely binding site for the metal complex on the SARS-CoV-2 spike protein epitope. The novel chelates were crystalized and found to adopt hexameric metallocycle architecture.
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    Are our Head Teachers okay? Decision-making processes during COVID-19 across South African independent schools
    (University of the Witwatersrand, Johannesburg, 2023-10) Pahl, Julia; Evans, Mary
    The COVID-19 pandemic significantly affected the education sphere globally and in South Africa. The impact on pupils and teachers has been investigated. However, the impact on Head Teachers in schools, particularly independent schools in South Africa, has received less attention. Head Teachers within independent South African Schools are the decision makers, leaders, and influencers who were placed in a key role during the COVID-19 pandemic. These Head Teachers were asked to lead, make decisions, and positively influence and manage those under their care while the educational landscape shifted. This shifting educational landscape placed Head Teachers within independent schools under increased pressure and stress. This study aimed to understand the technological and financial access and contexts of Head Teachers at independent schools within South Africa and explore their decision-making processes and the impact of their decisions on their well-being. An online survey was sent to independent Head Teachers, and four in-depth, one-on-one interviews were conducted. Head Teachers showed that their financial and technological contexts did not constrain their pandemic responses as the nature of their independent school allowed them to have access to adequate technological resources and alternative financial support sources. Key findings of this research were that Head Teachers were commonly influenced both positively and negatively by the complex communication networks and channels created and used during the pandemic and the complex decision-making drivers they had to navigate while leading during the pandemic. The decision drivers of well-being and shared moral purpose were more dominantly considered than the decision driver of National Government Directives, as Head Teachers had to consider their complex and multi-dimensional environments when deciding which decision driver was to be prioritized. Head Teachers had to navigate two main tensions: would they prioritize outcomes such as assessment and reports during the pandemic or would they prioritize awareness and well-being of staff and learners, and would they make their decisions from a compliance standpoint where full compliance was key or from a standpoint where complying as much as possible or enough for deniability was chosen. These results also associated increased communication networks during the pandemic with increased stress and burn-out levels and therefore a decreased well-being of Head Teachers, and increased numbers of Head Teachers leaving the profession. However, a positive outcome of the pandemic was that schools, staff, learners, and parents were forced to increase their device and/or internet access and technological skills to maintain education during the lockdown and the changing educational environment. When these results were studied across the geographical landscape of independent South African schools it was clear that the findings on access, well-being and decision-making were linked to the context of the Head Teacher and their school and not to their geographic location. Yet using complex, multi-faceted communication networks and the resultant stress was a country-wide experience and that National Government Directives was the country-wide main decision-driver for independent South African Head Teachers. Overall, this study identified six key lessons for education within any future South African pandemics: the need for clear and concise instructions within legislation, standard operating procedures need to consider access and context, blended education should become a norm in schools, consistency within education should be maintained throughout, personal boundaries should be maintained throughout and networking between leaders should be increased.