African population prevalent genetic variations of dihydropyrimidine dehydrogenase as the 5-flourouracil cancer drug metabolizing enzyme: computational approaches towards pharmacogenomics studies
- Authors: Tendwa, Maureen Bilinga
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432263 , vital:72856 , DOI 10.21504/10962/432270
- Description: In an era of newly emerging cases of non-communicable diseases such as cancer, research is vital for both the medical and economic well-being of humanity. Pharmacogenomics has laidthegroundworkfor the identification of potential genes in cancer progression and treatment outcome investigations. Researchers are increasingly discovering heterogeneity in the efficacy and toxicity responses of drugmetabolizing enzymes (DMEs) in diverse patient populations receiving anti-cancer therapy. DMEs comprise of Phase I (Cytochrome P450s) and Phase II (glutathione-S-transferases (GSTs), UDP-glucuronosyltransferases (UGTs), and dihydropyrimidine dehydrogenases (DPD)enzymes. The main cause of disparity in DME treatment outcomes is genetic variation,which causes missense mutations leading to structural and kinetic properties of the enzyme. These modifications have a deleterious impact on the pharmacodynamics and pharmacokinetics of drugs through multiple mechanisms. Presently, most cancer medicines are manufacturedin developed countries based on the genetic background of non-African subpopulations. Thus, these drugs may not be optimally effective or can cause adverse side effects. Even though heterogeneity in toxicity and efficacy of these drugs has been observed in African descent, the basis of this population variance remains partially understood. For instance,a deficiencyof DPD, the first-rate limiting metabolizing enzyme in the pyrimidinepathway, causes severe toxicity when exposed to 5-fluorouracil (5-FU) chemotherapy. However, minimum studies have been conducted to unravel itsmolecular mechanismwhich may unravel the observed drug treatment outcomes.The aim of this pharmacogenomics study was to determine the underlying mechanism by which DPD missense mutations, which are associated with an African ancestry subpopulation, provoke dysfunctional 5-FU metabolism, resulting in drug toxicity. This knowledge will be critical in designing drug modulators to aid in the restoration of DPD function, a hallmark of precision medicine. Therefore, in the first part of the research we identified and reviewed the general role of Phase I and Phase II cancer drug metabolizing enzymes. We then used World Health Organization (WHO) essential medicine and drug.com to authenticate the usage of 5-FU as an anti-cancer treatment agent. The 3D structure and chemical structure of the agent was then downloaded from the Drug bank. Subsequently, Human Mutation Analysis - Variant Analysis PORtal (HUMA) and Mendelian Inheritance in Man (OMIM) were used to obtain data on DPD non-synonymous genetic variants. Additionally, the aggregate information of DPD missense mutations and their relation to human health were extracted from ClinVar and Pharmacogenomics Knowledge Base (PharmKGB). This information, along with additional data from single nucleotide polymorphisms (dbSNP), 1000 Genomes Project and Exome Sequencing Project (ESP MAF) considering variants classified based on their minor allele frequency (MAF) of 0.001, as well as research articles, consolidated information on missense mutations associated with African subpopulations. Finally, the wild type (WT) and detected mutation sequences were obtained from the Universal Protein Resources database (UniProt). However, because the 3D structure of human DPD was missing, the dimeric wild type (WT) human 3-dimensional (3D) structure was modeled via MODELLER using the pig’s structure as a template. PRIMO, HHpred, and the Protein Data Bank (PDB) were all used to locate the suitable template. As a result, six clinical (C29R, M166V, Y186C, S534N, I543V, and D949V) and thirteen non-clinical (S201R, K259E, D342N, D432N, S492L, R592Q, A664S, G674D, A721T, V732G, T768K, R886C, and L993R) mutations were discovered. Using AMBER tools, we then determined accurate force field parameters for each monomer of DPD protein's Fe2+ centers. Following the creation of each mutation model structure in Discovery Studio, the resulting AMBER force field parameters were inferred. For each model structure, a drug free (inactive/open-conformation) and drug bound (active/closed-conformation) model structure was created (WT and mutations). The model structures were validated using the consensus of three validation programs, namely ERRAT, PROCHECK, and ProSA. Similarly, the impact on structural functionalities was predicted by consensus from Variant Analysis Porta (VAPOR) web server, which include three support vector machines (SVM)-based tools; PhD-SNP, MUpro, and I-Mutation. After protonation in the H++ web server, the six clinical and thirteen non-clinical (six active site and seven non-active site) mutations identified were then exposed to 600 ns molecular dynamic (MD) simulation. The non-clinical data was divided into two categories to better understand the impact of the mutation based on its position in the protein: six catalytic-domain (R592Q, A664S, G674D, A721T, V732G, and T768K) and seven remote (S201R, K259E, D342N, D432N, S492L, R886C, and L993R) missense mutations. The post-MD analysis was done using the typical existing computational global investigations [RMSD, all versus all RMSD, RMSF, RG, hydrogen bonds (H-bonds) and dynamic cross correlation (DCC)]. In addition, we used in silico tools newly developed within the Research Unit in Bioinformatics (RUBI) group, such as comparative essential dynamics (ED)-principal component analysis and dynamic residue network (DRN) multi-metric [betweenness centrality (BC), closeness centrality (CC), degree of centrality (DC), eigen-centrality (EC) and Katz centrality (KC)] analysis algorithms. From the analysis, it was observed that the loop regions of the mutation proteins had increased loop flexibility, particularly around the catalytic loop, which could account for the enhanced asymmetric behavior of the mutation’s monomers compared to the WT. Notably, the A664S mutant showed relatively lower fluctuations, deviating from the observed heightened flexibility in other mutants. A general decrease in hydrogen bonds was observed in the 5-FU binding environment of the mutations compared to the WT. In particular, 5-FU contact analysis of the WT versus the mutation revealed a reduction in contact between core 5-FU binding residues and catalytic residues Cys671 and Ser670, which form hydrogen bonds that initiate DPD catalytic action. Additionally, BC was used to quantify the importance of a protein residue based on how often it acted as a bridge along the shortest paths between other residues. It reflected the potential control or influence a residue may have over communication between different parts of a protein structure. DC assesses the number of connections or interactions a residue had with other residues in the protein, indicating its overall connectivity within the structure. In both drug free and drug bound state, DPD data from the active site hubs' BC and DC revealed a dimeric asymmetric communication pathway per monomer involving a cluster of newly introduced hubs ensemble along the oxidoreduction conduit from NADPH to 5-FU. The two BC communication pathways were located more on the interior of the oxidoreduction conduit, while the two DC communication pathways were located on the exterior. In both cases, one pathway dominated the other. Partially lost function reported in mutation systems could be credited to the compensation communication response to the catalytic site via the least compromised routes. Similar patterns were observed in allosteric communication pathways to the active site induced by remote mutations. Mutations may have destabilized the active-loop and 5-FU binding environment, resulting in a compensatory mechanism seen by the addition of new hubs to the communication network. Surprisingly, EC hubs in the WT were found within the catalytic site domain, indicating that the region is important in 5-FU metabolism. EC measured the importance of a residue by considering both its own degree of connectivity and the degrees of connectivity with its neighboring residues, highlighting its significance in information flow and communication. Herein, EC hubs in mutant systems were found to lose this importance, with active site domain mutations suffering the most. This could explain why non-clinical catalytic domain mutations R592Q, A664S, and G674D, as well as clinical catalytic domain mutations S534N and I543V, experienced drug exit in one of their monomers during simulation. In contrast, there was no 5-FU exit in the non-clinical remote domain. Additionally, aside from the active site, KC hubs were also found around the cofactors, indicating that these components were equally important in DPD overall function. KC combines the concepts of both degree centrality and eigen-centrality, it incorporated both direct and indirect interactions to evaluate the importance of a residue, assigning higher centrality to residues that have connections to other highly central residues. Hence, providing a more comprehensive measure of influence within the protein network. More importantly, CC is known to measure how efficiently a residue can interact with other residues in the protein, considering the shortest path lengths. It indicates the proximity of a residue to others, suggesting its potential for information transfer or functional integration. CC revealed that the majority of persistent hubs were found within the protein-cores known as cold-spots. Overall, this study highlighted the communication pathways triggered by active site domain mutations, as well as the allosteric communication pathways triggered by each remote mutation in both drug free and drug bound states of the DPD enzyme. Both clinical and non-clinical mutations revealed each protein's adaptive compensation mechanism, which results in partial function loss. In each case, the communication network of the different monomers changed from inactive to activated DPD protein. Cold-spot areas were discovered to contain key persistent residues involved in protein function and stability. These areas have been proposed as potential targets for new or repurposed pharmacological modulators that can restore enzyme function. In the pursuit of precision medicine, it also lays the groundwork for detecting and explaining the molecular mechanisms of other drug metabolizing enzymes related to the African-descent subpopulation. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2023
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- Date Issued: 2023-10-13
An analysis of power relations, affiliation and individuation in selected coup, secession, and inaugural speeches of Nigerian leaders, 1960-2015
- Authors: Unegbu, Osondu Chukwuemeka
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432399 , vital:72867 , DOI 10.21504/10962/432399
- Description: This study examines the positioning of Zimbabwe and the United Kingdom (UK) in the language of news articles about diplomatic relations between the two countries published in two prominent Zimbabwean newspapers, The Herald and The Standard, between 2016 and 2020, using Systemic Functional Linguistics (SFL) and Legitimation Code Theory (LCT). Zimbabwe's present diplomatic discourses are a product of its colonial and post-independence history. This thesis places The Herald and The Standard within the larger context of the Zimbabwean media landscape as a state-owned and a privately owned newspaper, respectively. It contends that the two newspapers influence the positioning of Zimbabwe and the United Kingdom in public spheres where readers engage with the news concerning diplomatic ties. The research begins with a corpus-based examination of 42 news articles published between 2016 and 2020 in The Herald and The Standard. The investigation identified several angles through which Zimbabwe and the UK are positioned in the coverage. Zimbabwe is positioned through reference to its reform agenda, intentions for free and fair elections, and its diplomatic re-engagement drive. The UK is positioned as a source of development funding and new trade agreements, while improved diplomatic relations and the removal of restrictive measures against Zimbabwe are anticipated. Fine-grained analysis was conducted on four articles, two from each newspaper, selected to reflect the trends found in the corpus analysis. The fine-grained analyses showed how linguistic resources contributed to the positioning of the UK and Zimbabwe. Complementary analyses of these articles were conducted using LCT and SFL to describe how readers' knowledge of diplomatic relations is built using language in The Herald and The Standard. The study used the concepts of constellations and cosmologies from LCT to demonstrate how diplomatic knowledge is built in these news articles. In the articles, the constellations are related to policies such as Zimbabwe's reform agenda, people (diplomats and government officials) and moral judgments. Both newspapers contain both positive and negative positioning of Zimbabwe and the UK. However, The Standard is generally critical of removing the UK's sanctions on Zimbabwe and of the Zimbabwean government's reform agenda. Meanwhile, The Herald justifies Zimbabwe's Fast-track Land Reform Programme as resulting from Britain's refusal to fund a land redistribution programme as per the 1979 Lancaster House Agreement. The use of SFL's Appraisal framework helps to examine the linguistic resources used by The Herald and The Standard to describe the positioning of the two countries in relation to each other. Lexical strings help to establish diplomatic positioning in the news articles. These couple with Appraisal to accomplish individuation and affiliation. Affect and Judgement resources revealed the decisions taken by the UK to solve the conflict by encouraging the implementation of a reform agenda by Zimbabwe. Negative evaluation is consistently used to disalign with sanctions. The emerging patterns in the data show that diplomats representing the UK affiliate with Zimbabwe's stated economic and political reforms, and the government of Zimbabwe affiliates with the new trade agreement between Zimbabwe and the UK. At the same time, the UK diplomats individuate away from human rights abuses and the Fast-track Land Reform Programme. Affiliation strengthens confidence in diplomatic ties between Zimbabwe and the UK because the emphasis is placed on restoring them despite the conditions attached. The Herald and The Standard position Zimbabwe as a reformed country ready to implement policies to improve citizens' lives and as a country violating human rights and the rule of law. They position the UK as asserting power over Zimbabwe, willing to resolve the crisis through its foreign policy, and credited for assisting Zimbabwe. This strengthens re-engagement in diplomatic relations and commercial trade between the UK and Zimbabwe. In light of these findings, Zimbabweans are encouraged to cultivate an awareness that enables them to reflect on the challenges associated with diplomatic discourses and the implications for critically analysing the re-engagement initiative. They can promote re-engagement by being cognisant of specific values portrayed in The Herald and The Standard and challenging these values in the light of policy transformation to revive the relations between the two countries. The re-engagement process requires a transformation in Zimbabwe's modus operandi to improve the country's positioning in the diplomatic relations between it and the UK. , Thesis (PhD) -- Faculty of Humanities, Linguistics and Applied Language Studies, 2023
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- Date Issued: 2023-10-13
Enhancing the electrocatalytic activity of phthalocyanines through finding the ideal combination of substituents in push-pull phthalocyanine-based systems
- Authors: Nkhahle, Reitumetse Precious
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432578 , vital:72882 , DOI 10.21504/10962/432578
- Description: Phthalocyanines (Pcs) are a class of synthetic pigments with a similar structure to porphyrins. The work presented in this thesis is centred around these electron-rich macrocycles and their use in electrocatalysis. This body of work provides a more rigorous analysis on asymmetric Pcs, focusing on finding the “ideal” combination of substituents in the synthesis of A3B-type Pcs and how these asymmetric structures compare with their symmetric counterparts (A4) in the electrocatalysis of hydrazine and nitrite. The choice in substituents in the syntheses of the Pcs was such that there is both electron-donating and electron-withdrawing groups to induce a push-pull effect. In the studies involving the electrocatalysis of hydrazine, asymmetric cobalt Pcs (CoPcs) possessing alkyl groups as the primary substituents, with variations in the acid-containing group, along with their symmetric counterparts, probes with potential for further improvement were identified. Using voltammetric and amperometric techniques, the analyte-electrode kinetics, mechanism in which the electrochemical reaction proceeds along with the limits of detection (LoD) were determined. In the general sense, the pentadecylphenoxy-derived CoPcs performed better than those containing the tert-butyl substituent as the dominant substituent with the asymmetric CoPcs producing more favourable results than their symmetric analogues. With respect to the probes designed for nitrite, a multi-dimensional approach was undertaken in that acetaminophen was chosen as the primary substituent whilst multiple changes in the asymmetric component were made. In addition to varying the carboxylic acid-containing substituent, alkyne- and amine-based substituents were also explored in which the alkyne-containing Pc was anchored onto the electrode surface through click chemistry while the amine-bearing Pc was covalently linked (and π-stacked) to nitrogen-doped graphene quantum dots (NGQDs). Another component that was altered was the central metal where CoPcs were compared to manganese Pcs (MnPcs). The most desirable peak oxidation potential for nitrite was observed in the MnPcs as it was the lowest with adsorption sometimes being a better suited method of electrode modification relative to clicking. The inclusion of NGQDs was found to be beneficial when combined with the symmetric CoPc whilst in the presence of an asymmetric Pc complex, less desirable results were observed. Overall, there were variations in the results with the symmetric CoPc sometimes being better than some of the asymmetric CoPcs demonstrating that a blanket-approach in terms of synthesizing and applying asymmetric Pcs is not always viable. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
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- Date Issued: 2023-10-13
Exploring the drivers of co-occurring multiple non-native fish assemblages within an invaded and flow-modified African river system
- Authors: Mpopetsi, Pule Peter
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431871 , vital:72810 , DOI 10.21504/10962/431871
- Description: Globally, there is growing concern on the negative impacts of species invasions and habitat disturbance because these have been shown to have the potential to disrupt native community structure and function. In some instances, these two stressors can occur in concert, such as in river systems associated with inter-basin water transfer (IBWT) schemes. The Great Fish River in the Eastern Cape, South Africa, is an example of a system affected by both habitat modification and multiple fish invasions largely because of an IBWT scheme. The opening of the Orange-Fish IBWT, which transfers water from the Orange River to the Great Fish River, modified the latter’s natural flow regime from irregular seasonal to perennial. In addition, the IBWT facilitated translocations of five fish species from the Gariep Dam (Orange River system) into the Great Fish River system. Proliferation of these non-native fish species, along with that of other fish species introduced for angling and biological control, raise questions on the mechanisms facilitating their existence within this highly modified river system. This thesis explored mechanisms associated with co-occurrences of these multiple non-native fishes within the Great Fish River. A comparison of historical and contemporary records on the ichthyofauna of the Great Fish River revealed that, of the 11 non-native fishes reported in this system, seven have established successfully, three have failed to establish and the status of one was uncertain. The Orange-Fish IBWT and angling were the main vectors of these invasions, accounting for 36% and 46%, respectively. The study also found that most established non-native fish species were large sized, had high longevity and wide habitat tolerance. Trait-based approaches were employed to investigate the role of functional diversity of non-native and native fishes in relation to their composition, distribution and environmental relationships. Although considerable interspecific variation in body morphology-related functional traits among species were observed, there was no clear distinction in these traits between native and non-native fish assemblages on a trait-ordination space. Furthermore, there were weak species-trait-environment relationships, suggesting that environmental filtering was less plausible in explaining the occurrence patterns of these fishes. Stable isotope-based trophic relationships were evaluated in three invaded sections: the upper (UGFR) mainstem sections of the Great Fish River; and lower (LGFR) mainstem sections of the Great Fish River; and its tributary, the Koonap River. It was observed that native and non-native fish assemblages exhibited variation in isotopic diversity typified by low isotopic diversity overlaps in UGFR and Koonap River, whereas the LGFR was characterised by high isotopic diversity overlap. Within the invaded sections, non-native fishes were found to have isotopic niches characterised by variable isotopic niche sizes and were more isotopically dissimilar with propensity towards trophic differentiation within the UGFR and Koonap River but were mostly characterised by high isotope niche overlaps in the LGFR. Overall, these results provided evidence of trophic niche differentiation as a probable mechanism associated with the co-occurrences of the non-native fishes. However, mechanisms facilitating these co-occurrences within the invaded sections appears to be complex, context-specific and, in some cases, unclear. Lastly, machine learning techniques, boosted (BRT) and multivariate (MRT) regression trees, revealed that the flow-disturbed habitats were invaded by multiple non-native species, whereas the non-disturbed headwaters remained invasion free. In addition, non-native species were predicted to co-occur with native species within the mainstem and large tributary sections of the Great Fish River system. Thus, the IBWT-disturbed mainstem sections were predicted to be more prone to multiple invasions compared to undisturbed headwater tributaries. , Tlhaselo ka mefuta ya diphoofolo-tsa-matswantle (non-native species), ha mmoho le phetolo/tsenyehelo ya bodulo ba diphoofolo-tsa-lehae (native species), di nkuwa ele tse pedi tsa tse kgolo ka ho fetisisa hara ditshoso tse kgahlanong le paballo kapa tshireletso ya diphoofolo-tsa-lehae tse phelang dinokeng kapa metsing. Maemong a mang, dikgatello tsena tse pedi dika etsahala ka nako e le nngwe, jwalo ka dinokeng tseo di amanang le maano a ho fetisa/tsamaisa metsi pakeng tsa dinoka tse fapa-fapaneng (IBWT). Enngwe ya dinoka tse jwalo, ke noka e bitswang ka Great Fish River, e fumanehang Kapa-Botjabela (Eastern Cape) ka hara naha ya Afrika Borwa (South Africa). Noka ena ya Great Fish River e angwa ke tshenyehelo ya bodulo ba ditlhapi-tsa-lehae, ha mmoho le tlhaselo ya tsona ka ditlhapi-tsa-matswantle. Tsena di etsahala hahololo ka lebaka la morero kapa leano la phepelo ya metsi le bitswang Orange-Fish IBWT, leo lona le ileng la fetola phallo ya tlhaho ya metsi a Great Fish River. Ho feta moo, leano lena la phephelo yametsi, Orange-Fish IBWT, le entse hore ho be bonolo ho fetisetswa ha mefuta e mehlano ya ditlhapi-tsa-matswantle ho tloha letamong le bitswang Gariep Dam, hoya kena ka hara noka ya Great Fish River. Ditla morao tsa tsena tsohle, ebile ho ata ha mefuta e mengata ya ditlhapi-tsa-matswantle ka hara noka ya Great Fish River. Ho ata hona ha ditlapi-tsa-matswantle ka hara noka ena ya Great Fish River, ho hlahisa dipotso mabapi le mekgwa e bebofatsang ho phela ha ditlhapi tsena tsa matswantle ka hara noka ena; hore ana ebe diphela jwang ka hara noka ya Great Fish River? Ka hona, sepheo le merero wa thuto ena ke ho phuputsa mekgwa e bebofatsang ho phela ha mefuta ena e fapaneng ya ditlhapi-tsa-matswantle ka hara noka ya Great Fish River. Dipheto tsa diphuputso di hlalosa hore, ha jwale, ka hara noka ena ya Great Fish River, hona le ditlhapi-tsa-matswantle tse leshome le motso o mong (11). Bosupa (7) ba tsona di phela ka katleho, ha tse tharo di hlolehile ho theha (3), mme e le nngwe (1) boemo ba teng ha bo hlake. Hare lekola hore ke efeng mekgwa e amanang le ho ata ha ditlhapi-tsa-matswantle ka hara Great Fish River, re fumana hore leano la phephelo ya metsi la Orange-Fish IBWT ka 36%, ha mmoho le boithapollo ba ho tshwasa ditlhapi (angling) ka 46%, ene ele tsona tsela tsa ho kena ha ditlhapi-tsa-matswantle ka hara Great Fish River, tse ka sehlohong. Re fumantsha hape hore katleho ya ditlhapi-tsa-matswantle e amahangwa le hore di boholo bo bokae, le hore diphela nako e ka kang. Mohlala, ditlhapi tse kgolo tse phelang nako etelele ka tlhaho ya tsona, di amahangwa le katleho ya ho theha ka hara noka ena. Ha tseo tse phelang nako e kgutshwanyane tsona disa amahangwe leho atleha ka hara noka ena. Tse ding tsa dipheto di hlalosa hore, ditlhapi-tsa-lehae le ditlhapi-tsa-matswantle, ka karolelano, hadi fapane haholo ka dibopeho tsa mmele, dihlopa tsena tse pedi diya tshwana. Re fumantsha hape hore dihlopa tsena tse pedi tsa ditlapi dija mefuta e fapaneng ya dijo. Eleng engwe ya dintho tse netefatsang katleho ya ditlhapi-tsa-matswantle ka hara noka ena ya Great fish river. Hona keka lebaka la hore, dihlopa tsena tse pedi hadi bakisane dijo, empa di phela ka mefuta e fapaneng ya dijo. Hare phethela, re fumantsha hore mefuta e fapafapaneng ya ditlhapi-tsa-matswantle e fumaneha feela ka hara madulo a amahangwang le phethoho ya phallo ya metsi (flow alteration), madulo asa amahangwang le phetoho ya phallo ya metsi ona ane a hloka ditlhapi-tsa-matswantle. Sena se bolela hore phetolo ya phallo ya metsi ya Great Fish River, ka lebaka la Orange-Fish IBWT, e fokoditse matla a noka ena ho lwantsha tlhaselo ya ditlhapi-tsa-matswantle. Ka hona, ho bobebe hore ditlhapi-tsa-matswantle di thehe ka katleho ka hara noka ena. Tsena tsohle keka baka la phetolo ya phallo ya metsi a Great Fish River e bakilweng ke leano la phephelo ya metsi la Orange-Fish IBWT. , Thesis (PhD) -- Faculty of Science, Faculty of Science, Ichthyology and Fisheries Science, 2023
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- Date Issued: 2023-10-13
From euphoria to disenchantment: the intangible in Black post-apartheid South African fiction
- Authors: Kenqu, Amanda Yoliswa
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432466 , vital:72873
- Description: Access restricted. Exptected release date 2025. , Thesis (PhD) -- Faculty of Humanities, Literary Studies in English, 2023
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- Date Issued: 2023-10-13
InVisible freedom fighter: a critical analysis of portrayals of women in archival photographs, independence monuments and contemporary art in Zambia (Northern Rhodesia) and Zimbabwe (Southern Rhodesia)
- Authors: Kalichini, Gladys Melina
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432433 , vital:72870 , DOI 10.21504/10962/432433
- Description: This doctoral dissertation in art history develops a notion of invisibility by critically analysing processes in which narratives about women are either concealed or uncovered in visual portrayals relating to the independence of Zambia (former Northern Rhodesia) and Zimbabwe (previously Southern Rhodesia). This study concentrates on three main visual categories that include archival photographs, national monuments, and visual art. It critically engages with concepts of memory and history through a framework of gender. The concept of invisibility developed in this thesis articulates a dynamic process in which independence narratives evolve over time, sometimes revealing memories associated with women and at other times rendering women invisible. National liberation in many African states is dominantly accredited to the political parties that were in power at the time of independence. In Zambia, the United National Independence Party (UNIP) is acknowledged for spearheading efforts to overthrow the colonial administration, while in Zimbabwe it is the Zimbabwe African National Union – Patriotic Front (ZANU – PF). Both political parties were headed by men, and the majority of their memberships was also comprised of men; as such, the dominant narratives largely illuminate the stories of men associated with these political parties. The overarching argument of this doctoral dissertation is that there is a gender bias inherent in dominant independence struggles narratives that are communicated through cultural heritage sites such as monuments and archives. In this study, art and art making inform theory as the methodological approach takes the direction in which selected artworks and visual materials are employed as a starting point of considering concepts that relate to the visibilities of stories about women. This approach cogitates the function of art, visual culture, and art history in the production of knowledges that foster in-depth understandings of concepts that explain social phenomena such as historical erasure. This doctoral dissertation in art history is divided into two parts, A and B, that conceptually complement each other. In section A which comprises of chapters one and two, the study develops an alternative visual archive that surveys the involvements of six specific women in the attainment of national independence in their respective countries, and critically analyses the Freedom Statue in Zambia and the National Heroes Acre in Zimbabwe as monuments dedicated to commemorating the independence struggle in the two countries. In Chapters three to five which form the second section of this dissertation, the emphasis of the discussion is on how selected visual artworks of three selected artists disrupt, counter or engage with dominant historical accounts that either exclude or marginalise narratives about women. The three artists include myself, Gladys Kalichini, and Zimbabwean born artists Kudzanai Chiurai and Gresham Tapiwa Nyaude. This thesis offers a culturally rich conversation about visual representations of social, political and cultural roles women performed in the colonial times in Northern and Southern Rhodesia and gives insight into the evolution of the luminosity of contemporary performances of women’s social collectives in Zambia and Zimbabwe. , Thesis (PhD) -- Faculty of Humanities, Fine Art, 2023
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- Date Issued: 2023-10-13
Playing it back: audible traces in contemporary African art
- Authors: Panchia, Bhavisha Laximi
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432455 , vital:72872
- Description: Access restricted. Exptected release date 2025. , Thesis (PhD) -- Faculty of Humanities, Fine Art, 2023
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- Date Issued: 2023-10-13
Porphyrinoid dyes for photodynamic anticancer and antimicrobial therapy treatments
- Authors: Soy, Rodah Cheruto
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432252 , vital:72855 , DOI 10.21504/10962/432252
- Description: The search for alternative therapies and non-toxic photosensitizer drugs that can efficiently generate cytotoxic reactive oxygen species for biomedical applications, such as in alternative photodynamic therapy (PDT) for cancer treatment and photodynamic antimicrobial chemotherapy (PACT) for drug-resistant bacteria treatment is on the rise. Nevertheless, the lack of photosensitizer dyes that absorb light strongly within the therapeutic window (620−850 nm) that can locally target the tumor and bacterial cells and generate singlet oxygen efficiently are some of the main challenges in PDT and PACT treatment. This study sought to address the challenges that impede PDT and PACT from realizing their full potential by synthesizing a series of meso-aryltetrapyrrolic photosensitizer dyes that absorb light within the therapeutic window. These include meso-tetraarylporphyrin (Por), A3-type meso-triarylcorrole (Cor), meso-tetraarylchlorin (Chl), and N-confused meso-tetraarylporphyrin (NCP) dyes with 4-thiomethylphenyl (1), thien-3-yl (2), thien-2-yl (3), 5-bromo-thien-2-yl (4), 4-methoxyphenyl (5), 3-methoxyphenyl (6), 4-hydroxyphenyl (7) and 4-hydroxy-3-methoxyphenyl (8) meso-aryl rings. Por, Cor, Chl and NCP dyes and and their Ga(III), P(V), In(III) and/or Sn(IV) complexes with 1-8, 1-4, 5-8 and 5 meso-aryl rings were studied, along with two A2B-type Ga(III) meso-triarylcorroles with pentafluorophenyl rings at the A2 positions and 3,6-di-t-butyl-9H-carbazole (9) or N-butyl-4-carbazole (10) rings at the B position that were prepared in the laboratory of Prof. Xu Liang of Jiangsu University in the People’s Republic of China. The carbazole nitrogen of 10-GaCor was quaternized at Rhodes University with ethyl iodide to form a cationic species (10-GaCor-Q) for PDT and PACT activity studies. The structures of the synthesized dyes were confirmed using UV-visible absorption and 1H NMR spectroscopy, and MALDI-TOF-mass spectrometry. 1-4-InPor In(III) porphyrins, 1-4-PVCor, 1-4-GaCor A3 PV and GaIII corrole dyes were also conjugated to gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) via sulfur-gold and sulfur-silver affinities. The successful conjugation of the dyes onto the nanoparticles to form dye-AuNP or dye-AgNP nanoassemblies was confirmed using transmission electron microscopy (TEM), energy dispersive X-ray (EDX) spectroscopy, X-ray powered diffraction (XRD), and (X-ray photon spectroscopy) XPS. The photophysicochemical, photostability, and lipophilicity properties of the dyes and their PDT and PACT activities were investigated, and the structure-property relationships were analyzed. This was accomplished by analyzing the changes in the properties of the dyes due to the meso-aryl substituents, central ions, molecular symmetry, and heavy atom effects. Time-dependent-density functional theory (TD-DFT) calculations were also used to further probe the electronic and optical spectroscopic properties of the dyes. The analysis of the photophysicochemical, photostability, and lipophilicity data for the synthesized dyes demonstrated that there are inherent structure-property relationships for the dyes studied. The TD-DFT calculations also assisted in rationalizing the observed optical spectroscopic data for the dyes. The introduction of different meso-aryl substituents resulted in minor absorption spectral changes on the parent structures of the dyes due to their inductive and mesomeric effects, while the insertion of Ga(III), In(III), and Sn(IV) electropositive metal centers resulted in marked red shifts of the B bands due to favorable interactions with the porphyrin or porphyrinoid ligand core. The lower symmetries of the corrole, chlorin, and N-confused porphyrin dyes resulted in enhanced absorption properties within the therapeutic window relative to porphyrins. The heavy atom effect from the Ga(III), In(III), and Sn(IV) central ions, the meso-aryl groups, and the external heavy atom effect from the AuNPs and AgNPs significantly reduced the fluorescence quantum yield values of the dyes resulting in high singlet oxygen quantum yields. The dye complexes also exhibited properly balanced lipophilic properties and high photostabilities. The P(V) ion of the A3 PV corrole dyes reduced the aggregation effects, enhanced cellular uptake, and lowered the lipophilicity values relative to the A3 GaIII corrole dyes. The porphyrin and porphyrinoid complexes studied exhibited relatively low in vitro dark cytotoxicity toward MCF-7 cancer cells, which is enhanced for AuNP nanoconjugates of 1-InPor, 1-3-PVCor, and 1-3-GaCor. The dyes also have low in vitro dark cytotoxicity toward planktonic and biofilm cells of S. aureus and E. coli. The complexes also exhibited favorable PDT and PACT activities toward MCF-7 cancer cells, and planktonic and biofilm S. aureus and E. coli bacteria due to their high singlet oxygen quantum yields. AuNP and AgNP nanoconjugates of 1-4-InPor, 1-4-PVCor, and 1-4-GaCor exhibited enhanced PDT and PACT activities due to the favorable synergistic effects of nanoparticles. The PDT and PACT activities of A3 PV corrole dyes and the nanoconjugates of 1-4-PVCor are slightly higher than those of A3-type GaIII corroles and their nanoconjugates due to decreased aggregation effects and enhanced PS drug uptake. The cationic 10-GaCor-Q species also exhibit favorable PDT and PACT activities in contrast to the neutral 9-10-GaCor dyes due to enhanced PS drug penetration into the tumor or bacteria cells. The complexes also exhibited high Log10 reduction values for planktonic S. aureus suggesting that the dyes are highly efficient PS dyes. The activities of the complexes toward planktonic E. coli bacteria are moderate except for 10-GaCor-Q, 2-4-PVCor-AgNPs, and 5-8-SnChl chlorins exhibiting relatively favorable activity with > 3 Log10 CFU.mL−1 values. The dyes also exhibit moderate activities toward the S. aureus and E. coli biofilm cells, which are lower than for the planktonic cells, as shown by their lower Log10 reduction values. The data demonstrate that the low symmetry corrole, chlorin, and N-confused porphyrin complexes that absorb light strongly within the therapeutic window have significantly enhanced PDT and PACT activities relative to their porphyrin analogs. , Thesis (PhD) -- Faculty of Science, Chemistry, 2023
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- Date Issued: 2023-10-13
Revisionist narratives: locating six Black artist-teachers onto the map of twentieth-century modern art in Zimbabwe
- Authors: Muvhuti, Tichapera Barnabas
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432444 , vital:72871 , DOI 10.21504/10962/432444
- Description: Job Kekana (1916-1995) was a South African sculptor and teacher who moved to Zimbabwe in 1944, where he founded the Kekana School of Art and Craft in the early 1960s. There were also a few Black Zimbabwean artist-teachers, namely, Sam Songo (1929-1977), Cornelius Manguma (b. 1935), Lazarus Khumalo (1930-2015), Joram Mariga (1927-2000) John Hlatywayo (b. 1928), who were either working with missionaries Canon Edward Paterson (1895-1974) and Father John Groeber (1903-1973) at the Cyrene and Serima workshops respectively and later on at the Mzilikazi Arts and Crafts Centre, or with Frank McEwen (1907- 1994) at the National Gallery school. This thesis examines the relative invisibility of Kekana and the selected Black artist-teachers in the dominant discourse of the history and development of modern art in Zimbabwe. Employing the biographical approach as a methodology, and modernism as an analytical tool and foregrounding African thinkers like Chika Okeke-Agulu Elizabeth Georgis, Emma Wolukau- Wanambwa and Salah Hassan, this research exposes the possible reasons for their exclusion from the canon, which are rooted in a gatekeeping culture shown by actors in the local art scene, including art historians and scholars, as well as cultural workers in institutions like the National Gallery of Zimbabwe who have not sufficiently questioned and possibly shaken the enshrined legacies of Paterson, Groeber and McEwen. Canons mostly tend to tell a story that privileges and excludes others from the art narrative of a nation. With the arrival of Frank McEwen on the scene in the late 1950s the stone sculpture tradition rose to prominence in such a way that it overshadowed other forms of art produced in the two mission schools or workshops at Serima and Cyrene. In the process, Kekana and his students at the Kekana School of Art and Craft were relegated to the peripheries of the canon as they carved in wood and tended to work in a more representational style. While there is literature acknowledging the role of the missionaries in laying the foundation of modern art in Zimbabwe, local artists-cum-teachers working with them are only recognised as a footnote on the nation’s map of modern art. Recognising that canons are always evolving and shifting, and without discrediting the work of the three mentioned expatriates – and to an extent that of Tom Blomefield of the Tengenenge Workshop – this thesis attempts to expand the canon by arguing for the inclusion of the critiqued overlooked six. Citing the efforts of researchers, scholars and curators in multicultural South Africa to bring the previously marginalised generation of Black modernists into the mainstream, this thesis demonstrates that it is possible to spotlight the narratives of the Black artists and teachers who continue to occupy peripheral space in the history of Zimbabwe. This comparative analysis is done bearing in mind the temptation of falling into the trap of glorifying ‘South African exceptionalism’. In analysing the Black artist-teachers’ contributions as a counter-narrative, this research proposes a more heterogeneous modernism and revisionist art history. , Thesis (PhD) -- Faculty of Humanities, Fine Art, 2023
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- Date Issued: 2023-10-13
The relevance of career counselling in higher education: a study following students at a South African university
- Authors: Lewis, Christine
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/432347 , vital:72863 , DOI 10.21504/10962/432348
- Description: Very few students in South Africa (SA) receive adequate career counselling at school and often arrive at institutions of higher learning without a clear sense of what their prospective careers will entail. The limited access to career counselling and assessment is further compounded by criticisms of popular career assessment instruments used in SA, where the primary goal of career counselling and assessment is to match clients to careers for job placement. This approach no longer serves the needs of a diverse SA population and disregards contextual influences on careers. Therefore, a need exists to understand and inform career counselling interventions and to guard against the provision of de-contextualised and contextually insensitive approaches. Moreover, changes in the workplace, where career change has become the norm as the world of work has moved away from stability and permanency to fluidity, calls for a contemporary response from career counselling theories, practitioners as well as researchers, to equip clients with the necessary skills to respond to these changes. Thus, SA institutions of higher learning need to innovate their practices to more inclusively, effectively, and justly serve the needs of a diverse student population for work success in a developing nation and a complex world. This study aimed to evaluate the relevance and effectiveness of a university’s career counselling services from the students’ perspectives. It focuses on gaining an indication of the perceived effectiveness of assessment measures used, and to ascertain the influences that impact on individual students’ career decision-making over the course of undergraduate studies. Due to the increasing recognition for the need to develop a contextualised approach to career development interventions, this study included the SACII, a locally developed interest inventory as part of a career assessment battery, with a group of university students. A pragmatic approach using mixed-methods was used. Multiple case studies of the career trajectories of a cohort of undergraduate students who had undertaken career assessments at the university career centre, were tracked longitudinally over the course of undergraduate studies. Data were generated through vignettes that included the 13 participants' career assessment reports, a service evaluation questionnaire and two successive follow-up interviews. Each participant's first follow-up interview occurred six months after their career assessment feedback session; and the second follow-up was in the final year of undergraduate studies, after eighteen months. Descriptive statistical analysis summarised the basic features of the quantitative data from the evaluation questionnaire. Thematic analysis was used for organisation and analysis of the follow-up interview data. Findings were that the career counselling and assessment facilitated greater self-knowledge in relation to career decision-making, assisted with selecting degree major subjects and enhanced career planning abilities. Using locally developed assessment measures in career counselling proved to be useful. Exploring career development from an overarching developmental contextual framework that is applicable and well-suited to the SA context provided a deeper understanding of contextual influences that impact on students' career decision-making processes. , Thesis (PhD) -- Faculty of Humanities, Psychology, 2023
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- Date Issued: 2023-10-13
The use of dynamic software to potentially enhance conceptual understanding and a productive disposition in the visual learning of algebra: an interventionist case study
- Authors: Junius, Daniel Franscius
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431542 , vital:72784 , DOI 10.21504/10962/431542
- Description: Over the decades, the didactics and practice of teaching mathematics has offered many unique challenges and opportunities for exploration and understanding. The introduction and development of technology into mathematics is one of the occurrences which has also contributed to a new discourse in teaching mathematics – in this case the teaching of algebra. Algebra is still seen as a gatekeeper and remains as one of the key reasons for a negative disposition amongst learners towards learning the subject. Across the globe psychologists, philosophers and educators continue to engage in debates and research projects in search of answers and solutions for the improvement of algebra teaching and an improvement in dispositions towards learning algebra. This thesis reports on a research project that focused on the use of dynamic software to enhance the conceptual understanding and productive dispositions of selected learners through the visual learning of abstract algebraic concepts. The research was executed as an interventionist case study. A case study methodological strategy was adopted with two groups of 30 Grade 9 learners. One group was a Grade 9 mathematics class of a school in Windhoek who scored above average in algebra but showed a very low disposition score, while the other group was made up of learners from a community project who scored high on the disposition scale but achieved below average results in algebra. The analytical framework of the case study is structured around a combination of complementary algebraic topics presented through visual learning, with GeoGebra as a medium of instruction. With the focus on visualisation and the use of technology the study investigated and attempted to understand how participants processed and internalised algebraic concepts to make sense of abstract algebraic concepts and eventually gain sustained conceptual understanding. The study was framed by the theoretical theories of constructivism and the Dual Coding Theory. For the collection of data, a mixed methods approach was adopted following three cycles. Three algebraic topics were taught with GeoGebra applets yielding both qualitative and quantitative data, through the observation of participants, screen captures and reflective interviews, using instruments designed specifically for the study and collecting quantitative achievement test results. The study, a journey that both the participants and the researcher embarked upon, revealed that the use of technology enhanced conceptual understanding for both groups and both groups showed a positive change in disposition towards learning algebra. The intervention with GeoGebra consistently and progressively improved in terms of conceptual understanding and dispositions towards learning algebra significant improvements in results were achieved. The findings showed that this approach to teaching algebra yielded positive results and gave new insights into visual teaching with technology. New opportunities for further research were created. , Thesis (PhD) -- Faculty of Education, Secondary and Post-School Education, 2023
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- Date Issued: 2023-10-13
Understanding critical concepts in engaged research to promote health resilience: the case of a systems analysis and epistemically just rural health development project in South Africa
- Authors: Duxbury, Theodore Orlando
- Date: 2023-10-13
- Subjects: Uncatalogued
- Language: English
- Type: Academic theses , Doctoral theses , text
- Identifier: http://hdl.handle.net/10962/431509 , vital:72781
- Description: Access restricted. Expected release date 2025. , Thesis (PhD) -- Faculty of Pharmacy, Pharmacy, 2023
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- Date Issued: 2023-10-13