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An in-silico study of the type II NADH: Quinone Oxidoreductase (ndh2). A new anti-malaria drug target

- Baye, Bertha Cinthia

Authors: Baye, Bertha Cinthia
Date: 2022-10-14
Subjects: Malaria , Plasmodium , Molecular dynamics , Computer simulation , Quinone , Antimalarials , Molecules Models , Docking , Drugs Computer-aided design
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365633 , vital:65767 , DOI https://doi.org/10.21504/10962/365633
Description: Malaria is caused by Plasmodium parasites, spread to people through the bites of infected female Anopheles mosquitoes. This study focuses on all 5 (Plasmodium falciparum, Plasmodium knowlesi, Plasmodium malariae, Plasmodium ovale and Plasmodium vivax) parasites that cause malaria in humans. Africa is a developing continent, and it is the most affected with an estimation of 90% of more than 400 000 malaria-related deaths reported by the World Health Organization (WHO) report in 2020, in which 61% of that number are children under the ages of five. Malaria resistance was initially observed in early 1986 and with the progression of time anti-malarial drug resistance has only increased. As a result, there is a need to study the malarial proteins mechanism of action and identify alternative treatment strategies for this disease. Type II NADH: quinone oxidoreductase (NDH2) is a monotopic protein that catalyses the electron transfer from NADH to quinone via FAD without a proton-pumping activity, and functions as an initial enzyme, either in addition to or as an alternative to proton-pumping NADH dehydrogenase (complex I) in the respiratory chain of bacteria, archaea, and fungal and plant mitochondrial. The structures for the Plasmodium knowlesi, Plasmodium malariae, Plasmodium ovale and Plasmodium vivax were modelled from the crystal structure of Plasmodium falciparum (5JWA). Compounds from the South African natural compounds database (SANCDB) were docked against both the NDH2 crystal structure and modelled structures. By performing in silico screening the study aimed to find potential compounds that might interrupt the electron transfer to quinone therefore disturbing the enzyme‟s function and thereby possibly eliminating the plasmodium parasite. CHARMM-GUI was used to create the membrane (since this work is with membrane-bound proteins) and to orient the protein on the membrane using OPM server guidelines, the interface produced GROMACS topology files that were used in molecular dynamics simulations. Molecular dynamics simulations were performed in the Centre for high performance computing (CHPC) cluster under the CHEM0802 project and the trajectories produced were further analysed. In this work not only were hit compounds from SANCDB identified, but also differences in behaviour across species and in the presence or absence of the membrane were described. This highlights the need to include the correct protein environment when studying these systems. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2022
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Date Issued: 2022-10-14

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Bioinformatics tool and web server development focusing on structural bioinformatics applications

- Nabatanzi, Margaret

Authors: Nabatanzi, Margaret
Date: 2022-10-14
Subjects: Structural bioinformatics , Proteins Structure , Protein structure prediction , Proteins Conformation , Protein complex
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365700 , vital:65777 , DOI https://doi.org/10.21504/10962/365700
Description: This thesis is divided into two main sections: Part 1 describes the design, and evaluation of the accuracy of a new web server – PRotein Interactive MOdeling (PRIMO-Complexes) for modeling protein complexes and biological assemblies. The second part describes the development of bioinformatics tools to predict HIV-1 drug resistance and support bioinformatics research and education. Recent technological advances have resulted in a tremendous increase in the number of sequences and protein structures deposited in the Universal Protein Resource Knowledgebase (UniProtKB) and the Protein Data Bank (PDB). However, the number of sequences has increased at a higher rate compared with the experimentally solved multimeric protein structures. This is partly due to advances in high-throughput sequencing technology. To fill this protein sequence-structure gap, computational approaches have been developed to predict protein structures from available sequences. Computational approaches include template-based and ab initio modeling with the former being the most reliable. Template-based modeling process can be achieved using either standalone software or automated modeling web servers. However, using standalone software requires familiarity with command-line interfaces as well as utilising other intermediate programs which could be daunting to novice users. To alleviate some of these problems, the modeling process has been automated, however, it still has numerous challenges. To date, only a few web servers that support multimeric protein modeling have been developed and even these provide little, if any user involvement in the process. To address some of these issues, a new web server – PRIMO-Complexes – was developed to model protein complexes and biological assemblies. The existing PRIMO web server could only model monomeric proteins. Part 1 of this thesis provides a detailed account of the development and evaluation of PRIMO-Complexes. The rationale for developing this new web server was based on the understanding that most proteins function as protein multimers and often the ligand-binding sites, and enzyme active sites are located at the protein-protein interfaces. It, therefore, necessitated developing capabilities for modeling multimeric proteins. PRIMO-Complexes web server was developed using the Waterfall system development life cycle model, is based on the Django web framework and makes use of high-performance computing resources to execute jobs. The accuracy of the algorithms embedded in PRIMO- Complexes was evaluated and the results were promising. Additionally, PRIMO-Complexes performs comparatively well in relation to other web servers that offer multimeric protein modeling. Another unique feature of PRIMO-Complexes is its interactivity. The webserver was developed with capabilities for allowing users to model multimeric proteins with an appreciable degree of control over the process. In the second part of the thesis several other bioinformatics tools are described, for example, a webserver for predicting HIV-1 drug resistance, the RUBi protein model repository, and a bioinformatics web portal for education and research resources. RUBi protein model repository stores verified theoretical models built using various modeling approaches. This enables users to easily access models to reproduce and/or further the research. This is described in chapter 5. Chapter 6 describes the design and development of the Human Immunodeficiency type 1 Resistance Predictor (HIV-1 ResPredictor), a web application that employs artificial neural networks (ANN) to predict drug resistance in patients infected with HIV-1 subtype B. The ANNs and subtype classifiers performed well making this web application potentially useful to both clinicians and researchers in this era of personalised medicine. Finally, chapter 7 describes a bioinformatics education web portal that equips students with information on how to use bioinformatics online resources. Being aware of these resources is not enough without a deeper understanding and guidance on how to apply bioinformatics methods to solve practical problems. This web portal was aimed at familiarising students with the basic terminology and approaches in structural bioinformatics. Students will potentially gain skills to conduct real-life bioinformatics research to obtain biological insights. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2022
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Date Issued: 2022-10-14

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Cape Fold Ecoregion fish community ecology and responses to stressors

- Broom, Casey Jay

Authors: Broom, Casey Jay
Date: 2022-10-14
Subjects: Cyprinidae South Africa Western Cape , Freshwater fishes South Africa Western Cape , Cyprinidae Habitat South Africa Western Cape , Food chains (Ecology) , Restoration ecology South Africa Western Cape , Riparian restoration South Africa Western Cape
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365644 , vital:65772 , DOI https://doi.org/10.21504/10962/365644
Description: Freshwater fishes are in global decline and fish as a group are the most imperilled of all vertebrates. Freshwater systems are among the most threatened globally, largely owing to their comparatively high species and habitat diversity while occupying a minute fraction of the Earth’s surface. In South Africa, invasion by non-native fishes has had a devastating effect on freshwater systems across the country. Numerous other stressors and anthropogenic impacts continue to impact these systems, including habitat degradation, water abstraction and global change effects. In general, South African freshwater systems are under-studied and there is a lack of baseline biological and ecological studies on many freshwater fish species. The Cape Fold Ecoregion (CFE) of South Africa is a particularly vulnerable region, with many range-restricted species and highly fragmented native fish ranges following high invasion rates. Within the CFE, the Olifants-Doring River System (ODRS) is of primary concern owing to the high endemism and imperilled status of its freshwater fish species. The Rondegat River in the ODRS is of notable conservation value, as it hosts populations of important endemic CFE species. This river is unique, being the site of the first alien fish eradication programme of its kind in South Africa. Thus the Rondegat River, and in particular its imperilled cyprinid assemblage, is used here as a case study of the responses and community dynamics of recovering freshwater fish species. The members of this cyprinid assemblage are Sedercypris calidus, Pseudobarbus phlegethon and Labeobarbus seeberi. Sedercypris calidus and L. seeberi are listed by the International Union for the Conservation of Nature (IUCN) as “Near-Threatened”, while P. phlegethon is listed as “Endangered”. Understanding the dynamics and responses to understudied vulnerable fish communities in the wake of restoration efforts was the overarching goal of this thesis. The first chapter served as a review of current knowledge of the CFE, the Rondegat River, the myriad stressors that have impacted on or are projected to affect this region, and the freshwater fish species on which those stressors act. My first investigations served as an extension of the existing Rondegat River monitoring programme, making use of remote underwater video (RUV) data to assess relative abundance and habitat associations of the focal species (Chapter 2). A relatively limited spatial range of P. phlegethon was established, which was suggested to be a result of relatively highly specialised habitat requirements and sensitivity to disturbance. Sedercypris calidus was confirmed as a relatively more abundant and ubiquitous species across the length of the Rondegat River, sharing much of the lower and middle reaches with L. seeberi. I sought to use experimental trials of functional response, as a proxy for feeding performance, across representative temperatures and relevant prey types, in the spatially overlapping S. calidus and L. seeberi (Chapter 3). Labeobarbus seeberi generally outcompeted S. calidus across temperature treatments and prey types. The ecomorphology and diet of all three species were used to construct trophic profiles, which suggested that there was a high degree of feeding capacity overlap between L. seeberi and S. calidus, while P. phlegethon diverged from the other two species (Chapter 4). Gut content suggested that all three species overlapped broadly in diet. This indicated that the realised trophic niche of these species is similar, despite some morphological specialisation. I then used RUV data to investigate in-situ feeding behaviours, with the aim to disentangle the nuances of community dynamics and mechanisms of coexistence in the cyprinid assemblage (Chapter 5). I found that, despite the higher feeding performance of L. seeberi (Chapter 3) and its overlaps in diet and feeding capacity with S. calidus (Chapter 4), S. calidus is able to mitigate competitive pressures through foraging mode switching and exploitation of allochthonous food inputs. Evidence for further habitat and prey selectivity in Pseudobarbus phlegethon was gathered based on dependence on complex habitats and pool refugia for the majority of its feeding, supporting this species as a headwater specialist; alongside signals of its spatial and habitat use patterns (Chapter 2). While S. calidus and L. seeberi were found to be less habitat-specific than P. phlegethon, caution was noted in the potential for ongoing stressors, such as habitat destruction, loss of river connectivity and global change effects, to impact on the reproductive success of these two species. Stressors affecting the habitats and sensitive invertebrate taxa upon which all three species depend continue to threaten the Rondegat system, highlighting the need to maintain ecosystem integrity through conservation interventions. There remains significant scope to maintain restoration efforts in the Rondegat River and other river systems of the CFE, through direct conservation actions, enhanced community awareness, indigenous riparian vegetation restoration and involvement of local stakeholders in various conservation-centred activities. , Thesis (PhD) -- Faculty of Science, Ichthyology and Fisheries Science, 2022
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Date Issued: 2022-10-14

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Colonial displacements and African coping strategies: The experience of BaTonga of Binga, Zimbabwe, 1956-2008

- Dhodho, Codelia Govha

Authors: Dhodho, Codelia Govha
Date: 2022-10-14
Subjects: Tonga (Zambezi people) Refugees , Subsistence farming Zambezi River Valley , Hunger Zambezi River Valley , Food security Zambezi River Valley , Adaptability (Psychology) , Food relief Zambezi River Valley , Non-governmental organizations , Kariba Dam (Zambia and Zimbabwe)
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/327642 , vital:61139 , DOI 10.21504/10962/327642
Description: This study examines the challenges faced by BaTonga in livelihood reconstruction after involuntary displacement and resettlement from the Zambezi valley to pave way for the Kariba dam reservoir. It shows how they were forcibly evicted without compensation because of the racist policies of Southern Rhodesia. Their resettlement into an arid region infested with marauding elephants, malaria and tsetse fly undermined their complex livelihoods and eroded their self-sufficiency, but the study argues that they were active and resilient agents who adopted complex coping strategies. It shows how they had to adapt to dry-land farming and counter the effects of wildlife which plundered their crops and managed to secure the harvest in the drought-prone region. The study shows that although they adopted precarious livelihoods, they managed to survive under extreme circumstances for decades without any external assistance until the coming of NGOs who began to distribute free food from 1982. It argues that prolonged distribution of emergence food aid may not have been necessary, but its coming for almost three decades largely served political interests of both the NGOs and their governments. This perpetuated poverty as BaTonga also manipulated its distribution as a coping strategy against fragile livelihoods. This caused dependency which further plunged them into chronic food insecurity because they abandoned their traditional coping strategies. The study argues that both the colonial and postcolonial government as well as NGOs failed to address the root causes of livelihood insecurity in Binga for the five decades under study. It is therefore the contention of this study that the problem of food insecurity in Binga was not only an issue of recurring drought but was deeply rooted and pervasive due to multiple complex factors which made it difficult for the people to establish sustainable food production after displacement. , Thesis (PhD) -- Faculty of Humanities, History, 2022
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Date Issued: 2022-10-14

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Composition Portfolio

- Hanmer, Paul Dylan

Authors: Hanmer, Paul Dylan
Date: 2022-10-14
Subjects: Composition (Music) , String quartets Scores , Symphonies Scores , Music South Africa
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/327283 , vital:61100 , DOI 10.21504/10962/327283
Description: Extract from Introduction: “In the cover bands I worked with, I used to do what all my colleagues in these bands were doing to learn and remember repertoire; transcribe “by ear” and then rehearse with the whole band. Later, when I joined “909” [a cover band named after the “909” model of drum-box developed and built by the Japanese company, Roland] I learned to extend that skill by notating my transcriptions and then playing from these self-made keyboard parts. All the instrumentalists in that band likewise played from their own notated transcriptions and, from that time onward it became rarer for me to do any kind of performance work without a set of self-made parts to read from or refer to. I had thus reverted to performing from musical notation. Even later, when I became involved almost exclusively in improvisational music performance, I never quite abandoned the notion of having notated keyboard or piano parts to hand, as a reference or guide. Since about 1990, I have led a life that has increasingly left pop music behind and instead embraced working with improvising musicians; those who wish to explore South African folk idioms in their compositional and performance output, as well as others who have a deep love of jazz music. At the same time, I have re-entered the realm of classical music and music-making; often through writing arrangements of my own music, which would incorporate classically trained players, as well as in response to commissions to compose [for particular musicians or groups of musicians] fully notated pieces of music – such as the works in this PhD portfolio. Yet, there are many circumstantial factors that feed into my composing, and exert an influence on my creativity. A major step in this particular direction came during 2002 when composer, Michael Blake, asked me to contribute to The Bow Project. This commission brought me into close contact with the [then intact and very active] Sontonga Quartet. Several further requests for, and commissions of, new works followed on from there. Two such works constitute the major portion of the portfolio to which these reflexive commentaries refer.” , Thesis (PhD) -- Faculty of Humanities, Music and Musicology, 2022
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Date Issued: 2022-10-14

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Demand-side factors and the employment of young people: A case study of the recruitment and selection strategies of selected firms in Johannesburg

- Gabobegwe, Maoshadi Keletso Amanda

Authors: Gabobegwe, Maoshadi Keletso Amanda
Date: 2022-10-14
Subjects: Unemployment South Africa , Underemployment South Africa , Unemployed youth South Africa , Labor market South Africa , Employees Recruiting South Africa , Employer attitude surveys South Africa , International Labour Organisation
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/327294 , vital:61101 , DOI 10.21504/10962/327294
Description: Unemployment is a long-standing and pressing socio-economic phenomenon that affects, markedly, both developed and developing countries. Although, in one way or another, many people are affected by unemployment, the reviewed literature concurs that youth unemployment is a critical component of the overall unemployment challenge. Indeed, the burden of unemployment is borne, tremendously, by young people, especially those who are Not in Education, Employment, or Training (NEETs). The International Labour Organisation (ILO) has declared youth unemployment a global crisis, with approximately 67,6 million unemployed young people worldwide in 2018. In South Africa, the youth unemployment rate escalated to 56.4 per cent in the second quarter of 2019. This disturbing level of unemployment among young people poses a serious threat—for as long as young people stay unemployed. Indeed, the cost of unemployment is too high, not only does it engender discontent among young people who are floundering in poverty and frustration, but it can also trigger or perpetuate all sorts of social, political, and economic effects. These effects only exacerbate the already intricate and onerous global agenda of tackling unemployment— because they give rise to other socio-economic ills (e.g., crime, among others) that also need to be addressed. Owing to this grave and perpetual challenge of unemployment, exploring and understanding the dynamics of youth unemployment continues to be of paramount importance worldwide. This thesis, in particular, seeks to investigate the factors that impede on the employment of the NEETs category, as it may be extremely difficult for them to enter the labour market— and they may lose hope of entering the labour market later in life, if they are unsuccessful while still young. Unlike graduates or other youth categories (i.e., matriculants) who have better chances in the labour market, some young people (by virtue of being ‘dropouts’, teenage moms/dads, having failed matric, among other reasons), remain the most vulnerable to unemployment. For this reason, the primary aim of this thesis is to examine the ways in which employers’ recruitment strategies advantage or disadvantage young people (NEETs). The secondary aims include: (a) examining how employers' perceptions and attitudes, regarding the NEETs youths, influence their recruitment decisions when it comes to employing young people; and (b) understanding the ways in which government strategies (devised to combat youth unemployment) influence employers’ decisions to recruit the youths’ or not. In essence, this study seeks to explore the demand-side factors in the labour market that can help us understand how employers’ recruitment decisions (or recruitment behaviour) affect the employment prospects of young people in the labour market. The focus on demand-side factors is motivated by Labour Market Segmentation (LMS) theories, which serve as the theoretical framework of this thesis. LMS theories’ significance lies in their opposition to neoclassical economics, that posit the existence of a unified labour market (which operates like all other markets), consisting of buyers and sellers in ‘free’ competition. According to neoclassical theory, the difference between workers’ employment and wages is determined by ‘individual preferences’ and investments in ‘human capital’ (skills, experience, formal education, etc.). By contrast, LMS theorists argue that labour markets are fragmented, and that differences on the demand side imply differences in compensations that are not totally determined by individual workers' human capital. Inspired by the claims of LMS theories, this study elected to explore demand-side factors by applying qualitative research methods and techniques to gather and analyse the data gathered, and to ultimately address the research objectives. In particular, non-probability sampling was used to sample 20 firms from four sectors (manufacturing, retail/hospitality, finance, transportation) in the Johannesburg (CBD) region. The respondents were all asked a series of semi-structured questions in order to yield qualitative results that would help determine the employers’ dispositions towards young people; and about the government’s strategies that address youth unemployment. The aim is to provide an in-depth, nuanced understanding of how the respondents’ dispositions influence the inclusion or exclusion of young people in the employers’ recruitment considerations. The aggregate results of the study generally indicate that—although there are innumerable factors that affect young peoples' employment prospects—young people (without skills and tertiary education or matric) are actually being employed, and are still being considered for employment by the majority of the sampled employers (predominantly from retail/hospitality firms). Only a minority of employers stated, categorically, that they do not employ young people, and do not intend to do so. Conversely, the results also reveal that the the majority of employers often recruit young people for general and entry-level jobs that are often offered on a non-standard employment basis. At face value, the employment of young people (without skills) in the majority of the sampled firms may seem to make a difference—and it probably does, for as long as young people are exposed to the world of work. However, in the 4 grand scheme of things, the kind of employment offered in these firms is also problematic, because it is, basically, transient and unsustainable. As such, the young people that occupy these jobs are most likely to find themselves back in the unemployment queues whenever the ‘part-time’ or ‘temporary’ employment contracts are terminated. These jobs are especially problematic because policies such as the National Development Plan (NDP) 2030—in line with Sustainable Development Goals—aim to reduce poverty by creating sustainable employment. Contrarily, these kinds of jobs make it hard to achieve poverty reduction, because they are inherently unsustainable and barely lift people (especially young people) from unemployment and poverty. Based on these results, it can be asserted that the proliferation of non-standard employment compromises the agenda for decent work, and it delays the already sluggish Sustainable Development goal of creating sustainable employment (among other goals). This, then, reveals that there is still a stark and long-standing need for more radical strategies that will ensure the creation of sustainable jobs—without which the unemployment crisis will be far from over. Moreover, the results further indicate that the reasons why the minority of the sampled employers do not employ young people boil down to the fact that young people usually do not have what employers look for in their potential recruits; or that young people do not have what employers believe will contribute to the growth and productivity of their firms. In essence, employers will never employ any young person (or any jobseeker in general) that will be a liability than an asset in their firms. Over and above, this thesis corroborates many of the explanations—encapsulated in the growing literature—for rising unemployment, as well as the claims that unemployment is highly pronounced among young people. However, the contribution of this thesis is that it further offers a nuanced view to understanding the demand-side factors (as additional determinants) that hinder the employment of young people (especially those who make up the NEETs category). , Thesis (PhD) -- Faculty of Humanities, Sociology, 2022
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Date Issued: 2022-10-14

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Disentangling the role of prokaryotes in regulating export flux via suspended and sinking organic matter in the southern ocean

- Dithugoe, Choaro David

Authors: Dithugoe, Choaro David
Date: 2022-10-14
Subjects: Microbial ecology , Bioinformatics , Biochemistry , Oceanography , Metagenomics , Carbon cycle (Biogeochemistry) , Prokaryotes
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365745 , vital:65782 , DOI https://doi.org/10.21504/10962/365745
Description: The role of phytoplankton in regulating atmospheric carbon dioxide in the marine environment has been the subject of extensive research. We lack, however, comparative insights regarding the functional contributions of bacteria, archaea, fungi, and viruses (the microbiota) to organic matter export especially in understudied polar marine environments such as the Southern Ocean. This knowledge deficit is in part due to the high levels of microbial diversity which obscures efforts to study the relationship between diversity and ecosystem functions including their roles in the sequestration of carbon and nitrogen. Elucidating their precise contributions to organic matter export may be central to potential ecosystems feedbacks to global climate change. We examined several factors which may influence organic matter export to depth including net primary production, phytoplankton biomass, temperature, and prokaryotic functional capacity in the Southern Ocean. A Marine Snow Catcher was used to collect suspended and sinking material 10 metres below mixed layer depth at Southern Ocean Time Series (SOTS) in autumn (March-April) and in the Atlantic sector of the Southern Ocean in winter (July-August) and spring (October-November) 2019. The suspended and sinking material was used to determine the particulate organic carbon and nitrogen concentrations which were then used to calculate fluxes and export ratio ((e-ratio) - particulate organic carbon flux divided by net primary production). Additionally, genomic DNA was extracted from the suspended and sinking material and sequenced to obtain Shotgun metagenomic data which was employed to reconstruct metagenome assembled genome (MAGs) and their functional capacity using bioinformatic tools such as DRAM. Data from the Atlantic sector of the Southern Ocean, demonstrate that net primary production and temperature were inversely related to the e-ratio which is consistent with previous findings from the northern region of the Southern Ocean. Genomic functional capacity from SOTS suggested that r-strategist (organisms adapted to live in unstable environments) bacteria (e.g., Gammaproteobacteria) were prominent in the suspended pool. By contrast, the sinking particle-pool appeared to be dominated by K- strategists (organisms adapted to stable environment). The opposite was true for the archaea. This finding (i.e., bacteria) differs from a previous study in the northern region of the Southern Ocean, showing that microbes with K-strategists were more abundant in the suspended fraction. K-strategists typically degrade sinking organic matter into suspended organic matter or dissolved organic matter reducing the organic carbon export efficiency. Furthermore, Data from the Atlantic sector of the Southern Ocean revealed that seasonal temperature changes might dictate the rate of regional prokaryotic degradation across the zones. Resulting in rapid degradation at the northerly warmer regions and slow degradation further south. The data further provide evidence of chemolithoautotrophic mechanisms, with prokaryotes harbouring key pathways, required to transform dissolved inorganic carbon into complex organic forms, including recalcitrant dissolved organic carbon. Collectively, the SOTS and Atlantic sector of the Southern Ocean data suggest that shifts in prokaryotic community structure and functional capacity may regulate (either degradation or synthesis of organic matter) carbon export to depth. , Thesis (PhD) -- Faculty of Science, Zoology and Entomology, 2022
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Date Issued: 2022-10-14

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Don’t let the little man live in your head for free: an interpretive phenomenological analysis of seafarers with reportedly high levels of well-being

- Brown, Lauren Natalie

Authors: Brown, Lauren Natalie
Date: 2022-10-14
Subjects: Seafaring life Psychological aspects , Sailors Mental health , Well-being , Phenomenology , Work environment
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/327653 , vital:61140 , DOI 10.21504/10962/327653
Description: The mental health of seafarers has become a growing issue of concern and has attracted the attention of researchers in recent times. Seafarers are predominantly men, spend months at sea with little to no contact with loved ones ashore, and usually must reside in confined spaces that often contain substantial levels of noise and heat. The underlying causes of mental illness among seafarers are known. Some of the causes include sleep deprivation, occupational stress, marital/relationship problems, fatigue, the threat of piracy, psychosocial workload, loneliness, social isolation, separation from families, lack of shore leave, cultural issues, and job security. Despite these stressors, there are many men and women seafarers who flourish in the industry and enjoy their careers. Very little research has been conducted into the well-being practices of those seafarers who enjoy high levels of well-being. This study explores the lived experiences of a group of seafarers with reportedly high levels of psychological well-being, as well as their experiences of workplace stressors and mental health interventions offered by the industry. This study is an interpretive phenomenological analysis, which is epistemologically underpinned by phenomenology, hermeneutics and idiography. Results revealed four focus areas: general lived experiences across two worlds and how this relates to identity, what seafarers with reportedly high levels of psychological well-being experience as stressors, well-being practices of these seafarers and how these seafarers experience and make sense of mental health interventions they have come across. , Thesis (PhD) -- Faculty of Humanities, Psychology, 2022
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Date Issued: 2022-10-14

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Dual and targeted photodynamic therapy ablation of bacterial and cancer cells using phthalocyanines and porphyrins in the presence of carbon-based nanomaterials

- Openda, Yolande Ikala

Authors: Openda, Yolande Ikala
Date: 2022-10-14
Subjects: Phthalocyanines , Porphyrins , Active oxygen , Biofilms , Breast Cancer Treatment , Nanostructured materials , Combination therapy , Photochemotherapy
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365945 , vital:65804 , DOI https://doi.org/10.21504/10962//365946
Description: Phthalocyanines (Pcs) and porphyrins bearing substituents that possess antibacterial/anticancer properties are used as photosensitizers (PS) for the first time in the work. For targeting specificity and improved photoactivity, the PSs were afterward functionalized with carbon nanomaterials such as graphene quantum dots (GQDs) and detonation nanodiamonds (DNDs) via covalent conjugation (amide or ester bonds) or by non-covalent conjugation (π-π stacking and electrostatic interactions). Furthermore, the PSs-DNDs nanoconjugates were conjugated to either chitosan-capped silver nanoparticles (CSAg) via amide bonds or to the bare silver nanoparticles (Ag NPs) using the silver- nitrogen affinity. The as-synthesized nanoconjugates were also fully characterized by spectroscopic and microscopic methods together with thermal analysis. The potential photocytotoxicity of the complexes alone and their nanoconjugates against S. aureus and/or E. coli planktonic and biofilm cultures has been evaluated in vitro. Compared to the non- quaternized PSs, the cationic analogs exhibited a higher photodynamic inactivation against the planktonic cells with log10 reduction values above 9 in the viable count using a concentration of ca. 1.25 μM following 30 min exposure to light (Light dose: 943 J/cm2 for Pcs and 250 mW/cm2 for porphyrins). Whereas, at a concentration of ca. 100 μM the cationic PSs showed complete eradication of biofilms upon 30 min exposure to light. As a result of conjugation to carbon-based nanomaterials and silver nanoparticles, the compounds proved to be more effective as they exhibited stronger antibacterial and anti-biofilm activities on the multi-drug resistant bacteria strains due to synergetic effect, compared to PSs alone. This suggests that the newly prepared nanohybrids (PS concentration ca. 100 μM) could be used as potential antimicrobial agents in the treatment of biofilm-related infections. The target nanoconjugates showed all the advantages of two different groups existing on a single entity. In light of the potential advantages of combined chemotherapy and photodynamic antimicrobial chemotherapy (PACT), this work reports for the first time the use of PACT-ciprofloxacin (CIP) dual therapy using selected indium quaternized PSs which showed higher photoactivity with complete eradication of both Gram-positive and Gram-negative bacteria biofilms at concentrations of 8 μM of PS versus 2 μg/mL of the antibiotic following 15 min irradiation time (light dose: 471 J/cm2 for Pcs and fluence: 250 mW/cm2 for porphyrins) on S. aureus. Whereas the total killing of E. coli was obtained when combining 8 or 16 μM of PS combined with 4 μg/mL of CIP. The combined treatment resulted in the complete eradication of the matured biofilms with the highest log10 reduction values of 7.05 and 7.20 on S. aureus and E. coli, respectively. Used as a model, positively charged dimethylamino-chalcone Pcs also exhibited interesting photodynamic therapy (PDT) activity against MCF-7 cancer cells giving IC50 values of 17.9 and 7.4 μM, respectively following 15 min irradiation. Additionally, the TD-B3LYP/LanL2DZ calculations were run on the dimethylaminophenyl- porphyrins to compare the singlet excitation energies of quaternized and non-quaternized porphyrins in vacuo. the study shows excellent agreement between time-dependent density- functional theory (TD-DFT) exciting energies and the experimental S1>S0 excitation energies. The small deviation observed between the calculated and experimental spectra arises from the solvent effect. The excitation energies observed in these UV-Vis spectra mostly originated from electron promotion between the highest occupied molecular orbital (HOMO) for the less intense band and the HOMO-1 for the most intense band of the ground states to the lower unoccupied molecular orbital (LUMO) of the excited states. , Thesis (PhD) -- Faculty of Science, Chemistry, 2022
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Date Issued: 2022-10-14

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Effect of Helicosporidium sp. (Chlorophyta; Trebouxiophyceae) infection on Cyrtobagous salviniae Calder and Sands (Coleoptera: Curculionidae), a biological control agent for the invasive Salvinia molesta D.S. Mitchell (Salviniaceae) in South

- Mphephu, Tshililo Emmanuel

Authors: Mphephu, Tshililo Emmanuel
Date: 2022-10-14
Subjects: Salvinia molesta South Africa , Weeds Biological control , Cyrtobagous salviniae , Ketoconazole
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365815 , vital:65792 , DOI https://doi.org/10.21504/10962/365815
Description: The effectiveness of established biological control agents depends on biotic and abiotic interactions in the introduced range. The weevil, Cyrtobagous salviniae Calder and Sands (Coleoptera: Curculionidae), was released as a biological control against Salvinia molesta D.S. Mitchell (Salviniaceae) in South Africa in 1985. This agent has been highly successful against S. molesta and has significantly reduced the weed’s populations around the country. However, in 2007, the parasitic alga, Helicosporidium sp. (an undescribed species), was detected in field-collected C. salviniae adults in South Africa. The distribution and impacts of this disease on the weevil and its efficacy as a control agent were not known. In this thesis, the prevalence, infection load, and impact of Helicosporidium sp. on C. salviniae was determined. In 2019, adult weevils were collected from 10 sites across the Eastern Cape, KwaZulu-Natal, Limpopo, and Western Cape provinces and screened to determine the occurrence, infection load, and geographic distribution of Helicosporidium sp. Transmission mechanisms of this disease in C. salviniae were then evaluated. The possible impact of Helicosporidium sp. was assessed by comparing the feeding rates and the reproductive output of the diseased and healthy adults of C. salviniae. An attempt was then made to eliminate the disease in C. salviniae through the application of the antibiotic, ketoconazole. Further, the role of temperature on infection load in C. salviniae was also assessed. Finally, recommendations for the long-term biological control programme against S. molesta in South Africa were made. The disease covers the entire distribution range of C. salviniae in South Africa, with the disease occurrence rate ranging from 92.15% to 100% insects infected per site. Helicosporidium sp. was found to transmit vertically within the populations of C. salviniae. Infection by the Helicosporidium sp. disease reduced the reproductive output of C. salviniae as well its impact on biomass reduction of S. molesta when a diseased culture was compared to a healthy culture from the USA. 98.44 to 98.55% of Helicosporidium sp. loads were reduced through multiple applications of ketoconazole concentrations under in vitro trials. In vivo treatments resulted in 70% control of Helicosporidium sp. in the adults of C. salviniae that were fed ketoconazole three times over a 21 day period. Adult C. salviniae feeding and survival performances were similar when fed fronds of S. molesta inoculated with ketoconazole and water. The lowest and highest disease loads of Helicosporidium sp. were recorded when the weevils were reared at 30°C and 14°C, respectively. As expected, the highest impact and reproductive output of C. salviniae were at 30°C. The evaluations discussed in this thesis highlight the role of diseases in biological control agents, and gaps in both the pre-release and post-release monitoring that should integrate screening of diseases in these studies. Although the combined application of the antibiotic and temperature will reduce Helicosporidium sp. loads and impact, this technology is most likely only applicable where the weevils are reared in small numbers in a rearing facility and not really applicable to the field situation. It is important to release healthy agents that will cause efficient control of the target weed plant species, therefore, when introducing new biological control agents, the health status of such agents needs to be understood. Therefore, long-term field monitoring and assessment of the impact of C. salviniae on S. molesta should be conducted to track all the changes that may result due to the presence of Helicosporidium sp. This long-term monitoring and assessment will give a more informative role of Helicosporidium sp. in field populations of C. salviniae. , Thesis (PhD) -- Faculty of Science, Zoology and Entomology, 2022
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Date Issued: 2022-10-14

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Fucoidans from South African brown seaweeds: establishing the link between their structure and biological properties (anti-diabetic and anti-cancer activities)

- Mabate, Blessing

Authors: Mabate, Blessing
Date: 2022-10-14
Subjects: Fucoidan , Diabetes Treatment , Cancer Treatment , Brown algae
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365677 , vital:65775 , DOI https://doi.org/10.21504/10962/365677
Description: Type 2 diabetes mellitus (T2DM) and cancer are major non-communicable diseases causing a heavy morbidity-mortality and economic burden globally. The therapeutic efforts in managing these diseases are primarily chemotherapeutic and are associated with demerits, including side effects and toxicity, limiting the prescribed amounts. These dosage limits may cause drug resistance, another major challenge in maintaining quality global health. The pursuit of novel natural bioproducts is a reasonable strategy to add to the arsenal against T2DM and cancer. Fucoidans, sulphated fucose polysaccharides abundant in brown seaweeds, have recently become popular for their biological activities, including anti-diabetic and anti-cancer properties. However, endemic South African brown seaweeds have not been adequately explored. Therefore, this study sought to characterise fucoidans extracted from South African brown seaweeds and elucidate their structure to their biological activities. Also, this study highlighted carbohydrate and glucose metabolism as major target processes in the control efforts of T2DM and cancer using fucoidans. Harvested brown seaweeds were identified as Ecklonia radiata and Sargassum elegans. E. maxima was kindly donated by KelpX. The fucoidans were then extracted using hot water, EDTA assisted, and acid extraction protocols. The integrity of the extracted fucoidan was confirmed through structural analysis using FTIR, NMR and TGA. The fucoidan extracts were then chemically characterised to determine their carbohydrate and monosaccharide composition and sulphate content. The characterised fucoidans were profiled for inhibiting the major amylolytic enzymes, namely α-amylase and α-glucosidase. The mode of inhibition by fucoidans and synergy experiments with the commercial anti-diabetic drug acarbose were also investigated. Furthermore, the fucoidans were screened for potential anti-cancer activities on the human colorectal HCT116 cancer cell line. The cytotoxicity of fucoidans was quantified using the resazurin assay. The effect of fucoidan on HCT116 cell adhesion on the tissue culture plastic was also investigated using the crystal violet-based cell adhesion assay. In addition, cancer antimigration properties of fucoidans were also investigated using 2D wound healing and 3D spheroid-based assays. Furthermore, the long-term survival of HCT116 cells was investigated through the clonogenic assay after treatment with fucoidans. Lastly, glucose uptake and lactate export assays revealed the influence of fucoidan on glucose uptake and the glycolytic flux of HCT116 cells. Fucoidans were successfully extracted with a yield between 2.2% and 14.2% on a dry weight basis. EDTA extracts produced the highest yields than the water and the acid extracts. Ecklonia spp. fucoidans displayed the highest total carbohydrate content, with glucose and galactose being the major monosaccharides. S. elegans and commercial Fucus vesiculosus had lower carbohydrate contents but contained more sulphates than the Ecklonia spp. fucoidans. Furthermore, the extracted fucoidan contained little to no contaminants, including proteins, phenolics and uronic acids. In addition, the extracted fucoidans were determined to be >100 kDa through ultracentrifugation. Mass spectrometry also detected the most abundant peak for all fucoidans to be around 700 Da (m/z). Extracted fucoidans inhibited the activity of α-glucosidase more strongly than the commercial anti-diabetic agent acarbose but were inactive on α-amylase. Fucoidans were also shown to be mixed inhibitors of α-glucosidase. Compellingly, fucoidans synergistically inhibited α-glucosidase in combination with the anti-diabetic agent acarbose, highlighting prospects for combination therapy. Finally, fucoidans demonstrated some anti-proliferative characteristics on HCT116 cancer cells by inhibiting their ability to adhere to the tissue culture plate matrix. Furthermore, some fucoidan extracts inhibited the migration of HCT116 cancer cells from 3D spheroids. Some of our fucoidan extracts also inhibited HCT116 colony formation, demonstrating inhibition of long-term cell survival. The E. maxima water extract also inhibited glucose uptake by HCT116 cells, thereby influencing the glycolytic flux. In conclusion, biologically active fucoidans were successfully extracted from South African brown seaweeds. These fucoidans demonstrated anti-diabetic and anti-cancer properties, revealing their relevance as potential drugs for these diseases. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2022
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Date Issued: 2022-10-14

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Functional biogeography: evaluating community assemblage patterns and ecosystem functioning in intertidal systems using trait-based approaches

- Gusha, Molline Natanah C

Authors: Gusha, Molline Natanah C
Date: 2022-10-14
Subjects: Biogeography , Marine algae , Benthic ecology , Invertebrates , Functional redundancy , Ocean temperature , Biology Classification
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365792 , vital:65790 , DOI https://doi.org/10.21504/10962/365792
Description: Analyses of taxonomic diversity patterns within coastal systems has been critical in the development of the theory of biogeography. Increasing evidence, however, shows that the variety of functions that species perform in ecosystems (rather than their taxonomic identity) is a better predictor of the influence of the environment on the species. This information has been useful in predictive ecology leading to the development of trait-based approaches (TBA). Until the late 1970s, however, limited effort (particularly in marine systems) was channeled towards patterns in functional species traits and how they may be affected by changes in environmental gradients. Here, I mapped the functional biogeography of the South African coastline based on a suite of species' reproduction and development traits. Because species composition is one of the key tools used by zoogeographers to map species distribution patterns, I expected lower variability in trait composition within main biogeographic regions than in intervening transition zones based on the habitat templet theory and following the biomass ratio and limiting similarity hypotheses. In brief, the habitat templet theory proposes that “the habitat provides a templet upon which evolution forges species characteristics”, while the biomass ratio hypothesis assumes that the most abundant species traits determine ecosystem functioning. The limiting similarity hypothesis also sometimes referred to as the niche complementarity hypothesis, however, predicts that species can coexist if their niches complement one another. In light of the habitat being an evolutionary templet, abiotic and biotic habitat patterns were measured as nearshore SST and chlorophyll-a gradients, respectively. I expected the SST gradient to act as the stronger key filter of trait diversification because temperature is often considered the most influential environmental factor affecting species survival with seasonality of SST affecting the timing of spawning and along with food availability, possibly influencing fecundity. Functional trait data were thus compiled for macroinvertebrate species collected from fifty-two rocky shore sites from three main bioregions (east, south, and west) and two transition zones (south-west and south-east). Biological trait analysis and functional diversity indices were used to evaluate how traits related to species development and reproduction respond to temperature and chlorophyll -a (used as a proxy for food availability) gradients along the coastline. GLMM and hierarchical cluster analyses showed distinct patterns/shifts in SST and chlorophyll-a gradients across bioregions, with two main breaks in SST separating the east and south-east overlap (SEO) bioregions from the south, south-west overlap (SWO) and west bioregions. In contrast, chlorophyll-a exhibited three major breaks with the east, SEO–south–SWO, and west clustering independently of each other. The RLQ analysis (a type of co-inertia analysis) which simultaneously ordinates 3-matrix datasets [i.e., (environment × site[R]), (species × site[L]) and (species × traits [Q])] showed that the higher SST gradient on the east and SEO promoted higher abundance and biomass of simultaneous hermaphrodites while higher chlorophyll-a gradients on the SWO and west coasts strongly promoted reproductive maturity at larger-sizes. The combined fourth-corner analyses showed that the modalities within the development trait domain responding to chlorophyll-a gradients primarily included filter feeders, sessile and swimming species and also species living on the infratidal zone. In addition, the reproduction trait domain showed higher sensitivity and association to differences in chlorophyll-a and SST gradients than development traits. Overall, SST and chlorophyll-a gradients influenced the distribution of the most dominant traits as indicated by shifts in community-weighted mean trait values across bioregions. This suggests the importance of habitat filtering on coastal species reproduction. A separate study evaluating the influence of large-scale biogeographic effects vs the micro-scale biogenic habitat structure offered by coralline seaweeds across 24 sites revealed some notable effects of both factors on the diversity and abundance of macroalgal epifauna. There was a notable biogeographic influence on epifauna, with the SEO recording the highest epifaunal species richness and abundance, followed by the south coast, then the SWO and lastly the west coast. In addition, the total biomass gradient of the corallines followed a similar trend. The epifauna however, showed no host-specificity, illustrating that epifauna may not be species–centric as commonly assumed, and the higher diversity of epifaunal diversity may well be simply because those corallines are the available habitat within the sampled part of the coastline. Lastly, macroinvertebrate trait distribution on the South African coastline confirms that the habitat, particularly the biotic filter (in this case chl-a) provides a templet upon which evolution forges species traits. However, since temperature is a proxy for nutrient availability (cold upwelling brings nutrients), then temperature drives chlorophyll-a. Subsequently this means the abiotic component indirectly drives trait distribution by influencing the biotic environment (chl-a). For epifauna species, also, the coralline diversity and composition can also be regarded as a biotic filter influencing the epifaunal abundances and composition across different bioregions. Moreover, since temperature is regarded as a conservative trait in seaweeds, temperature tolerance defines the biogeographical boundaries of seaweeds, therefore temperature may be indirectly affecting epifauna abundances through coralline species diversity and biomass. In summary, considering the deterministic processes governing ecosystem functioning and community assemblage, the mass ratio and limiting similarity hypotheses showed complementary effects. Different bioregions provided variable support for these two hypotheses, but overall, the mass ratio hypothesis (weighted by species biomass) received stronger support and may be more meaningful to the interpretation of ecosystem functioning and persistence within rocky shore systems. Lastly, although, the SWO showed some of the characteristics of a subtraction zone based on the relatively low abundance, diversity, and biomass measures. Nonetheless, there was evidence of high functional redundancy across all other four bioregions. This suggests that in the context of development and reproduction traits, the rocky shore ecosystem along the SA coastline may be functionally stable at this stage. , Thesis (PhD) -- Faculty of Science, Zoology and Entomology, 2022
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Date Issued: 2022-10-14

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Human Development, the Capability Approach and the Mediating of Sustainable Rural Livelihoods: a case study of women’s empowerment through expansive learning in the Mzimvubu Catchment of the Eastern Cape province, South Africa

- Conde Aller, Laura

Authors: Conde Aller, Laura
Date: 2022-10-14
Subjects: Expansive learning , Social learning , Transformative learning , Capabilities approach (Social sciences) , Women's rights South Africa Mzimvubu River Watershed , Women Economic conditions , Women Social conditions , Sustainable agriculture South Africa Mzimvubu River Watershed
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/366236 , vital:65845 , DOI https://doi.org/10.21504/10962/366236
Description: This study makes a contribution to the field of sustainable agricultural development and women empowerment in rural South Africa by examining the transformations derived from an expansive learning process with a women farmers group in terms of their food production capability expansion and empowerment as well as the well-being of their local catchment or landscape where their activity was situated. The study took place in the Lutengele villages along the upper reaches of the lower Mzimvubu Catchment near Port St Johns in the Eastern Cape province of South Africa. Women in southern Africa are significant contributors to household livelihoods through their household food production practices and at the same time they are also one of the primary natural resource users in rural landscapes. In this case study, historical and contemporary ethnographic and situational data revealed disjuncture between existing practice and the fulfilment of women aspirations with regard to food security and social and ecological well-being at large. As a result, central to this study were the concepts of aspirations and capabilities and the role that these played in transformative learning processes via formative intervention research (after Engeström’s concept of expansive learning). Expansive learning emerges from Vygotsky’s early work on mediation of learning through language and culture, which gave raise to Cultural Historical Activity Theory (CHAT). Whereas the Capability Approach (CA) recognises that development interventions or initiatives should focus on “expanding the freedom that deprive people from enjoying their valued beings and doings” (Sen, 1999, p. 3), in other words, what people value or have reason to value. The Capability Approach coupled with CHAT deepens the contextual understanding of the agricultural activity system in light of the engendered power dynamics associated with women having access to productive resources, their culturally expected roles and responsibilities in the institution of their households, their families and the community at large, and most importantly, aspects of gerontocracy defined by their age and status in society. In addition, drawing on the Capability Approach as a lens to view agricultural development, social transformation and empowerment, provided the tools to conceptualise participants’ aspirations, their true value and the capabilities necessary for such aspirations to be realised in a context filled with socio-cultural and political power relations and dynamics faced especially by women. The first phase of the study set out to map the context in which the participants’ small-scale food production activity was situated, their aspirations relevant to sustainable agricultural livelihoods, food security, well-being and lastly, the main factors or contradictions inhibiting participants from attaining the aspired food production goals. During the initial phase of the expansive learning cycle I was able to address the first research question: What tensions and contradictions in aspiration-practice relationships shape household food security in the context of catchment management of the women farmers’ group or river forum in the Lutengele area? Twelve contradictions were identified from the historical and contemporary socio-cultural analysis of the home-based food production practices and agricultural activity in relation to the research participants’ envisaged aspirations, which under further scrutiny were thereafter considered by the participants as critical capabilities to pursue during the collective and transformative learning process in the second phase of the study. In the second phase of the study, a series of second stimuli were introduced in the form of conceptual and material tools and tasks with the aim to move participants along the expansive learning process. This led to the unfolding of the collectively defined Capability Learning Pathways for sustainable food production or expansion of their agricultural capability in the context of sustainability of the local micro-catchment or landscape. Through the various Change Laboratory workshops and supporting mini-cycles in the last stages of the formative interventionist research, participants’ learning and development was supported in a way that not only brought individuals together to co-design relevant solutions, strategies and working groups or committees, but also catalysed and amplified transformative agency and the expansion of food production capability, sustainable land use practices and ultimately empowerment. This answered the second and most important research question: Can, and if so, how can expansive social learning processes shape conversion factors for turning available resources into functionings that enhance household food security capabilities and ecological well-being? The methodology of expansive learning and formative interventionist research design intervention, with supporting mediating tools, has proven a positive intervention in the attainment of capabilities (or functionings) in relation to the participant’s aspired livelihoods and consequently improving their well-being as well as their ability to navigate through the various gendered power dynamics, especially for the young women participating in this study. The study proposes expansive learning as a suitable critical and transformative learning theory and methodology for the mediation of collective deliberations and the pursuit of capability development as charted by the learners’ collective and individual aspirations. This is a learning process that not only pursues the learners’ attainment of material and cognitive changes but also opens up new opportunities and most importantly, the freedom to exercise their agency no matter the circumstances they find themselves in – in other words, the freedom to aspire and to be, do and become what one values as instrumentally and intrinsically critical to live a life that they have reason to value. In sum, the unfolding of the expansive learning process happened at three levels: at the value clarification level in terms of human and non-human relationships and social relationality, the institutional level and the practices level. The study recommends further research on the suitability of expansive learning and Change Laboratories as a Capability Expansion Methodology involving human development and Capability Approach practitioners, particularly those with an interest in informal learning and community-based empowering initiatives. Additionally, further studies are also suggested for examining formative interventionist research as a participatory action research approach for capability development work in education and learning research and in different study fields and contexts. , Thesis (PhD) -- Faculty of Education, Education, 2022
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Date Issued: 2022-10-14

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Identification of novel compounds against Plasmodium falciparum Cytochrome bc1 Complex inhibiting the trans-membrane electron transfer pathway: an In Silico study

- Chebon, Lorna Jemosop

Authors: Chebon, Lorna Jemosop
Date: 2022-10-14
Subjects: Malaria , Plasmodium falciparum , Molecular dynamics , Antimalarials , Molecules Models , Docking , Cytochromes , Drug resistance , Computer simulation , Drugs Computer-aided design , System analysis
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365666 , vital:65774 , DOI https://doi.org/10.21504/10962/365666
Description: Malaria continues to be a burden globally with a myriad of challenges deterring eradication efforts. With most antimalarials facing drug resistance, such as atovaquone (ATQ), alternative compounds that can withstand resistance are warranted. The Plasmodium falciparum cytochrome b (PfCytb), a subunit of P. falciparum cytochrome bc1 complex, is a validated drug target. Structurally, cytochrome b, cytochrome c1, and iron sulphur protein (ISP) subunits form the catalytic domain of the protein complex having heme bL, heme bH and iron-sulphur [2FE-2S] cluster cofactors. These cofactos have redox centres to aid in the electron transfer (ET) process. These subunits promote ET mainly through the enzyme’s ubiquinol oxidation (Qo) and ubiquinone reduction (Qi) processes in the catalytic domain. ATQ drug has been used in the prevention and treatment of uncomplicated malaria by targeting PfCytb protein. Once the mitochondrial transmembrane ET pathway is inhibited, it causes a collapse in its membrane potential. Previously reported ATQ drug resistance has been associated with the point mutations Y268C, Y268N and Y268S. Thus, in finding alternatives to the ATQ drug, this research aimed to: i) employ in silico approaches incorporating protein into phospholipid bilayer for the first time to understand the parasites’ resistance mechanism; ii) determine any sequence and structural differences that could be explored in drug design studies; and iii) screen for PfCytb-iron sulphur protein (Cytb-ISP) hit compounds from South African natural compound database (SANCDB) and Medicines for Malaria Venture (MMV) that can withstand the identified mutations. Using computational tools, comparative sequence and structural analyses were performed on the cytochrome b protein, where the ultimate focus was on P. falciparum cytochrome b and its human homolog. Through multiple sequence alignment, motif discovery and phylogeny, differences between P. falciparum and H. sapiens cytochrome b were identified. Protein modelling of both P. falciparum and H. sapiens cytochrome b - iron sulphur protein (PfCytb-ISP and HsCytb-ISP) was performed. Results showed that at the sequence level, there were few amino acid residue differences because the protein is highly conserved. Important to note is the four-residue deletion in Plasmodium spp. absent in the human homolog. Motif analysis discovered five unique motifs in P. falciparum cytochrome b protein which were mapped onto the predicted protein model. These motifs were not in regions of functional importance; hence their function is still unknown. At a structural level, the four-residue deletion was observed to alter the Qo substrate binding pocket as reported in previous studies and confirmed in this study. This deletion resulted in a 0.83 Å structural displacement. Also, there are currently no in silico studies that have performed experiments with P. falciparum cytochrome b protein incorporated into a phospholipid bilayer. Using 350 ns molecular dynamics (MD) simulations of the holo and ATQ-bound systems, the study highlighted the resistance mechanism of the parasite protein where the loss of active site residue-residue interactions was identified, all linked to the three mutations. The identified compromised interactions are likely to destabilise the protein’s function, specifically in the Qo substrate binding site. This showed the possible effect of mutations on ATQ drug activity, where all three mutations were reported to share a similar resistance mechanism. Thereafter, this research work utilised in silico approaches where both Qo active site and interface pocket were targeted by screening the South African natural compounds database (SANCDB) and Medicines for Malaria Venture (MMV) compounds to identify novel selective hits. SANCDB compounds are known for their structural complexity that preserves the potency of the drug molecule. Both SANCDB and MMV compounds have not been explored as inhibitors against the PfCytb drug target. Molecular docking, molecular dynamics (MD) simulations, principal component, and dynamic residue network (DRN; global and local) analyses were utilised to identify and confirm the potential selective inhibitors. Docking results identified compounds that bound selectively onto PfCytb-ISP with a binding energy ≤ -8.7 kcal/mol-1. Further, this work validated a total of eight potential selective compounds to inhibit PfCytb-ISP protein (Qo active site) not only in the wild-type but also in the presence of the point mutations Y268C, Y268N and Y268S. The selective binding of these hit compounds could be linked to the differences reported at sequence/residue level in chapter 3. DRN and residue contact map analyses of the eight compounds in holo and ligand-bound systems revealed reduced residue interactions and decreased protein communication. This suggests that the eight compounds show the possibility of inhibiting the parasite and disrupting important residue-residue interactions. Additionally, 13 selective compounds were identified to bind at the protein’s heterodimer interface, where global and local analysis confirmed their effect on active site residues (distal location) as well as on the communication network. Based on the sequence differences between PfCytb and the human homolog, these findings suggest these selective compounds as potential allosteric modulators of the parasite enzyme, which may serve as possible replacements of the already resistant ATQ drug. Therefore, these findings pave the way for further in vitro studies to establish their anti-plasmodial inhibition levels. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2022
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Date Issued: 2022-10-14

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Land degradation and livelihood strategies in rural Zimbabwe: the case of two A1 farms in Shurugwi District

- Nciizah, Tendai

Authors: Nciizah, Tendai
Date: 2022-10-14
Subjects: Land degradation Zimbabwe , Sustainable livelihood , Shurugwi District , Conservation of natural resources Zimbabwe , Land reform Zimbabwe
Language: English
Type: Academic theses , Doctoral theses , text
Identifier: http://hdl.handle.net/10962/365989 , vital:65808 , https://doi.org/10.21504/10962/365989
Description: Land degradation is a global phenomenon which is having serious negative consequences for rural livelihoods, which depend quite fundamentally on land and its resources. At the same time, one of the key conditions contributing to land degradation relates to rural livelihood practices, insofar as these practices fail to protect the land. Hence, there sometimes exists a mutually-reinforcing process of decline, in relation to both land vitality and livelihoods vitality over time. This thesis seeks to investigate and understand this complex land-livelihoods process through a case study of two fast track farms in the Shurugwi District of contemporary Zimbabwe. In the year 2000, the Zimbabwean government introduced the fast track land reform programme which fundamentally reconfigured the rural landscape. In particular, it led to the formation of A1 farms (containing small-scale farming units called A1 plots), onto which people were resettled for purposes of enhancing their livelihoods. The case study focuses on two A1 farms in the district, namely, Selukwe Peak and Adare farms. Through a longitudinal study of land and livelihoods on these A1 farms, this study seeks to identify the multi-faceted character of land degradation on the farms, the multi-layered conditions (or causes) facilitating land degradation (specifically, the farm-based livelihood practices) and the effects of this land degradation on these very livelihood practices. This includes a focus on farmers’ understandings of land degradation and how these understandings may or may not condition livelihood practices on the two farms. Of particular importance is the presence of not only agricultural practices, but also high levels of illegal and legal mining on the farms and in the surrounding areas. In pursuing this study, the thesis draws upon the Sustainable Livelihoods Approach alongside Margaret Archer’s morphogenetic sociological perspective. Combined, they provide an intricate understanding of the relevance of both structure and agency to the analysis. A qualitative methodology was used, and this involved a questionnaire survey, in- depth interviews, life histories, focus group discussions and transect walks. The study concludes that the livelihood strategies undertaken by the villagers of Selukwe Peak and Adare farms are key causes of land degradation, as are the land-degrading activities of illegal and legal miners. The A1 villagers are aware that their activities are causing land degradation but they continue these activities because they are pushed by circumstances beyond their control. Hence, both proximate and underlying causes are of some significance in understanding land degradation and livelihoods on the two farms, and their interrelationships. , Thesis (PhD) -- Faculty of Humanities, Sociology, 2022
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Date Issued: 2022-10-14

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