Electronic Theses and Dissertations (PhDs)

Permanent URI for this collectionhttps://hdl.handle.net/10539/38017

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    In Silico Exploration of Endocannabinoid Receptor–CB1 and CB2–Interactions Comparing Cannabidiol and Cannabidiol Diacetate: A Comprehensive Computational Study
    (University of the Witwatersrand, Johannesburg, 2024-09) Soobben, Marushka; Achilonu, Ikechukwu Anthony; Sayed, Yasien
    In the rapidly evolving field of cannabinoid research, acetylated phytocannabinoids such as cannabidiol diacetate (CBDDA) have shown prominence due to its enhanced effects compared to its natural counterpart, cannabidiol (CBD). Despite the growing popularity in the consumption of acetylated phytocannabinoids, in-depth research on its pharmacological impact, especially on CB1 and CB2 receptors, remains scarce. With rising reports of adverse reactions to acetylated phytocannabinoids, a molecular understanding of their interaction with endocannabinoid receptors (CBRs) is imperative. This study aimed to fill this knowledge gap by analysing receptor interactions of CBDDA in comparison with receptor interactions of CBD. The study showed that CBDDA forms stronger interactions with CBRs than CBD. Recognised for its heightened potency, the potential of CBDDA as a biopharmaceutical product was examined. CBR interactions with known endocannabinoids, agonists and inverse agonists validated the computational models used to determine the difference in conformational dynamics upon ligand binding. In this work, bioinformatics, molecular docking, and molecular dynamics (MD) simulations were used to determine the structural differences of CBRs when bound to CBD/CBDDA. Simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and water environment successfully mimicked physiological conditions. Subsequent high-throughput virtual screening (HTVS) was conducted using CBDDA as a reference where ligands 142730975 and 21568811 were identified as the top scoring hits for CB1 and CB2 receptors, respectively. The identification of these ligands via HTVS highlights the therapeutic potential of targeting CBRs and the biopharmaceutical potential of CBDDA. This study elucidates the specific interactions of CBD and CBDDA with CB1 and CB2 receptors, laying a foundation for assessing the safety and efficacy of acetylated phytocannabinoids. Overall, the differential interaction of CBDDA compared to CBD with CBRs suggests that acetylation changes the conformational dynamics of CBRs thereby potentially affecting signalling. The identification of ligands 142730975 and 21568811 as strong interactors with the receptors may provide valuable leads for the development of new cannabinoid-based therapies.
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    Genome sequencing of the Southern Ground Hornbill (Bucorvus leadbeateri)
    (University of the Witwatersrand, Johannesburg, 2024-10) Patel, Jasmin Bharatkumar; De Maayer, Pieter; Mollett, Jean
    The Southern Ground Hornbill (SGH – Bucorvus leadbeateri) is one of the largest hornbill species worldwide, known for its complex social structures and breeding behaviours. These birds, endemic to Africa, have been of great concern due to their declining populations and disappearance from historic ranges. Despite being the focus of numerous conservation efforts, with research forming an integral part of these initiatives, there is a lack of knowledge regarding the molecular biology aspects of this bird species. This study bridges the gap by presenting the first whole genome sequence of the SGH. The SGH genome was further explored using comparative genomics, genetic variant, and selection analysis, providing deeper insights into the evolution and adaptation of this species. Chapter 1 comprehensively reviews pertinent literature on various aspects of avian evolution, including the role genomics has played in elucidating how these species have adapted and evolved. Furthermore, the current body of knowledge on the SGH is explored. In Chapter 2 the entire genome sequence of the SGH was sequenced using Illumina short-read and Pacific BioSciences long-read datasets. Subsequently, the performance of various assembly approaches was evaluated to attain a high-quality assembly of the SGH. This was coupled with parameter optimisation and reference-based refinement to improve the SGH draft genome assembly. The final draft genome assembly was structurally annotated, providing insight into the genetic blueprint underpinning the SGH. Chapter 3 presents the comparative genomic analysis of the SGH with the genomes of available hornbill species from the genera Bucorvus (Bucorvus abyssinicus and SGH) and Buceros (Buceros bicornis and Buceros rhinoceros subsp. silvestris). This included analysis of the pangenome of the hornbill species, functional characterisation of the core and genus-specific elements of the pan-genome and analysis of orthogroups with evidence of paralogy. In Chapter 4, a species-level comparative genomic analysis of the SGH and the Abyssinian Ground Hornbill (AGH) was performed. Here differences in the species-specific proteome of the two species were analysed and the functional implications of these differences on the adaptation and survival of these species were evaluated. Furthermore, genetic variations between the SGH and AGH were identified and selection analysis of key protein-coding genes with high-impact variants was undertaken. This provided insight into the genetic diversity between the SGH and AGH. Finally, the implications of the study on the understanding of the genetic basis underlying the evolution and adaptation of the SGH is discussed and the future perspective of large-scale population genetic studies is provided.
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    Moving towards landscape initiatives: an analysis of environmental frameworks, protected areas, and community perspectives in the vhembe district, limpopo province, South Africa
    (University of the Witwatersrand, Johannesburg, 2024) Dalziel, Alexandra; Evans, Mary
    ConservaBon strategies have shiMed towards a landscape-centric approach, emphasising conservaBon corridors and ecological networks. However, exploraBon of these strategies within the South African context is incomplete. This research aims to address this gap by applying various methods, including a systemaBc literature review, policy analysis, spaBal analysis using GIS, and conducBng interviews and surveys, resulBng in four key contribuBons invesBgaBng the potenBal for conservaBon corridors and networks. The first is a comprehensive literature review underscoring the significance of corridors and networks while highlighBng the discourse surrounding these emerging approaches in South Africa. The findings revealed a substanBal global interest in landscape iniBaBves. However, South Africa’s contribuBon is geographically limited, with 82% of studies focusing on the KwaZulu-Natal province. Understanding the efficacy of these studies in South Africa necessitates a comprehensive examinaBon of the underlying regulatory frameworks governing protected areas and conservaBon efforts. Therefore, the second contribuBon evaluated protected areas and conservaBon legislaBon and policies to assess their alignment with landscape-focused iniBaBves. The study reveals a lack of explicit provisions supporBng landscape-based conservaBon methods. The third study draws on these findings and uses the Vhembe District in the Limpopo Province as a case study to illustrate the overlooked potenBal of landscape iniBaBves. IniBally, the protected areas in the district were evaluated. Subsequently, the analysis employed Key and CriBcal Biodiversity Areas to highlight the inadequacies within the exisBng protected area network. The findings revealed that although protected areas cover 38% of the Vhembe District, over 70% of CriBcal Biodiversity Areas and 60% of Key Biodiversity Areas lack protecBon. Over 2,000 km2 of unprotected CriBcal and Key Biodiversity Areas were idenBfied along the Soutpansberg Mountain Range and marked as ideal for a conservaBon corridor. The fourth contribuBon centres on community engagement, an essenBal consideraBon for sustainable long-term conservaBon. The results underscored strong community support for a corridor in the Vhembe District, primarily moBvated by the anBcipated socio-economic benefits. However, while landscape iniBaBves promise socio-economic improvement, such outcomes are not guaranteed. Moreover, other potenBal challenges, including development, land rights, and financial constraints, were idenBfied as possible impediments to corridors in the Vhembe District. The invesBgaBon into corridors and networks in South Africa, specifically the Vhembe District, revealed that the discourse on landscape iniBaBves is in its nascent phase. Nevertheless, when prioriBsing community engagement, these iniBaBves harbour tremendous potenBal. New legislaBon and policies that account for these factors will guide proponents of these iniBaBves and propel landscape iniBaBves into South Africa’s conservaBon toolbox.