http://theses.ncl.ac.uk/jspui/handle/10443/5256 Tue, 02 Jun 2026 09:37:07 GMT 2026-06-02T09:37:07Z http://theses.ncl.ac.uk/jspui/handle/10443/6799 Title: Complexity of primate cognition through audio-visual sensory convergence Authors: Zhang, Zhipeng Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6799 2025-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6797 Title: Evolutionary divergence of drug-binding sites in ribosomes Authors: Ekemezie, Chinenye Loveth Abstract: Ribosome-targeting drugs are widely used in medicine, research, and agriculture. However, most of our knowledge about how these drugs work comes from studying a few model organisms—such as Escherichia coli and Thermus thermophilus (for bacteria), and yeast and humans (for eukaryotes). As a result, it is often assumed that drug-binding sites are the same across all organisms. However, emerging evidence suggests otherwise. We aimed to understand how drug-binding sites in ribosomes vary across different organisms and how many organisms in nature bear rRNA substitutions in the drug-binding sites of their ribosomes. To answer this, we developed a novel approach to address issues such as data bias, sequencing errors, pseudogenes, and chimeric sequences. Using this method, we systematically analysed drugbinding sites in eukaryotic ribosomes and identified lineages bearing rRNA substitutions in the drug-binding sites of their ribosomes compared to humans and yeast. We then extended our analysis to bacterial species, comparing the conservation of the drug-binding sites of their ribosomes to that of the common model bacterium E. coli. Our findings suggest that the diversification of ribosomal drug-binding sites in bacteria began long before separation of the some of the earliest bacterial phyla, indicating that these variations are ancient. By using Streptomyces ribosomes—which have a modified drug-binding site—as a model, we explored how natural rRNA substitutions affect the orthosomycin family of drugs. Our analysis showed that while some substitutions may change how drug binds to the ribosome, others have little or no effect. Overall, this study offers a detailed understanding of how rRNA changes in the drugbinding site influence drug interactions. This knowledge can guide the precise use of these drugs and support the development of drugs targeting specific organisms. Description: PhD Thesis Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6797 2025-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6795 Title: Synthesis and SAR evaluation of novel imidazo[1,2-a]pyridine derivatives as potential mycobacterium tuberculosis PafA inhibitors/ Authors: Alsubaie, Haya Saad N Abstract: Tuberculosis (TB) continues to be a significant global health challenge, with the rise of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains increasing the demand for new therapeutic agents with novel mechanisms of action. Proteasome accessory factor A (PafA) is of particular interest due to its role in the virulence of Mycobacterium tuberculosis (Mtb) and its poor sequence conservation in humans. This study focuses on the design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridine analogues as antitubercular agents. Specifically, threeseries of imidazo[1,2-a]pyridine-substituted amino acid hydrazides 44, comprising a total of 120 novel compounds, are synthesised and evaluated for their activity against both drug-resistant and drug-susceptible Mtb strains utilising the Resazurin Microtiter Assay (REMA). A comprehensive structure–activity relationship study is conducted, focusing on the imidazo[1,2-a]pyridine scaffold and its three distinct components: the amino acid moiety (R), the hydrazine component (R1), and the phenyl ring attached to the scaffold (R2). Key SAR findings indicate that an increased amino acid side chain size and the incorporation of small halogens at the meta position of the phenylhydrazine enhance biological activity. To further elucidate these results, the most active compounds are subjected to in silico molecular docking studies to predict their binding interactions with PafA. These findings contribute to ongoing efforts to develop novel and effective antitubercular agents, ultimately advancing therapeutic strategies against TB. Description: PhD Thesis Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6795 2025-01-01T00:00:00Z http://theses.ncl.ac.uk/jspui/handle/10443/6785 Title: Determining Previously Undefined Immune Regulatory Networks in Regulatory T Cells and Innate Lymphoid Cells within the Tumour Microenvironment Authors: Lim, Jing Xuan Abstract: Regulatory T cells (Tregs) are essential for immune suppression, employing multiple mechanisms, including co-inhibitory receptor expression. However, the role of the programmed cell death-1 receptor (PD-1) in Treg function remains controversial. Here, we identify PD-1 as a key checkpoint in Tregs, orchestrating a unique co-inhibitory receptor network that shapes their function in tumour immunity. We demonstrate that PD-1 regulates the expression and activity of CD30, a central driver of Treg suppressive function within the tumour microenvironment (TME). Mechanistically, PD-1 deficiency amplifies STAT5 signalling in Tregs, leading to upregulated CD30 expression and thus suppressive capacity. Consistently, in stage IV metastatic melanoma patients, anti-PD-1-resistant individuals exhibit increased CD30 expression on Tregs compared to responders. Thus, we uncover a novel role for PD-1 in restraining CD30 expression, thereby modulating Treg-mediated immunosuppression. These insights provide a rationale for targeting PD-1 and CD30 in combination therapies to improve cancer treatment outcomes. Innate lymphoid cells (ILCs) also play a crucial role in tissue immunity and are influenced by co-receptor signalling. Here, we define a subset of tumour-infiltrating ILCs characterised as Tbet⁺NK1.1⁻, which express PD-1 within the TME. We demonstrate that PD-1 profoundly regulates the function of Tbet⁺NK1.1⁻ ILCs in murine B16 melanoma. PD-1-deficient Tbet⁺NK1.1⁻ ILCs exhibit significantly increased production of IFN-γ, granzyme B, and granzyme K, correlating with diminished tumour growth. These findings highlight a novel regulatory axis through which PD 1 modulates anti-tumour responses in ILCs, suggesting potential therapeutic avenues to enhance immune-mediated tumour clearance. Description: Ph. D. Thesis. Wed, 01 Jan 2025 00:00:00 GMT http://theses.ncl.ac.uk/jspui/handle/10443/6785 2025-01-01T00:00:00Z