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Publication Open Access Investigating the relationship between Toll-like receptor activity, low-grade inflammation, cognitive deficits, and antipsychotic drug dose in schizophrenia patients: a moderation analysis(Cambridge University Press, 2026-03-03)Background Schizophrenia (SZ) is a debilitating psychiatric disorder where patients experience cognitive decline. Antipsychotic drugs alleviate positive symptoms but do not improve cognitive performance. We previously demonstrated that Toll-like receptors (TLRs), involved in cytokine production, can predict cognitive deficits in SZ patients. In this study, we aim to investigate the potential moderating effects of antipsychotic drugs on the associations between cytokines, TLRs, and cognition. Methods In total, 280 participants (201 controls and 79 cases of SZ) were recruited in Ireland. Venous blood from the participants was stimulated with TLR ligands. Levels of cytokines were measured from plasma and post-blood stimulation. The participants were administered a battery of cognitive tasks using the Cambridge Neuropsychological Test Automated Battery and Wechsler Adult Intelligence Scale-IIIR. Olanzapine equivalents were calculated using the defined daily dose method. Results The results indicate that antipsychotic drug dose does not predict TLR activity or cognition, indicating that antipsychotic drug dose does not have a direct effect on cognition or TLR activity. However, the relationship between TLR4 activity and visual learning and memory is moderated by the antipsychotic drug dose (B = −0.065; p < 0.001), where increasing doses have a decreasing impact on their relationship. Conclusions Our data indicate that the dose of antipsychotic drugs alone cannot predict changes in cognitive performance and TLR4-activity. It also suggests that antipsychotic drug doses significantly affect TLR activity and its relationship with cognition. These effects are more pronounced on some domains than others. These findings open up new avenues for understanding the complex interplay between antipsychotic drugs, TLRs, and cognitive deficits in SZ.Publication Embargo Selective synthesis of N-Glycosyl Aziridines and their evaluation as Glycomimetics(University of Galway, 2026-03-06)Chapter 1 gives a brief introduction to topics which form the discussion in the later chapters. Carbohydrate structure, the anomeric/exo-anomeric effects, and examples of their application as chiral auxiliaries in asymmetric synthesis are briefly summarised. The Huisgen 1,3-dipolar cycloaddition, which forms an important part of this thesis work, is described: the reactivity of different dipolarophiles, along with existing experimentally-determined selectivity is discussed. Methods of aziridine synthesis commonly found in the literature, including examples of their synthesis from triazolines and through Lewis acid catalysis are introduced. A background to continuous flow chemistry is also provided in chapter 1, mentioning flow chemistry equipment, its advantages over batch reactions, and the application of cycloaddition and carbohydrate chemistry processes to flow methodology. Finally, an introduction to glycosyl hydrolases (glycosidases) and their inhibition is given. In Chapter 2, triazoline and aziridine derivatives were prepared via diastereoselective Huisgen 1,3-dipolar cycloaddition of 2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl azide 3 with the activated acyclic dipolarophile ethyl 4,4,4-trifluorocrotonate. Compared to a sealed tube reaction, conducting the cycloaddition reaction in a continuous-flow reactor shortened the reaction time and permitted the use of EtOAc as a greener solvent, improving overall safety. Thermolysis of the resulting trans-triazolines yielded trans-aziridines, whereas treatment with boron trifluoride diethyl etherate (BF3·OEt2) or benzyl triflate (BnOTf) stereospecifically produced cis-aziridine. X-ray crystallography and NMR spectroscopy facilitated the stereochemical assignments. Regioselective and stereoselective aziridine ring-opening with a nucleophile is also demonstrated Chapter 3 builds on the methodology established in chapter 2. However, it focuses on access to new N-glycosyl aziridines through the azide-alkene cycloaddition of N- phenylmaleimide, a strained cyclic alkene, with glycosyl azides. The synthesis of a fructopyranosyl aziridine and a galactopyranosyl aziridine from fructopyranosyl azide 20 and galactopyranosyl azide 3 respectively was achieved via thermolysis of diastereomeric triazoline intermediates. Continuous flow chemistry improved the intermolecular cycloaddition reaction time and facilitated tandem one-pot synthesis of the fructopyranosyl aziridine. Chapter 4 describes the stereoselective synthesis of a new N-galactosyl aziridine derivative of norbornene and its evaluation as a glycosyl hydrolase inhibitor (Michaelis-Menten enzyme kinetics is introduced in chapter 4). The Huisgen cycloaddition reaction of galactopyranosyl azide 3 with norbornene proceeded in a diastereoselective manner to give exo triazoline derivatives of norbornane. DFT-calculated 13C NMR spectra helped to further verify the observed diastereoselectivity. The removal of acetyl protecting groups from the galactopyranoside, followed by silica gel mediated decomposition of the intermediate triazolines gave exo N-galactopyranosyl norbornane aziridine (NGNA). NGNA displayed potent mixed inhibition of Aspergillus oryzae (A. oryzae) !-galactosidase and showed high selectivity as an inhibitor for A. oryzae !-galactosidase when compared to the "-galactosidase from green coffee beans. Irreversible inhibition causing enzyme inactivation was ruled out through a !-galactosidase incubation assay. The biological evaluation of derivatives of the N-galactosyl 2-trifluoromethyl-3- carboxylate aziridines synthesised previously is explored in Chapter 5. Their initial assessment as !-galactosidase inhibitors via a glycosidase inhibition assay showed them to be weak competitive inhibitors. This was followed by the synthesis of 3’-O-sulfated aziridine derivatives, targeting the inhibition of galectin-8N (Gal-8N; topic introduced in chapter 5). They were found to be relatively weak ligands compared to existing Gal-8N inhibitors. Molecular docking proposed improved affinity for the primary alcohol aziridine analogue, whose synthesis is demonstrated.Publication Open Access The multifaceted role of Rad9 in the DNA damage response of Saccharomyces cerevisiae(Wiley, 2026-03-04)To maintain the integrity of the genome, cells have evolved a complex signalling system, termed the DNA damage response (DDR), which detects DNA damage and promotes DNA repair. To date, over 600 proteins have been identified that play an integral role in the DDR. RAD9, encoding a DDR mediator protein, was the prototypical DNA damage checkpoint gene, establishing the genetic regulation of transient cell‐cycle delays upon DNA damage. Rad9, identified 38 years ago in the budding yeast Saccharomyces cerevisiae as a damage‐dependent cell‐cycle regulator, is now known to regulate additional responses to DNA damage including both cell‐cycle recovery and repair. The Rad9 protein is extensively phosphorylated both during a normal cell cycle and following DNA damage and several of these modifications have been linked to specific Rad9 roles within the DDR. Proteins structurally and functionally related to Rad9 exist in mammalian cells (e.g., 53BP1, BRCA1, MDC1) and insights into their regulation and mechanism of action have been informed by studies in yeast. This review will discuss the cellular mechanisms governing the DDR with an emphasis on the multifaceted role of Rad9 in sensing and responding to DNA damage, and how phosphorylation events regulate its function within the DDR. As the cellular events governing the DDR are well conserved, discoveries in yeast can be extrapolated to humans and may lead to the identification of additional novel protein targets, with several DDR inhibitors currently in clinical use or showing promise in clinical trials.Publication Embargo Piecing the puzzle together: Analyses in plants at the single-cell resolution(Elsevier, 2025-11-05)In recent years, single-cell and single-nuclei-omic technologies have advanced rapidly in plant research, with RNA sequencing being widely adopted, and chromatin accessibility profiling through assay for transposase-accessible chromatin with sequencing steadily expanding. These approaches have provided unprecedented insight into plant development, cell identity, and stress responses. Integrating transcriptomic and chromatin accessibility data has made it possible to link regulatory elements with gene expression across diverse plant tissues. The goal of this review is to provide a practical guide synthetizing current methods, bioinformatic tools, and applications for a clear perspective on the opportunities and challenges of implementing these technologies in plants. We place particular emphasis on the technical aspects of single-cell/single-nuclei methods, with the aim of enabling informed decisions regarding the choice of protocol. We also highlight emerging multi-omic strategies, the bioinformatic frameworks that enable their analysis, and applications across diverse plant species. In light of the current progress, we discuss that expanding the use of these technologies in plants will advance fundamental biology and generate actionable insights for crop improvement, driving the translation of single-cell discoveries into agricultural innovation.Publication Open Access The β-amyloid-induced increased tonic conductance, impaired long-term potentiation and cognitive deficits characteristic of Alzheimer's disease are reversed by an α5 inverse agonist of the GABA type A receptor(Elsevier, 2026-02-27)Alzheimer's disease is a chronic, progressive neurodegenerative disorder characterized by cognitive impairment, which may arise from disruptions in the excitatory/inhibitory balance within the brain. Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the central nervous system, plays a crucial role in maintaining the excitatory/inhibitory balance and regulating neuronal activity involved in memory. In Alzheimer's disease, changes in α5 GABA A type receptor expression and activity increase tonic inhibition, disturbing the neuronal excitatory/inhibitory balance and ultimately impairing cognitive processes. Therefore, targeting the α5 GABA A receptor offers a promising therapeutic strategy to mitigate impairments in these processes. This study examined the potential of an α5 GABA A receptor-selective inverse agonist, α5IA, for treating β-amyloid-induced cognitive deficits and the underlying mechanism of action, using ex vivo microelectrode array and patch clamp electrophysiology. The inverse agonist, α5IA, improved impaired long-term potentiation, reduced elevated tonic conductance in CA1 hippocampal neurons and improved long-term spatial memory deficits induced by β-amyloid. These findings highlight α5IA's ability to restore excitatory/inhibitory balance and, thereby, cognitive function. The selective targeting of α5 GABA type A receptors with α5 GABA A receptor inverse agonists, such as α5IA, represents a promising direction for developing novel Alzheimer's disease therapies.