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Publication Embargo Model development for surrogate fuel components by auto-generation and rate rule optimization(University of Galway, 2026-06-05)This work presents the development of an automated computational framework for chemical kinetic modelling of large surrogate fuel components, with a focus on large alkenes. The MAMOX++ framework is upgraded and extended to enable the automated generation of detailed kinetic models for large alkenes. By incorporating 52 alkene reaction classes, the framework allows systematic construction of sub-models for a wide range of linear and branched alkenes (> C4) with minimal manual intervention. In combination, the Optima++ framework is employed to perform global, data-driven optimization of rate rules within their prior uncertainty bounds. A total of 323 rate rules are optimized against a comprehensive experimental database, including IDTs and species profiles, achieving improved agreement across a wide range of operating conditions. This framework significantly enhances the accuracy and efficiency of kinetic models for complex hydrocarbon fuels. The developed models are applied to investigate structure–reactivity relationships in alkene oxidation. Shifting the double bond from terminal to internal positions is found to reduce fuel reactivity at low and intermediate temperatures due to the suppression of hydroperoxyl alkenyl radical formation, which weakens low-temperature chain-branching pathways. For linear 1-alkenes, reactivity increases with increasing carbon chain length (C5–C12) due to the increasing number of hydrogen abstraction sites, particularly at secondary carbon sites and diminishing effect of the primary carbon and the C=C double bond, thereby approaching a limit at higher carbon numbers of approximately C12. Notably, highly branched alkenes, represented by tetramethyl ethylene (XC6D2), exhibit a distinct behaviour compared to 1-alkenes, showing a monotonic increase in reactivity with temperature and exceeding the reactivity of their alkane counterparts (XC6H14) at intermediate temperatures. This is attributed to the absence of inhibiting β-scission pathways and the lack of negative temperature coefficient (NTC) behaviour. In contrast, 1-alkenes consistently exhibit lower reactivity than their corresponding alkanes. This work further examines interactive oxidation chemistry in surrogate fuel systems. In methane (CH4)/n-decane (nC10H22) mixtures, non-linear reactivity enhancement for CH4 is observed with the addition of nC10H22 due to radical interactions, where early ȮH formation from nC10H22 oxidation promotes methane consumption, while CH3Ȯ2 radicals formed during CH4 oxidation, in turn, accelerate nC10H22 oxidation. Furthermore, through a systematic kinetic modelling approach for the oxygenated fuel (ethyl tert-butyl ether, ETBE), this study elucidates the competitive decomposition pathways of ETBE under high-temperature conditions between alcohol elimination and C–O bond scission pathways, identifying this competition as a key factor governing the prediction of key intermediate species, particularly carbon monoxide (CO), which is essential for understanding the combustion chemistry of sustainable oxygenated fuels. Overall, this work establishes a systematic and extensible framework for automated kinetic model development and optimization of large alkene fuels. The results provide new insights into alkene oxidation chemistry and fuel interactions, contributing to improved surrogate fuel design and more accurate predictive combustion modelling.Publication Embargo AI-guided drug-discovery of small molecule inhibitors of Apoptotic Protease Activating Factor-1(University of Galway, 2026-06-05)Apoptotic protease activating factor-1 (Apaf-1) is a central regulator of intrinsic apoptosis and mediates apoptosome assembly following cytochrome c release from mitochondria. Dysregulated activation of this pathway contributes to pathological cell loss in conditions including neurodegeneration, ischemic injury, and ototoxicity, making Apaf-1 a potential therapeutic target. However, pharmacological inhibition of apoptosome signalling remains challenging due to the structural and mechanistic properties of Apaf-1. This thesis investigated two complementary strategies for targeting Apaf-1 signalling: disruption of the Apaf-1:Caspase-9 CARD-CARD interaction and targeting of the Apaf-1 nucleotide-binding pocket. To address these aims, NanoBiT split-luciferase complementation assays were developed to monitor CARD-domain interactions and apoptosome-associated signalling in biochemical and mammalian cell systems. These approaches were combined with recombinant protein purification, peptide inhibition studies, Caspase activity assays, computational docking, alanine-scanning analyses, and AI-assisted virtual screening workflows. NanoBiT assays successfully detected specific interactions between Apaf-1 and Caspase-9 CARD domains and enabled evaluation of peptide and small-molecule inhibitors. Several literature-reported Apaf-1 inhibitors reduced NanoBiT signal intensity; however, additional biochemical analyses demonstrated that some compounds also inhibited Caspase-9 independently of Apaf-1, highlighting the importance of mechanistic specificity controls. Computational analyses further suggested that the Apaf-1:Caspase-9 CARD interface represents a structurally challenging target for conventional small-molecule inhibition. 19 To explore alternative approaches, AI-guided virtual screening was used to identify compounds predicted to interact with the Apaf-1 nucleotide-binding region. Selected compounds were evaluated using mini-apoptosome reconstitution assays and mammalian-cell NanoBiT systems, where several compounds reduced apoptosome-associated signalling outputs. Overall, this work establishes complementary experimental platforms for studying Apaf-1 signalling and provides further insight into the opportunities and limitations associated with pharmacological modulation of the apoptosome. The findings support continued investigation of Apaf-1 as a therapeutic target while emphasising the importance of mechanistic validation and pathway specificity in apoptosome-directed drug discovery.Publication Open Access Valorisation of perennial rye grass pressed cake to Γ – polyglutamic acid(University of Galway, 2026-06-05)Poly-γ-glutamic acid (γ-PGA) is a valuable biopolymer whose production costs limit widespread application. Utilising lignocellulosic biomasses such as rye grass pressed cake (RGPC) as alternative feedstock offers economic and sustainability advantages but requires addressing key technical challenges including identifying microbial strains capable of fermenting lignocellulosic hydrolysates, reducing biomass recalcitrance through effective pretreatment, and optimising fermentation conditions for high γ-PGA yields. This thesis develops an integrated approach to γ-PGA production from RGPC by systematically addressing each of these challenges. Seven Bacillus strains from B. licheniformis and B. subtilis species were screened for γ-PGA production capacity. B. licheniformis strains demonstrated superior performance, with B. licheniformis DPC6338 achieving the highest titre (59.5 g/L) and was selected as the candidate strain. Genomic analysis confirmed the presence of γ-PGA metabolic pathways, including genes for precursor biosynthesis, polymerization, racemization, and degradation in B. licheniformis DPC6338, while in-silico safety assessment validated its suitability for industrial application. Systematic optimization of nutritional and culture parameters including carbon and nitrogen sources, mineral composition, temperature, initial pH and inoculum concentration, improved γ-PGA titre and peak productivity in shake flask fermentation to 75.35 ± 0.38 g/L and 1.3 g/L/h, representing a 27 % and 4 % improvement respectively over screening conditions. Scale-up to bioreactor conditions further enhanced final titre and early-phase volumetric productivity by approximately 30 % and 80 %, respectively. Natural deep eutectic solvents (NADES) are eutectic mixtures of naturally derived compounds that associate through hydrogen bonding. NADES are finding increasing applicability in biomass pretreatment due to the ease of preparation, low-cost, greenness, sustainability, chemical and thermal stability, high solubilisation power, high stabilizing ability and tunability. In this study, NADES prepared from different molar ratios of citric acid (CA) and glycerol (Gly) were characterised, examined as a medium for the pretreatment of RGPC and optimized using Taguchi orthogonal array design. Optimal conditions were identified through signal-to-noise ratio analysis and ANOVA. NADES pretreatment achieved 72 - 84 % hemicellulose solubilization, 59 - 82 % lignin removal, and 50 - 71 % cellulose recovery, with structural characterization confirming significant biomass modification. The optimized pretreatment condition (citric acid:glycerol 1:2, 2 hours) yielded 95 % enzymatic saccharification efficiency when validated experimentally. Fermentation studies using RGPC hydrolysates demonstrated the practical application of this integrated approach. Batch fermentation of combined NADES and water extract produced 10.2 g/L γ-PGA at 72 h, which improved to 14.77 g/L under fed-batch conditions. Enzymatic hydrolysate alone yielded a maximum titre of 25.88 g/L after 72 h. Collectively, these fractions represent a total γ-PGA production of 40.65 g/L from the original RGPC biomass, demonstrating the technical feasibility of converting agricultural residues to high-value biopolymers. This work establishes B. licheniformis DPC6338 as a robust platform for γ-PGA production and demonstrates that RGPC can support commercially relevant γ-PGA titres in an integrated fermentation process. These findings provide a foundation for scaling γ-PGA lignocellulosic production from renewable feedstocks, contributing to the development of circular bioeconomy approaches in biopolymer manufacturing.Publication Open Access Development of novel tools and applications to enhance the applicability and usability of whole-body metabolic models(University of Galway, 2026-06-04)Human metabolism is an intricate system due to the complex interactions between human physiology, the gut microbiome, and nutrition. Understanding these interactions in vivo is difficult, which is why alternative methods are needed. One such method is the constraint-based reconstruction and analysis (COBRA) framework. The COBRA method has been used to create human organ-resolved sex-specific whole-body metabolic models (WBMs). The strengths of the WBMs lie in their predictive capability and their personalisation using physiological, metagenomic, and nutritional data. However, the use of WBMs by the wider scientific community has been limited, in part due to the in-depth knowledge required for metabolic modelling conventions, the COBRA toolbox, MATLAB modelling, and the WBMs themselves. In this thesis, we aimed to reduce the knowledge threshold required to work with WBMs, expand their applicability, and demonstrate the range of analyses that can be performed with the WBMs. To achieve these aims, we created a semi-automated pipeline, Persephone, that includes all the functions and sanity checks required to work with WBMs. We further expanded the applicability of the WBMs by incorporating novel metabolites and reactions of ω-3 and ω-6 polyunsaturated fatty acids, which are involved in regulating inflammation. Additionally, we developed the nutrition toolbox, which enables rapid and efficient creation of in silico diets by mapping dietary items to publicly available databases containing metabolite measurements for various foods. Finally, Persephone and the nutrition toolbox were applied to a dietary intervention study. WBMs were personalised with metagenomics and nutritional data. We found changes in metabolites related to secondary bile acid metabolism, vitamin B12, and glutamic acid, which were corroborated by the original study. Additionally, we sought to link microbial species to the observed metabolic changes. Taken together, the work presented in this thesis made working with the WBMmore accessible to the wider scientific community, enabled its use in novel applications and showcased the current capabilities of the WBMs. These advancements in WBM modelling provide a solid foundation for future methodologies and more complex analyses.Publication Embargo Linguistic code-switching in Bethu Brigte, the old Irish life of St. Brigit(University of Galway, 2026-06-03)Bethu Brigte, the Old Irish Life of St. Brigit, is a ninth-century composition written in a fascinating blended language, mixing Latin and Old Irish. Barbara Bullock and Almeida Jacqueline Toribio in The Cambridge Handbook of Linguistic Code-Switching define “codeswitching” as “the alternating use of two languages in the same stretch of discourse by a bilingual speaker.” Historical code-switching is a new and evolving field which is currently witnessing a substantial rise in international scholarly attention. Ecclesiastical communities blended Latin and Irish in the Early Middle Ages, centuries before this mixing occurs in Western Europe. Much remains to be answered as to why this linguistic blending should occur in Ireland several centuries before similar phenomena occurred on the continent; apparent and significant linguistic differences clearly exist between Latin and Irish, while the vernacular languages of Italy, France, and Spain derive from Latin. The colourful language of Bethu Brigte, as survived in its single extant manuscript (Oxford, Bodleian Library, Rawlinson B 512), is roughly one-third Latin; Latin words, phrases, dialogues, even entire episodes are interspersed throughout this Irish text. The purpose of this research is to assess why and how Bethu Brigte alternates between Latin and Old Irish to such a varied and extreme degree, by applying methodologies developed within the linguistic study of codeswitching in both contemporary and historical contexts: these methodologies include Emmanuel Rhoidis’ diglossia, Alan Bell’s Audience Design, and Pieter Muysken’s Typology of Code-mixing. In the process, the study of BB led to a new interpretation of Muysken’s Typology. This linguistic study of code-switching in Bethu Brigte aims to help us answer long-unanswered questions about this and other texts connected with St. Brigit, as well as to make a significant and unique contribution to the growing research areas of Medieval Latinity, Early Irish, pre-modern multilingualism, and historical sociolinguistics.