College of Science, Engineering and Food Science - Doctoral Theses
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- ItemMetaheuristics and machine learning for joint stratification and sample allocation in survey design(University College Cork, 2022-01) O'Luing, Mervyn; Prestwich, Steve; Tarim, Armagan; European Regional Development Fund; Science Foundation IrelandIn this thesis, we propose a number of metaheuristics and machine learning techniques to solve the joint stratification and sample allocation problem. Finding the optimal solution to this problem is hard when the sampling frame is large, and the evaluation algorithm is computationally burdensome. To advance the research in this area, we explore and evaluate different algorithmic methods of modelling and solving this problem. Firstly, we propose a new genetic algorithm approach using "grouping" genetic operators instead of traditional operators. Experiments show a significant improvement in solution quality for similar computational effort. Next, we combine the capability of a simulated annealing algorithm to escape from local minima with delta evaluation to exploit the similarity between consecutive solutions and thereby reduce evaluation time. Comparisons with two recent algorithms show the simulated annealing algorithm attaining comparable solution qualities in less computation time. Then, we consider the combination of the k-means and clustering algorithms with a hill climbing algorithm in stages and report the solution costs, evaluation times and training times. The multi-stage combinations generally compare well with recent algorithms, and provide the survey designer with a greater choice of algorithms to choose from. Finally, we combine the explorative properties of an estimation of distribution algorithm (EDA) to model the probabilities of an atomic stratum belonging to different strata with the exploitative search properties of a simulated annealing algorithm to create a hybrid estimation of distribution algorithm (HEDA). Results of comparisons with the best solution qualities from our earlier experiments show that the HEDA finds better solution qualities, but requires a longer total execution time than alternative approaches we considered.
- ItemInvestigating the host-microbe dialogue in aging(University College Cork, 2022-12-16) Killian, Christina; Joyce, Susan; Clarke, David J.; Eli Lilly and CompanyThis thesis aimed to investigate the role of the gut microbiota and their associated functionality in the context of aging and life stage related diseases. The focus was maintained on key inter-kingdom signalling molecules, host produced but bacterially modified Bile acids (BAs) and on dietary microbially derived Fatty acids (FAs) as key elements to indicate gut microbial potential impactful roles. In the context of Chapter 3, this thesis examined the levels of BAs and FAs, to identify convergence on specific microbially produced, or modified, metabolites in the two neurological disease states representing (1) early life (murine model of Autism Spectrum Disorder (ASD)) and (2) later life (human Parkinson’s Disease (PD)). It further established the potential to redress the balance through microbial intervention, as a cause or consequence in the case of ASD. BAs converged during the healthy aging process, in Chapter 4, to determine the nature of these specific interactions, based on nuclear receptor conservation. The Caenorhabditis elegans nematode model of aging was employed to determine and genetically decipher potential individual BA influences. Chapter 5 built on recognising that gut microbes and the pathobiont Escherichia coli HM605 induced inflammation. This chapter also focused on the mechanisms by which Escherichia coli HM605 could influence the aging process.
- ItemRegulation of intracellular trafficking of the insulin-like growth factor I receptor(University College Cork, 2023) Godsmark, Grant; O'Connor, Rosemary; Science Foundation Ireland; Swiss Forum for International Agricultural ResearchInsulin-like Growth Factor 1 and its receptor (IGF-1R) are required for normal cellular growth, but aberrant expression is linked to the progression and development of many malignancies. Despite IGF-1R being a promising cancer therapeutic target, clinical targeting has not been generally successful. This has also highlighted gaps in our knowledge on IGF-1 signalling and how the IGF-1R and its regulatory regions function. Two tyrosine residues Tyr1250/1251 located within the 1248SFYYS1252 signalling motif of the IGF-1R are required for receptor internalisation, transformation and Golgi localisation. This thesis aimed to further investigate how this region and the C-terminal tail contribute to IGF-1R trafficking, sub-cellular localisation and regulation by using a range of cell lines and IGF-1R receptor mutants. Phosphorylation of Tyr1250/1251 was shown to be required for IGF-1R localisation to the Golgi and that a phosphomimetic EE (Y1250E/Y1251E) IGF-1R mutant is less stable, is more ubiquitinated and undergoes more rapid proteasomal degradation than wild type IGF-1R. Three lysine residues (Lys1256, Lys1294, Lys1324) were identified within the IGF-1R C-terminal tail as putative ubiquitin binding sites, but mutation of these to arginine in mutational studies established that all of these sites have a minor function in receptor ubiquitination. Peptides encompassing the hydrophobic Tyr1250/1251 site in the IGF-1R were recently proposed as a cargo-sorting motif that binds to the protein trafficking ESCPE-1 (SNX5/SNX6) complex, which rescues the IGF-1R from lysosomal degradation. This was tested this using full-length receptors expressed in different cell models and using siRNA-mediated suppression of SNX5/SNX6. However, our data did not replicate the published observations on SNX5/SNX6 knockout causing reduced IGF-1R protein expression. Furthermore, no effect of SNX5/SNX6 suppression on IGF-1R protein levels or location at different sub-cellular compartments including the Golgi was observed. Interestingly, SNX5/SNX6 suppression induced lysosomal accumulation at the leading edge of cells as well as decreased cellular migration. SNX5/SNX6 was observed to interact with the IGF-1R, but the hydrophilic Y1250E/Y1251E mutant exhibited a stronger interaction, than the hydrophobic Y1250F/Y1251F mutant, which suggest that this interaction may be modulated by phosphorylation in the full-length receptor. In summary, the findings confirm the importance of the IGF-1R C-terminal tail, in particular, Tyr1250/1251, in IGF-1R signalling and regulation. These tyrosines facilitate ubiquitin binding, SNX5/SNX6 interaction and Golgi localisation of the IGF-1R which all contribute to the transformed phenotype. Further research on the associated mechanisms should assist in tailoring future cancer therapy treatments to improve clinical efficacy.
- ItemIGF-1 signalling controls mitochondrial morphology and basal mitophagy in cancer(University College Cork, 2023-01-06) Murray, Joss; O'Connor, Rosemary; Science Foundation IrelandInsulin-Like Growth Factor 1 (IGF-1) signalling is known to support oncogenic transformation and the promotion of cancer development. A growing body of evidence has outlined the protective effect IGF-1 signalling has on the mitochondria, however this has been relatively underexplored in cancer. Therefore, this thesis aims to elucidate the mechanisms by which IGF-1 promotes mitochondrial protection in cancer. Previously, we determined that the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is induced by IGF-1 to support mitochondrial turnover and protection. Here, we analysed a publicly available gene expression dataset of breast cancer cells stimulated by IGF-1. Gene ontology classification revealed a signature of genes induced and repressed by IGF-1 involved with mitochondrial functions. Further analysis to classify genes by biological process suggested that genes involved with apoptosis and suppression of mitochondrial metabolism were most enriched in the gene groups regulated by IGF-1. To further interrogate mitochondrial dynamics downstream of IGF-1 signalling, we assessed mitochondrial morphology. Lack of IGF-1R promoted mitochondrial fusion, while IGF-1 stimulation promoted mitochondrial fragmentation. Mitochondrial fragmentation was associated with increased mitochondrial transport to the leading edge of invasive breast cancer cells. Pharmacological inhibition of mitochondrial fission inhibited the migration of cells expressing the IGF-1R but was ineffective at moderating migration of cells lacking the IGF-1R. Finally, we interrogated the function of BNIP3 downstream of IGF-1 stimulation. While BNIP3 is induced, IGF-1 stimulation suppressed mitophagy. However, BNIP3 turnover was higher in basal cell culture conditions than in nutrient deprived conditions, suggesting that BNIP3-mediates basal mitophagy in cancer cells. Indeed, IGF-1R knockout reduced the basal turnover of BNIP3 implying that IGF-1 regulates basal mitophagy via BNIP3. In totality, this thesis presents evidence that IGF-1 signalling promotes mitochondrial protection by regulating genes involved with redox homeostasis while tempering mitochondrial metabolism. Mitochondrial fragmentation is induced by IGF-1 and can also regulate cancer cell migration, while also supporting basal mitophagy mediated by BNIP3. These findings demonstrate that targeting IGF-1 signalling in cancer could impair mitochondrial protection mechanisms, which offers an avenue for novel therapeutic opportunities.
- ItemDietary quality of school-aged children and teenagers in Ireland by demographic characteristics and eating location(University College Cork, 2022-10) Rusu, Ioana; Kehoe, Laura; Flynn, Albert; Cashman, Kevin; Walton, Janette; O'Mahony, Jim; Department of Agriculture, Food and the Marine, IrelandBackground: Childhood and the teenage years are distinctive life stages characterised by unique dietary needs. Data from nationally representative dietary surveys of children and teenagers across Europe have shown that intakes of key nutrients are not in line with recommendations. Furthermore, demographic characteristics such as sex, age, socio-economic status and weight status may have an influence on dietary quality in children and teenagers. It has also been shown that eating location can influence dietary quality, with some locations such as ‘home’ and ‘school’ being associated with better dietary quality than other locations, such as ‘restaurants’, ‘takeaways’ and ‘shops’. Objectives: The overall aim of this thesis was to examine the dietary quality of school-aged children and teenagers in Ireland by demographic characteristics and eating location using data from the National Children’s Food Survey II (NCFS II) (2017-18) and the National Teens’ Food Survey II (NTFS II) (2019-20). Methods: The analyses for this thesis were based on data from the NCFS II and the NTFS II which are two nationally representative dietary surveys of children (5-12 years, n 600) and teenagers (13-18 years, n 428) living in the Republic of Ireland. Dietary intake data were collected at brand level using a 4-day weighed food diary for both surveys. Dietary quality was determined using energy-adjusted (%E or /10MJ) intakes of nutrients and food groups. ‘Eating location’ was defined as the location where food was prepared or obtained, irrespective of where it was consumed. For eating location analysis, consumers were defined as those who consumed food at a given location at least once during the four-day recording period. Results: The overall dietary quality of children and teenagers in Ireland was found to be unfavourable and there were very few differences observed across sex, age groups, categories of socio-economic status and weight status. Intakes of key food groups were not in line with food-based dietary guidelines (FBDG) for either children or teenagers. In both children and teenagers, dietary intakes were driven by the ‘home’ location. While the majority of children (73%) and teenagers (78%) consumed food from ‘outside of the home’, most eating occasions took place at ‘home’ for both children (89%) and teenagers (85%), accounting for a large proportion of the energy consumed (88% in children and 81% in teenagers). The contribution of food consumed from ‘outside of the home’ was higher in teenagers than in children (19% vs. 12%). Younger children had higher intakes of energy from food consumed from ‘other homes’ than older children and both children and teenagers of parents with primary/intermediate education only had higher intakes of energy from food consumed from ‘fast food/takeaways’ than children and teenagers of parents with tertiary education. There were no other differences observed in these eating patterns across any other demographic characteristics examined. Food consumed from ‘home’ and the ‘participant’s own home’ was better in terms of dietary quality than food consumed from ‘outside of the home’ and ‘other homes’. Of all ‘out of home’ locations, ‘school’ provided the best dietary quality for children, but this was not seen in teenagers. Conclusion: This thesis has shown that the overall dietary quality of children and teenagers in Ireland was unfavourable and there were few differences found across demographic characteristics. Dietary intake was driven by the home environment, with ‘home’ and the ‘participant’s own home’ being associated with better dietary quality than ‘other homes’ and ‘outside of the home’. The findings of this thesis can be of use to policy makers when introducing healthy eating policies aimed at school-aged children and teenagers such as taxation on unhealthy foods and regulation around marketing of unhealthy foods.