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Publication The evolution and future of the Irish MedTech cluster(University of Galway, 2024-12-11) McKernan, David; McDermott, OliviaThis research examines how high-cost locations can maintain a competitive advantage in a global world where multinationals can move location seeking lower cost labour. The Medical device cluster in Galway is used as the case study. The research supports the academic theory that competitive advantage is a highly localised. Firms cluster in geographic locations areas often as small as 5 to 10km square. Maintaining a competitive advantage is difficult; new techniques and methods can be copied by others – hence, best practice is rapidly diffused, and rivals imitate one another’s improvements (Porter, 1996). A clustering effect can provide a competitive advantage that is difficult for other firms outside the region to copy. The effect is highly dependant on people and social interactions and the presence of key stakeholders. The cluster evolves around key stake holders that are essential for the cluster’s health. Competitive strategies depend on maintaining the health of the cluster. Clusters provide a competitive advantage to nations and regions. Although many discussions highlight the national competitive advantages of clusters, this research shows clusters are contained in a small geographic region (Evans, 2023). Distance and gravity matter. Having similar industries close together generates benefits that decline as the distance increases (Ferretti et al., 2022). In the case of the Galway cluster, most firms fit in a square with 5km sides (McKernan & McDermott, 2024b). The research supports the Rosenthal and Strange (2003) findings that the advantages of a cluster attenuate with distance and are measurable in the real world with distances as little as two to five miles. The example of Galway is not unusual; even Silicon Valley is concentrated in a few hot spots with collaboration firms that are often in the same street or building (Guzman & Stern, 2015). Porter (1990) states the nation provides an environment that enables firms to improve and innovate, and focuses on the nation as the key differentiator for providing a competitive advantage. The research shows that the nation does provide the overall environment, but to understand why clusters are established and successful or what interventions are required, a much smaller geographic space must be considered. The research supports Porter’s assertion that the competitive advantage is defined in narrow industrial segments (Porter, 1990). Many pivotal researchers have highlighted the importance of location, factor conditions, investment, transport and education systems (Etzkowitz and Leydesdorff, 1995; Krugman, 1991; Porter, 1990; PRED, 1966; Sinclair, 1967). This research agrees with these findings but has highlighted the importance of individual entrepreneurs, culture, and a region’s ability to attract people to create and sustain the success of the cluster. This research shows how firms in the Galway cluster have a common lineage encouraging an open and collaborative culture (McKernan and McDermott, 2024a). It agrees with Stephens et al. (2019) findings that social and institutional connectiveness is essential to supporting and maintaining the cluster. Soft infrastructure is critical to attracting and maintaining human capital (Gertler, 2004). Cities with a rich and vibrant arts and culture scene help in creating a highly innovative cluster (Florida, 2014).Publication Artificial intelligence as an enabler of agri-food supply chain resilience(University of Galway, 2024-12-05) Smyth, Conn; Scott, Murray; Dennehy, Denis; Fosso Wamba, SamuelSupply chain organisations have endured increasing levels of pressure in recent years due to unprecedented levels of uncertainty. These issues are exacerbated for agri-food supply chain (AFSC) organisations, as they are faced with meeting demanding food production targets (United Nations, 2022), while combating issues such as limited farmland, reduction of natural resources, and climate change (Spanaki et al., 2021). While disruptions are costly for all supply chain organisations due to the perishable nature of agri-food products, disruptions pose a significant concern for AFSC organisations as disruptive events cause products to edge closer to expiry, adding to unintentional food loss and cost of production. Hence, developing the capability to minimise the impact of disruptive events is crucial for AFSC organisations. Therefore, this doctoral research aims to examine the potential of AI as an enabler of AFSC resilience. Five research questions were outlined to achieve this overarching research objective, which was achieved through four studies. Study 1A conducts a systematic literature review focussing on understanding the applications, challenges, and benefits of AI in supply chain research. AI and supply chain research is largely fragmented into streams based on different types of AI technologies across several supply chain contexts and through varying disciplinary perspectives. Study 1A is the first review to synthesise this fragmented body of knowledge, giving direction to both researchers and practitioners. Study 1B is a practitioner-focused paper that combines the outputs of Study 1A, in addition to data collected from 147 AFSC respondents, to provide an insight into the view of AFSC practitioners on AI applications. Study 1B extends the findings of Study 1A, giving this research a strong understanding from both literature and industry on AI's applications, challenges, and benefits in the AFSC industry. Collectively, this provides a foundation to guide the remainder of the studies conducted in this doctoral research. In Study 2, this research provides empirical evidence on AI and SCR. Drawing on organisational information processing theory, this research provides a novel perspective to understanding how AFSCs can deploy AI-based information processing, utilising organisational mindfulness (OMIN) and organisational flexibility (OLFEX) to build resilient supply chains. Furthermore, Study 3 extends the research model proposed in Study 2 by drawing on dynamic capability theory to empirically test AI assimilation as an enabler of SCR under the moderating effect of environmental dynamism. pg. 9 Collectively, these studies make specific and distinguishing contributions to AI and supply chain research and practice. Study 1A contributes to the accumulative building of knowledge by extending theoretical discourse about the specificities of AI for prescriptive analytics to enable SCR. Study 2 is among the first empirical studies to draw on organisational information processing theory to examine AI-based information processing for developing AFSC resilience as well as the mediation effects of OFLEX and OMIN on this relationship; therefore, addressing the lack of theoretical development and understanding how AI-enabled information processing affects SCR (Belhadi et al., 2021), particularly in the context of AFSCs. Moreover, Study 3 is among the first to draw on dynamic capability theory to examine the impact of AI assimilation on SCR as well as the mediation effects of OMIN and OLFEX on this relationship. This is a considerable contribution to AI literature, as it provides a theoretical basis and empirical evidence of the importance of organisational competencies for leveraging AI technologies to improve SCR. In terms of practical implications, this research helps decision-makers gain a better understanding of AI and its applications, specifically, how AI can be leveraged to develop SCR. Study 1A proposed a strategic AI resilience framework to support supply chain decision- makers and enhance the use and value of prescriptive analytics as an enabler to developing a resilient supply chain. Studies 2 and 3 demonstrate the important role of OMIN and OFLEX for AFSC managers seeking to use AI technologies to develop SCR. This implies that the employment of AI technologies to promote SCR requires managers to adopt the principles and practices of OMIN and OFLEX. Besides illustrating the importance of developing resilience for performing successfully in the turbulent environment that AFSCs operate in, this research also demonstrates that developing resilience can enhance AFSC performance and be a source of competitive advantage, giving further reasoning to AFSC managers to develop SCR.Publication A modelling and computational study of biofilm dynamics: Exploring the role of initial attachment and horizontal gene transfer(University of Galway, 2024-12-03) Vincent, Julien; Frunzo, Luigi; Mattei, Maria Rosaria; Tenore, Alberto; O’Flaherty, Vincent; Project M2ex - Marie Curie grant agreement 861088; Marie Skłodowska-Curie Actions, European UnionBiofilms are ubiquitous in nature and one of the most successful lifestyles on earth. This success is largely due to the high level of interactions within biofilms, leading to the specialisation of subpopulations and subsequent heterogeneity. Biofilms have gathered research attention because of their potential use in engineering, but also because of the need to control their formation in man-made systems. However, due to their complexity and heterogeneity, biofilm systems can be cumbersome to analyse. In this context, model biofilm systems, whether they are experimental or mathematical, offer a reduction of the system to a more observable one through simplifying assumptions and hence allow easier analysis. This thesis aims to propose innovative biofilm models, focusing on diverse key aspects of biofilm ecosystems. More specifically, this dissertation is divided between an original experimental model system, proposed to investigate cross-kingdom interactions in anaerobic communities during biofilm formation and four novel mathematical models, introduced to describe the main regulatory effects of trace metals on microbial biofilms. To this aim, novel mathematical functions are introduced to describe key phenomena linked to trace metals in biofilms dynamics: bacterial attachment (and subsequent biofilm initiation) and horizontal gene transfer, one of the drivers of genotypic diversity and antibiotic resistance. The experimental model system is an undefined, engineered model system mimicking growth conditions in an Upflow Anaerobic Sludge Blanket reactor. It was studied with a sampling campaign during the first five days of the biofilm establishment, followed by biofilm characterisation with fluorescence microscopy and DNA sequencing at different time points. To complement DNA sequencing, a network-based analysis was carried out to investigate correlations between fungal and bacterial populations in different samples. This exploratory study into an unknown biofilm type brought to light the importance of the interactions between the bacterial microbiome and its fungal counterpart. The mathematical models in this thesis are continuum models, formulated as systems of non-linear partial differential equations. Non-linear hyperbolic PDEs govern the advective transport and growth of the solid-phase species forming the biofilm, while parabolic quasi-linear PDEs model the diffusion-reaction of soluble substrates and bacteriophages. The first model presented focuses on the influence of ionic strength on bacterial attachment and subsequent biofilm formation, and is formulated as a 1D free boundary problem. This model focuses on drinking water distribution systems biofilms and their invasion by pathogenic bacteria Legionella pneumophila, with a focus on the necrotrophic metabolism of the latter, which gives it the ability to persist in biofilms. The second model is formulated as a free-boundary problem describing the impact of conjugation on plasmid spread in biofilm communities. More specifically, conjugation is modelled as a mass-action kinetics process subsequent to gene expression, modelled as a nonlocal term to account for recipient-sensing. The existence and uniqueness of the solutions are proved using the method of characteristics and the fixed point theorem. The third model is formulated as a multidimensional problem, and proposes a modelling framework to natural transformation in biofilms, modelled as a frequency-dependent process. It investigates the comparative influence of conjugation and transformation on the spread of antibiotic resistance and biofilm compartmentalisation due to differences in metabolisms and sensitivities to toxic stressors. Finally, the last model describes the interaction between bacteriophages and biofilm communities and includes generalised transduction. This model is the first biofilm model that includes the three main horizontal gene transfer mechanisms: conjugation, transformation and transduction. All models are integrated numerically through the implementation of original code in MatLab and Comsol Multiphysics. Numerical simulations allow investigating the behaviour of the models, which are able to describe and predict key phenomena of biofilm dynamics. The results of the experimental section demonstrate the adequacy of model systems for investigating biofilm formation. The mathematical models can reproduce crucial elements of biofilm ecology, namely initial bacterial attachment and the main aspects of plasmid spread, such as horizontal gene transfer, the impact of selective pressure on vertical gene transfer or bacteriophage activity.Publication A comparative analysis of calibration methods for the SEIR influenza model using synthetic and surveillance data, and extending the SIR model to assess the impact of misinformation(University of Galway, 2024-11-28) Mumtaz, Nabeela; Duggan, Jim; University of GalwaySystem Dynamics is a computer-aided approach to strategy and policy design aimed at understanding complex, dynamic systems. Despite its utility, unresolved questions remain regarding model validation, calibration, and structural analysis. Our contributions to the field include: • First, we explored and compared bootstrap and Hamiltonian Monte Carlo (HMC) methods across various dimensions for parameter estimation in the SEIR model, highlighting their respective strengths and weaknesses. The bootstrap method can be adapted for estimating parameters, although it is computationally intensive. In contrast, HMC offers efficiency, precision, and faster convergence rates. • Second, a case study on the calibration of the SEIR model using seasonal influenza surveillance data demonstrates that the HMC method provides better model fit and reliability compared to the bootstrap method. This is evidenced by lower MASE values, more precise results, and quicker convergence rates. This study also emphasizes the role of both synthetic and real data in the understanding of statistical methods. • Third, a case study on the comparative assessment of the SEIR and our SEIR-D compartmental models. The SEIR-D incorporating a time delay to enhance the accuracy of disease spread predictions. This assessment evaluates the impact of seasonal onset delays on model dynamics and improves the estimation of infectious disease parameters crucial for outbreak monitoring and vaccination strategies. • Fourth, we extended the SIR model structure, introduced two interacting contagion SIR models and applied the Loops That Matter (LTM) method for model structural analysis. This analysis investigated the influence of misinformation on infectious disease transmission dynamics, highlighting its significant impact on disease attack rates and emphasizing the need for targeted interventions to mitigate its effects. Through these contributions, this research advances System Dynamics by proposing methodologies for model calibration and structural analysis, thereby improving model reliability.Publication An exploration of the effect of pension communications on employee pension understanding using a multiple case studies approach and a bounded rationality framework(University of Galway, 2024-11-14) Maloney, Maureen; McCarthy, Alma; Smyth, LeoTitle: An Exploration of the Effect of Pension Communications on Employee Pension Understanding Using a Multiple Case Studies Approach and a Bounded Rationality Framework Research question and objectives: Using a bounded rationality framework, how do variations in pension communication policies at organisational level assist employee understanding of their DC (defined contribution) occupational pension plan? The objectives of this research are to: • Evaluate the differences between organisational pension plans; • Analyse organisational differences in developing, analysing and reviewing pension communications policies; • Evaluate pension communications used within the organisation in relation to frequency, timing, individualisation, segmentation, targeting and simplicity; and • Explore the interaction between pension communication and employee pension understanding. This research question and the objectives were explored in four companies operating in Ireland using a multiple case study methodology. Topic importance: Defined contribution (DC) occupational pension plans, currently a voluntary benefit offered by many employers in Ireland, are the main source of non-State retirement savings. Employees bear the risk for these complicated pension plans and are expected to make decisions about the amount to save, the choice of investment funds and the potential value of State benefits at retirement. These decisions are onerous for non-professional investors. Employee understanding of their pension options is especially important if they are to bridge the gap between pension poverty and pension adequacy. Looking at the connection between organisation communication and employee understanding was the original subject of this thesis. Key gaps: There is little academic pension research conducted in workplace settings where pension information is given to employees and pension decisions are made. Academic reward management research examined to date does not consider the engagement of the employer in formulating and implementing pension policies. Most bounded rationality pension research focuses on pension structure, rather than communications and pension coverage/adequacy while ignoring employee understanding. Pension research, examined to date, uses bounded rationality concepts to explain unexpected results, generally after a change in pension structure. Key contributions: This research contributes to empirical pension research by using the case study method to examine employee understanding within the workplace context where employees learn about pensions. It adds to bounded rationality theory by providing a model that visualises the relationship between organisation pension policies, their framing effects and individual cognitive processes. This research contributes to the multiple case study research method by identifying transparent criteria applied across case study organisations providing a foundation for meaningful comparisons. It contributes to pension theory development by incorporating Cognitive Load Theory, a branch of bounded rationality theory. Intrinsic and extraneous cognitive load provide the vocabulary and theoretical construct to analyse, operationalise and measure pension plan complexity. This research adds to the policy debate by suggesting that DC plans are so complex that only the most diligent employee is likely to understand enough about pensions to make reasoned decisions. Theoretical lens: The model developed for this research was based on the concept of bounded rationality, identified by Herbert Simon (2008, p. 893) “… to designate rational choice that takes into account the cognitive limitations of the decision-maker—limitations of both knowledge and computational capacity.” This was supplemented by the work of behavioural psychologists Tversky and Kahneman (1981) who operationalised the cognitive process and identified heuristics and biases that often hinder rational decisions. This work informed the development of a model that suggested certain communication practices could improve the cognitive process. When preliminary findings indicated that even these practices did not give clear evidence of promoting employee understanding, the theoretical lens was broadened to include Cognitive Load Theory (CLT), a branch of bounded rationality theory developed by educational researchers. Simplicity was added as both a communication and a structural policy that could positively impact human cognition. Research findings and recommendations: This research confirmed the findings of other research: if a pension plan is voluntary, a significant percentage of employees will not join, losing the employer match and tax relief. Further, several employee interviewees were unaware of the amount of the employer match or the impact of tax relief on take-home pay. The poor understanding of the employees working in organisations with relatively well thought out pension communications suggested that other factors were interfering with the cognitive process. Pension complexity is often acknowledged. However, this research operationalised a method of measuring pension complexity using criteria to measure both intrinsic (based on pension plan content) and extraneous cognitive load (based on communication presentation) in pension documents. Evidence of high intrinsic and extraneous cognitive load suggests that DC plans, as they are currently structured and communicated, are beyond the cognitive capacity of pension plan members. This controversial finding requires further evidence to confirm or deny its veracity and to explore the limitations of human cognition when faced with a DC pension plan. At the very least, a simple structure and simple communication should be the goal of the State, regulators and employers. This research adds to the mounting research suggesting that defaults change behaviour but reduce employee engagement and understanding. Because employees are held responsible for their pension ‘choices’, the ethics of defaults need further explanation. No companies participating in this research had a pension communication strategy. This led to conflicting objectives within the organisation and with third parties, diminishing the effectiveness of this expensive benefit. A recommendation to employers is to develop a pension communication strategy that is shared with employees and stakeholders. This is necessary if a pension is to be used as a retention tool in a competitive labour market.Publication MicroRNAs-mediated regulation of muscle wasting in cancer-associated cachexia(University of Galway, 2024-11-13) Borja González, María; Goljanek-Whysall, Katarzyna; Dwyer, Róisín; Irish Research Council and Hardiman Scholarship, University of GalwayCancer-associated cachexia (CAC) affects approximately 70% of cancer patients and is responsible for up to 22% of cancer deaths. CAC is a severe syndrome characterised by significant muscle wasting, systemic inflammation, and metabolic disturbances, which greatly contribute to the increased mortality among cancer patients. MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression. Changes in the expression of specific miRs during cachexia, including those with known roles in muscle function, have been observed. However, there is limited understanding of sex-specific molecular changes during cachexia, early alterations in muscle during tumour development, or the potential of miRs to regulate key signalling pathways involved in cachexia. I hypothesised that modulating miRs levels during cancer cachexia could prevent or slow the progression of muscle wasting associated with cancer. In vivo and in vitro models of cachexia, combined with miR overexpression and inhibition, followed by global and molecular phenotype characterisation, were performed to determine the role of miRs in cancer cachexia. The work in Chapter 3 used global proteomic and transcriptomic approaches to demonstrate sex-specific changes in muscle in an in vivo model of early stages of cachexia at the proteome and transcriptome levels. In males, the main pathways affected were mitochondrial respiration and oxidative phosphorylation, whereas in females, pro-inflammatory pathways were more prominently affected. Mitochondrial function and protein folding pathways were affected in both males and females during early stages of cachexia. These findings are consistent with observations previously demonstrated in the late stages of cachexia in mice and humans. In Chapter 4, the systemic delivery of miR-379-3p during initiation of cachexia, resulted in a partial rescue of muscle mass loss resulting from tumour presence, with a more pronounced effect observed in females. miR-379-3p improved mitochondrial function, particularly in males, and exhibited potential anti-inflammatory effects in females, where it also improved neuromuscular homeostasis markers, for example genes associated with myelination. In Chapter 5 the delivery of miR-26a-5p in vitro preserved myotube size by enhancing mitochondrial biogenesis, reducing apoptosis, and modulating inflammatory pathways. These findings suggested the potential of miR-26a-5p in maintaining muscle function in cachectic conditions and warrant further in vivo experiments. In Chapter 6, I explored a combinatorial miR therapeutic approach through concomitant overexpression of miRs downregulated in muscle of cachectic mice and humans: miR-379-3p, miR-26a-5p, miR-181a-5p, and inhibition of miR overexpressed in muscle of cachectic mice and humans: miR-24. The results from this chapter indicated only modest improvements in muscle preservation and did not necessarily yield synergistic benefits, suggesting that further work is needed to determine optimal combination of miRs and their potential benefit over single miR manipulation. Overall, this research advances our understanding of the molecular drivers of the early stages of cancer cachexia, as well as sex-specific characteristics, providing potential therapeutic candidates with mechanistic involvement in muscle wasting during cancer. Moreover, it demonstrates the potential of miR-379-3p as a therapeutic agent to tackle muscle wasting during cachexia. These findings suggest that early intervention with miR therapies targeting mitochondrial function, apoptosis, and inflammation could mitigate muscle wasting and enhance the quality of life for cancer patients suffering from cachexia. Future research should focus on optimising these therapeutic strategies, considering patient-specific factors such as sex and the stage of disease, and exploring the integration of miR therapies with existing cancer treatments.Publication Unstable ontologies: The self-conscious fantastic of Lord Dunsany(University of Galway, 2024-11-11) Sanabria Barba, María; Ó Cinnéide, Muireann; Cronin, Nessa; Doctoral Scholarship, University of GalwayThis doctoral dissertation examines the narrative configuration of the impossible domain as manifestations of the fantastic in selected prose writings by Edward Plunkett, Lord Dunsany (1878-1957). This examination elucidates that there is a consistent presence of ontological tension, implicit or explicit, which disrupts the internal coherence coding the text as mimetic or as fantasy, thereby interrogating the instability of both domains (the possible and the impossible). The analysis conducted in this thesis demonstrates that the configuration of Dunsany’s fiction forces the reader to assess the discourses challenged by diegetic tension, thereby highlighting the erosion of truth and reality, the dissolution of nature, the construction of the other, and the non-human in modernity. This critical reappraisal disputes previous interpretations of Dunsany’s work that posit the manifestations of the impossible in his texts as fantasy, stable within its self-standing ontology; or alternatively, as the product of uncomplicated orientalism or escapism. Instead, this thesis demonstrates that Dunsany’s work exhibits a fluctuation in ontological dominance from text to text, regardless of genre, yet maintains a consistent, self-conscious ontological instability that situates it firmly within the field of the fantastic. Extended scholarly analyses of his work through the lens of its narrative configuration, leveraging theories of the fantastic and metafiction, have not been explored in a sustained critical manner heretofore. This research contributes to the fields of the fantastic and metafiction, offering a revised theorization of the fantastic. The fantastic, as posited here, is not a restrictive model based on epistemological instability or specific configurations reliant on dominance of the domain of the possible, but a mode of narration based on an ontological tension or problematization—it is an intrinsically self-conscious narrative mode in that it appeals to the reader to consider the notions of possibility, impossibility, the limits of language and the concept of the “real” itself. My approach critically repositions Dunsany more firmly within the modern Irish literary canon, challenging the frequent reception of his work as an isolated phenomenon. I also advance the conceptualization of the fantastic as a narrative mode within the field of Irish Studies, the significance of which necessitates further theoretical concretization, investigating it as transgressive and destabilizing to established discourses and paradigms of reality and possibility.Publication The assessment of the therapeutic potential of induced pluripotent stem cell-derived mesenchymal stromal cells(University of Galway, 2024-11-08) Creaven, Dale; Murphy, Mary; AutoCRAT ProjectOsteoarthritis (OA) is a chronic disease that affects synovial joints. OA progression leads to loss of articular cartilage and inflammation. OA is the leading cause of adult disability worldwide. Currently, there are limited regenerative treatments for OA, and the modern standard of care focuses on reducing pain and improving mobility. Mesenchymal stromal cells (MSC) are the most widely studied cell in the cell therapy field. In vitro and in vivo data suggest that MSC are a promising treatment for several disorders, including OA. MSC mediate disease progression by modulating the immune system via cell-to-cell contact, secreted factors, and apoptosis. Although pre-clinical studies show MSC to be a promising candidate for cell therapy, progression to the clinic has failed to meet the pre-clinical hype. The heterogeneity of MSC from different sources and donors is a plausible rationale for MSC failing to gain widespread regulatory approval. Secondly, many clinical trials report minimal efficacy of MSC treatment groups compared to placebo. Induced pluripotent stem cell (ISPC) technologies have revolutionised the field of cell therapies and offer an alternative method for cell production. iPSC-MSC or iMSC might offer an alternative source of MSC with improved expandability and reduced heterogeneity. Subsequently, licensing or the in vitro priming of MSC was shown to be a viable method to attempt to improve MSC therapeutic capacity. iMSC and MSC were compared for their ability to undergo tri-lineage differentiation, secrete antiinflammatory factors and modulate the activation of immune cells, T lymphocytes and monocytes. Also, the response of both cell types to licensing with tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) was examined using these methods. As apoptosis of implanted MSC as a mode of action of MSC has gained more interest in recent literature, the role of apoptosis derived and secreted apoptotic bodies was assessed. The apoptotic bodies from naïve and licensed MSC or iMSC were first isolated and characterised. Next, the apoptotic bodies’ ability to repair OA cartilage, reduce T lymphocyte proliferation, polarise M1 macrophages to their M2 phenotype and miRNA cargo was investigated. Here, we show that the MSC and iMSC, although not identical, are similar in their ability to differentiate, secrete anti-inflammatory factors and modulate the immune system. Likewise, the apoptotic bodies from untreated MSC and iMSC shared similar but not identical characteristics. Also, we demonstrated that licensing with inflammatory factors does improve the immunomodulatory capacity of MSC, iMSC and their apoptotic bodies. Further analysis and in vivo studies will be required to validate these findings. Still, in vitro iMSC behave similarly to MSC, with variations similar to that seen for MSC from alternative sources. iMSC offer greater expandability, reduced cost, and reduced heterogeneity. Additionally, licencing is a realistic alternative approach to improve MSC efficacy. iMSC and licensing may improve the clinical outcome of MSC trials and, therefore, bridge the gaps from clinical trials to the market for MSC cell therapy.Publication ZC3H14, a new player in the early response to DNA double strand breaks(University of Galway, 2024-11-07) Kieffer, Shaylee; Lowndes, Noel; Hardiman Research Fund, University of GalwayThe primary goal of all organisms is to pass down intact genetic information to the next generation, despite mutagenic threats from both endogenous and exogenous sources. To prevent accumulation of DNA damage, cells have developed complex mechanisms that detect and respond to different forms of lesions. These complex pathways are collectively called the DNA damage response (DDR). Impaired responses to DNA damage drive oncogenesis, neurodegeneration, and immunodeficiencies. Both DNA damaging agents and drugs which target specific repair proteins are a mainstay of modern current therapeutic approaches. Thus, to understand the aetiology of disease, the impact of current therapeutic interventions, and to develop further precision medicines, it is vital to understand the complex series of pathways involved in the DDR. One of the major protein kinases involved in signal transduction within the cells’ response to double strand breaks (DSBs) is Ataxia-telangiectasia mutated (ATM). Previous research from Prof. Noel Lowndes’ laboratory identified a zinc-finger protein, ZC3H14, as a DNA damage-dependent ATM-interacting partner. This is an unexpected interaction as ZC3H14’s canonical roles are in mRNA processing, including regulation of poly(A) tail length and mRNA nuclear export. Similarly to ATM and other DDR proteins, ZC3H14 has both neurological and links to cancer when it its function is impaired. This novel data implicates ZC3H14 in the DDR, as well as placing it in a disease-critical pathway. Unpublished data has placed ZC3H14 in the ‘Early’ response to DSBs, which occurs minutes after break formation. Cells lacking ZC3H14 showed striking repair defects: cells become sensitive to ionising radiation (IR); depletion of ZC3H14 results in a persistent increase in the damage markers γH2AX foci and ATM-pS1981; and knockdown of ZC3H14 ablated irradiation-induced foci (IRIF) of ‘Early’ DNA damage response proteins downstream of MDC1. In addition, ZC3H14 co-immunoprecipitated with both ATM and MDC1. Preliminary data suggests that ZC3H14 is more involved in NHEJ than HR, despite its placement in the response upstream of pathway choice. Here, we aim to deepen our understanding of the role of ZC3H14 in the DDR using bioinformatic, cellular and molecular geology, and biochemical methodology. We generated ZC3H14KO cells, allowing us to study the placement of ZC3H14 in the DDR pathway, and to confirm the defect of DDR protein recruitment via independent methods. These cells show an increase in endogenous damage and impaired foci formation. We designed GFP-ZC3H14 domain mutants that truncate the N-terminal PWI-like domain or the five tandem C-terminal zinc finger domains in order to explore the mechanisms of these domains on ZC3H14’s role in repair. We were able to determine that ZC3H14 is a damage-specific substrate of ATM, and that it localises in proximity to damage-activated ATM-pS1981 in vivo. Despite these interactions, we were unable to visualise ZC3H14 at damage foci, and hypothesise that due to ZC3H14’s heavy localisation to nuclear speckles, there may be only a subset of ZC3H14 at the speckle’s periphery that is phosphorylated and responsive to damage. As well, ZC3H14 has a large intrinsically disordered domain which could contribute to its localisation. Interestingly, we used the newly released AlphaFold3 server to predict that ZC3H14 could contain a disorder-toorder region which has an alpha-helixes rich folded structure in the presence of DNA and other DDR proteins, but not nuclear speckle proteins. All of this points to a damageactivated phosphorylated form of ZC3H14 which has some as-yet unsolved role at DSBs. This role is likely in regulating the recruitment of MDC1 or RNF8, but could also have to do with phase separation of IRIF condensates, or provide a link between mRNA processing and DNA repair. The project aims to characterize a novel role for a zinc-finger protein, ZC3H14, in the DNA damage response (DDR): its interactions with Ataxia-telangiectasia mutated (ATM), its effect on cell survival, its impact on formation of irradiation-induced foci (IRIF), its mechanism of action, and its signature in human diseases. ZC3H14 has not been previously implicated in DNA repair. Many proteins within this pathway can be targeted for synthetic lethality, to be taken advantage of both for molecular tools for further study, and for druggable targets with the advent of personalised medicines.Publication Mechano-dysfunction of Purkinje cells in Ataxia telangiectasia patients(University of Galway, 2024-10-23) Lowndes, Conor; Foiani, MarcoAtaxia telangiectasia (A-T) is a cerebellar ataxia caused by mutations in the ATM gene, leading to the progressive loss of Purkinje cells, though the mechanisms underlying this cell death are still largely unknown. While ATM is mainly recognized as a DNA damage response protein, it also plays a crucial role in many other cellular processes. Recently, it has emerged as a regulator of mechanotransduction. Using immunofluorescence, Brillouin microscopy, and laser microdissection proteomics, we investigated how mechanical dysfunction contributes to the degeneration of Purkinje cells in A-T patients. We found that Purkinje cell nuclei exhibit unique mechanical and elastic properties, making them especially vulnerable to chromatin hypermethylation and nuclear envelope invaginations in the absence of ATM. Furthermore, laser-capture proteomics of Purkinje cells from A-T patients revealed dysregulated mechanotransduction and chromatin remodeling pathways. Finally, we present in vitro evidence that promoting chromatin relaxation through various inhibitor treatments can rescue the nuclear shape defects in A-T Purkinje cells. Our findings suggest that mechanical stress in A-T Purkinje cells may contribute to their degeneration in Ataxia telangiectasia and highlight innovative therapeutic strategies targeting nuclear mechano-dysfunction in A-T patients.Publication Investigating the feasibility of vehicular communications with modern wireless access technologies(University of Galway, 2024-10-22) Clancy, Joseph Sean; Glavin, Martin; Jones, Edward; Deegan, Brian; Lero; Science Foundation Ireland; European Regional Development FundVehicle-to-Everything (V2X) communications is a technology intended to facilitate information exchange among connected vehicles, targeting improved road safety and traffic efficiency. The wireless access segment of V2X communications is responsible for providing this connectivity to vehicles. Of the portfolio of wireless communication technologies currently in use today, Dedicated Short-Range Communication (DSRC) and Cellular Vehicle-to-Everything Communications (C-V2X) are the primary candidates to enable wireless access for V2X communications. Despite its potential benefits, V2X communications has not been widely adopted to date, indicating lingering technical challenges and thus motivating the primary research objective of this thesis: to investigate and characterise the wireless access challenges facing V2X communications as an industry vertical. Firstly, a review of the state-of-the-art in wireless access technologies for V2X communications is provided, beginning with an overview of V2X communications, its history, and standardisation. This is followed by a description of the two primary wireless access technologies, DSRC and C-V2X, and the presentation of a comprehensive review of the literature surrounding their candidacy. Results indicate that C-V2X is likely to be the most appropriate candidate wireless access technology due to its wider application support and potential for growth. Finally, active research areas that have the potential to address the challenges identified in the literature review are discussed. Secondly, a novel dataset is generated to evaluate and characterise the capabilities of early 5G New Radio (NR) cellular deployments, thus characterising the potential challenges towards the large-scale adoption of V2X communications. Results demonstrate that new 5G NR deployments can indeed outperform the existing 4G Long Term Evolution (LTE) cellular system in ideal conditions. However, results also indicate that the new 5G NR deployments are subject to a significant degree of variability and are much less reliable than the existing 4G LTE system. In particular, handovers were found to be a significant source of unreliability in V2X scenarios, with the inter-RAT (Radio Access Technology) handover type emerging as the primary contributor due to demanding control signalling and radio management requirements. Lastly, given the challenges associated with large-scale deployment of V2X communications, a small-scale Vehicle-to-Infrastructure (V2I) application intended for safety-critical use cases is proposed as a potential solution. The feasibility of the network architectures of the proposed V2I system is evaluated with particular consideration of the trade-offs associated with implementation constraints, i.e. cost, performance and security. Results show that the system is indeed feasible, however, several open questions about the system performance requirements of such safety-critical use cases remain. In summary, this thesis indicates that while non-safety-critical V2X applications are feasible with current wireless access technologies, significant advancements will be required to support safety-critical applications at scale. To this end, a number of potential solutions are proposed to bolster the capabilities and capacity of current networks and thus provide a path towards the large-scale adoption of V2X communications technology.Publication Novel statistical models and computational tools for gene set analysis(University of Galway, 2024-10-14) O'Shea, Dónal; Seoighe, Cathal; Science Foundation Ireland under Grant number [18/CRT/6214]The gene is often treated as an observational unit in biology. The signals in a trancriptomic assay are mapped to genes, while the results of genomic and functional assays are frequently linked to genes to increase biological interpretability. However, the function of a particular gene is not always known and can change depending on cellular context. Furthermore, the number of genes identified as worthy of interest can be far too great for researchers to interpret and extract biological insights from them one by one. Analysing groups of genes related by function, partaking in a common biological pathway or sharing biochemical similarities can address these pitfalls. The criteria and knowledge used to construct gene sets are incorporated into the downstream analysis of transcriptomic, genomic and functional assays, focussing the researcher's attention on a comparatively small number of well-defined pathways. In Chapter 2, we outlined the log-fold change distribution as a conceptual framework that can be used to understand the different null hypotheses being tested by various gene set analysis (GSA) tools in the context of differential gene expression. This framework led to the development of a set of GSA tests based on modelling the log-fold change (LFC) distribution as a mixture of Gaussian random variables. The different tests provide parallels to popular GSA methods with significant advantages in sensitivity and interpretability in both simulations and real data analysis. In Chapter 3, we developed additional GSA tests to interpret the results of cell-type-specific differential expression analyses. Inference of cell-type-specific differential expression from a heterogenous sample is associated with high levels of uncertainty. This uncertainty necessitated the development of non-parametric GSA tests based on the LFC distribution, making fewer assumptions and leading to more robust results. Both parametric and non-parametric tests were made available in an R package and an Rshiny application, which allows researchers to efficiently run GSA tests and visualise and interpret results across all cells in the experiment. In Chapter 4, the focus of the thesis shifts from enrichment in the context of differential gene expression to enrichment for variants in genomic regions. We performed genomic enrichment tests on de-novo variants in autism spectrum disorder probands. Groups of genomic regions could be compared with the rest of the genome or between cases and controls. The former tests (internal in that they compared different regions of the genome with each other) aimed to model the distribution of variants across the genome to detect regions with a significantly higher number of variants than expected. The latter (external tests), through the use of an appropriate control cohort, avoided making any assumptions about the distribution of \textit{de-novo} variants along the genome and was better suited for the testing of large numbers of variants not previously associated with the trait.Publication Motion tracking analysis in elite soccer: Pattern discovery(University of Galway, 2024-10-08) Nejadi, Pouyan; Newell, John; Sangachin, Davood Roshan; Irish Research Council (IRC); Orreco LTdIn modern soccer (football), extensive motion tracking data are collected, capturing players’ movements at a rate of 25 times per second. Traditionally, these data have been utilised for tactical analysis, focusing on aspects such as team formation and identifying motion patterns. However, my research aims to leverage these data in a novel manner, prioritising player performance, injury management, rehabilitation, and player welfare. This thesis seeks to develop new statistical methods to identify personalised patterns of movement, enabling the creation of tailored training sessions that address the physiological demands specific to each player’s position. Additionally, by analysing the types of movements and associated physical forces, sports scientists can design rehabilitation programs for injured players more effectively. To this end, advanced modelling techniques are incorporated to enhance the analysis of motion tracking data. The bivariate generalised linear model (GLM) offers a sophisticated approach to jointly modeling angular change and speed change in player trajectories. By characterising trajectories into interpretable parameters, such as angular change and speed change, this model provides valuable insights into the underlying patterns of player movement. Furthermore, the bivariate GLM facilitates the clustering of trajectories based on the estimated parameters, allowing for the identification of similar movement patterns among players.Publication Vulnerability as a technology of EU migration management in the Aegean: From humanitarian exceptions to border violence(University of Galway, 2024-10-08) Keady-Tabbal, Niamh; Mulally, SiobhánThis thesis conceptualises vulnerability as a technology of migration management in order to reveal the relationship between international law, and the production and normalisation of border violence. It sheds light on an exclusionary logic of humanitarian exceptionalism that structures racialised migrants’ access to territory and protection in international and European law. On land and at sea, access to protection for the world’s ‘unwanted’ migrants, whose right to cross national borders is unrecognised, and who lack the necessary passport and financial means to travel freely, is, in practice, increasingly contingent on the logic of humanitarian exceptionalism. In the context of the EU border and migration management policies in Greece, this logic plays out in the way that two parallel concepts of vulnerability determine access to asylum: increasingly, we see that in order to gain admission, asylum seekers must be recognised as ‘vulnerable’ on land or ‘in distress’ at sea. Both function as criteria for protection and have been employed through migration management policies in a way that is, in practice, limiting the core right to seek and enjoy asylum at the external borders of the EU. By demonstrating the role of vulnerability as a technology of migration management, this thesis advances an understanding of the relationship between the paradigm of European migration management, the erosion of the right to seek asylum and the increasing forms of violence, both ‘slow’ and ‘spectacular,’ against irregularised migrants at external borders of the EU.Publication Sustainability reporting in higher education institutions: Barriers, opportunities, case studies and toolkits(University of Galway, 2024-10-08) Adams, Thomas; Goggins, Jamie; Science Foundation IrelandThis thesis investigates the role of sustainability reporting in Higher Education Institutions (HEIs), focusing on their potential to foster sustainable development and act as agents of change. Through a comprehensive analysis of published academic literature, this research identifies significant barriers to effective sustainability reporting, including lack of standardised frameworks, data collection challenges, financial constraints, limited stakeholder engagement, and organisational complexities. A sustainability report was completed as part of the literature review, in order to critique the reporting process and to identify particularly challenging areas to focus this research on. The Sustainability Tracking, Assessment & Rating System™ (STARS®) was used as the assessment tool, with Education for Sustainable Development (ESD) and Carbon Footprint (CF) reporting as the two chosen focal research areas. The aim of the thesis was to explore the identified barriers to sustainability reporting, through the lens of ESD and CF reporting. This was done through the creation of innovate tools, the application of these tools in demonstration cases, and engagement with stakeholders. The Sustainable Development Goals (SDG) keyword scanning and carbon footprint calculator tools, which were developed as part of this work, are published as open-access resources to enhance data collection efficiency and accuracy. The SDG keyword scanning tool automates the identification of relevant SDG content within curriculum materials, providing a baseline measure for ESD. The carbon footprint measurement tool offers a robust method for calculating scope 3 emissions for organisations in Ireland, particularly from purchased goods and services. By applying these tools, the thesis highlights the practical difficulties and opportunities in implementing effective sustainability reporting in HEIs. The ESD demonstration cases published as part of this thesis include a sample ESD baseline for University of Galway, an example of ESD implementation into an engineering programme and an ESD baseline for civil engineering programmes across Ireland. The carbon footprint demonstration cases include a carbon footprint report for University of Galway covering the years 2017-2023, an analysis of the impacts of COVID-19 on the university’s carbon footprint, a supply chain analysis and a roadmap to net-zero greenhouse gas emissions. The demonstration cases and practical applications demonstrate how these tools can be tailored to local contexts, thereby addressing specific institutional needs. The research underscores the importance of engaging stakeholders, developing comprehensive data management systems, and securing financial and administrative support to achieve sustainable practices. Engagement with key stakeholders through emails, workshops, surveys and student assignments revealed that stakeholders are also struggling with the identified barriers and are eager for more supports and resources for effective sustainability reporting, planning and development. The findings contribute to the broader understanding of how HEIs can overcome common barriers to sustainability reporting, emphasising the necessity for adaptable, user-friendly tools and frameworks. This work supports the ongoing effort to integrate sustainability into higher education, ultimately enhancing the capacity of HEIs to contribute to global sustainability goals.Publication Assessing translocation outcomes and revealing behavioural insights in two red squirrel populations in the West of Ireland(University of Galway, 2024-04-15) Reilly, Emily; Lawton, ColinThe red squirrel (Sciurus vulgaris) population suffered a dramatic decline in Ireland following the introduction of the invasive grey squirrel (Sciurus carolinensis) in 1911. Two red squirrel translocations, the intentional movement of a living organism from one area to another, were undertaken as part of efforts to conserve the species. These translocations took place in 2005 and 2007 at two sites in the west of Ireland, outside the range of grey squirrels: Derryclare in Co. Galway and Belleek woods in Co. Mayo. In the years following the translocations, monitoring efforts were implemented to observe and assess both populations. The most recent survey, conducted in 2012, provided evidence of the sustained presence and growth of both populations. The core aim of the present study was to investigate the current status of the translocated populations. At this stage the translocated populations were expected to have reached the regulation phase, exhibiting a continued presence and stabilised density. Following the introduction of the red squirrel population to Derryclare in 2005, the woodland underwent significant changes. Clear-felling operations, both expected and unexpected occurred frequently, owing to the woodland's commercial nature. This activity, combined with a significant forest fire in 2011, resulted in substantial habitat loss. We investigated the extent of this habitat loss and its effects on the carrying capacity of the woodland. We utilised digitised historical maps to compare past and present habitat, revealing a 53% reduction in habitat since 2005. A feeding survey was conducted, and the results were compared to previous feeding survey data, allowing us to track the changes in the estimated squirrel abundance and carrying capacity of the woodland. Carrying capacity estimates declined by 41–81%, with the lowest estimate at 65 individuals. Deterioration of the quality of the habitat, due to a shift in the proportion of tree species towards the less favourable species, further reduced the suitability of the woodland. Feeding surveys estimated a total of 2-4 individuals in the woods, illustrating the negative effects of habitat loss and deterioration. The Derryclare population was monitored using a combination of non-invasive and invasive techniques from January 2020 to January 2023. Trail camera, hair tube, and feeding survey data indicated a sparse squirrel presence throughout the entire woodland, with squirrel activity concentrated in patches of higher quality. Live trapping data revealed an eighteen fold decline in density compared to previous estimates, averaging at 0.032 squirrels/ha, or 6.5 total individuals. Breeding and recruitment rates were low, and squirrels were underweight compared to other red squirrel populations, including Belleek. Home ranges, estimated using trapping data, averaged 19.61ha. The large size of these ranges indicates a poor quality habitat. A feeding survey in nearby woodlands did not reveal any signs of dispersal, making it likely that carrying capacity was never reached in Derryclare. It was deemed that the translocation will ultimately not be successful, due to the low likelihood of the population’s recovery. The Belleek population were monitored from February 2020 to March 2023. Hairtube and trail camera surveys revealed a uniform population distribution throughout the woods. A live trapping study estimated an average density of 0.41 squirrels/ha, or 24.6 individuals, aligning with other healthy red squirrel populations. Breeding, recruitments rates and squirrel body weight were all indicative of a healthy population. Radiotracking was employed, revealing an average home range of 4.02ha. A citizen science survey conducted from March 2021 to January 2023, revealed a significant expansion of the Belleek population’s range, estimated to span 738.5km2 . The success of this translocation was attributed to the maintenance and persistence of consistent suitable habitat and the abundance of food, bolstered by continuous supplementary feeding. In contrast, ongoing loss and deterioration of habitat in Derryclare was believed to be responsible for this population’s decline. The behaviour of individuals in both populations was analysed during live trapping sessions to gain insights into their behavioural diversity. Additional open field tests and mirror image simulation tests were performed on a subsample of individuals in Belleek. While it was hypothesised that these populations would exhibit multiple differences due to their contrasting habitats, only one significant difference was identified. Belleek squirrels displayed a diminished flight response compared to Derryclare, possibly owing to their habituation to humans. A trade-off between reproduction and longevity was observed in Belleek females. In Belleek males, boldness was found to be associated with smaller individuals and increased longevity, while in Belleek females, boldness was linked to larger individuals and a higher reproductive output. These personality differences impact population dynamics and therefore have implications for conservation management. The recent resurgence of the pine marten has caused a decline in the invasive grey squirrel in Ireland, allowing for a red squirrel population recovery. The coevolutionary history between the red squirrel and pine marten, and the naivety of the grey squirrel to this novel predator are thought to be responsible for the contrasting outcomes of both squirrel species. We used trail cameras to record pine marten and red squirrel visits to feeders, and analysed the behaviour of the red squirrel following recent pine marten presence. We found that red squirrels visiting within 48 hours of a pine marten displayed an enhanced antipredator response involving increased sniffing and vigilance, and decreased feeding. These results support the hypothesis that red squirrels have avoided predation by the pine marten due to their behavioural adaptations. The divergent outcomes at Derryclare and Belleek underscore the intricacies of translocation projects, providing valuable insights into factors influencing their success or failure. In particular, this study has provided insights into the importance of habitat quality as a determinant of translocation success. We recommend that future translocation projects choose stable habitats, and place greater emphasis on habitat quality during the planning phase of the project. Additionally, our findings stress the significance of post-release monitoring, suggesting that monitoring is conducted at least until the regulation phase of the project, in order to reveal the true outcome of the project. Additionally, this study yields insights into red squirrel behaviour and ecology, emphasizing the need for behavioural screening in translocation projects. It also contributes to our understanding of the dynamics between red squirrels and pine martens, shedding light on the red squirrel's recovery in Ireland. We believe the insights gained from this study can provide valuable insights for future translocation projects, aiding in their successful planning and execution.Publication The role of the domestic and international law in enabling and constraining internment: A case study of Northern Ireland during ‘the Troubles’ and Guantánamo Bay during the ‘War on Terror’(University of Galway, 2024-10-07) Portuondo, Maria Cristina; Smyth, Ciara; Hanly, ConorWhen States are confronted with a terrorist attack that threatens the life of the nation, they typically react by adopting emergency legislation to enable the use of counter-terrorism tactics. While there is extensive literature on this topic, little has been written about the precise role that domestic law and international human rights law play in both enabling and constraining such tactics. This thesis investigates how the law and courts (including quasi-judicial bodies) have at once enabled and constrained counter-terrorism tactics, using a comparison of internment in Northern Ireland during ‘The Trouble’ (a period in time when international human rights law was a newly emerging body of law) and Guantánamo Bay in the context of the present day Global War on Terror (with international human rights law now a well-established area of law with a broad range of treaties and case law). These two case studies were selected due to the similarities between them in terms of the counter-terrorism tactics and used the alleged human rights violations, despite the differences in terms of temporal scope, geographic location, and the state of development of international human rights law. Ultimately, this thesis shows that despite the considerable enabling function of the law, in the form of deference to the executive by courts and legislatures, as well as sovereignty deference mechanisms built into the very fabric of human rights law, the law also constrains the nature and extent of counter-terrorism tactics. This study not only adds to the literature on States’ obligations to protect the general public and national security in response to a terrorist threat but develops the idea of a civil liberties and human rights duty to protect suspected terrorists. Finally, it explores the role and limits of the law in finding a durable solution to the vexed problem of terrorism.Publication Evaluation of the potential for genomic selection in an Irish breeding population of sitka spruce (Picea sitchensis (Bong.) Carr))(University of Galway, 2024-10-07) Cashell, Ronan; Farrelly, Niall; Spillane, CharlesGenomic selection is a form of breeding predicting for phenotypic traits within a population, using allelic data drawn from individuals within this population as the explanatory variable. Genomic selection has been widely evaluated within livestock and crop species, and is now an established part of breeding endeavours within such species. In the era of increasingly cheaper whole-genomic sequencing strategies, the potential for genomic selection is increasingly being investigated in more niche species with features that otherwise discourage evaluation such as long generational intervals or particularly large genomes. Sitka spruce (Picea sitchensis) is one such species, yet equally is also one of great importance to Irish forestry. Efforts to breed Sitka spruce in Ireland have been have resulted in a national breeding program, but have not yet attempted to incorporate any of the recent advances regarding genetic and genomic breeding. In this thesis, I investigated the the potential for genomic selection among the Irish breeding population of Sitka spruce. I evaluated the suitability of phenotypic data generated from the breeding program for the used as traits of interest within a genomic selection model. Comparing the historical data of the program to contemporary data, I investigated the assumptions of correlation of the genetic control of a traits across different ages which underpins breeding in many long-lived species. Combining the available phenotypic data of the breeding program, derived from families of half-siblings, with genomic data generated from their maternal parent through Genotype-by-Sequencing, I explored the potential for genomic selection in Irish Sitka spruce with respect to the nature of these data. Finally, using a sub-population of full-siblings derived from the breeding program's genotypes, I examined the effectiveness of genomic selection against more conventional breeding methods such pedigree-based breeding. In totality, this thesis demonstrates a clear potential for viable genomic selection in the Irish Sitka spruce breeding population as is, and highlights opportunities for changes to current practices which would further improve genomic selection within this population.Publication Development of pre-clinical models for evaluating performance of self-expanding nitinol stents for peripheral artery applications(University of Galway, 2024-10-07) Nandan, Swati; Vaughan, Ted; Dolan, Eimear; Hellmuth, RudolfThe femoropopliteal artery (FPA) is the most commonly affected site for peripheral artery disease due to its complex biomechanical environment, whereby it experiences extreme loading conditions during limb flexion. This has significant impact on the devices placed in this region and the associated haemodynamics. While self-expanding Nitinol stents are preferred in this region due to their better flexibility, crush recoverability and reduced foreshortening, they have still been associated with restenosis and stent fracture rates as high as 65%. While it is critically important to enhance existing stent designs to improve clinical outcomes, there remains major challenges in this area as complex implanted environment of FPA stents is difficult to faithfully represent ahead of clinical studies. The objective of this thesis was to develop novel pre-clinical models of device performance across in-vitro, ex-vivo and in-silico settings to better understand functional performance and ensure the safety and efficacy of the devices. Firstly, a computationally-informed in-vitro bioreactor system has been designed capable of delivering combination of haemodynamic forces found in native peripheral arteries for endovascular stent device testing upto 4 days. Secondly, an ex-vivo cadaveric model was used to assess the biomechanical performance of two different self-expanding Nitinol stent designs implanted in healthy and calcified legs of Thiel embalmed cadavers. This provided, for the first time, a quantitative approach to investigate the true deformation magnitudes of the FPA stents implanted in Thiel embalmed cadavers upon limb flexion. Finally, in-silico steady state and transient computational fluid dynamics (CFD) models were developed to explore the specific flow characteristics of a novel prototype spiral-flow (SLF) self- expanding Nitinol stent design in straight artery configuration. It was demonstrated that the numerically verified in-vitro bioreactor design captured endothelial (EC) response to self-expanding Nitinol stent deployment subjected to haemodynamic flow conditions comparable to native peripheral arteries for day 1 time point and showed a sustained EC injury response contributing to neointimal growth and development of in-stent restenosis for day 4 time point. Further the developed ex-vivo cadaver model showed true curvature peaks within the ranges of 0.08–0.14 mm- 1 and 0.06–0.18 mm-1 for pre- and post-intervention configurations respectively, during extreme flexed postures of gardening and crossed leg. True flattening peaks within the range of 0.3-0.53 were observed in the pre-intervention configuration for extreme flexed postures while notable peaks in the range of 0.2-0.53 were observed adjacent to stent placement in post-intervention configuration. These peaks of true curvature and flattening were mainly located in adductor hiatus and popliteal regions of the FPA segment suggesting localisation of severe deformations. Interestingly, cadaver leg with calcification and maximum age resulted in maximum bending and notable peaks of flattening deformation in both pre- and post-intervention implying that factors such as presence of calcification, stent placement and age could contribute to increased FPA deformations. It is suggested that the SLF stent design could have lower bending stiffness than control stent providing more flexibility to accommodate severe bending deformations but this required further investigation due to small sample size considered in this thesis. Finally, the developed in-silico CFD models demonstrated that the prototype SLF stent was effective in increasing the wall shear stress in the intra strut region and downstream of the device region improving swirling efficiency, especially at higher Re number. Moreover, SLF stent provided an optimal balance between swirl efficiency and swirl flow propagation downstream. This could make it well-suited for operation within a defined range of Re number and implantation at specific locations in the cardiovascular system. The study demonstrated that the SLF stent effectively eliminated recirculation and separation zones, particularly within the intra-strut region, reducing areas of low time- averaged wall shear stress (TAWSS) and high oscillatory shear index (OSI) typically associated with vascular pathology in the control stent.Publication Exploring community stewardship through place-based learning: A case study from the Burren(University of Galway, 2024-10-07) Bird, Áine; Fahy, Frances; Reilly, Kathy; Irish Research CouncilThis dissertation presents a comprehensive exploration of the intertwined concepts of place-based learning and community stewardship, drawing upon the work of Burrenbeo Trust, a landscape charity located in the west of Ireland. Through a practitioner-led study, this research aims to address key questions assessing the impact of the Trust’s initiatives, providing both theoretical insights and practical frameworks for future endeavours in this domain. Framed around three central research questions, the study is presented in the form of a compilation thesis, where three peer reviewed publications form the central focus with each paper building on the findings of the previous. The first paper presented as part of this dissertation scrutinises programme evaluation practices from the practitioner’s standpoint, leveraging insight from environmental education, evaluation methodologies and practitioner research. Through a meta-evaluation spanning a decade of data, the paper assesses the effectiveness of place-based learning initiatives delivered by Burrenbeo Trust, offering critical reflections on evaluation processes and outcomes. The second paper delves into the process of scaling-up a place-based learning initiative, using the Heritage Keepers programme as a case study. Through an examination of the programme’s inception, assessment and achievement, alongside discussion on scaling-up community stewardship approaches, this paper identifies necessary steps for successful implementation and broader implications for similar initiatives. Finally, the third paper, builds on the perspectives of the previous two papers, introducing a practical framework for community stewardship designed to facilitate and promote this process. Drawing from empirical research within a community stewardship initiative, the framework synthesises insights from facilitator observations, participant feedback and literature review. Comprising five essential components – Care, Knowledge, Facilitation, Agency and Action – augmented by Collective Action, this framework offers valuable guidance for researchers and practitioners alike, transforming the abstract notion of community stewardship into actionable steps applicable across diverse contexts. By integrating findings from the three papers, this dissertation contributes a nuanced understanding of place-based learning, community stewardship and their symbiotic relationship. It serves as a valuable resource for researcher, practitioners and policymakers, providing insights and frameworks to inform future research, practice and policy in the realms of environmental education, community development and sustainability. The primary findings of the research indicate the importance of practitioner evaluation and suggest a meta-evaluation approach could be beneficial. For organisations such as Burrenbeo, effective engagement in place-based learning and community stewardship is enhanced by active programmes, broad topics, fun elements, and the appropriate facilitators. Scaling-up local stewardship initiatives presents challenges and benefits, emphasising the importance of organisational knowledge, pilot phases, networks, peer learning, and collective action. Community stewardship initiatives significantly impact participants by increasing local heritage knowledge, action capacity, pride, and cohesion, with tangible environmental benefits such as tree planting and monument maintenance. Additionally, the practitioner-led framework identified informs researchers, practitioners and policymakers, with the essential components necessary for community stewardship: Care, Knowledge, Facilitation, Agency, Action and Collective Action.