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Enrichment and expansion of human umbilical cord mesenchymal stem cells as an angiogenic therapy for critical limb ischemia
No full textCritical Limb ischemia (CLI) or which is otherwise known as Chronic limb threatening ischemia is the advanced form of PAD, which can lead to ischemic rest pain, non healing wounds, ulcers gangrene, and in its worst form to limb amputation and consequent death. CLI occurs due to atherosclerosis in the arteries supplying the lower extremities. This causes the tissues below the plaque to be deficient in oxygen and nutrients; and leads to micro and macro vascular complications. Among the CLI patients, the non-revascularizable percentage of 10%-50 % or the “no-option” segment has poor prognosis with high mortality rates and reduced quality of life. The no-option patients have to undergo limb amputation; even upon amputation in addition to loss of quality of life, 50% die in 5 years and 70% die in 10 years of amputation. There is no effective treatment for CLI; hence a therapy for CLI is an unmet medical need.
In response, a scalable, reproducible sterile system using 3D microbioprinting methodology was developed, to allow high-throughput bioprinting of GMP compliant, sorted and Quantum closed bioreactor expanded 3D UC-362- MSC-gel platforms. Innovative devices were developed and prototyped in this approach, and their proof of concept was sought. An invention disclosure form (IDF) for the novel innovative device was prepared and filed at the University of Galway Technology Transfer Office. The system received an Enterprise Ireland feasibility grant for obtaining IP rights and a startup development. The IP application process was initiated in this regard. The novel innovation will benefit numerous 3D bioprinting applications in different fields by enhancing their capacities.
An in vivo randomized study was carried out in a nude BALB/c HLI mouse model for evaluation of the angiogenic capacity of the umbilical cord derived CD 362-MSC-bioprinted-cell gel platform and consisted of four groups with 12 animals in each. The treatment groups included saline/ sham, UC-362-MSC-IDO cells alone, UC-362-MSC-IDO-gel platforms, and acellular-gel platforms. Although the perfusion imaging methods of laser Doppler imaging and the novel HLI-MSOT used for the first time ever in HLI perfusion imaging did not detect increases in perfusion among treatment groups, the highest gains in capillary density with greatest significance (p<0.0001) were observed in the calf muscle of UC-362-MSC-IDO-gel platform recipients (368 BV /mm2 ± 197 s.d.). Muscle analysis of the ischaemic posterior calf muscles revealed high capillary densities in UC-362-MSC-IDO-gel treated animals (368 BV /mm2 ± 197 s.d.), and in UC-362-MSC-IDO cell treated animals (341 BV /mm2 ± 293 s.d.) compared to the saline treated group (p<0.0001). On average, the UC-362-MSC-IDO-gel treated animals developed 2.6 times more blood vessels per unit area compared to that of the saline recipients. The muscle fiber diameter analysis revealed the average of the median Feret fiber diameter was significantly higher in UC-CD-362-MSC-IDO cell treated (p<0.0001) and in UC-CD-362-MSC-IDO-gel platform treated (p<0.05) mice compared to the saline treated mice. The nature of added benefits the UC-362-MSC-IDO-gel platform can confer over UC-362-MSC-IDO cells alone warrants disease-specific application analysis. Therefore, based on the present study, the high-throughput 3D microbioprinted UC-362-MSC-IDO-gel platform with potent in vitro and in vivo proangiogenic capacity may require further dose-based fine-tuning through HLI in vivo studies for more amplified therapeutic benefit, before its use in critical limb ischemia.
Additionally, a novel three-dimensional imaging modality for mouse hind limb ischemia based on multi-spectral optoacoustic tomography (MSOT) was developed and compared against the standard laser Doppler imaging modality. A comprehensive description of methodology, process, benchmark values for ischemia HLI-MSOT, and dos and don’ts were introduced for conducting MSOT in mouse HLI studies based on the learning experience and results.
In the proof of concept studies, the novel mouse HLI-MSOT method was successful in detecting all ischemic events with 100% specificity and sensitivity relative to the standard LDI system in the ischemic mouse foot pads. The novel HLI-MSOT imaging modality would enhance the accurate determination capabilities of small animal-based HLI perfusion studies particularly in the thicker denser tissue 3D space which is not sufficiently addressed by the LDI based imaging. Thus, the novel MSOT based HLI imaging system could therefore be utilized successfully as either a stand-alone three-dimensional perfusion data acquisition modality instead of the LDI system, for more accurate perfusion information acquisition; or as a complementary system to the standard LDI already in use in a conjunctive manner in mouse HLI studies.
Abbreviations-: Indoleamine-2,3-dioxygenase (IDO); umbilical cord derived CD-362-MSC and IDO secreting cells: UC-362-MSC-IDO;3D bioprinted umbilical cord derived CD-362-MSC and IDO secreting cell-hydrogel platforms: UC-362-MSC-IDO-gel; blood vessels: BV; Standard deviation: s.
Uncovering the role of nucleotide metabolism in the control of beta-lactam resistance in Staphylococcus aureus and the identification of novel treatment strategies for Methicillin Resistant S. aureus (MRSA) infections
No full textStaphylococcus aureus is an opportunistic pathogen that can negatively impact human healthcare. It has a range of virulence factors that make it a formidable human pathogen with the ability to cause death. This is further complicated by the emergence of methicillin resistant S. aureus (MRSA) which is resistant to the most commonly used antibiotics; beta-lactams. This leads to poorer treatment outcomes and options for patients that contract MRSA infections.
This thesis describes the identification and characterisation of mutations associated with increased beta-lactam resistance in MRSA strain JE2. These mutations included genes encoding transporters for xanthosine, guanosine and guanine. Specifically, transposon insertions in pbuG, pbuX and nupG were implicated in higher levels of resistance to the anti-staphylococcal beta-lactam oxacillin. Conversely, the addition of guanosine or xanthosine reduced oxacillin resistance of JE2, supporting the conclusion that guanosine and xanthosine uptake regulates beta-lactam resistance. Notably, exposure of MRSA cells to exogenous adenosine increased oxacillin resistance, while the purine inosine, which can be fluxed to ATP or GTP only marginally reduced resistance. The addition of guanosine in combination with oxacillin to culture media was shown to reduce c-di-AMP levels providing an insight on the mechanism of action of this antibiotic/adjuvant combination. These discoveries highlighted the importance of guanosine metabolism in altering c-di-AMP levels and beta-lactam susceptibility.
Exposure to guanosine or adenosine resulted in contrasting effects on the MRSA proteomes and metabolomes. The abundances of enzymes responsible for cell wall synthesis including FemA, MurA, DapA, DapB and DapD were decreased by guanosine, whereas adenosine grown cells exhibited increased abundances in DapB and DapD. Guanosine grown cells also showed decreased intracellular levels of both glutamine and thymidine. Consistent with the reduced levels of thymidine, guanosine potentiated the activity of the anti-folates sulfamethoxazole (SMX), trimethoprim (TMP) and SMX-TMP as well as the pyrimidine analogues 5-fluorouracil (5-FU), and 5- fluorouridine (5-FUrd). Furthermore, the use of oxacillin at low concentrations provided “double synergy” with guanosine/thymidine inhibitor combinations.
Compounds used for treatment of cancer that target nucleotide metabolism also modulated beta-lactam antibiotics in a similar manner to guanosine and adenosine. Notably these compounds regulated expression of the lysine biosynthesis operon possibly identifying a novel pathway controlling beta-lactam resistance. Regulation of lysine biosynthesis by nucleotide analogues may suggest their usefulness as betalactam adjuvants to improve the treatment of MRSA infections. Further work also revealed the ability of these compounds to inactivate biofilms particularly when coadministered with known anti-biofilm antibiotics such as rifampicin, linezolid or daptomycin
Shuffling forth: An exploration of the evolution of the Little Zombie Girl
No full textAlthough academic interest in the zombie has flourished in the last twenty years the little zombie girl has been largely ignored so my research aims to address this lacuna. This thesis examines how the little zombie girl relates to gender, sexuality, reproduction, and power structures, focusing on three primary texts: George Romero’s Night of the Living Dead (1968), AMC’s The Walking Dead (2010-2022), and M.R. Carey’s The Girl with all the Gifts (2014). Utilising theories from gender and sexuality studies, helped me to approach the sense of disquiet that surrounds the little zombie girl. These theories underpin my argument that the little zombie girl derives much of her power from her position as Other. In my research I have shown how the little zombie girl is unique and she stands out from the zombie horde because she embodies the juxtaposition of not just the living and the dead, like all zombies do, but also the juxtaposition of an innocent child in need of protection and a threatening monster to be protected against, a little girl yet a markedly othered creature, a subject that is both pre-pubescent yet reproductive in her own right, a character that is both irresistible yet repulsive. I have looked at how the little zombie girl allows us to interrogate our fears surrounding things like the end of Anthropocene, fear of the Other, and also what it is to be human. By unpacking these concerns, I have shown that the little zombie girl is a powerful and subversive figure because she challenges our assumptions around heteronormativity, patriarchy, and human superiority and she derives her power by disrupting societal norms, subverting expectations, and rebelling against the status quo
Exploring complementarity: A study of the Colombian integrated system for peace between normative development and participants' perspectives
No full textThis research provides an in-depth, short-term assessment of the normative and practical development of the ongoing Colombian Integrated System for Peace (SIP). The SIP is the first domestic-led experiment in which TJ measures are designed from the outset as part of a cohesive process. This includes careful timing, sequencing, and institutional coordination. This study investigates the relationship between SIP's judicial and extra-judicial measures by gathering insights from professionals involved in the system, as well as from the perpetrators who have interacted with it. Using qualitative methods and extensive fieldwork, this research explores how intentional collaboration between judicial and extra-judicial bodies can improve the pursuit of truth and justice. The findings of this study highlight three key factors that influence the advancement or hindrance of complementarity among the bodies of SIP: the importance of timing, sequencing, and synchronicity in TJ measures when establishing a regime based on judicial conditional incentives; the significance of building on past experiences while considering the necessary learning curve for TJ measures to operate effectively and the pivotal role played by the ‘human component’ in implementing transitional measures.The PhD project was funded by the Irish Research Council Government of Ireland Postgraduate Scholarship (2020-2024) and the NUIG School of Law Doctoral Fellowship (April 2020 - October 2020
Unraveling the chromosome dynamics and DNA metabolism functions of the SMC5/6 complex
No full textThe Structural Maintenance of Chromosomes (SMC) protein family harbors cohesin, condensin and the SMC5/6 complex. SMC5/6 plays critical roles in preserving genome stability by regulating DNA repair, replication, and chromatin organization but its mode of action is not well understood. In this work, we investigated SMC5/6 functions in DNA homeostasis and genome organization by using integrative approaches including RNA-seq, Hi-C, and BLISS analyses. We uncovered functional interplay between SMC5/6 and BRCA1 in genome maintenance and common roles in limiting inflammatory response activation. Our results show that loss of SMC5/6 or BRCA1 induces genomic instability characterized by replication stress, fork degradation and double-strand breaks (DSBs), triggering activation of the cGAS/STING pathway and pro-inflammatory signaling. This is linked to increased micronuclei formation, nuclear envelope fragility, and defects in chromatin architecture. Genome-wide Hi-C analysis revealed that SMC5/6 depletion disrupts chromatin compartmentalization, TAD insulation, and long-range chromatin interactions, favoring a shift from repressive (B) to active (A) compartments. Affecting 2% of the genome, these changes precede transcriptional upregulation of inflammatory and cancer-related genes, with significant effects on pathways involved in DNA damage response and immune regulation. Integrating DSB mapping and chromatin organization data, we found that fragile sites such as CpG-rich promoters and early-replicating fragile sites (ERFs) exhibit increased DSB accumulation and gene expression dysregulation upon SMC5/6 depletion. Mechanistically, SMC5/6 safeguards stressed replication forks by preventing excessive fork reversal and degradation, cooperating with BRCA1 to protect their integrity and maintain replicationtranscription homeostasis. Loss of SMC5/6 accelerates fork restart but compromises fidelity, leading to accumulation of fragmented DNA and persistent genome instability. Additionally, changes in chromatin folding induced by SMC5/6 loss impact immune regulation by derepressing inflammatory genes, potentially linking chromatin structural changes to innate immune activation. This study underscores the multifaceted roles of SMC5/6 in maintaining genome integrity through chromatin organization, replication fork protection, and transcriptional regulation. It highlights how SMC5/6 dysfunction contributes to immune dysregulation and cancer progression, providing insights into therapeutic strategies targeting SMC5/6-associated pathways in cancer and immune disorders
Implementation of the primary science capital teaching approach in a scientist-facilitated intervention
No full textThis research explored how the Primary Science Capital Teaching Approach (PSCTA) can be implemented in a once‑off, scientist‑facilitated, non‑formal classroom intervention and examined its short‑term impacts on children’s perceptions of science and scientists. The PSCTA is rooted in Bourdieu’s concept of science capital, which encompasses the knowledge, attitudes, experiences, and social contacts that an individual possesses related to science. This study focused on children’s perceptions of science and scientists, and their levels of science capital, to explore the outcomes of a discussion‑based Q&A intervention that incorporated the teaching approach in its design and scientist training.
The mixed‑methods research involved 365 children (ages 9-13) from 15 schools and 27 scientist facilitators across four design cycles. Most children held medium (67.9%) or low (21%) levels of science capital, with only 11% possessing high levels of science capital. Children predominantly viewed scientists as ‘smart’ and lab‑based, although many believed anyone could be a scientist. Following the intervention, 44% of children reported that science was more interesting, 77% knew more about scientists’ lives, and 41% felt science was more relevant to everyday life. Small‑group discussions, prompt boxes, and personal storytelling were valued most by children and supported high levels of participation. Scientist facilitators implemented the PSCTA through sharing personal stories, linking science to children’s lives, and prompting discussion, while reflecting on their own practice and experiences as scientists.
This study provides the first systematic measure of primary children’s science capital in Ireland and demonstrates that a brief, low‑cost, discussion‑based intervention can humanise scientists and broaden children’s views of ‘what and who counts in science’, even in a single encounter.University of Galway Hardiman Scholarship 2021-2022 and Research Ireland Postgraduate Scholarship 2022-2025 (GOIPG/2022/250
Towards best practices in the pedagogy of human rights clinics: Movement lawyering, its emotional impacts on students and the question of teaching resilience
No full textThis thesis investigates approaches to human rights clinical legal education that can develop the resilience skills needed by students and staff to mitigate the negative impacts of emotional distress caused by engaging with human rights violations. The thesis contends that human rights-focused Movement Lawyering as a form of Clinical Legal Education has the potential to expose human rights law students to the experiences of people who were traumatised as a result of human rights violations. Thus, while Movement Lawyering creates interpersonal connections and promotes diverse skill-building, this type of experiential pedagogy may at the same time play a role in inducing negative emotional experiences in research students. The possibility of exposing law clinic students to emotional stress necessitates that human rights law clinics include lessons in their curricula that educate students on the realities of human rights work and prepare them to manage their emotions in such settings.
The thesis identifies and responds to a gap in traumatology literature, and in research studies on the negative emotional effects of human rights work on clinic students. The literature on emotional resilience is ambiguous and does not offer clear-cut methodologies for teaching students how to manage their emotions in stressful situations. The thesis used three methods of enquiry to propose solutions that may enable law clinics to better prepare human rights students for their professional careers. The methodology involved auto-ethnography and other qualitative methods of researching a case study of the Human Rights Law Clinic at the University of Galway, Ireland. It examined students’ reflective essays, and the findings of interviews conducted with LLM students and former professional human rights careerists. The interviews provided knowledge about how students conducted movement lawyering projects, and the effects of those projects both positive and negative on their emotional wellbeing.
The findings from the research indicated that Movement Lawyering as a basis for clinical education, as it is utilised in the Human Rights Law Clinic at the University of Galway, is a positive platform for incorporating skills of emotional resilience. The Human Rights Law Clinic was deliberatively designed using a movement lawyering model, and it already significantly incorporates consideration of emotional resilience and therefore is poised to engage with ongoing reform to adapt to student needs, such as the guided recommendations for improvements in future human rights law clinics that are provided in this thesis. The recommendations are structured such that they can be replicated and adapted according to the educational requirements of university law schools globally
Thinking critically about cancer misinformation: The Informed Health Choice-Cancer (IHC-C) programme
No full textIntroduction
Cancer remains one of the leading causes of death worldwide, with incidence rates expected to continue to rise. As digital technology evolves, those impacted by cancer increasingly turn to online resources to support their health choices, with approximately one in three people actively seeking health-related information online. However, amid the ongoing ‘infodemic’ where false or misleading content circulates widely, the quality of cancer-related information has become a major concern. Evidence suggests that nearly one in three pieces of cancer-related content contains misinformation, posing significant challenges to individuals’ ability to access trustworthy and accurate health content. This undermines informed decision-making, influences health behaviours, and erodes public trust. Limited public health literacy and a general lack of skills in critically appraising health claims further amplifies the risks posed by misinformation. At the individual level, misinformation can delay appropriate treatment and lead to avoidable harm, including death; at the population level, it can distort public attitudes, behaviours, and health policies, ultimately undermining the collective capacity to make informed health choices.
In response, there is an urgent need for accessible interventions that strengthen health literacy and critical thinking, both of which are essential for navigating an increasingly complex health information landscape and mitigating the harmful effects of misinformation.
Aim and Objectives
This research aims to develop and test an online educational programme called Informed Health Choices-Cancer, designed to equip individuals impacted by cancer with the skills and knowledge necessary to think critically about the reliability of health claims and make well-informed choices. The research objectives are to: 1) prioritise and identify the most relevant Key Concepts from the Informed Health Choices framework for those impacted by cancer; 2) based on the prioritised Key Concepts, create a plain-language, cancer-centred learning resource through an iterative process that incorporates input from individuals impacted by cancer; and 3) design a pilot randomised trial to assess the feasibility and acceptability of the learning resource as an intervention to enhance health literacy, critical thinking, and decision-making regarding cancer and health information.
Methods
A mixed-method approach was used to address the research objectives.
To address objective one, a structured two-round prioritisation process was conducted to identify the most relevant Key Concepts for those impacted by cancer, collaborating with key stakeholders from both a patient and public involvement group (including cancer patients, survivors, caregivers, and loved ones) and a multidisciplinary steering group (composed of healthcare professionals, educationalists, and researchers). Participants received pre-reading materials and attended training sessions to familiarise themselves with the Key Concepts and the prioritisation process. Each concept was evaluated using a standardised judgement form. Quantitative and qualitative data from each prioritisation round were analysed to reach a consensus on the final set of concepts selected for inclusion.
To address objective two, a human-centred design approach incorporating iterative refinement was used to co-develop the learning resource. Guided by the prioritised Key Concepts, structured templates were initially developed to define the overall architecture of the learning resource, including unit structure, learning outcomes, the need for tailored cancer-specific content, and appropriate multimedia formats. One prioritised Key Concept was expanded into a prototype unit, and an iterative cycle of drafting, reviewing, revising, and refining was conducted to ensure rigorous educational standards and effective communication of intended learning outcomes. The prototype was then pilot tested with key stakeholders from the prioritisation phase to assess accessibility, usability, and real-life relevance. Feedback was systematically incorporated to refine both the prototype unit and the templates. Subsequently, the remaining units were developed using the refined templates as a guide. The same iterative cycle of drafting, reviewing, revising, and refining was conducted, and the complete learning resource was integrated into an online learning platform. It was further evaluated through two successive pilot tests: first with small stakeholder groups and subsequently with a broader sample, including newly recruited patient and public involvement participants. Quantitative ratings and qualitative feedback were collected and used to assess and enhance the accessibility, usability, and practical relevance of the learning resource.
To address objective three, a pilot randomised trial was designed to evaluate the feasibility and acceptability of delivering the Informed Health Choices-Cancer learning resource and to inform the design of a future definitive trial. The trial design defines participant recruitment strategies, randomisation procedures, control group allocation, the selection of primary and secondary outcomes, demographic data collection, and data analysis methods.
Findings
Objective one: Thirty-five participants, including those impacted by cancer, healthcare professionals, educationalists, and researchers, took part in five training sessions and two rounds of a structured prioritisation process. Through two consensus meetings, the original list of 49 Key Concepts was initially narrowed down to 21 and ultimately reduced to a final set of nine. These nine concepts were identified as the most relevant to the needs and experiences of those impacted by cancer.
Objective two: Structured templates were created to guide the design of the learning resource and its individual units. Fourteen participants who were impacted by cancer, completed the initial pilot testing of the prototype unit. The results showed alignment of the learning resource with intended learning outcomes, clarity of content, and relevance to users’ needs. Qualitative feedback indicated a need for further simplification of language, prompting refinements to both the prototype and the templates. The revised templates were then used to develop all remaining units. Nineteen individuals impacted by cancer participated in two rounds of pilot testing. Over 80% of participants found the overall learning resource ‘very well aligned’ with the learning outcomes, ‘very easy to understand’, ‘very relevant’ to the needs of individuals impacted by cancer, and ‘very easy to navigate’. The final version of the resource was also perceived as useful in supporting critical thinking, facilitating informed decision-making, and reflecting the real-world experiences of individuals impacted by cancer.
Objective three: The pilot randomised trial has been designed and is ongoing. Participants are being recruited through both traditional and online channels and randomised to either the Informed Health Choices-Cancer intervention or a waitlist control group. Primary outcomes include feasibility metrics such as recruitment and retention rates, while secondary outcomes assess acceptability, such as participant satisfaction and perceived usefulness. Demographic and cancer-related data are being collected to characterise the cohort and support future recruitment planning. Preliminary measures of health literacy, critical thinking, and decision-making skills are also being gathered to inform outcome selection for the future trial.
Conclusion
The findings from this research demonstrate the development, feasibility, accessibility, and acceptability of the Informed Health Choices-Cancer learning resource as an educational intervention for individuals impacted by cancer. The structured prioritisation process effectively identified Key Concepts most relevant to this population. The iterative user-centred design approach resulted in a structured learning resource that was well received for its clarity, usability, and relevance to users’ real-world needs. Pilot testing is planned to provide preliminary evidence on the resource’s potential to improve health literacy and critical thinking, empower informed health choices, and reducing vulnerability to cancer-related misinformation. As a practical, accessible, and evidence-informed tool, the Informed Health Choices-Cancer programme offers a novel approach to integrate health literacy and critical thinking education into cancer care, supporting more informed health choices. These findings provide a solid foundation for a future definitive trial to evaluate the effectiveness of the Informed Health Choices-Cancer learning programme on critical thinking, eHealth literacy, and decision-making skills
À la quête de la femme de personne: textual deliverance of the female body within contemporary Moroccan women's writing
No full textThis thesis presents a study of Francophone Moroccan women’s writing since its emergence in the 1980s to the present day. Drawing on the works of three authors who span the history of the literary tradition of the novel; Noufissa Sbaï, Houria Boussejra and Leïla Slimani, the study offers an overview of the socio-political context of the genre as it has evolved, while also providing a literary analysis of the primary themes and characteristics that dominate women’s writing. Historically, women have been excluded from the domain of written culture within Morocco, and until the 1980s, their histories were written primarily from the male perspective. Similarly, the study of novels produced by female authors has also been neglected at the academic level. This thesis attempts to pay homage to the corpus of works produced by female authors in French by examining how and why the female author writes. The political, social and aesthetic significance of women’s writing is explored through a feminist lens informed by theorists Hélène Cixous, bell hooks and Fatima Mernissi, revealing a shared desire amongst female authors to both challenge and rewrite the place assigned to woman within the patriarchal social imaginary. Their novels underscore the link between agency and voice and the vital role that writing can play in reappropriating one’s history and in expressing one’s subjectivity. The authors within this corpus are emblematic of what Suellen Diaconoff has termed “storytellers with a purpose,” and have answered Cixous’ call for woman to write woman in order to liberate the female body from patriarchal discourse and limiting social norms. Through the medium of the novel, Sbaï, Boussejra and Slimani have created a public space of resistance where previous representations of woman can be recontextualised; where women are encouraged to express and define their identities on their own terms. Sbaï, Boussejra and Slimani have transgressed the traditional space and place of the Moroccan woman in search of “la femme de personne” – the woman who belongs to no one – the woman who is free. By rewriting the female body from the perspective of woman and in reframing the narratives of traditional female stereotypes, the authors of our corpus are actively engaged in what Cixous envisaged as écriture féminine and the symbolic revolution of woman; in the creation of la femme de personne. It is the conviction of this author that it is by writing la femme de personne into the social imaginary that women writers succeed in offering textual deliverance to the female body