Cell type-specific genome stability in the non-ageing animal Hydractinia symbiolongicarpus

The marine cnidarian Hydractinia is highly regenerative, does not age, develops no spontaneous neoplasia, and is highly resistant to ionizing irradiation (IR). These features are thought to depend on a population of adult pluripotent stem cells, called i-cells. I hypothesized that these features are supported by a highly stable genome in some or all Hydractinia cell types. Studying the mechanisms that underlie genome stability in this animal was the main aim of my PhD. As a first step, I show that Hydractinia possesses no unique protection against IR-induced DNA double-strand breaks (DSBs). Furthermore, DSB repair occurred within 24, in line with other organisms. However, in contrast to other animals, Hydractinia stem cells (i-cells) are not more sensitive to IR when compared to differentiated cells. Following irradiation, i-cells exited the cell cycle for an extended period but remained alive as demonstrated by flow cytometry. Eventually, cell cycle re-entry was observed, followed by the animals complete resumption to clonal growth and sexual reproduction. To explore genome stability at single cell level, high quality omics resources are required. I participated in the chromosome-level genome assembly and analysis for male clone 291-10. An additional chromosome-level assembly was generated for the female clone 295-8. A male cell type atlas of 200,000 cells was generated by mapping barcoded RNA reads from single-cell ACME SPLiT seq to the reference genome. All known cell types and some novel ones were identified, including a stolon enriched type. An additional female single cell dataset was generated and merged with the male atlas, identifying an oogenesis-specific cluster with novel marker genes. To assess IR response, I generated a single cell dataset from animals at 1- and 9-days post exposure to 50 Gy. I merged the post IR libraries with the reference atlas and found that all major cell types were captured in the IR dataset. I demonstrate, on a single cell level, that the mutational load decreases significantly between 1- and 9-days post IR, and is generally lower in i-cells, indicating the presence of a post DSB repair mutation elimination (PRiME) mechanism in some or all cell types. Such a mechanism has never been recorded previously in any organism. I identified Hydractinia homologues for 163 genes implicated in DNA damage response in humans, including all genes required for canonical homologous recombination and non-homologous end joining. I searched for genes involved in PRiME by assessing differential expression of genes between specific cell types during recovery from high dose IR, providing candidate genes for future functional studies. Understanding the mechanisms involved in PRiME could provide insight into cnidarians' overall resilience to age-related degeneration and cancer, and have future applications in human disease research.2026-05-2

Essays on estimating effects of star arrival in small open economies: An event-study analysis

As the economy’s growth becomes more dependent on innovation, science policy is increasing in importance as an instrument for shaping the direction and impact of science on economic development, especially in small open economies. Policymakers in small open economies have shown increased interest in various science policies to stimulate the development of national innovation systems. A potentially attractive strategy in the science-policy mix is the targeted recruitment of star scientists designed to catalyse the development of research clusters in targeted research areas. However, there is little evidence on how stars impact the productivity of their peers in small open economies. In this context, the objective of the thesis is to provide an evidence-based evaluation of the impact of star scientists on their peers. It addresses five specific goals aligned with the objective in five separate empirical and methodological papers. A better understanding of the knowledge spillovers from the star can support the development of star recruitment policies intended to recruit stars and integrate them into local networks to catalyse productivity. Thus, the first paper of this thesis focuses on the co-authorship channel, examining how forming a co-authorship relationship with a co-located star affects the productivity of the co-author, both including and excluding star co-authored output. The latter effect provides a measure of the extent to which star collaborations crowd out/in other output. The analysis is conducted on a matched sample for treated and control authors obtained using coarsened exact matching. An event-study model is employed on the matched sample to estimate the dynamic effect of the star co-authorship on quality-adjusted productivity. In addition, I explore the heterogeneity by period, field, and whether the authors have multiple star co-authorships. While the first study offers valuable insights into the co-authorship relationship with the star, the second paper investigates the dynamic effects of star arrival on the arriving department. It is hoped that the arriving star can positively impact department productivity through channels such as access to better training and knowledge, changing norms relating to research, and even creating collaboration opportunities. An event-study model estimates the dynamic effects of a star arrival on quality-adjusted research output at both the department and matched individual incumbent levels. The matched individual-level sample allows us to make more credible causal inferences about the star arrival effect. To help further understand star impacts on peers, the third paper examines how relatedness to the arriving star modifies the size of the productivity effect on co-located peers. The paper assumes a non-linear relationship between the level of relatedness and the productivity effect, given that higher relatedness, on the one hand, can increase absorptive capacity and, on the other hand, aggravate potential knowledge redundancy. A difference-in-difference model is utilised to estimate the treatment effects for different intensities of treatment, where the intensity is proxied by the relatedness measure. In addition, an event-study model is employed to provide evidence of a causal effect on incumbent productivity from star arrivals, where I use coarsened exact matching to identify a control for each treated incumbent. The previous three papers provide an evidence-based evaluation of star impact using difference-in-difference and event-study research designs. In addition, difference-in differences and event-study research designs are one of the most common methods to estimate treatment effects in the economics of science literature. However, recent developments in the literature on difference-in-differences and event-study models have raised important concerns that when effects are heterogeneous and treatment is staggered, the two-way fixed effects (TWFE) difference-in-differences/event-studies regression can provide biased estimates. Thus, policy formed based on studies using these biased approaches may not be effective. To this end, the fourth paper (a methodological paper) addresses this concern by exploring the relative performance of five alternative estimators with the TWFE estimator for estimating treatment effects on binary and count outcomes within a simulation exercise. Following this, the fifth paper (a replication paper) implements the alternative estimators on a prior published study and compares the results with the original study, highlighting the need for policymakers to pay particular attention to research design before drawing strong policy-related conclusions. The fourth and fifth paper indirectly affects evidence-based policymaking and addresses the broad objective of the thesis. The thesis is a novel contribution to the Irish and international economics of science empirical and policy literature, given the paucity of information currently available on the impact of star scientists in small open economies. This thesis has significant implications for policymakers and institutions designing recruitment strategies and post-arrival support. I hope the results of the five studies undertaken for the thesis will be particularly useful for policymakers and funding agencies in Ireland and other small open economies to form evidence-based star recruitment policies

ResPoNCE (Respecting Persons with disabilities’ Needs and rights in Crisis and Emergency): Final report

The project sought to examine whether the rights of persons with disabilities were respected in accordance with the UN Convention on the Rights of Persons with Disabilities (CRPD) during the Covid-19 pandemic. In doing so it examined the impact of the pandemic-related laws and policies in seven European countries ¿ Ireland, the UK, Spain, France, Sweden, Italy and Germany - on the health and wellbeing of people with disabilities.This research was funded by the Health Research Board: COV19-2020-144non-peer-reviewe

Civil war in El Salvador and the origins of rights-based humanitarianism

This article traces the global humanitarian sector s late twentieth-century embrace of human rights to the brutal civil conflict in El Salvador in the 1980s. Drawing on evidence from NGOs in three Anglophone states (Britain, Canada, and Ireland), it examines the moral and political debates that accompanied the breakthrough for human rights activism in that period, and how they conditioned contemporaneous understandings of aid . From that foundation, the article makes two claims. First, it argues that the triumph of human rights in the late twentieth century was the product of a complex set of diplomatic, intellectual, and ideological factors that were of global, rather than simply of Western, origin. Second, by tracing what could and could not be done in the name of humanitarianism, the article brings us closer to understanding how even the most outwardly progressive vision of intervention was produced within a very specific hierarchical and paternalistic imagining of the Global South.peer-reviewe

Extreme resilience and dissipation in heterogeneous elasto-plastomeric crystals

We present a microstructure-topology-based approach for designing macroscopic, heterogeneous soft materials that exhibit outstanding mechanical resilience and energy dissipation. We investigate a variety of geometric configurations of resilient yet dissipative heterogeneous elasto-plastomeric materials that possess long-range order whose microstructural features are inspired by crystalline metals and block copolymers. We combine experiments and numerical simulations on 3D-printed prototypes to study the extreme mechanics of these heterogeneous soft materials under cyclic deformation conditions up to an extreme strain of >200% with strain rates ranging from quasi-static (5.0 × 10−3 s−1) to high levels of >6.0 × 101 s−1. Moreover, we investigate the complexity of elastic and inelastic “unloading” mechanisms crucial for the understanding of shape recovery and energy dissipation in extreme loading situations. Furthermore, we propose a simple but physically intuitive approach for designing microstructures that exhibit a nearly isotropic behavior in both elasticity and inelasticity across different crystallographic orientations from small to large strains. Overall, our study sets a significant step toward the development of sustainable, heterogeneous soft material architectures at macroscopic scales that can withstand harsh mechanical environments.peer-reviewed2024-11-0

Proactive esophageal cooling during laser cardiac ablation: A computer modeling study

Background and Objectives Laser ablation is increasingly used to treat atrial fibrillation (AF). However, atrioesophageal injury remains a potentially serious complication. While proactive esophageal cooling (PEC) reduces esophageal injury during radiofrequency ablation, the effects of PEC during laser ablation have not previously been determined. We aimed to evaluate the protective effects of PEC during laser ablation of AF by means of a theoretical study based on computer modeling. Methods Three-dimensional mathematical models were built for 20 different cases including a fragment of atrial wall (myocardium), epicardial fat (adipose tissue), connective tissue, and esophageal wall. The esophagus was considered with and without PEC. Laser-tissue interaction was modeled using Beer¿Lambert's law, Pennes' Bioheat equation was used to compute the resultant heating, and the Arrhenius equation was used to estimate the fraction of tissue damage (FOD), assuming a threshold of 63% to assess induced necrosis. We modeled laser irradiation power of 8.5¿W over 20¿s. Thermal simulations extended up to 250¿s to account for thermal latency. Results PEC significantly altered the temperature distribution around the cooling device, resulting in lower temperatures (around 22°C less in the esophagus and 9°C in the atrial wall) compared to the case without PEC. This thermal reduction translated into the absence of transmural lesions in the esophagus. The esophagus was thermally damaged only in the cases without PEC and with a distance equal to or shorter than 3.5¿mm between the esophagus and endocardium (inner boundary of the atrial wall). Furthermore, PEC demonstrated minimal impact on the lesion created across the atrial wall, either in terms of maximum temperature or FOD. Conclusions PEC reduces the potential for esophageal injury without degrading the intended cardiac lesions for a variety of different tissue thicknesses. Thermal latency may influence lesion formation during laser ablation and may play a part in any collateral damage.peer-reviewe

Nonlinear vibration and stability of a dielectric elastomer balloon based on a strain-stiffening model

Limiting chain extensibility is a characteristic that plays a vital role in the stretching of highly elastic materials. The Gent model has been widely used to capture this behaviour, as it performs very well in fitting stress-stretch data in simple tension, and involves two material parameters only. Recently, Anssari-Benam and Bucchi (Int. J. Non. Linear. Mech. 128:103626, 2021) introduced a different form of generalised neo-Hookean model, focusing on the molecular structure of elastomers, and showed that their model encompasses all ranges of deformations, performing better than the Gent model in many respects, also with only two parameters. Here we investigate the nonlinear vibration and stability of a dielectric elastomer balloon modelled by that strain energy function. We derive the deformation field in spherical coordinates and the governing equations by the Euler-Lagrange method, assuming that the balloon retains its spherical symmetry as it inflates. We consider in turn that the balloon is under two types of voltages, a pure DC voltage and an AC voltage superimposed on a DC voltage. We analyse the dynamic response of the balloon and identify the influential parameters in the model. We find that the molecular structure of the material, as tracked by the number of segments in a single chain, can control the instability and the pull-in/snap-through critical voltage, as well as chaos and quasi-periodicity. The main result is that balloons made of materials exhibiting early strain-stiffening effects are more stable and less prone to generate chaotic nonlinear vibrations than when made of softer materials, such as those modelled by the neo-Hookean strain-energy density function.Open Access funding provided by the IReL Consortium.peer-reviewe

Metal-based glycoconjugates as molecular sensors for lectins and anti-adhesives

The anti-microbial resistance crisis has been inexorably developing at ever more alarming levels in the 21st century. The WHO regularly updates a list of bacterial and fungal critical priority pathogens for which new treatment strategies and diagnostic tools are urgently needed. We postulate that exploiting the ubiquitous nature of carbohydrate-ligand interactions in infection processes, along with the unique and underutilised properties of metal complexes could give us access to new molecular sensors and therapeutic agents against a variety of pathogens. Chapter 1 sets the context of this project, including a comprehensive literature review of inhibitors known for P. aeruginosa’s carbohydrate-binding proteins. This thesis presents the development of glycoconjugate ligands with known metal binding motifs as targeted inhibitors for bacterial lectin LecA in order to exploit the highly specific nature of the carbohydrate-protein interaction for sensing and/or anti-biofilm inhibition properties as a diagnostic or theranostic tools. To this end, in Chapter 2, the first known lanthanide glycoconjugate complex capable of reliably sensing unlabelled bacterial lectin LecA is reported, as part of a completely new sensing paradigm. With a four-fold “switch-on” increase in emission intensity, low micromolar affinity to its target lectin, and no bacteriostatic or bactericidal properties. Derived compounds in complex with transition and lanthanide metal ions are described in Chapter 3, which demonstrated anti-biofilm activity towards P. aeruginosa of up to 50% and anti-adhesion activity against C. albicans of 60% at 0.1 μM, two pathogens of critical importance for the development of new anti-microbial treatments and strategies. This includes the first known, easily accessible, glycoconjugate complex to act as adhesion inhibitor against C. albicans infection of human buccal epithelial cells and an uncommon low micromolar Gal-Tz inhibitor for LecA. Furthermore, in Chapter 4, an extensive derivatisation of glycoconjugate ligands by a variety of critically-informed structural modifications is presented, to achieve higher affinity to the target lectin and probe into the mechanism of action of the above sensing paradigm. Six total ligands were assessed as lectin binders by three different techniques (fluorescence polarisation assy, isothermal calorimetry and surface plasmon resonance), with most demonstrating low micromolar affinities (under 10 μM). Of this library of glycoconjugates, two were earmarked as very high affinity ligands for further development (0.5 and 0.3 μM by SPR respectively). We conclude that metal glycoconjugates are an underexplored class of molecules with promising applications; that lanthanide glycoconjugates give us access to a completely new direct sensing paradigm of unlabelled bacterial lectins; that simple glycoconjugate ligands when complexed to metals give us access to non-lethal treatments for two priority pathogens thus demonstrating the importance of metal complexation in assembling higher complexity functional systems from simple building blocks; and finally, that affinity to a target lectin can be increased in a variety of ways to hopefully expand the sensing capabilities of the corresponding lanthanide complexes as valuable tools in the fight against antimicrobial resistance

‘It was in the Air’: Micro and macro flows in the changing soundscape of Irish traditional music in Galway, 1961 to 1981

This thesis investigates the emergence of a vibrant Irish traditional music scene in Galway City and explores changes in its soundscape, from 1961 to 1981. Changes in the world of traditional music, embedded in Irish traditional and Anglo-American folk music revival processes of the 1960s and 1970s, were also the result of societal and economic developments. Crucially, the novel playing of Irish traditional music in pubs, relocated from performances in dance halls and private spaces (homes), provided access, aided transmission and propelled music revival at local level and functioned as a fertile cultural ground. The theoretical lens of this historical ethnography focuses on micro and macro flows, and – extending anthropologist Arjun Appadurai’s concept – fluid spaces. This analytical prism enables a nuanced understanding of socio-cultural occurrences at the intersection of personal and societal spheres. Three particular stimuli emerge for Galway’s metamorphosis into an urban centre for Irish traditional music practice: revival efforts of Comhaltas Ceoltóirí Éireann, the second wave of Anglo-American folk revival, and site-specific circumstances. The latter comprise the city’s status as regional economic centre; transient and migration flows with surrounding, culturally rich rural areas; and grassroots flows with the University of Galway. Drawing an atlas of cultural practice, this thesis expands the knowledge of Irish traditional music in Galway and advances research on urban music revival. Crucially, it presents an original understanding of Galway’s cultural landscape, placing Irish traditional music at the root of Galway’s emerging festival culture, 1961 to 1981.2026-04-1

Learning from what goes well: Improving the quality of general practice

Improving the quality of primary care is a global imperative, one only increasing in importance as health systems internationally move towards community-based models of care, and patients, tasks, technologies, practice environments and expectations get increasingly complex. Contemporary approaches to improvement, focused on learning from instances of poor performance, have not generated sustained improvement in quality and are likely insufficient to address the increasing complexities of delivering care in the general practice setting. Recently, new approaches to understanding quality and safety have been advocated, that emphasise learning from when things go well, or even exceptionally well. One such approach, the ‘positive deviance’ approach focuses learning on exceptionally high-performing individuals, teams or practices, and applications of the approach in primary care thus far have been promising. Given the increasingly complex healthcare landscape, applying strengths-based approaches like PD is an attractive strategy as it allows us to engage patients and staff to learn from positive deviations in care and attend to key systems and contextualising factors that impact the success of improvement efforts. The current thesis applied the principles of positive deviance and strengths-based learning to identify and disseminate the key factors and strategies that support the delivery of exceptional care in general practice to stimulate learning and improvement in this domain of healthcare.Irish Research Council (GOIPG/2020/977