Open Research Exeter - University of Exeter
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Exercise testing for cystic fibrosis in the UK: a registry-based analysis
No full textPoster presented at the 48th European Cystic Fibrosis Conference, 4–7 June 2025, Milan, Ital
Impaired oxygen pulse during exercise following lung transplant in cystic fibrosis: a case series
No full textWorkshop presented at the 48th European Cystic Fibrosis Conference, 4–7 June 2025, Milan, Ital
Developing a marathon training advice resource for people with cystic fibrosis
No full textPoster presented at the 48th European Cystic Fibrosis Conference, 4–7 June 2025, Milan, Ital
Evolutionary Insights into the Length Variation of DNA Damage Response Proteins Across Eukaryotes
No full textAcross the tree of life, DNA damage response (DDR) proteins play a pivotal, yet dichotomous role in organismal development and evolution. Here, we present a comprehensive analysis of 432 DDR proteins encoded by 68 genomes, including that of Nucleospora cyclopteri, an intranuclear microsporidia sequenced in this study. We compared the DDR proteins encoded by these genomes to those of humans to uncover the DNA repair-ome across phylogenetically distant eukaryotes. We also performed further analyses to understand if organismal complexity and lifestyle play a role in the evolution of DDR protein length and conserved domain architecture. We observed that the genomes of extreme parasites such as Paramicrocytos, Giardia, Spironucleus, and certain microsporidian lineages encode the smallest eukaryotic repertoire of DDR proteins and that pathways involved in modulation of nucleotide pools and nucleotide excision repair are the most preserved DDR pathways in the eukaryotic genomes analysed here. We found that DDR and DNA repair proteins are consistently longer than housekeeping and metabolic proteins. This is likely due to the higher number of physical protein-protein interactions which DDR proteins are involved. We find that although DNA repair proteins are generally longer than housekeeping proteins, their functional domains occupy a relatively smaller footprint. Notably, this pattern holds true across diverse organisms and shows no dependence on either lifestyle or mitochondrial status. Finally, we observed that unicellular organisms harbour proteins that are tenfold longer than their human homologues, with the extra amino acids forming interdomain regions with a clearly novel albeit undetermined function
Measuring the Circular Economy: (de)coupling during strategic organisational transitions
No full textExacerbated and unprecedented global challenges demand the need for sustainable practice and effective governance. As organisations respond to these institutional pressures with systems-centric circular economic (CE) policy and practices, an observable gap exists between what they are enacting and their achievements.
The research investigates performance measurement as a mechanism to couple or decouple CE from business strategy. It combines insight from CE and management and organisational literature, namely means-ends decoupling, material coupling and performance measurement and management.
A qualitative, multi-method study was adopted, comprising a cross-sectoral analysis and multiple embedded case study. Data was collected via semi-structured interviews, supplemented by documentary evidence and research feedback sessions. Data was analysed using Gioia’s coding methodology and thematic analysis.
The cross-sectoral study found evidence of means-ends decoupling in CE transitioning organisations, leading to the generation of a means-ends decoupling behaviours typology. Further, the case study investigation determined the factors that affect the coupling of CE to business strategy within organisations, resulting in the development of a material coupling tensions framework.
This research delimits the confines of management theorisation by contextualising within the CE, providing a better theoretical understanding of the systems-centric approach to fostering successful CE transitions. It expands means-ends decoupling theory by identifying micro-organisational behaviours that attribute to the extrapolated macro consequences. It extends and adds nuance to material coupling theory in a CE transitioning organisational context by determining the perceived roles of performance measurement in helping or hindering the coupling of CE to business strategy. Finally, the research contributes to improving understanding of the relationship between means-ends decoupling and material coupling by addressing the micro level of operations.
This research helps practitioners navigate complex CE transitions by adopting a systems-centric mindset, building knowledge of organisational behaviours that lead to means-ends decoupling, and harnessing measurement tensions to couple CE to business strategy
Aspergillus and allergic bronchopulmonary aspergillosis in children and young people with cystic fibrosis
No full textBackground
Aspergillus infection is common in children and young people with cystic fibrosis (CF), yet there is poor understanding of its significance and long-term impact, leading to variable diagnosis and treatment. The overall aim of the research presented in this thesis is to gain a greater understanding of Aspergillus infection in children and young people with CF, specifically to evaluate clinical predictors and long-term outcomes, and to consider future perspectives.
Objectives
The work presented in this thesis, focussing on Aspergillus infection in children and young people (0 to <18 years old) with CF, aims to 1) provide a comprehensive literature review, 2) assess the long-term outcomes of infection, 3) identify clinical predictors for allergic bronchopulmonary aspergillosis (ABPA), 4) establish whether Aspergillus infection is a risk factor for severe coronavirus disease 2019 (COVID-19), 5) provide a perspective on factors behind the early termination of the cASPerCF randomised controlled trial, and to 6) provide a commentary on future directions.
Methods
Three observational studies are presented in this thesis. Two longitudinal cohort studies were undertaken with anonymised UK CF Registry (UKCFR) data from 2009 to 2019 from patients aged 8-17 years in 2009-2010 (n=1675 and n=1612). The main longitudinal analyses used were linear mixed-effects models and complementary log-log regression models. The third observational study, a European CF Society Patient Registry (ECFSPR) study (n=1099), was completed using anonymised data collected from 22 countries from 2019-2021. Logistic regression models were used to assess the association between pre-existing Aspergillus colonization and/or ABPA and COVID-19 severity.
Results
The longitudinal effects study UKCFR shows that ABPA was significantly associated with increased decline in lung function, whereas Aspergillus colonization was not associated with increased decline in lung function in children with CF. The clinical predictors for ABPA UKCFR study demonstrates an association of lower lung function, Aspergillus colonization and Pseudomonas aeruginosa infection with subsequent development of ABPA, whereas there was a negative association between ivacaftor treatment and development of ABPA. The ECFSPR study identified an association between pre-existing Aspergillus colonization and ABPA and increased COVID-19 associated hospitalization.
Conclusions
The results demonstrate the importance of Aspergillus infection in children and young people with CF. ABPA, but not Aspergillus colonization, worsens long-term lung function decline. Key clinical predictors for ABPA were found and for the first time a protective association of ivacaftor and ABPA was shown. Pre-existing Aspergillus colonization and ABPA is a risk factor for COVID-19 associated hospitalisation
‘Old man and the Sea’ – Unravelling historical reference points for marine resources in the Maldives
No full textAs countries commit to preserving and enhancing their biodiversity, they often lack knowledge of historical baselines to help shape their targets and measure progress. For countries such as the Maldives, these baselines are needed to understand long-term marine ecosystem changes and informing current conservation strategies. This study established a baseline of marine resources in the Maldives by combining historical records and Local Ecological Knowledge (LEK) interviews. Archaeological, ethnographic, and epigraphic evidence were analysed from 50 BC to 1975, complemented by LEK interviews capturing changes since the 1950s across two regions. Despite environmental and human pressures, coral reefs in the studied areas maintained high live coral cover until the late 20th century. However, in recent decades, all three investigated marine habitats have declined, particularly coral reefs and mangroves. This study identified several historical seagrass and mangrove areas that were previously undocumented in literature. Although economic demand for tuna and bait fish remained relatively high until 1975, evidence suggests little long-term impact on these populations. Technological advancements in recent decades have increased their catch, yet many participants reported declines in nearshore tuna populations and insufficient bait fish catches. Since the 1970s, significant declines were also observed in the catches of reef fish, sea cucumbers, and octopus. Declines in turtle, bird, and whale populations were reported during the 19th and 20th centuries, with no improvements observed in recent trends. This is particularly concerning given the loss of numerous turtle nesting beaches and reports of local extinction of Dromas ardeola (crab plover) from several islands. Conversely, participants observed relative stability in dolphin and ray populations, along with signs of recovery in shark populations, indicating some success of conservation measures. These findings provide critical historical context for marine resource management and highlight both conservation successes and areas requiring immediate attention
Scarcity, willingness to pay for species, and imperfect substitutability with market goods
No full textThe impacts of biodiversity loss on human well-being depend on how much we value benefits from nature and the extent to which substitutes exist in the market for these benefits. The lack of markets for environmental goods and services, coupled with non-linearities and irreversibility in socio-environmental systems, present unique challenges for understanding the consequences of biodiversity loss. We use a rationed-good framework to explore how species scarcity impacts marginal WTP for species and its income elasticity. We note that marginal WTP need not be decreasing in species abundance and may even be increasing, particularly if the associated suite of benefits contributes to real income via reductions in defensive expenditures. Using a new dataset of species abundance and species-level WTP estimates, we test our predictions that species abundance will impact marginal WTP and its income elasticity. Our point estimates of the income elasticity of WTP (0.44 − 0.51) are stable across a range of model specifications. Under the assumption of homothetic preferences, this value suggests that the species in our dataset are generally weakly substitutable with market goods (σ = 1.96 − 2.27); however, we show that complementarity between species and market goods increases as the species’ level of threat increases:
η = 1.135, σ = 0.881 for critically endangered species. The observed relationships cannot be captured by the functional forms for utility used in many models driving policymaking
Rising Tide to Silent Tsunami: Unveiling the Role of Plastics in Driving Antimicrobial Resistance
No full textPollution caused by plastic production and waste has severe consequences on global economies, social inequalities, and ecosystems. Likewise, antimicrobial resistance (AMR) is one of the greatest One Health challenges. These threats are typically considered in isolation, but there is likely a complex interplay between the two. By adopting a systems approach and looking across the whole life cycle of plastics, we propose the range of ways in which plastic may influence AMR. Starting with raw material extraction processes where the leaching of potentially AMR co-selective chemicals used in pumping or piping of plastic feedstocks may influence AMR development in environmental microbial communities. Then, during production and manufacture, the use of plastic additives may impose selection for AMR. Finally, during use, collection or disposal, plastics can transport AMR biofilms in the community, clinical, agricultural, or aquatic settings. By linking these two important One Health threats, we may be better equipped and informed to combat them
Dissecting the Mechanisms Underlying Heterogeneous Antimicrobial Accumulation in Isogenic Bacterial Populations
No full textAntimicrobial resistance increasingly threatens the viability of modern medical interventions. There is a dire need to develop novel therapies, especially to counter resistance mechanisms employed by starved or slow-growing pathogens that are refractory to conventional antimicrobial therapies. Antimicrobial peptides have been advocated as potential therapeutic solutions due to their unique mechanisms of action and low levels of genetic resistance observed in bacteria.
This thesis investigates the link between the accumulation and efficacy of the antimicrobial peptide, tachyplesin-1, establishing a clear link between intracellular accumulation and efficacy. Accumulation solely on the bacterial membrane was shown to be insufficient for bacterial eradication. Furthermore, it was shown that certain subpopulations of stationary phase Escherichia coli and Pseudomonas aeruginosa can survive tachyplesin treatment without genetic mutations, relying instead on phenotypic adaptations.
Transcriptomic and lipidomic analyses revealed that these phenotypically tachyplesin-tolerant cells differentially regulated processes including efflux, outer membrane vesicle section, proteolytic activity, modifications to their membrane lipids and composition, and metabolism, suggesting potential mechanisms facilitating phenotypic tachyplesin-tolerance.
The formation of phenotypically tachyplesin-tolerant cells was prevented in ΔqseB, ΔqseBΔqseC, and ΔacrAΔtolC mutants, as well as when tachyplesin was combined with efflux pump inhibitors, including two clinically approved drugs, sertraline and verapamil, and metabolic stimulants. These findings highlight the role of efflux in phenotypic tachyplesin-tolerance and suggest a potential strategy to combat antimicrobial-refractory stationary phase bacteria.
Lastly, virtual high-throughput screening was conducted to identify potential inhibitors of EvgA, the response regulator in the EvgAS two-component regulatory system. This was motivated by the inferred upregulation of EvgA in phenotypically tachyplesin-tolerant cells in the transcriptomics analysis. Although deletion of evgA and evgS did not prevent the emergence of phenotypic tachyplesin-tolerant cells, the role of EvgAS in multidrug and acid resistance may support future efforts to identify adjuvants that could enhance antibiotic efficacy