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Neutrophil extracellular traps (NETs) in thermal and traumatic injuries
No full textSevere thermal injuries and trauma result in considerable immunological and haemostatic disturbances, increasing the risk of sepsis, disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). The formation of neutrophil extracellular traps (NETs), an essential innate response to infection and tissue damage, leads to elevated circulating levels of NET-derived chromatin and cell-free DNA (cfDNA), which act in defence but also as a trigger for immunothrombosis. Our research indicates that post-burn and trauma cfDNA primarily consists of nucleosome fragments (~150 bp), with higher molecular weight nucleosome oligomers (i.e., ~ 300 and 450 bp) in ultra-early samples (< 1 hour) obtained from trauma patients. However, absence or low nucleosome levels in the majority of admission samples in burns were confirmed along with the presence of increased levels of large undegraded NET-derived chromatin captured using microfluidic chips. CfDNA levels also correlate with neutrophil activation and the extended neutrophil parameter Y (NEUT-Y). The breakdown of NETs into circulating cfDNA in the form of nucleosomes, increased NEUT-Y levels with production of Immature Granulocytes (IG) are potential early biomarkers for predicting sepsis in burns.
Moreover, high levels of IL-8 are released and are major mediators of NET formation in burns. Haematological studies demonstrated classical post-injury nadir and recovery patterns in platelet counts following thermal injury. Severe burns also led to high significant impairment of high shear platelet function in the early days after the injury (e.g. day 3) and were associated with reduced ex vivo thrombus formation. Additionally, post-injury high levels of VWF and low levels of ADAMTS13 although not correlated with platelet function correlated with NET biomarkers, NEUT-Y and cfDNA, providing a further important contribution to NETosis.
This thesis illustrates the importance of the mechanisms and dynamics of NET production and breakdown as biomarkers, therapeutic targets and in the pathogenesis of post-injury sepsis, DIC, and MOF
Understanding the role of UPF1 and related factors in eukaryotic gene expression.
No full textThe evolutionary conserved RNA helicase UPF1 has mostly been studied for its role in the mRNA degradation pathway of nonsense-mediated mRNA decay (NMD), a cytoplasmic, translation-linked process. However, recent studies from this laboratory demonstrate a role in the nuclear processes of gene expression which involves an association with the nascent RNA. A spin-off of these studies indicated that UPF1 operates in mitochondria. This agreed with primary observations of other laboratories using S. cerevisiae, where UPF1 was able to suppress deficiencies in mitochondrial splicing. Here we have characterised UPF1 mitochondrial localisation in different Drosophila cell types, including during spermatogenesis. It was discovered that UPF1 is seemingly required for the expression of mtDNA genes. This research also revealed that UPF1, but not the other NMD factors are essential for spermatogenesis and seems to be required for the elimination of paternal mtDNA from elongated spermatids. Something which had only been described for EndoG and POLG1 in Drosophila. RNA-seq experiments indicate that spermatogenesis fails as UPF1 is required for the expression of genes involved in chromosome segregation and cytokinesis. These experiments also indicate that UPF1 is required for correct pre-mRNA splicing. A second project explored the role that NMD plays within two Drosophila neurodegenerative disease models: frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are induced by the expression of CHMP2BIntron5 and C9orf72 transgenes, respectively. It was previously suggested upon its discovery that CHMP2BIntron5 may be a substrate of NMD, but it was never experimentally shown. Here we present evidence that CHMP2BIntron5 is a substrate of NMD, and associated phenotypes are suppressed by the overexpression of all UPF factors. This is likely due to degradation of the transcript. Functional NMD had also been implicated previously in ameliorating ALS associated with C9orf72. However, UPF1 was the only UPF factor capable of suppressing phenotypes associated with the expression of C9orf72. This indicates that UPF1 may act independently of NMD in this context, which is likely due to reduced translation of cytotoxic dipeptides produced by C9orf72. The final stage of this project investigated the role of exon junction complex (EJC) proteins in these disease models. Although the EJC is not required for NMD in Drosophila, previous observations from this laboratory demonstrated that the EJC plays a broad role in gene expression, like UPF1. This could be linked to their association with nascent RNA. Of the core EJC proteins, Y14, MAGO and eIF4A3; we show that only overexpression of the DEAD-box RNA helicase eIF4A3 strongly suppresses the expression of both disease-inducing transgenes. This indicates a potential role of eIF4A3 in the expression of specific genes, and a so far, undocumented role in ameliorating these disease states
Law and governance frameworks for oil spill response in Nigeria: towards an ecological restoration approach
Full text linkMuch of the world’s ecosystems, including those vital to human well-being, have been destroyed despite ongoing nature conservation efforts. One of the best examples is the Niger Delta in Nigeria, which is also one of the world’s richest biodiversity hotspots: decades of cumulative crude oil pollution have devastated the region’s dense wetland ecosystems. Within the last century, crude oil production has tragically led to massive ecological changes, primarily due to repeated oil spills that have negatively impacted entire ecosystems, destroying biodiversity that provides essential ecosystem services. The ‘restoration’ of the damaged ecosystems has not been a high priority for Nigerian law and policy, emphasising the ‘prevention’ of future environmental harms. Instead, Nigeria’s law and governance frameworks regarding oil pollution only require remediating specific oil spill sites within limited spatial and temporal parameters while mainly ignoring the restoration of ecosystems destroyed by oil spills and unsuccessful remediation efforts over the years. This thesis examines the adequacy or otherwise of developing moves towards ecological restoration law in Nigeria by contrasting ecological restoration with environmental remediation law and creating a ‘multi-stakeholder’ conceptual framework for what is necessary for successful ecosystem restoration governance in that country. This study aims to identify the most critical considerations for laws and regulatory institutions that ought to mandate ecosystem restoration. The thesis argues that for public authorities to realise that community involvement is an indelible requirement of successful restoration governance, future ecological restoration legal provisions must explicitly incorporate participation mechanisms. In this light, the thesis contends that local community involvement is crucial to good ecological restoration governance in Nigeria and worldwide today. The results highlight Nigeria’s need for law and governance reforms due to fundamental issues with the country’s state-centred environmental remediation approach
Investigating the efficacy of a novel microfluidics-based bioprinting system to construct blood vessel mimics for tissue engineering
Full text linkThe shortage of bone tissue donors despite the rising cases of bone fracture incidences, as well as complications with current transplant methods, has spurred intense research into tissue engineering as a promising alternative. However, existing tissue engineering strategies face critical limitations, especially in supplying physiologically relevant levels of oxygen and nutrients to cells within the bone tissue scaffolds. To address this issue, a novel microfluidics-based chip for 3D-printing vascular structures was developed. The purpose of this research project was to investigate the efficacy of this novel microfluidic-based chip for fabricating hollow cell-compatible fibres, which are structurally adjustable, durable and can be perfused to mimic physiological blood flow for tissue engineering purposes.
The range of hollow core-shell fibres that can be generated with a defined width and geometry by changing the extrusion flow rates of core solutions, between 125-2000 μl.min–1, was demonstrated. Straight, wavy and helical core shapes were generated that have the potential to be used for recapitulating different flow rates found physiologically.
To optimise the printing conditions and materials for cell biocompatibility - cytotoxicity, cell adhesion and cell morphology were assessed. This revealed that 10 wt% (100 mg/ml) calcium chloride bath solution provides optimal cell viability as well as structural integrity of the 2 wt% (20 mg/ml) alginate fibres. Gelatine blended with alginate at 1:1 concentration supported cell adhesion while ensuring core-shell fibres could be formed. However, with the optimisation of printing conditions, such as temperature regulation, gelatine with higher concentrations can be used for enhancing cell adhesion.
Furthermore, the impact of the extrusion method, material composition and prolonged culture on viability of cells encapsulated in fibres with different structures, alongside the influence of storage and incubation conditions on fibre degradation and morphology was evaluated. The results demonstrated that fibres degrade over time when cultured in cell culture media for 28 days at 37 °C. This suggested the optimisation of shell material to improve the mechanical stability of fibres in culture is needed for future studies.
Finally, the hollow core-shell fibres were perfused using gravity and cannulation to confirm the structural integrity and uniformity of the fibre’s core for replicating blood flow. The cannulation method and loading of fibres in channels to create a set-up that can potentially be used for generating vascularised bone tissue were explored.
From this project, it can be concluded that, although the materials used for fabricating the fibre need optimisation, the novel microfluidic chip has shown great potential to create a variety of core-shell fibres to mimic human blood vessels for vascularised bone tissue engineering
Enhancing structural performance of concrete structures with recycled steel fibers through improved mechanical, dynamic, and shear properties
Full text linkThis thesis explores the potential of recycled steel fibres (RSF) as an innovative and environmentally friendly reinforcement material for concrete, addressing the urgent need for cost-effective and sustainable alternatives in the construction industry. RSF, sourced from discarded tires and construction waste, can partially replace industrial steel fibres (ISF), offering benefits such as cost reduction, lower carbon emissions, and enhanced structural strength. This dual advantage not only mitigates environmental pollution but also conserves resources.
The first part of the thesis involves a comprehensive study of the engineering characteristics of RSF, including its mechanical properties, dynamic performance, and structural shear resistance. An essential part of the study is the development of a set of improved shear capacity prediction formulas for high strength steel fibre concrete (HSFRC) beams, based on modifications to the TR63 standard. Additionally, the cradle-to-grave life cycle analysis was conducted to evaluate the carbon footprint of RSF. In the second part, the thesis focuses on modelling and predicting the overall performance of HSFRC beams using experimental data and machine learning techniques. Various machine learning (ML) models were employed to predict key parameters, and finite element modelling (FEM) was used to establish the mechanical behaviour model. Surrogate models were developed to streamline the modelling process, ensuring quick and accurate parameter estimation. With the help of reliable collected experimental database, the study provides a thorough analysis of the reliability of HSFRC beams, offering recommendations to balance safety and economic efficiency. The research also presents a simplified model for assessing the performance of HSFRC beams in corrosive environments, highlighting the material's time-dependent reliability. In summary, RSF emerges as a possible, low-cost, and sustainable substitute for ISF, which has enormous implications for the construction sector
‘Inclusive for whom?’: the experiences of Syrian refugee children with disabilities and their families in accessing education in Lebanon
No full textThis work is about the unexpected spaces of confinement reproduced by the ‘inclusive’ rhetoric in education within humanitarian contexts, where Syrian refugee children with disabilities come to be relegated. It responds to a critical void in the literature, theory, policy and practice concerning
education in humanitarian settings, particularly at the intersection of refugeehood and disability. While education for refugees and people with disabilities have been explored separately, there remains a significant gap in addressing the educational rights of refugee children with disabilities. The study originates from this underexplored intersection and contributes to the growing body of work aimed at bridging this gap. The research explores the lived experiences of Syrian refugee children with disabilities and their families in accessing education and other basic services in Lebanon. It also investigates how ‘inclusion’ is framed for education in humanitarian contexts, and the consequences of this framing of inclusion for Syrian refugee children with disabilities. Moreover, it analyzes the strategies participants have in place to respond to and to deal with the multiple challenges and crises they face daily.
It is an empirical qualitative research project that takes an interdisciplinary and multidimensional approach. Located within an interpretive/social constructionist paradigm, it employs Constructivist Grounded Theory as a data analysis tool (Charmaz, 2006). The data were collected between August and December 2022 and are constituted by semi-structured interviews with 11 Syrian refugee children and youth with different types and severity of disabilities, 25 Syrian families living in Lebanon, and 21 representatives of organizations of people with disabilities (OPDs), international and Lebanese non-governmental organizations, civil society organizations and UN agencies.
The findings reveal that humanitarian actors in the region often employ emergency discourses to justify their failure in implementing inclusive education programs and strategies, contributing to the de /prioritization and structural exclusion of people with disabilities. Inclusion within these efforts is operationalized according to cost-benefit assessments, whereby the level and nature of inclusion is defined according to people’s capacity to fit within neoliberal and ableist normative standard of productivity, efficiency, and ability. Children who best comply with these standards are prioritized for inclusion, while those with severe and complex disabilities are systematically excluded due to the perceived higher costs their inclusion would require. Syrian parents denounce the lack of education opportunities for children with severe and complex disabilities, stating that their children are ‘left to themselves’, prevented to exercise, and access their basic human rights, and ‘treated like if they do not exist’. It is in this instance that these children come to embody what Agamben calls bare life, a life which is stripped of all legal, political, and social rights, being circumscribed in a state of exception. Moreover, building on Syrian parents and their children with disabilities’ lived experiences, the study addresses different forms of agency and resistance within spatiality of exception, disrupting and challenging the broader Western dominant humanitarian narrative of vulnerability, passivity, and helplessness through which Syrian refugees come to be constructed and represented.
Through this work, I have expanded critical understanding of the co-opted notion of inclusive education in the Global South by introducing and developing the (C)GT’s core category of ‘Letting die through Neoliberal Inclusion’. In conceptualizing this notion, I argue that education in humanitarian contexts, through the reproduction of emergency discourses, which legitimize the advancement of neoliberal significations of inclusion, contributes to the construction of Syrian refugee children with disabilities, especially with severe and complex ones, as Homo Sacer, someone who can be killed, or in this case ‘let to die’, by anyone with impunity.
The study underlines the urgency to promote more interdisciplinary research and multi-stakeholders’ collaboration to critically re-think the ways in which humanitarian actors, and the broader society, define and operationalize inclusion. The recommendations drawn from this work emphasize the need to develop a shared conceptual foundation across different disciplines and actors working on education in humanitarian contexts to advance theory, policy and practice. It also advocates for translating research into accessible formats for non-academic stakeholders to advance critical conversations on the field, and to work more collaboratively with affected communities, OPDs and other partners. Other recommendations suggest the development of interdisciplinary training for humanitarian actors, educators and other stakeholders to strengthen capacity for inclusive education, and to enhance transparency in monitoring and evaluation practices to address the gaps identified in service provision
Investigating JMJD5 loss of function models to identify and characterise lethal interactions in cancer
No full text2-Oxoglutarate (2-OG) Oxygenases are biologically important enzymes involved in both the hydroxylation and demethylation of nucleic acids and proteins. These enigmatic enzymes play important roles in several human diseases, including cancer. JMJD5 is an essential gene that belongs to the ‘JmjC-only’ sub-family of 2-OG oxygenases. It was originally identified as a histone demethylase, but more recent evidence supports its assignment as a protein hydroxylase with complex roles in cancer. JMJD5 has been implicated in a plethora of biological processes, with emerging evidence supporting a role in DNA damage repair (DDR). In this thesis, I have begun to investigate the effect of JMJD5 mutations and loss of function in cancer. We show thatcancer variants impair JMJD5 expression, activity and function in GS. We subsequently
demonstrate that JMJD5 knockdown causes replication stress in tumour cell lines and that this phenotype is dependent on its enzymatic activity. Importantly, we demonstrate that loss of JMJD5 can sensitise cancer cells to various DNA-damaging agents including PARP, ATM and
ATR inhibitors, highlighting its potential as a therapeutic target. Finally, we evaluated the effect of first-in-class inhibitors of JMJD5 on cancer cell lines. We showed that these novel JMJD5 inhibitors decreased cancer cell viability, increased replication stress, and caused cell cycle
perturbations. We also evaluated their ability to sensitise cells to DDR inhibitors and obtained promising results. Overall, our work supports the role of JMJD5 as a promising target for anticancer therapies, particularly in combination with other agents
UK military nurses’ experience of ethical decision-making on deployment: a reflexive thematic analysis.
Full text linkBackground:
Military nurses are frequently exposed to complex, dangerous situations and trauma on a scale their civilian colleagues are unlikely to ever experience. Additionally, the role of the military nurse on operations is constantly redeveloping due to advances in healthcare, education, and responsibility as well as the changing character of conflict and deployment profiles. The unfamiliar situations and complex environments encountered in evolving combat and humanitarian operations, combined with advances in practice, means that deployed military nurses are increasingly likely to become more involved in, or lead, ethical decision-making (EDM) in military treatment facilities. The researcher conducted a PhD study which aimed to explore how military nurses experienced EDM, with the research question “How do UK military nurses experience ethical decision-making on combat and humanitarian deployments?” This was in a bid to determine how best to practically prepare this unique professional group for the future deployed ethical landscape.
Methods:
This qualitative study analysed the narratives of 30 semi-structured interviews with serving and retired miliary nurses, whose experiences spanned a period from the 1950s to the 2020s. A Reflexive Thematic Analysis of the data was undertaken according to the principles of Braun and Clarke. Line-by-line analysis immersed the researcher in the data, and codes were openly generated as analysis progressed. The coding and theme development constantly evolved throughout the analysis to ensure they remained true to the data, prioritised participants’ voices, and maintained academic rigour. Two broad themes, the first with a sub-theme, were developed.
Findings:
The first theme is: ‘Doing the right thing’, with a sub-theme relating to the utility of written codes and guidelines as a handrail to ethical nursing practice. The second theme is: ‘The deployed context influences the EDM of military nurses’. The study demonstrated that military nurses felt very strongly about the importance of quality EDM and ‘doing the right thing’, even if they could not always be as involved in the process as they would have liked. Opinion was divided as to whose responsibility it is to make ethical decisions in both the military and healthcare professional contexts, reporting hierarchy as a monolithic barrier in many cases. Participants felt that in the deployed military space, EDM is inevitably messier and more complex than in their ‘firm base' practice in the NHS. This is due to additional complicating ethical factors such as issues of dual loyalty conflict, scarce resource allocation, two-tiered care, impartiality, and interoperability with international colleagues. Military nurses regarded the good character expected of a nurse, a solid ‘moral architecture’ (including a healthy dose of moral courage), and their identity as military nurses (which was sometimes confused) as the cornerstones of ethical practice, and which governed their internal ‘moral compass’. There was also varying reliance on written codes and guidelines as an ethical handrail, from something to slavishly adhere to, to something to ignore in favour of their own judgment.
Conclusions:
To the best of the researcher’s knowledge, this is the first empirical study examining UK military nurses’ understanding and experience of EDM across a wide chronological and operational range. The deployed context influences the EDM of military nurses who are constrained from adhering to peacetime ethical principles, which international legal and ethical frameworks tell them they should, by the “big and decisive hammer” of military necessity (Gross and Carrick, 2013, p.5). There is confusion amongst participants in resolving the duality of their professional roles as nurse and serviceperson, which should be distinct, but pragmatically cannot. Some also appear to believe that they exhibit a higher level of moral sensitivity than their doctor colleagues, making them indispensable in the collegial EDM process. Pre-deployment training has been identified as the weak link in preparing military nurses to experience deployed EDM, and ethics education in the Defence Medical Services needs to be ‘front-loaded’ to rectify this. Use of the MOD’s Four Quadrant Approach as an EDM tool, in combination with case-based learning rooted in real-world experience, has been identified as the optimal method of achieving this
Learning during times of failure and blame: how English local government responds to central government intervention
Full text linkHow policymakers learn from failure is a perennial question. Some argue that blame avoidance hinders nuanced reflection and learning, suggesting that less blame could lead to more focus on avoiding repeated policy failures. However, the conceptual and empirical relationship between failure, learning and blame is underdeveloped in political science. By uncovering the way policy actors interpret failure, learning and blame, this thesis argues that learning is the means by which failure and blame are known. This finding results from an interpretive comparative case study analysis of the “dilemmas” and “narratives” English local government actors encountered during central government interventions. Specifically, the interventions into Birmingham City Council (2014-2020) and Northamptonshire County Council (2018-2021). The dilemmas were shaped by two governance “traditions” – centralisation and autonomy – each with competing ideas about local government’s purpose, power, and accountability. By identifying the narratives that emerged and how they changed over time, this thesis finds that local actors shifted from contesting failure to accepting wrongdoing and responsibility.
By showing that groups learn to shift from contestation to consensus over failure and blame, this thesis provides a novel connection between concepts which past research has only narrowly examined. This thesis also contributes to the policy failure literature by demonstrating that actors compete over the boundaries of failure as a means to delimit and/or expand notions of change embedded within. By tackling the under-researched topic of “blame-games” outside of the public view, this thesis shows that those who witness their colleagues “lose” blame-games draw lessons from such experiences and apply these to future conflicts. Finally, this research contributes to the policy learning literature by demonstrating that learning can entrench, rather than challenge, ideas about power within governance
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