University of Birmingham
University of Birmingham Research Archive, E-theses RepositoryNot a member yet
11811 research outputs found
Sort by
Structural and biochemical characterisation of phospho-regulation in the DNA damage response
No full textThe human phosphoproteome constitutes as many as 90,000 (pSer/pThr/pTyr) phosphorylation sites, however most phosphosites remain functionally uncharacterised. Phosphorylation events drive allosteric protein regulation, recruitment of phospho-binding domains, and assembly of multi- domain complexes that serve as a direct link between phosphorylation, ubiquitination, and SUMOylation pathways. The DNA damage response (DDR) is an essential signal transduction pathway that maintains genome stability and demonstrates the precision and efficiency of phospho- protein regulation. This thesis investigates the structural and biochemical basis of phospho- regulation of MDC1-TQxF motifs, Rad50-T690, and Sae1-S185 in DDR signalling. In the first instance, binding experiments and the crystal structure of the PellinoFHA:MDC1pT765 phosphopeptide complex supported a revised Pellino DNA damage recruitment model, which is dependent on MDC1-TQxF phosphorylation status, rather than gH2AX. We found no consistent evidence for a phosphorylation-dependent interaction between Rad50 and the PLK1 Polo Box domain, despite extensive biophysical binding experiments and attempts at complex purification. Despite this setback, site-specific incorporation of a phosphothreonine residue at Rad50-T690 into a recombinantly purified zinc-hook coiled-coil fragment was successful. This reagent represents a technical breakthrough for further structural and biochemical analysis of phospho-regulation of Rad50 and the MRN. Finally, we found no significant phospho-S185-dependent difference in SUMO E1 activity. Nonetheless, purification of recombinant Sae1 with site-specific incorporation of phosphoserine at S185, and the corresponding Sae1-pS185:Sae2 heterodimer, was successful. Both tools will provide useful for future investigations into alternate modes of phospho-regulation of the SUMO E1
Environmental injustices in Robinson Jeffers’s and Denise Levertov’s ecopoetry
Full text linkThis thesis explores critiques of environmental injustices in the poetry of Robinson Jeffers (1887-1962) and Denise Levertov (1923-1997). The anthropocentrism typical of American culture constantly imposes hierarchal division and underestimation of otherness which cause injustices to people and nonhumans. In urban, war, and natural environments, the poets investigate the impact of modernity, imperialism, and environmental degradation on changing environmental conditions and ecological wholeness. Jeffers and Levertov establish in their poetry a shared trajectory where they start with a description of injustices and their destructive impacts, progress towards a condemnation of the politics behind these injustices, and propose alternative ecological values. In their trajectories of critique across these three contexts, their poetry attempts to bridge the divide between the city and nature, between the Americans and the Vietnamese, and between humans and nonhumans. It provides a model for the reconstruction of anthropocentrism toward ecological relations of integrity. Their poetry reveals situations of the environmental ‘unconscious’ and attempts to draw a vision of environmental imagination and justice.
Chapter 1 of the thesis registers Jeffers’s response to modernity. It explores his presentation of the city as a centre for accumulating change and corruption that separates man from nature. He presents the struggle of presence within the confinement of urbanization, mechanization, and rapid changes against human instinctual freedom and cultural values, a crisis he resists with his philosophy of Inhumanism. Instead, he urges a withdrawal to nature where he affirms in the landscape timeless and holistic values as contrasting models to human values. Chapter 2 investigates Levertov’s account of the Vietnam War as breeding violence and destruction to people's safety and emotional wellness. She presents victimization, loss, and emotional stasis which she supports with her political poetry of resistance. She encourages empathy, solidarity, and the need to maintain safety for others. Chapter 3 traces the poets’ presentations of exploitation, destruction, and cruelty to land and animals in their poetry. In the poems, both poets point out nonhuman forces that wrestle with humanity's injustices which they represent through myth and figuration. In their presentation of nonhumans, they highlight existing ideologies that underestimate nonhumans and seek in their poetry to affirm nonhuman agency and consciousness.
In my investigation of their critique of injustices, my thesis draws on recent developments and turns of ecocriticism. It reframes the poets’ critiques through Environmental Justice theory, looking at human alienation in the city, the victimization of people in the Vietnam War, the exploitation of lands, and the cruelty to animals as environmental injustices. Under these thematic discussions, my thesis analyses the affective forces that emerge in response to injustices across these contexts. Jeffers’s presentation of the hopelessness of people in the city, Levertov’s depiction of the victimized emotions in Vietnam, and their presentation of nonhuman struggle in the degraded environments underscore the poets’ awareness of the notion of interdependency in the universe. The thesis also demonstrates the material forces of nonhumans that wrestle with human denial of them and affirm their existence instead. These recent developments in ecocriticism, which resonate with the poets’ critiques, elucidate the fundamental dynamics of existence and challenge the anthropocentric ideology that fosters such injustices
The behavioural phenotype of children with charge syndrome
Full text linkBackground: CHARGE syndrome is a highly variable, rare multisystemic condition, with an estimated prevalence of 1 in 8500 live births. Given the multitude of medical difficulties experienced by children with CHARGE syndrome, research to date has focused on understanding the physical phenotype. However, while there is limited research available, the studies that have been undertaken suggest that there may also be a behavioural phenotype associated with the syndrome, and that delineation of this phenotype could help to improve the availability and specificity of clinical support provided to people with CHARGE syndrome.
Methods: A large-scale systematic review and meta-analysis yielding 42 articles including 1556 participants was employed to elucidate the prevalence of phenotypic characteristics and variability in CHARGE syndrome. A syndrome profile comparison survey was conducted to compare sleep and behaviour characteristics between CHARGE syndrome and five clinical neurodevelopmental groups matched on age and ability level. The sample included 26 participants (13 female) with CHARGE syndrome (Mage = 8.12 years; SD 3.47). A multi method sleep study (N=7, Mage=8.14; SD = 3.39) using actigraphy and standardised questionaries was conducted to identify the sleep profile of children with CHARGE syndrome and to examine how this compared to an age-matched typically developing group. Finally, an interview study was conducted to assess the severity and function of behaviours that challenge in children with CHARGE syndrome with a particular focus on aggressive
behaviour (N=14; Mage = 9.91; SD = 3.46).
Results: The meta-analysis revealed a high prevalence of aggressive (48%) and self-injurious behaviours (44%) and a high prevalence of sleep problems in CHARGE syndrome (45%). iii However, syndrome profile comparisons revealed no significant difference between CHARGE syndrome and the five age and ability matched clinical groups on behaviours that challenge. The thesis found weak evidence for the null and alternative hypotheses in the Bayesian t-tests comparing children with CHARGE syndrome to typically developing children on sleep and behaviours that challenge. The interview study revealed that aggression commonly required immediate intervention, and that reinstatement of routine / repetitive
behaviour was a common function for behaviours that challenge.
Conclusion: This thesis has provided a robust delineation of several, clinically relevant aspects of the behavioural phenotype of children with CHARGE syndrome. The behavioural phenotype of CHARGE syndrome includes behaviours that challenge and sleep difficulties. Specifically, it includes aggressive behaviour. Regular assessment is important to ascertain when behavioural intervention is required, and functional assessment can be used as part of this assessment to help tailor interventions
Reading the grain: forestry and woods-work in modern and contemporary American literature
No full textReading the Grain is a thesis that explores the worked and managed forest in modern and contemporary American literature. In doing so I make the case for bringing a more conscious awareness of forestry into literary criticism. Analysing the ways in which authors engage with forestry and woods-work allows one to ask questions of stewardship, labour, conservation, utility, and beauty. These themes – that run throughout the texts of this thesis – coalesce in a complex relationship between people, trees, wood, and text.
I offer readings of the contemporary novels; Barkskins (2016) by Annie Proulx, The Overstory (2018) by Richard Powers, and Damnation Spring (2021) by Ash Davidson. I place these contemporary novels in conversation with one of the United States Forest Service’s greatest literary proponents, Norman Maclean. In addition to Maclean’s work, I also analyse one of the most well-storied seasonal jobs in the Forest Service in a chapter that examines the literature of fire lookouts from the beat authors Jack Kerouac and Gary Snyder to modern day lookout Philip Connors and his memoir Fire Season (2011). Through these texts I engage with various forms of woods-work from the worlds of logging, wildland fire-fighting, and experimental forest laboratories to name just a few
Serratus Anterior Plane Blocks: Effectiveness in the management of pain associated with multiple traumatic rib fractures.
No full textBackground
Patients with multiple rib fractures are at significant risk of respiratory complications such as pneumonia if their pain is not controlled. Regional analgesia with thoracic epidural is seen as the optimal method, but its use is limited to between 3% and 18.4% of patients. Opioids despite causing respiratory depression and sedation still dominate [1-5].
Serratus anterior plane blocks (SAP) with their ease of insertion, haemodynamic stability and perceived safety, are increasing in popularity; however, conclusive evidence for their use in rib fractures is lacking[6]. This research aims to understand better the role of SAP analgesia in patients with traumatic rib fractures.
Objectives
(i) Improve understanding of the mechanisms by which SAP blocks produce
analgesia in patients with rib fractures.
(ii) Assess the clinical effectiveness and safety of SAP analgesia.
(iii) Evaluate the impact of SAP analgesia on patient outcomes.
Methods
To answer these questions, the thesis is split into:-
a) A systematic review of existing literature,
b) A cadaveric study
c) Propensity matched retrospective studies comparing SAP analgesia to thoracic epidural, paravertebral catheters, and opioid medication.
Results
A review of the literature and the findings of the studies presented in this thesis support the opinion that SAP analgesia is a safe technique that improves analgesia and respiratory mechanics in patients with multiple rib fractures
Characterising the phenotypic and functional role of monocyte-derived foam cells in atherosclerosis
No full textAtherosclerosis is a chronic inflammatory disease characterised by the accumulation lipid deposits within the arterial wall, leading to restricted blood flow and increased risk of cardiovascular events. Central to the development of atherosclerosis is the formation of foam cells which are derived from macrophages as a result of excessive accumulation of modified low-density lipoproteins (LDL). Upon oxLDL internalisation, macrophages transform into foam cells through the storage of lipid droplets that are primarily composed of cholesteryl esters which can be hydrolysed to generate free cholesterol. The balance between lipid uptake, storage, and degradation within foam cells is critical to maintain cholesterol homeostasis.
Dysregulation in these processes contribute to foam cell persistence and plaque progression. Foam cells contribute significantly to the inflammatory microenvironment within plaque, causing perpetual local inflammation, recruitment of immune cells and plaque instability. The interplay between lipid metabolism and inflammatory signalling within foam cells exacerbates their retention and survival.
Understanding the inflammatory role of foam cells in atherosclerosis is crucial for identifying novel therapeutic targets aimed specifically at reducing foam cell-driven inflammation. However, till today identifying and characterising foam cells within atherosclerotic plaques remains a challenge due to significant overlap in markers with other immune cells. One of the aims of this study is to characterise foam cells both at a protein and genomic level via flow cytometry analysis, bulk RNA-sequencing and whole genome spatial transcriptomics to identify potential markers specific to foam cells themselves. Contradictory to the nature of a foam cell phenotype, our results show that foam cells exhibit an anti-inflammatory and lipid metabolising profile genomic profile which coincides with existing data from recent transcriptomic studies.
Given that plaque is a heterogenous cellular environment, investigating the role of foam cells in isolation may not accurately represent their realistic function. Therefore, in this study I also examined the functional characteristics of foam cells in co-culture with endothelium in vitro. This approach allowed us to identify changes in lipid mediator secretion due to cell-cell crosstalk where I identified an enrichment in pro-inflammatory prostaglandin secretion in foam cell-endothelial cell co-cultures compared to foam cells alone.
In conclusion this study explores the characterisation of foam cells using multiple different avenues. I found that minimal differences were observed between macrophage and foam cell profiles and that monocyte-origin appear to have little to no effect on the genotype of foam cells. Additionally, I show that the foam cells potentially exhibit their pro-inflammatory functional phenotype through cellular crosstalk with endothelium via the secretion of pro-inflammatory lipid mediators
The effects of children's departure, financial development, and internet access on mental health and obesity: evidence from China
No full textThe impact of a rapidly developing economy and dramatically changing social structure on the health and well-being of Chinese citizens has received increasing attention. In this thesis, we examine how key socioeconomic factors affect the physical and mental health of Chinese individuals. Specifically, we focus on three main areas: the impact of young leaver on depression, the effects of financial development on mental health, and the relationship between internet use and overweight/obesity.
In Chapter 2, we explore the impact of the departure of young family members on the mental health of the left-behind older household members. Using data from the 2011 and 2013 waves of the China Health and Retirement Longitudinal Study (CHARLS), our findings challenge the conventional belief that the departure of younger family members worsens the mental health of older adults. Instead, we discover that the mental health of those left behind improves following the departure of a member of younger generation aged 25 or above. This improvement in mental well-being can be attributed to the benefits associated with increased consumption and financial transfers, which outweigh the negative impact of losing household members. Our study contributes to the existing literature by examining how broader family structure changes and the characteristics of the young leavers influence mental health outcomes.
In Chapter 3, we evaluate the extent to which local financial development influences the prevalence of depression in China. To assess the effects of financial development, we combine the CHARLS dataset covering the period from 2011 to 2018 with a unique set of city-level financial development indicators, including key dimensions of financial depth, accessibility, and digitalisation. Our analysis reveals a significant positive relationship between financial development and the mental health of the local population. Specifically, a 10 % increase in the ratio of a city’s total bank and non-bank loans to its gross regional product (GRP) is associated with a 3.6 percentage point reduction in the likelihood of exhibiting depressive symptoms. Further investigation suggests that financial development improves mental health by alleviating the financial constraints that individuals face.
In Chapter 4, we examine the relationship between Internet use and overweight/obesity in China, focusing on both children and adults. Drawing on data from the China Health and Nutrition Survey (CHNS) over the period 2004 to 2018, we investigate how Internet usage impacts weight gain. We find that there is a significant positive correlation between Internet use and the likelihood of being overweight or obese, especially among children. Adults (children) face a 1.8 (7.9) percentage point higher risk of being overweight than those who do not use the internet. This effect is especially pronounced in rural areas, where Internet penetration has grown rapidly. Our analysis also highlights three key mechanisms through which Internet use contributes to weight gain: increased consumption of unhealthy foods, reduced physical activity due to prolonged sedentary behaviour, and sleep deprivation.
Chinese residents are facing an increasingly severe mental health crisis, while the growing epidemic of overweight /obesity issue also poses a significant threat to public health. We present three separate studies that offer new insights into the impact of young leavers, financial development, and Internet use on both mental and physical health outcomes. The findings from this thesis contribute empirical evidence that is crucial for informing policy interventions aimed at improving the overall well-being of the Chinese population
Baric Axial Algebras of Jordan type
No full textAn axial algebra is a non-associative commutative algebra and generated by special idempotents (axes) satisfying a prescribed fusion law. An axial algebra is baric if there exists a surjective homomorphism from the algebra onto the ground field, which does not send axes to zero. In this text, we investigate baric algebras within the class of algebras of Jordan type η. We show that such algebras only exist when η=2 or η=1/2. We completely classify the case η=2 by showing that baric algebras of Jordan type 2 are exactly the Matsuo algebras of Moufang type and their factors. The case of η=1/2 is more complicated as it includes Jordan algebras. We demonstrate the existence of the universal k-generated baric algebra of Jordan type 1/2 and in doing so we also establish a few interesting facts about more general axial algebras in terms of magma algebras. We also explicitly construct the 4-generated baric axial algebras of Jordan type 1/2, which turns out to have dimension 54, which is quite below the known upper bound of 81. As a consequence of this calculation, we also deduce that the universal k-generated baric algebra of Jordan type 1/2 is Jordan for all k
Contemporary literature and evolving conceptions of memory's mediative function
No full textThis thesis examines evolving conceptions of memory and media in contemporary fiction. I read representations of memory and media in Kazuo Ishiguro’s The Unconsoled (1995), Margaret Atwood’s Oryx and Crake (2003), Don DeLillo’s Falling Man (2007), and Patricia Lockwood’s No One Is Talking About This (2021), to argue that the representation of memory in these novels reaches an understanding which is analogous with the ecological view emerging in contemporary memory studies, including that which highlights the particular effects of digital transformations. Ecological memory, a concept which draws particularly from work on ecologies in media studies, cognitive psychology, and memory studies, is broadly defined as the cognitive entanglement of a memoring subject with their environment.
My selection of each of the novels studied in this thesis, written between the early onset of networked digital technologies in 1995 and the post-digital landscape of 2021, is broadly guided by three interrelated criteria: i) the representation of memory objects is thematically, structurally, and/or formally significant; ii) the representation of media other than the novel is similarly thematically, structurally, and/or formally significant; iii) the text engages with the contemporary media landscape in which it was written and published. In showing how these novels depict an ecological model of memory, I demonstrate how this can, in turn, expand the concept as it is currently deployed; in other words, how this fiction (knowingly or otherwise) exhibits an ecological model can be used to extend the understanding of that model.
The first chapter of this thesis argues for reading The Unconsoled as a media novel – whilst acknowledging its anti-media overtones – which depicts memory as the presentification of the narrator’s biography within the physical space of an unknown city. I recognise this spatial disposition of events as a reordering of time representative of an ecological model of memory.
Chapter Two focuses on social meaning-making and linguistic memory objects. This chapter contends that Atwood’s depiction of language as a means of mediating memory in Oryx and Crake demonstrates the embeddedness of linguistic memory objects within a broader ecological system, and the importance of understanding linguistic memory objects as created and encountered within that context.
Chapter Three considers the representation of the re/mediation of events – and particularly of news events – in Falling Man and the role of the novel as a cultural document of or response to a significant contemporary moment. This forms the basis of a study of shared memory objects as an application of an ecological approach to memory.
Chapter Four reiterates that the ecological entangling and re-ordering of the past is not simply a new phenomenon introduced by digital media, but can also be applied to the relationship between memory and media more broadly as a cognitively distributed act. By applying an ecological understanding of memory to Lockwood’s No One Is Talking About This, this chapter analyses the aspects of the contemporary media landscape which make digital cultures the vantage point from which the concept of ecological memory has been made visible.
By undertaking a detailed analysis of literary representations of memory alongside the ecological model as outlined above, this thesis i) establishes the roots and foundations of this ecological memory and in doing so ii) explores the boundaries of ecological terminology as applied to literary scholarship, iii) illustrates the cultural and phenomenological resonance of this idea through close reading of contemporary novels, and iv) expands the applications of ecological memory beyond its current association with digital media to include literature
Investigating the role of DIAPH1 in double strand break repair as the underlying cause of a novel DNA repair syndrome in humans
No full textDNA double-strand break (DSB) repair is crucial for maintaining genome stability and preventing disease. The cell cycle phase and chromatin context largely determine which DSB repair pathway is used to restore damaged DNA. Several human diseases are associated with defective DSB repair and often arise from inherited variations in genes with critical roles in DSB repair pathways. One of the most well characterised human DSB repair deficiency disorders is Nijmegen Breakage Syndrome (NBS), which is caused by biallelic mutations in the NBN/NBS1 gene. Typically, NBS patients display a range of neurodevelopmental defects that include microcephaly, short stature, dysmorphic facial features, intellectual disability and immunodeficiency. Moreover, affected patients also have an increased risk of developing tumours, particularly those of lymphoid origin.
Recently, it has been shown that nuclear actin filaments play an important role in clustering DSBs to facilitate repair by homologous recombination (HR). However, the specific mechanism with which nuclear actin and various actin nucleating factors regulate HR remains unclear. Interestingly, patients with biallelic mutations in the actin nucleating factor DIAPH1 exhibit clinical features that significantly overlap with those typically associated with NBS, such as microcephaly, short stature, intellectual disability, immunodeficiency and tumour predisposition. This indicates that DIAPH1 may play a role in regulating HR, and that some of the clinical deficits associated with DIAPH1 mutations could stem from a DSB repair defect.
Consistent with this clinical similarity, this study demonstrates that cells derived from patients with biallelic mutations in DIAPH1 have a HR repair defect comparable to loss of Nbs1. Notably, this DSB repair defect is observed in a subset of patients with Baraitser-Winter Cerebrofrontofacial (BWCFF) Syndrome caused by de novo mutations in ACTG1 (-actin) but not ACTB (β-actin). Lastly, this study shows that DIAPH1 and -actin support HR-dependent repair by facilitating the relocalisation of the MRE11/RAD50/NBS1 (MRN) complex to sites of DNA damage to initiate DNA-end resection. Consequently, loss of DIAPH1 protein compromises the entire HR pathway, which inevitably gives rise to genome instability. These findings offer a novel mechanistic explanation for the overlapping clinical symptoms observed in patients with biallelic DIAPH1 mutations, BWCFF Syndrome, and NBS, and provides further insight into the role of actin and actin-nucleating factors in DSB repair
Data sources:
Access Repository Dashboard
Do you manage Open Research Online? Become a CORE Member to access insider analytics, issue reports and manage access to outputs from your repository in the CORE Repository Dashboard! 👇