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Arabidopsis NOT4 E3 ligases: key regulators of TOR signalling and co-translational protein quality control
No full textProtein synthesis and degradation are both essential for regulating proteome homeostasis and cellular function. In eukaryotes the predominant mechanism for regulated protein degradation is via the ubiquitin proteasome system (UPS), where substrates are marked for degradation through the addition of a polyubiquitin chain by enzymes called E3 ubiquitin ligases. The UPS is important for degrading proteins when they are no longer needed, but also plays a key role in clearing misfolded proteins that arise during stress or in response to translational errors as proteins are synthesised. In yeast and metazoans, the NOT4 E3 ligase has been shown to play a role in co-translational mRNA and protein quality control to limit translational errors, but the presence and functions of NOT4-like proteins in plants has not been investigated.
Three putative NOT4 E3 ligases (AtNOT4A, B and C) were identified in Arabidopsis and shown to contain the unique and characteristic combination of a RING domain and RNA recognition motif (RRM), which places their function at the interface of proteolysis and RNA biology. Phenotypic and RNA-seq analyses of single and combination Atnot4 mutants revealed redundant functions for these proteins in controlling plant growth – likely due to energy deficiencies – and regulating the expression of genes linked protein translation. Further analyses showed that plants lacking functional AtNOT4s have increased global translation rates, accumulate polyubiquitinated proteins, and are sensitive to protein-folding elicitors, which is indicative of increased error rates during protein biogenesis.
AtNOT4s had previously been identified as targets of the AtTOR kinase, a master regulator in energy- and nutrient-responsive translation. Given the growth and translational phenotypes observed in Atnot4 mutants, an assessment of their relationship to AtTOR signalling was undertaken. Atnot4 mutants were found to have increased basal rates of AtTOR activity, which may explain the increased rates of translation in these mutants. Moreover, biochemical, plant growth, and RNA-seq analyses showed that Atnot4 mutants are sensitive to chemical inhibitors of the AtTOR signalling cascade, suggesting that they are required for normal AtTOR functions.
In summary, the data presented in this thesis describe for the first time a role for plant NOT4-like proteins in regulating protein translation linked to AtTOR signalling, suggesting they function as part of a conserved co-translational surveillance mechanism that coordinates and safeguards protein production. This has important implications for our understanding of proteostatic quality control mechanisms across kingdoms, whilst also identifying new potential targets for enhancing plant performance through improving translational fidelity under normal and stress conditions
The role of pre-sleep arousal and frontoparietal circuitry in ADHD: a dimensional approach
No full textAttention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder currently estimated to be diagnosed globally in around 3.1% in adults and 8% in children and adolescents (Ayano, Demelash, et al., 2023; Ayano, Tsegay, et al., 2023). The primary diagnostic trait of ADHD is impeded executive functioning, and symptoms negatively impact across multiple facets of day-to-day life including familally, socially, educationally and vocationally (Luo et al., 2019). One executive function which is impaired in ADHD is response inhibition (Penadés et al., 2007; Pievsky & McGrath, 2018; Willcutt et al., 2005; Wright et al., 2014). Response inhibition relies on recruitment of the left intraparietal sulcus (IPS), and its recruitment in ADHD is dictated on a specific frontoparietal functional circuitry between the inferior frontal gyrus (IFG) and the IPS (Kolodny et al., 2017, 2020). Chapter 2 investigates the role of white matter structure underpinning this frontoparietal circuitry in ADHD and its role in impaired response inhibition, finding that individual differences in the structural properties of the IPS-IFG circuit, including tract volume and diffusivity, were linked to IPS activation and even predicted response inhibition performance outside the scanner. These findings highlight the structural-functional coupling of the IFG-IPS circuit in response inhibition in ADHD and suggest a structural basis for maladaptive functional top-down control in deficient inhibition in ADHD. Building upon these findings, chapter 3 investigated the impact of lIPS inhibition via continuous theta-burst transcranial magnetic stimulation (cTBS) on response inhibition. I report that the disruption to response inhibition by lIPS inhibition is increased in individuals with greater ADHD traits, which may reflect individuals with greater ADHD traits may having reduced compensatory mechanisms or the complex relationship between TMS and activation state in the targeted region may also explain our these findings, such as ADHD-related differences in ongoing lIPS activity or increased cognitive load in the disorder
Processing of lamellar structured liquids
No full textIn today’s society where health and sustainability are two key consumer trends, global FMCG companies like Unilever are driven to innovate, adapt, and adopt responsible practices. Aligning with consumer expectations enhances Unilever's market position and supports long-term business sustainability. Therefore, this thesis aims to improve insights into the hair conditioner manufacturing process to reduce energy and resource consumption while ensuring the desired product microstructure (a lamellar gel network) can be manufactured efficiently every time.
Hair conditioner improves manageability and enhances the appearance and shine of hair - a key indicator of hair health. Consumers expect a thick, opaque cream product that spreads evenly over hair and provides detangling and conditioning through deposition of beneficial ingredients. These physical and rheological properties are achieved through a lamellar gel network (LGN) microstructure - a product of the ingredients used and the manufacturing process. Insights into the influence of processing conditions on the LGN microstructure are limited due to the complexity of the product limiting the availability of process monitoring and characterisation techniques.
In this thesis, rheological mapping using a rheometer and 3D-printed scaled-down geometries to imitate the batch manufacturing vessel, was applied to generate viscosity-time profiles for LGNs at various speeds, times, and temperatures. Samples were characterised by their rheological properties and power requirements, comparing yield stress to qualitatively assess process optimisation strategies. Shorter mixing times, ending after the peak viscosity was reached, produced higher yield stress products, presenting energy-saving opportunities. The importance of monitoring viscosity during LGN mixing was highlighted, informing further studies on the application of mixer-viscometer approaches to
partially-filled batch vessels (25% to 100% liquid height to impeller length). The torque curve method and Couette analogy were applied to torque-speed data for various fluids, including LGNs. However, changes in fluid contact with the impeller as a function of speed, geometry, and fluid rheology showed no measurable relationships, limiting the application of mixer-viscometer techniques due to the consequent impact on torque measurement. Finally, data-driven models were investigated to predict online viscosity from torque for mixing systems at three scales (0.045 L, 2 L. 50 L). A random forest regression model used mixer diameter, speed, fill level and torque as inputs, and apparent viscosity as the output. The model indicated signs of over-fitting, likely due to an uneven dataset favouring lower viscosity values. Despite this, the work provides an initial contribution towards applying soft sensors to predict online viscosity during manufacture of formulated products.
This research provides Unilever with valuable techniques for monitoring microstructure formation using rheological approaches to enable process and product optimisation, aiding in achieving their net-zero targets and enhancing product superiority
Health insurance, sleep, and healthcare utilization: evidence from China
No full textChina's health insurance system has witnessed significant changes over the past few decades. In 1998, the Urban Employee Basic Medical Insurance (UEBMI) was established. In 2002, the Urban Resident Basic Medical Insurance (URBMI) started, followed by the New Rural Cooperative Medical Insurance (NRCMI) in 2007. Subsequently, some provinces launched pilot programs to merge URBMI and NRCMI into the Urban and Rural Resident Medical Insurance (URRMI), and by 2021, this unification was largely completed across all provinces. How do these changes affect middle-aged and older adults and children in this policy context?
Firstly, this study examines the effects of three public health insurance (NRCMI, URBMI, and UEBMI) and private health insurance on the mental health of middle-aged and older adults. It also explores how transitions between these public insurances impact mental health. Additionally, it investigates the influence of the URRMI pilot policy on mental health.
Secondly, this research explores how health insurance affects children's healthcare utilization. It compares children with public health insurance to those with private insurance in terms of healthcare utilization. Furthermore, it investigates how the URRMI merger policy impacts healthcare use among children. This research also explores how insurance status affects income-related inequalities in children's healthcare utilization.
Finally, this study investigates how sleep duration and sleep quality relate to out-of-pocket (OOP) medical expenditure and the likelihood of catastrophic health expenditure (CHE) for middle-aged and older adults
The utility of intact light chain mass spectrometry-based assays for the detection of plasma cell disorders and the assessment of treatment responses
No full textMass spectrometry (MS) assays have been emerging over the last few years as a new and potentially more sensitive way to track monoclonal proteins in the serum patients with plasma cell disorders (PCD), although limited data on their prognostic utility is available. In addition, no studies have explored their potential utility in patients with multiple myeloma with low-level monoclonal protein production. Despite the use of intact light chain MS-based assays in lieu of immunofixation being approved by the Internal Myeloma Working Group in 2021, MS testing to monitor patients with PCD is currently only available at a single institution who have developed an in-house test. This thesis presents work undertaken alongside the Binding Site Ltd to develop a regulatory approved intact light chain MS-based assay and clinical studies undertaken independently to assess the utility of this assay for monitoring patients with PCD.
Assay optimisation work conducted as part of this thesis has shown that the combination of free light chain (FLC) specific reagents in addition to a five bead matrix-assisted laser desorption/ionisation time-of-flight MS (MALDI-TOF MS) assay provides a more sensitive panel for the detection of low-level residual monoclonal FLC. However, the application of MALDI-TOF MS to urine did not provide any additional sensitivity to the serum-based MALDI-TOF MS-based assays. The sensitivity of FLC-MS for the detection of low-level residual monoclonal FLC was also enhanced by on-bead de-glycosylation in patients with light chain N-linked glycosylation.
The first clinical study included in this thesis explored the sensitivity and prognostic utility of MALDI-TOF MS in patients being treated with carfilzomib, cyclophosphamide, lenalidomide, and dexamethasone (KCRD) in the Myeloma XI trial. In this work MALDI-TOF MS provided greater sensitivity for the detection of residual monoclonal protein compared to electrophoretic techniques and MALDI-TOF MS negativity was associated improved progression free survival (PFS). In addition, FLC-MS negativity in patients with no residual monoclonal protein detection by immunofixation electrophoresis at the end of induction, day+100 post autologous stem cell transplant (ASCT) and six months post maintenance randomisation was associated with reduced PFS.
The second clinical study evaluated the utility of MALDI-TOF MS in patients with non measurable myeloma. This study showed that 91% of patients classified as having non-secretory myeloma using standard techniques have detectable monoclonal protein in the serum using MALDI-TOF MS. MALDI-TOF MS also provided greater sensitivity for monitoring patients with oligo-secretory myeloma. Further studies should therefore be undertaken to establish criteria for measurable disease using MS.
The third clinical study included in this thesis evaluated the utility of a FLC specific MALDI-TOF MS assay in patients undergoing treatment for AL amyloidosis in the ALchemy study. This is the first study to evaluate the prognostic utility of a FLC specific MS-based assay in patients with AL amyloidosis and found that achieving FLC-MS negativity at six and 12 months post treatment initiation was associated with improved overall survival. There was also an improved rate of renal responses amongst patients who achieved FLC-MS negativity at 12 months.
The final clinical study included in this thesis is the first study to evaluate the prognostic significance of light chain N-linked glycosylation in patients undergoing treatment for PCD. This study included patients treated with KCRD and ASCT for multiple myeloma and bortezomib-based treatment for AL amyloidosis. In contrast to the higher risk associated with light chain N-linked glycosylation in patients with monoclonal gammopathy of undetermined significance previously described by Dispenzieri et al this work found that light chain
glycosylation was not associated with inferior responses to treatment or reduced survival
Making up madness in the novels of Ford Madox Ford
No full textFord Madox Ford (1873-1939) was an important writer in a period of exciting changes in the way that madness was conceptualised. He lived through the development of psychology and psychiatry as new medical disciplines and the emergence of psychoanalysis and participated in the literary shift towards representing individual consciousness, putting the mind on the page. The First World War challenged both medical professionals and writers to find new responses to madness. Ford was at the intersection of these changes, with a personal history of mental breakdown, a preoccupation with insanity and direct experience of serving at the Somme in 1916.
Ford wrote about people who were mentally or emotionally disturbed throughout his writing career, in letters, essays, autobiographies and fiction. The novels he published between 1892 and 1939 leave a rich repository of depictions of madness which acknowledge but are not constrained by its increasing medicalisation. This valuable collection of literary representations of madness has been under-explored. The most comprehensive and influential accounts are biographical and interpret the novels largely as an expression of Ford’s own psychological needs and problems.
This thesis addresses the question of what Ford’s novels have to say about madness, rather than about Ford himself. It considers how he represents madness, charting continuities and changes over his oeuvre, and to what effect. Methodologically the thesis takes a hybrid approach. It uses quantitative analysis to explore Ford’s language of madness; archival and empirical research to shed new light on how his treatment for a nervous breakdown in 1904 impacted on his fiction; and close readings of thirteen novels from across the oeuvre which exemplify different aspects of his depictions of madness. It offers sustained readings of some of Ford’s less studied novels, such as The Benefactor (1905) and When the Wicked Man (1931), alongside re-examinations of those already extensively discussed: The Good Soldier (1915) and the Parade’s End tetralogy (1924-28).
The thesis demonstrates that the theme of madness in Ford’s novels traces a trajectory of explanations for it from the personal, to the interpersonal, and to the societal and systemic. Ford’s novels produce progressively nuanced and complex explanations for who is labelled as mad and why, with the power of language and the literary central to this. They unsettle distinctions between the rational and irrational, the imagination and delusion, and ultimately the sane and the mad. Increasingly his novels implicate readers in ways which destabilise any sense of their own immunity from madness, showing it to be more ordinary than exceptional. Ford’s insights into how madness is created and experienced remain relevant today
Enhancing Radioiodide uptake by modulating NIS Endocytosis and degradation pathways
No full textThe effectiveness of radioiodide therapy for differentiated thyroid cancer is often compromised by the mislocalisation of the sodium/iodide symporter (NIS) away from the plasma membrane, as well as its dysregulated expression. While increasing NIS expression has been the focus of previous and on-going studies, mislocalisation remains a significant barrier. This thesis investigates aspects of the post-translational processing of NIS, identifying critical therapeutic opportunities to enhance its function.
Key NIS interactors, including the AP2 adaptor complex, PBF, moesin, and VCP, were explored for their potential roles in NIS endocytosis and trafficking. This revealed that disrupting specific motifs within the NIS C-terminus, particularly the diacidic and dileucine motifs, significantly impacts NIS localisation and function. The efficacy of the specific VCP inhibitors CB-5083 and CB-5339 was appraised in breast cancer cell lines, demonstrating an increase in radioiodide uptake at specific concentrations. However, the effects were not NIS-mediated in all cases. Structural analogues of clotrimazole and NMS-873 were also developed to address bioavailability challenges, demonstrating modest improvements in radioiodide uptake and providing an alternative strategy to modulate NIS degradation. Additionally, the critical impact of NIS dimerisation on its function and trafficking was investigated. Mutations at key residues within the dimerisation interface, particularly K554 and R555, were found to impair NIS dimerisation, reduce iodide uptake, and affect NIS protein expression and localisation.
Thus, new insights into NIS subcellular localisation, processing, function and pharmacological modulation were derived, allowing new strategic approaches to enhancing radioiodide uptake in thyroid cancer to be identified
Public opinion, message framing and deliberative democracy: striving for a progressive consensus
Full text linkPublic opinion theories highlight a degraded civic and media discourse on crime. They also highlight the inter-relationship between political rhetoric on crime, rising public punitive sentiment, scapegoating of poorer communities and reactionary government policies. However, theories oversimplify public opinion and omit analysis of opinion formation mechanics and effective public engagement methodology for crime debates. Addressing limitations, this thesis presents a theoretical analysis of opinion formation mechanisms, including message framing. It also takes a position within deliberative democracy theory for enhancing public discourse on crime, while incorporating opinion formation mechanics including factual and emotional learning. To explore this theory, deliberative democracy exercises with public participants were conducted. It analysed the impact of deliberating on crime opinions by comparing pre and post-deliberation interview answers. This thesis found that deliberations brought participants to a progressive consensus. It also shifted punitive participants’ perspectives towards more progressive opinions, stimulated civic inspiration and found that a mix of rational and emotional information was persuasive for influencing crime opinions. Public deliberation could therefore enhance public crime debates as a precursor to policy reform. However, further work is required to realise this potential, including overcoming logistical barriers for scaling-up deliberation to widen public participation
An exploratory study of global citizenship education in different curricula contexts within English secondary schools
Full text linkThe double-edged sword of globalisation has transformed spaces into transnational arenas that all students must negotiate daily (Nolan 2009; Waters and Brooks 2012). Equally, it has left many disenfranchised and exposed to inequality fuelling movements like Black Lives Matter and #MeToo in search of understanding, voice, and social change. Situated in this is global citizenship education (GCE). Dynamic discourse in the field and recent efforts to map those discussions offer an opportunity for researchers and educators to use GCE as a navigating tool for students at school in 2024 (Pashby et al. 2020; Stein 2015).
Situated between the International Baccalaureate (IB) and the English context, this study explores interpretations and enactments of GCE, and the potential role curriculum plays within that. It aims to understand different manifestations of GCE across IB and A level, state and independent settings and navigate how GCE can be better integrated in all schools to address global crises, embrace diversity, and prepare students for an uncertain future.
Framed within comparative international education, this project takes a small-scale case study approach. To understand GCE in England and offer actionable ideas, it states research must be grounded in such a comparative framework (Bray and Thomas 1995; Flyvbjerg 2001). The study uses four sites to act concurrently towards a single case in England (Day Ashley 2021; Yin 2009). The research works with a process-orientated approach proposed by Bartlett and Varvus (2017). It is an active process, beginning with lesson observations and adapting knowledge from those to later interviews and focus groups alongside document analysis. Rather than binding sites to look for pre-determined ideas of GCE, data collection lets the culture and context of those sites drive their own data in an active process of sense-making (Erickson 2011). As such, the case study – of GCE in England – becomes the phenomenon of study and each geographical site a constituent part.
All four schools in the study exhibited a demand for and actions relating to many forms of GCE; both A level and IB settings were adapting their pedagogies, content, and co-curricular offerings to include different knowledges. This is a significant change in the area of global citizenship education. Those did, however, exist at different stages. A level settings were beginning to explore alternative perspectives but, simultaneously, remained grounded in narratives on charity and responsibility. IB schools though were moving beyond that to critiquing single-story approaches and embracing reciprocal service learning and equity in the classroom. Whilst arguably still in their early stages, this research highlights the importance of findings as one of very few studies done in UK but also covering both the state and independent sectors. Moreover, the overwhelming message was GCE beyond individualised endeavours – directly countering other academic findings (Lauder 2007; Resnik 2012; Weenink 2008). Indeed, it was A level schools that were more pre-occupied with attainment and GCE as a competency tool.
The research offers four important academic contributions. First, the study aimed to answer earlier and ongoing calls for more empirical work in GCE particularly within England at 16 plus. Second, the research found GCE to be a complex web within all school settings, arguing the value in that complexity and calling for other research to sit in the nuance and complexity to develop narratives of schools that are representative of action on GCE. Third, within the complexities of GCE, all four school sites showed evidence of connections across different understandings of GCE that was both interesting and encouraging. Findings suggested that change was beginning to occur in the education world that reflects the rich discussion on GCE in the academic world. Finally, there was a clear connection from all findings on GCE, that self-reflection and reflexivity permeate many forms of GCE and could be a starting point for students and teachers as they embark on the global citizenship education journey.
Moving forward, the research calls for further empirical research in countries like UK that connects dynamic discussions on the connections between types of global citizenship education found in the literature with exciting and equally dynamic activities in schools; enactments that are beginning to question dominant narratives, increasingly cover more voices and co-curricular endeavours that are moving from charity to partnership in an effort to engage global citizens in contemporary challenges facing the world
Mathematical modelling of chemical reactions: the vitamin C clock reaction
Full text linkThe thesis presents a mathematical model and accompanying analysis to gain insights into the chemical clock reaction associated with vitamin C, hydrogen peroxide and iodine. Chemical clock reactions are identified by a reproducible induction period that is followed by in a rapid change in a solution triggered by a rise in a specific chemical concentration. In the vitamin C clock reaction, vitamin C converts iodine to iodide (the fast reaction) and simultaneously hydrogen peroxide converts iodide to iodine (the slow reaction). The fast reaction dominates until the vitamin C is depleted, at which point the iodine concentration rises, resulting in a rapid colour change in the system. Three new models are presented. Firstly, both the fast and slow reactions are considered under the assumption that hydrogen peroxide levels are moderate. Secondly, the slow reaction is considered in isolation and in more detail, revealing the effect of hydrogen peroxide concentration on the reaction kinetics and resolving differences in the existing literature. Thirdly, the fast reaction is reincorporated with the more detailed slow reaction to create a unified model that can capture the clock reaction dynamics under both moderate and high hydrogen peroxide regimes. All models are studied through numerical and asymptotic analysis. Using asymptotic analysis, formulae are derived that can predict the length of the induction period. Finally, experiments are carried out to generate data to parameterise the models and test the associated formulae, which are shown to be accurate for both hydrogen peroxide regimes
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