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Investigations into transition metal dichalcogenides for electrocatalysis
No full textTransition metal dichalcogenides have emerged as promising candidates for the hydrogen evolution reaction (HER) due to their unique properties and low costs compared to platinum-group metals (PGMs). Despite recent advancements, there is still a gap in reporting the electrochemical rate constants and detailed kinetics for improved HER activity due to transition metal dichalcogenides (TMDs) as well as the potential effects of mixing various TMDs for enhanced HER performance. This study investigated the HER electrocatalytic activity of TMDs as well as novel strategies for enhancing their catalytic activity and determining the reaction kinetics. Different structural morphologies (bulk and nanoparticle) of one TMD, MoS, were investigated to ascertain how it affects HER electrocatalytic activity. The impact electrochemistry technique was incorporated to study the nanoparticulate forms. The MoS nanoparticles registered an improved onset potential of -0.10 V (vs RHE) through impact electrochemistry compared to 0.29 V (vs RHE) of the bulk MoS for HER.
TMD heterostructures were also investigated, and they were synthesized using a method distinct from those that have been reported in the literature. Two methods were employed to create the heterolayers: utilising a drop-cast nanoparticle layer and an electrodeposited film. The heterolayers were evaluated for HER, and the heterostructures with an overlay of MoS displayed superior stability compared to those with an overlay of MoSe. The stable heterolayers registered standard electrochemical rate constants (k0) of (3.20 ± 0.10) × 10 cm s and (1.73 ± 0.03) × 10 cm s for WS/MoS and MoSe/MoS respectively, which was an overall improvement compared to reported rate constants for electrodeposited MoS. After evaluating the heterolayers, a novel mechanochemical approach was used to synthesize binary and ternary mixtures of TMDs to enhance the catalytic activity of the resulting hybrids. Electrochemical testing of the hybrids for HER exhibited improved HER performance in terms of onset potential and electrochemical rate constants compared to the individual TMDs. These ranged from 0.52 × 10 cm s to 8.2 × 10^{-3 cm s, with hybrids containing selenium having higher electrochemical rate constants. This improvement was due to the increased active sites, the exfoliation of the TMDs that generated 1T-monolayer components known for their higher activity in HER, and the combined effect of mixing two or more catalytically active materials
Essays in networks, conflict and contests
No full textMy thesis has three chapters which look at: (i) the centralised network design in the presence of infiltration, (ii) an experiment, analysing the impact of voluntary disclosure of information in a model of asymmetric contests under incomplete information and, (iii) optimal contracts between a politician and agent in deciding resource allocation in a scenario of conflict. The summaries of each chapter are as follows:
Chapter 1: Terrorist organisations face a dilemma: increased connectivity can enhance their benefits but also increase the risk of infiltration. In this paper, we examine how infiltration by law enforcement authorities affects the structure of terrorist networks. We model the network structure in the presence of infiltration and solve for an efficient network. The efficient network is determined by the probability of an individual terrorist being captured through direct and indirect connections. If capturing an individual terrorist is possible through both direct and indirect connections with equal probability, the efficient structure will form of maximally connected sub-structures i.e., `components'. If the probability of an individual terrorist getting caught through direct connections is higher than indirect connections then non-maximally connected sub-structures may arise. The efficient network can have either symmetric or asymmetric components, depending on the probability of infiltration. For some parameter values the efficient network is composed of only symmetric components.
Chapter 2: In many contest scenarios, such as space races, R\&D, and military conflicts, participant's abilities are publicly known, while their costs remain private. This paper experimentally investigates the incentives for voluntarily disclosing private information about marginal costs in an asymmetric one-shot contest. Our between-subjects experimental design with two players includes a baseline with incomplete information with no disclosure, and two treatments with incomplete information with two-sided disclosure and one-sided disclosure. Participants risk preferences were elicited during the experiment to better understand their decision-making processes. We report the findings of our experimental study on bidding behaviour (average investment levels), probabilities of winning, and expected payoffs in ex-ante asymmetric contests. We explore whether participants consistently choose to reveal their private information when given the option. Additionally, we examine how investment levels, winning probabilities, and expected payoffs vary by ability and disclosure decisions. Our results show that participants do not always reveal their private information when given the opportunity to do so, and this decision depends on their unit cost.
Chapter 3: We analyse a principal-agent model where a politically elected leader of a group (citizens) negotiates division of resources with another group (insurgents). Citizens have preferences over resources that have economic and ideological value but keeping more resources leads to more conflict with the insurgent group. Leaders differ in their ability which affects both the cost of conflict as well as the value of the resources net of costs of conflict. We illustrate when leaders of different abilities and ideologies choose to cede more or less of the resources to the insurgent group. The first best contract from the citizens point of view is characterised. We find that in the first best contract, the amount of resources ceded to the insurgent group can be non-monotonic in ability of the citizen's leader. We provide illustrations of such non monotonic contracts. We further show what the optimal choice is by the leader when he is re-elected vs replaced in the first best contract
Physical activity, exercise, and sedentary behaviour on fatigue in rheumatoid arthritis
No full textRheumatoid arthritis (RA) is a chronic inflammatory autoimmune joint disease characterised by chronic high-grade systemic inflammation. Individuals with RA experience symptoms like fatigue, pain, inflammation, and joint stiffness, along with wellbeing and psychological challenges that affect their general quality of life. People with RA often have relatively low levels of physical activity (PA) and have relatively high levels of sedentary behaviour (SB).
This aim of this thesis was the explore the associations between PA, exercise, and SB with fatigue in people with RA using different methodological approaches. The thesis includes a review which examined these associations (Chapter 2). A novel aspect of this work was the inclusion of observational, longitudinal, and intervention studies in the same review to get a detailed understanding of the existing literature. The findings from the review showed that observational studies provided more substantial evidence for associations between PA and fatigue, whereas exercise interventions appeared to be more effective in reducing fatigue. Few studies explored the associations between SB and fatigue in RA. The review also found a lack of consistency of measuring fatigue in these studies, with some using validated multidimensional measures of fatigue, whereas others included a unidimensional fatigue measure.
In the subsequent chapters, different methods and assessments were used to measure fatigue. Chapter 3 examined the diurnal variation in PA and SB and its associations with a multidimensional measure of fatigue. The findings indicated
that people with RA tend to be more sedentary and less physically active in the evening compared to the morning and afternoon. In addition, sedentary time, standing and stepping are differentially associated with dimensions of fatigue in RA, with stepping behaviours (time and intensity) demonstrating the most consistent associations across all fatigue dimensions.
Chapter 4 used both a multidimensional measure of fatigue as well as unidimensional assessment which was recorded throughout the day for 1 week to provide an overall measure of fatigue in university students, as well as a device-based measures of PA and SB. It was found that daily PA and sedentary time were not associated with multidimensional aspects of fatigue in this population. Using ecological momentary assessment (EMA) was a suitable method to capture unidimensional fatigue over the course of a week. However, these measures were not associated with PA or sedentary time in this population.
The combined findings of this thesis indicate a plausible role of increasing PA (including exercise) for managing fatigue in RA. However, limited evidence exists for the role of sedentary time. In all cases, more research is required to uncover the complexities of the associations between these movement behaviours and fatigue in RA, particularly when considering the complex and multidimensional nature of the experience of fatigue. EMA-methods employing multidimensional measures of fatigue, alongside device-based assessments of PA and sedentary time, may show some promise, but further development and validation work of fatigue measurement is required prior to implementing such studies in RA
Chronic hypoxia and the carotid body: the role of CD73 in carotid body hyperactivity and cardio-respiratory function
Full text linkCarotid body hyperactivity is increasingly recognised as a major contributor to neurogenic hypertension, particularly in cardiovascular-respiratory related diseases including chronic obstructive pulmonary disease (COPD). In COPD, chronic hypoxia persistently excites the carotid body, driving excessive sympathetic outflow contributing to hypertension. However, the mechanisms underlying carotid body hyperactivity remain unclear. CD73, an ecto-nucleotidase, plays a crucial role in setting basal carotid body activity and hypoxic sensitivity. Whether CD73 contributes to chronic hypoxia-induced carotid body hyperactivity is unknown. This thesis initially characterised and validated a chronic hypoxia model in rats using 10 days exposure to 12% FiO2. Experiments subsequently investigated alterations in the cellular distribution of CD73 in the carotid body in response to chronic hypoxia and the functional importance of CD73 in promoting chemoafferent hyperexcitability. Final experiments examined whether in vivo pharmacological targeting of CD73 produced beneficial cardiovascular alterations in chronically hypoxic animals. Chronic hypoxia increased the number of CD73+TH+ cells within the carotid body. Pharmacological inhibition of CD73 abolished chronic hypoxia-induced basal chemoafferent hyperactivity and normalised heightened hypoxic sensitivity ex vivo. CD73 antagonism in vivo reduced blood pressure in a carotid body-dependent manner while preserving cardiovascular-respiratory reflexes during hypoxia. This research suggests that CD73 is an important modulator of carotid body hyperactivity in chronic hypoxia. The work highlights a potential new strategy for reducing carotid body hyperactivity and blood pressure without impairing hypoxia responsiveness. These findings should promote the development of carotid body/CD73-targeted treatments for chronic hypoxia-related conditions such as COPD
Optimising CAR-T cells for enhanced activity in the tumour microenvironment
Full text linkAcute myeloid leukaemia is a cancer of the myeloid cells in the bone marrow. AML alters the bone marrow niche, creating an immunosuppressive microenvironment. AML increases tryptophan metabolism and cystine uptake. T-cells require sufficient nutrients to function. Due to a lack of clinical activity, CAR T-cell therapies are currently only used in a limited number of cancers. We hypothesised that the lack of nutrients in the AML microenvironment supresses CAR T-cell function.
This work discusses how the availability of tryptophan and cystine affected T-cell and CAR T-cell proliferation. We designed CAR T-cells with the overexpression of tryptophan or cystine transporters, SLC7A5 and SLC7A11, respectively. We first demonstrated that the addition of SLC7A5 and SLC7A11 to Jurkat CAR T-cells provided increased metabolic rates in low tryptophan and cystine environments, respectively. The addition of SLC7A5 and SLC7A11 to CAR T-cells increased tryptophan and cystine uptake, respectively. CAR T-cells with SLC7A5 or SLC7A11 overexpression had increased proliferation in low tryptophan and cystine environments, respectively. The CAR T-cells with overexpression of SLC7A5 and SLC7A11 improved cancer clearance in murine models. Performing RNA sequencing of CAR-T cells following interaction with tumour cells, we showed a significant alteration of pathways associated with T-cell activation, metabolism, and migration, caused by the addition of the transporters to the CAR T-cells. These results demonstrate that the addition of SLC7A5 and SLC7A11 could improve CAR T-cell function in low amino acid environments
Use of high-density transposon libraries to analyze oxidative protein folding and protein translocation in Escherichia coli
No full textTransposon mutagenesis is a widely used method to introduce random mutations into bacterial genomes. Transposon directed insertion-site sequencing (TraDIS) combines transposon mutagenesis with next-generation sequencing to identify genes required for viability under experimental conditions, which provides linkage of phenotype to genotype. In this study, the Tn5-based transposon mutant libraries were used to investigate the oxidative protein folding in Escherichia coli (E. coli) cytoplasm and the azide resistance in E. coli K-12 strain MG1655. SHuffle strains are engineered to produce disulfide bonded proteins to high yields within the cytoplasm. TraDIS was used to analyze the physiology differences between SHuffle strains and their wild type strains by comparing the essential genes in each strain. SHuffle B was identified to have nearly two-fold unique essential genes that are mainly involved in cell response to oxidative stress, suggesting that the SHuffle mutations might cause more oxidative stress in E. coli B. The transposon libraries were further used to probe the genomic requirement to suppress the temperature sensitivity of SHuffle B. Insertion disrupting genes involved in aerobic respiration decreased susceptibility of SHuffle B to higher temperatures. TraDIS was also used to investigate the possible function of trigger factor (TF) and DsbC by determine the essential genes of E. coli strains containing ∆tig and ∆dsbC mutations, which increase susceptibility to sodium azide. Since the mechanism of azide was yet unknown, six transposon mutations conferred azide-resistance were isolated from the transposon library. All of affected genes were involved in ribosomal biogenesis. SecA migrated as two isoforms in SDS-PAGE, the large isoform was fulllength SecA and the small isoform was determined to be C-terminal tail truncated SecA. Expression of both isoforms increased in the isolated azide-resistant mutants in the presence of azide. However, only the small isoform accumulated in the azide-resistant secA mutants in the presence of azide, suggesting that the expression of the small isoform could affect the susceptibility to azide and two isoforms might have distinct physiological roles in vivo. The results presented highlight the potential applications of transposon mutagenesis in dealing with complex biological questions
Development of polymer lipid particle technology for drug discovery
No full textG Protein-Coupled Receptors (GPCRs) represent 30-40% of all drug targets and have a massive therapeutic potential. Investigations into GPCR structure and function are often limited by their instability, flexible structure and location within the plasma membrane. Improved methodology to produce stable soluble GPCRs in an environment like the plasma membrane would be impactful for drug discovery. Amphipathic polymers, such as poly(styrene-co- maleic acid) (SMA), can be used as a solubilisation agent to produce polymer lipid particles (PoLiPa). These nanodiscs can encapsulate membrane proteins and surrounding lipids. PoLiPa have been shown to have a stabilising effect lending itself to GPCR investigations.
This project shows the expression, solubilisation and purification of GPCRs using PoLiPa technology, and preliminary data showing evidence that GPCRs are functional in an SMA lipid particle (SMALP). Firstly, the production of soluble human Neurotensin Receptor (hNTR1), expressed in E. coli, with a wild-type sequence was proven possible utilising SMA but low expression prevented its purification. Secondly, two MBP-fused GPCRs (rat NTR1 and Cannabinoid Receptor 2 (CB2)), expressed in E. coli, were solubilised and purified using SMA and were resistant to unfolding. Thirdly, mammalian cell expressed GPCRs (hNTR1 and CB2) were solubilised with different polymers and CB2 was successfully purified. Finally, SMALP-encapsulated GPCRs were proven suitable for functional analysis by fluorescent tryptophan spectroscopy (FTS), fluorescent correlation spectroscopy (FCS) and spectral shift assays. Key findings include the preferential solubilisation of GPCR oligomers or glycosylation forms dependent on the polymer type and hydrophobicity; the importance of resin types and excess polymer concentration on purification yield and allosteric modulation of Mini-G proteins for GPCR ligand binding.
It is anticipated that this project will be a starting point for other GPCR investigations to optimise the use of PoLiPa technology. This project presents key hurdles in the GPCR production process and a toolkit to overcome issues such as low expression, instability, and purification contamination
Dissecting the lifestyle of Klebsiella pneumoniae and Vibrio cholerae using chemical genomics
No full textKlebsiella pneumoniae and Vibrio cholerae are important human pathogens with increasing antimicrobial resistance in the clinic. Although, genome sequencing information are available for both strains, their genomes are still poorly annotated. This hinders our better understanding of their lifestyles, which is important in discovering new drug targets and tackling antimicrobial resistance. In this thesis, we applied chemical genomics to improve functional annotations of the genomes of both organisms. To do this, we systematically assessed the fitness of ordered single gene deletion transposon mutant libraries of K. pneumoniae (4346 mutants) and V. cholerae (3060 mutants) against ~200 chemical and environment perturbations (stresses) targeting different cellular processes. The resulting stress-response datasets showed high replicate reproducibility with correlation coefficient greater than 0.7 in all experiments and benchmarking against known biology of functionally related genes having similar responses across all the stresses indicated that our datasets are of good quality. The responsive genomes, which are genes inactivated in mutants with significant responses to a stress, were 42% and 52% of the genome of K. pneumoniae and V. cholerae respectively. More so, we identified 348 and 240 genes essential for growth in different stress conditions in K. pneumoniae and V. cholerae respectively.
Additionally, functions were predicted to hundreds of hypothetical genes with the functions further validated via computational methods using Alpha Fold, ChimeraX and Dali. For example, KPNIH1_22370 was predicted to be a membrane protein with its mutant showing reduced fitness in triton-x and correlation coefficient of 0.64 with yidD. Then, possible interactions were validated between KPNIH1_22370 and yidD on ChimeraX. Similarly, VC_0032 was predicted to be involved in carbon starvation with its mutant showing reduced fitness in minimal carbon stresses and correlation coefficient of 0.79 with vcc collagenase. Then, possible interactions between VC_0032 and vcc collagenase were validated on ChimeraX and Dali. Furthermore, in K. pneumoniae, single mutants of envC and hflC genes showed reduced fitness in aminoglycosides while single mutants of nuo, cyo and sdh genes showed increased fitness in aminoglycosides. This suggests that with leaky membrane from the inactivation of envC and hflC, more aminoglycosides get into the cell and inhibit protein synthesis. Additionally, inactivation of nuo, cyo and sdh genes resulting in increased fitness suggests there is a reduction in aminoglycosides uptake in dysfunctional electron transport chain. More so, mutants of tcpP showed reduced fitness in carbon starvation and acidic condition in V. cholerae. This suggests that tcpP plays an important role in the survival of V. cholerae in aquatic environments and in human host.
In addition, our small-scale screens showed that chemical genomics is applicable in screening few strains against few conditions. In this thesis, we evaluated the fitness of six mutants of beta barrel assembly machinery (Bam) associated proteins in 28 unique stress conditions to show that the Bam associated proteins do not phenocopy each other. Similarly, we assessed the fitness of 34 single and double mutants of peptidoglycan (PG) enzymes in nine unique envelope stresses to show that PBP1B, encoded as mrcB, is important for fitness in salt stresses. More so, chemical genomics was adapted in evaluating the minimum inhibitory concentrations (MIC) of 96 clinical isolates in chlorhexidine with isolates of K. pneumoniae with the highest MIC. In conclusion, our stress-response datasets from evaluating the fitness of the strains in the stresses are rich in information that helped us to better understand the biology of the organisms
Bis-perylene diimide macrocycles for chiroptical materials
Full text linkThis thesis aims to explore the intramolecular and intermolecular interactions between chiral core-twisted PDIs using a novel bis-PDI macrocyclic scaffold (nicknamed the “Pink Box” due to its colour in solution), with a view towards applications as organic chiroptical materials.
Chapter 1 provides an overview of chiroptical activity and of perylene diimides (PDIs), with an emphasis on their supramolecular self-assembly and on chiral bis-PDI macrocycles.
Chapter 2 outlines the development of the Pink Box macrocyclic scaffold, as well as the characterisation of its intramolecular homochiral PDI-PDI dimer using a range of experimental
techniques.
Chapter 3 established a strategy for making the Pink Box macrocycle chirally locked by varying the imide group on the PDIs to prevent an “intramolecular somersault”. With stable enantiomers in hand, the aggregation behaviour of enantiopure vs racemic macrocycle samples is studied by UV-vis spectroscopy and X-ray crystallography. It is found that the intramolecular PDI-PDI dimer within the macrocycle is always homochiral and H-type, while intermolecular PDI-PDI contacts are heterochiral and slip-stacked.
Chapter 4 provides a fundamental understanding of the chiral conformations of “Pink Box” type macrocycles to unlock further potential as efficacious chiroptical materials. A 3rd generation Pink Box macrocycle is developed in which the homochiral stereoisomers can populate two different chiral conformations upon changing the solvent, leading to inversion of the CD spectrum (chiroptical switching). Additionally, a stable heterochiral diastereomer is isolated and shown to exhibit a “slipped-stack” J-type dimer.
Chapter 5 describes the synthesis and characterisation of a series of Pink Box-type macrocycles with alternative linkers, to understand the impact of linker length and rigidity on the interaction between the PDI units in a bis-PDI macrocycle. Guest binding studies are also performed.
Chapter 6 provides a summary of the major conclusions from the research described in this thesis.
Experimental details and methodologies are provided at the end of each research chapter.
Appendix A provides details of the computational studies carried out by Prof Martijn Zwijnenburg to complement the research presented in this thesis
Purposeful parenting: An exploration into LGBTQ+ parental decision-making
Full text linkThe increasing number of LGBTQ+ families in the UK, driven by more inclusive legal rights and access to reproductive technologies, offers a unique opportunity for research into how these families form and navigate parenthood. LGBTQ+ families tend to be more egalitarian and less bound by traditional gender roles compared to heterosexual families, presenting a unique demographic for research. Whilst there is substantial literature on lesbian and gay parent family formation, existing models are outdated, largely overlook the broader spectrum of parental decisions beyond the initial choice to start a family and there is limited research on LGBTQ+ parents beyond gay and lesbian identities. Furthermore, although research on heterosexual parents' work-home decision-making exists, similar studies focusing on how LGBTQ+ parents navigate parenthood through their work and family lives are lacking. Alongside what decisions these parents make, this thesis explores the factors that influence LGBTQ+ parents’ initial decision to start a family, through to decisions around how to start a family, and finally through to work-home decisions beyond family formation. Understanding both family formation and work-home decisions, and the factors that both enable and constrain them, can enhance our knowledge of the decisions LGBTQ+ parents make when navigating parenthood, and increase understanding around how organisations and government can account for this when creating policy.
Through semi-structured dyadic and follow-up individual interviews with 20 LGBTQ+ parents, this research delves into the pivotal family formation and work-home decisions made throughout their parenting journeys and the factors that influence them. An intersectional intracategorical approach is employed to explore the diverse lived experiences across various identities within the LGBTQ+ community. Additionally, this study adopts a Queer Theory lens to challenge hetero- and homonormative assumptions within both queer studies and the wider literature on parenting, reflecting on the impact this perspective has on both the research and the researcher.
This thesis makes several significant contributions to the existing body of knowledge on LGBTQ+ parental decision-making and the broader literature on work-home decisions. It updates existing models of lesbian mothers’ ART decision-making by incorporating modern technologies and legal challenges. It also introduces a comprehensive decision-making model for LGBTQ+ family formation, encompassing diverse identities and methods of family creation. By conceptualising parental leave as a temporary role exit decision, this research brings LGBTQ+ voices into the conversation on work-home decisions. Finally, the findings of this thesis deepen our understanding of the factors influencing family formation and work-home decisions among LGBTQ+ parents, extending these considerations to decisions beyond initial family formation and beyond the decisions of lesbian mothers and gay fathers. These insights have profound implications for policy and practice, providing actionable recommendations for industry professionals and policymakers to better support LGBTQ+ families
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