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Essays on the effects of upstream intergenerational support: from adult children to parents
Full text linkThis thesis presents three novel chapters that aim to provide causal evidence on the impact of intergenerational ties through care, education, and support from adult children on parental wellbeing and how work-related policies affect the provision of informal caregiving. The main innovations of the chapters address a common empirical challenge: drawing robust causal inferences by controlling for endogeneity concerns within observational data.
Chapter Two examines the causal effect of flexible working arrangements in the workplace on parental informal care provision in the UK, using the UK Household Longitudinal Study (2010-2022) with both fixed effect and two-stage least squares estimation methods. The findings reveal a significant positive effect of flexible working arrangements on informal care provision. Access to such arrangements significantly increases the probability of children providing care to their parents. This effect varies according to the intensity of care provided and is heterogeneous according to family composition.
Chapter Three investigates the causal impact of children's college attainment on parental mental health in the US, using the US Health and Retirement Study (1998-2018). Employing nonparametric partial identification analysis that relies on weak and credible assumptions to produce bounds on the population average treatment effect, the findings show a noteworthy positive causal effect of children’s college attainment on parental mental health status. The findings indicate that having a college graduate child improves parental mental health score, measured by the Center for Epidemiologic Studies Depression Scale.
Chapter Four examines the causal effect of receiving intergenerational support in the form of both financial and instrumental support from adult children on their parents’ wellbeing, measured by self-reported health and activities of daily living. Using the Indonesia Family Life Survey and instrumental variable strategy, the findings reveal a significant positive impact of receiving support on parental wellbeing. This effect is driven primarily by financial transfers. The effect varies by parents’ gender, age group, and region of residence. The mechanism analysis across the three chapters indicates that intergenerational support in its various forms and institutional and cultural settings is mostly mediated through time freedom and availability, financial relief through transfers and the exchange of knowledge-based and emotional support
Predictability and familiarity effects on top-down processing in primary visual cortex
No full textAbstract not currently available
Decolonising British higher education: underrepresentation of women academics of colour (WAC) in science, technology, engineering and mathematics (STEM) faculties
No full textThis study explores the underrepresentation of women academics of colour (WAC hereafter) in British STEM academia, building upon a substantial body of research highlighting the glaring and seemingly intractable lack of diversity within UK STEM faculties (Advance HE, 2024a; HESA, 2025a; Royal Society, 2024; WISE, 2023) and across global STEM academia that reflects a broader pattern of exclusion as documented in international reports (for e.g., UNESCO, 2023b, 2024a). Situated within the context of numerical inequity and epistemological otherness, the study explores how the career experiences of WAC are shaped by particular power relations and dynamics reflected in academic cultures and institutional practices. In particular, I sought to unpack the extent to which gendered and racial identities intersect to influence and constrain the career experiences of WAC, particularly in relation to their progression and retention in STEM. Simultaneously, I explored how WAC subvert the power of dominant discourses through micro-practices of resistance and the ‘technologies of self’ - to exercise power, negotiate and sometimes reproduce the very hegemonic cultures that serve to marginalise them. In search for answers around the underlying processes that pose barriers towards equitable representation for these women, I drew majorly on Saidian post-colonial (including other post-colonial scholars and feminist) and Foucauldian poststructuralist feminist lens to conceptualise knowledge/power relations both as a discursive force that produces epistemological binaries of East (the orientalised Other) and West (the civilisational other) and as fluid, discursively constructed, and temporally relational. This allowed for an analysis that shifts subjective narratives to a structural understanding of how broader institutional cultures and practices serve to perpetuate inequities along gender and ‘race’ lines, informing an analysis of the ways in which discursive practices, potentially linked to epistemologically orientalist power dynamics, shape and influence the conduct of WAC in STEM spaces, and how they are constituted as subjects of knowledge. Methodologically, the study is grounded in an interpretivist onto-epistemology, employing a qualitative research approach through 17 semi-structured online interviews (15 with WAC and two with senior faculty members) facilitated through timeline maps designed to foreground participants’ agency in shaping the trajectory of the research focus as well as enabling a nuanced understanding of pivotal moments, institutional dynamics, and identity negotiations that shaped their career trajectories. Drawing on a mix of thematic and discourse analysis, the findings of the study are underpinned by four overarching themes that revolve around intersecting discourses that shape the marginalisation of WAC in STEM, including dynamics of tokenistic visibility, the masculinisation of scientific identity, institutional penalties linked to care and partnership, and the tension of negotiation of belonging. Together, these findings foreground how gendered and racialised structures constrain career progression while also producing ambivalent forms of resistance that both challenge and, at times, inadvertently reproduce exclusionary norms
Examination of role and function of the Coiled-Coil domain of φC31 integrase
Full text linkφC31 Integrase (Int) is a recombinase enzyme used by the φC31 bacteriophage to integrate its DNA into the chromosome of a host bacterium at initiation of the lysogenic cycle. The enzyme has several useful properties, such as strong recombination site specificity, high reaction efficiency in optimal conditions and unidirectionality of the recombination, which can be reversed in the presence of a Recombination Directionality Factor (RDF) - a secondary protein factor. For those reasons, it (and other related integrases from the Large Serine Recombinase (LSR) family) have been used in biotechnological and genetic applications, such as targeted insertion/excision of large DNA fragments.
Despite this interest in the applications of the enzyme, the biochemistry underlying properties of its activity is still not fully understood and is under ongoing examination, especially with regard to directionality control. During the forward reaction φC31 Int targets and forms a synapse on a heterologous pair of sites called attP and attB, forming hybrid sites attL and attR as products of the reaction. The presence of RDF allows φC31 Int to form a synapse on attL and attR sites and inhibits synapse formation at attP and attB, resulting in a reverse reaction. Several structural studies in closely related LSRs have provided evidence of involvement of the Coiled-Coil (CC) domain (located near the C-terminus of the φC31 Int, between residues G445 and A531) in the formation of a tetrameric complex during synapse formation. This could mean that CC domain interactions are part of the control mechanism for φC31 Int reaction directionality.
This project aims to expand the knowledge on φC31 Int reaction specificity and directionality by examining several point mutations in the CC domain. Residues of interest were chosen based on sequence alignments with other LSRs, and are thought to be analogous to residues responsible for CC-CC interactions during formation of the synaptic complex in those LSRs. Information on their role in φC31 Int activity and specificity could be important for understanding the biochemistry of the enzyme, and subsequently could help unlock the ability to create designer versions with altered properties for genetic engineering and synthetic biology applications.
Mutants of L474 and Y475 residues, as well as a complete CC deletion (ΔCC) variant were produced. Other identified residues of interest included L468, L471, E472, V487, H491, F492, R493, Q496, L499, T500 and E507. In vitro assays for reaction efficiency (including tests with att sites associated with different LSRs to check for site specificity disruptions) as well as synaptic binding (including experiments with unorthodox att site pairings), were conducted for the produced mutants. The alanine mutant of L474 showed some activity, albeit reduced in comparison with wild-type. Y475A and ΔCC mutants were unable to facilitate the recombination reaction under any conditions, cementing the view that the CC domain is vital during the synapsis, as well as confirming the suspicion that Y475-mediated interactions are important to CC domain function. Interestingly, the Y475H mutant showed activity in a forward reaction, which may imply that the interactions this residue takes part in are at least partially dependent on the shape and size of the tyrosine sidechain. However, it was almost completely inactive on attL x attR substrates, suggesting that its polarity might be important for interactions enabling the reverse reaction. All active mutants retained high site specificity
A heuristic for the distribution of ray class groups of number fields
Full text linkWe propose a conjecture for the distribution of the ‘good part’ of the ray class group ClK(m) of a number field K, for K running over a natural family of Galois extensions of a fixed base number field F and fixed modulus m given by an integral ideal of OF. It can be seen as a generalisation of earlier conjectures by Pagano–Sofos for the family of imaginary quadratic number fields and by Bartel–Pagano for the family of real quadratic number fields. Our conjecture is phrased in terms of the Arakelov ray class sequence of a number field introduced by Bartel–Pagano and postulates that the ‘good part’ of the latter behaves randomly in the sense of Cohen–Lenstra. To be able to state it, we develop a commensurability theory for automorphism groups of chain complexes, extending the commensurability theory of Bartel–Lenstra for automorphism groups of modules.
We show that our conjecture implies the Cohen–Lenstra–Martinet heuristics as reformulated by Bartel–Lenstra and predicts equidistribution of the reduction map O × K → (OK/m) ×. We further obtain from our conjecture a general formula for the average ℓ-torsion, ℓ a good prime, of ClK(m) in families of abelian extensions. We explicitly calculate the predicted average ℓ-torsion of ray class groups of cyclic cubic fields with fixed rational modulus for ℓ ̸= 2, 3
Transcriptomic and glycobiological profiling of synovial fibroblasts in rheumatoid arthritis: the role of sialylation in fibroblast-macrophage crosstalk
Full text linkRheumatoid arthritis (RA) is a chronic autoimmune disease in which synovial fibroblasts (SFs) and macrophages perpetuate inflammation and tissue destruction. While immune cell directed therapies are effective, treatment resistance underscores the importance of stromal contributions. Glycosylation, particularly sialylation, has emerged as a key regulatory mechanism in stromal-immune crosstalk.
Here, we investigated the role of sialylation in shaping SF function and macrophage responses. Bulk RNA sequencing of human RA synovia revealed TNF-α driven remodelling of glycosylation pathways, with upregulation of ST3GAL family members, indicating a pro–α2-3 bias in inflamed fibroblasts. Single-cell RNA-seq mapped these alterations to discrete fibroblast subsets and linked them to lectin receptor expression in tissue-resident macrophages, including Siglecs and Galectins.
Using an in vitro desialylation model, we demonstrated that selective removal of α2-3 sialic acids reprogrammed SFs toward a pro-inflammatory phenotype, enhancing cytokine secretion. Conditioned media from these fibroblasts induced M1-like polarisation of bone marrow derived macrophages, with increased Il1b, Nos2, CD80/CD86, and pathway enrichment for TNF and NF-κB signalling, In contrast, broad α2-3/α2-6 cleavage elicited mixed macrophage responses, while less α2-3 linked sialic acid removal had minimal effects. Protein-level analyses confirmed increased PD-L1 in macrophages exposed to desialylated fibroblast supernatants.
These findings identify stromal sialylation as a molecular checkpoint regulating joint inflammation. Loss of α2-3 sialylation above certain thresholds functions as a pro-inflammatory switch in SFs, amplifying macrophage activation and sustaining chronic inflammation. Targeting stromal glycosylation offers a potential therapeutic avenue and biomarker strategy in RA
Direct cell to cell spread of influenza A viruses
Full text linkInfluenza A viruses (IAVs) continue to cause widespread morbidity and mortality across the globe, driven by their evolutionary capacity to evade immune responses and adapt to spread between diverse hosts. Despite extensive surveillance of population-level transmission, the mechanisms governing IAV spread between individual cells within infected tissues remain incompletely understood. The intercellular spread of IAVs can either occur by the release of virus particles or by the transfer of viral genomes directly between cells (direct cell to cell spread). Infection by extracellular viruses is well-studied, but the importance and wider implications of direct cell to cell spread during IAV infection is unclear. To investigate this, I first established tissue culture models in which I could quantify the frequency of IAV direct cell to cell spread. I show that, even in the presence of drugs that completely inhibit extracellular virus spread, up to 40% of IAV infected cells are able to infect their neighbours, an effect that was consistent between IAV strains with different virion morphologies. Direct cell to cell spread of IAVs can occur by the induction of intercellular membrane connections known as tunnelling nanotube-like structures (TLSs), which are capable of trafficking the viral genome between cells. I show that TLSs are formed by IAV infected cells in vivo, and used in vitro models to ask how IAVs induce their formation. I found that TLS formation is not induced by cytokine signalling from infected to uninfected cells, but induction requires intracellular IAV replication. I therefore looked at the intracellular responses to infection and found that the ability of IAVs to drive TLS formation can be modulated by chemically inhibiting, or inducing apoptosis. I then found that inhibiting apoptosis, which prevents IAVs from inducing TLSs, lead to a significant reduction in the ability of IAVs to directly spread between distant cells. Interestingly, I found that direct cell to cell contacts allow uninfected cells to suppress apoptosis of neighbouring infected cells, with data revealing a potential role of uninfected cell mitochondrial transfer to infected cells. The results of this thesis, which suggest that IAVs efficiently perform direct cell to cell spread and control their ability to so through a regulation of host cell apoptosis, identifies a new way in which a virus can manipulate its host to evade antiviral immune responses, ensuring its continued spread even within the restrictive environment of the respiratory tract
Assessments for arterial toxicity in patients receiving systemic anti-cancer therapies
Full text linkCardiovascular (CV) toxicity is a recognised complication of numerous anticancer treatment regimens. Many cancer therapies may be associated with arterial injury. The mechanism underlying arterial toxicity from cancer treatment is not well understood and the risk may be underappreciated. Immune checkpoint inhibitors (ICI) are an effective anticancer therapy that may be associated with atherothrombotic events such as myocardial infarction (MI) and ischaemic stroke. It is proposed that ICIs induce T-cell infiltration into plaque leading to inflammatory atheroma and plaque rupture. ICIs are used in combination with vascular endothelial growth factor inhibitors (VEGFI). VEGFI alone are associated with hypertension, heart failure and MI. It is unclear if the combination of drug classes has an additive effect on atherothrombosis and ischaemic events. ICI-associated atherothrombosis is supported by basic science and observational retrospective studies. This association has not been observed in randomised clinical trials. Trial design within oncological studies may not be suitable to adequately capture CV events and trial participants may not be representative of the population seen in clinical practice. The true risk, if any, of ischaemic events with ICI is not yet known.
Inflammation plays a role in the development of numerous CV conditions and may be relevant in arterial toxicity from anticancer treatments. While cardiotoxicity is a well-known side effect of anthracyclines, they are also associated with arterial injury. Inflammation is implicated in development of anthracycline cardiotoxicity but the role of inflammation in anthracycline associated arterial injury is not yet known.
Fluorodeoxyglucose positron emission tomography computed tomography [18F]FDG-PETCT is a metabolic imaging technique used for assessment of arterial inflammation and is a surrogate marker of inflammatory atheroma. Quantitative assessment of arterial uptake is performed using the maximal tissue-to-background ratio (TBRmax). Inflammation assessment should be performed using specific imaging parameters. The European Association of Nuclear Medicine (EANM) provided recommendations on how PET protocols should be performed in 2016. However, these recommendations may be out of date with the advances in PET technology, such as the advent of digital PET scanners. The optimal parameters for assessment of arterial inflammation by contemporary digital PET scanners are not well-defined, nor are methods for comparing one PET-CT protocol to another.
[18F]FDG-PETCT may offer mechanistic insight into the possible association of ICI and ischaemic events. [18F]FDG-PETCT assessment of ICI associated arterial inflammation has been previously assessed in small retrospective studies with conflicting results. There have been no prospective studies. No study has assessed the potential additive effect of VEGFI combined with ICI on arterial inflammation.
Aims
The aims of my thesis were: 1) to assess how trial eligibility criteria and CV adverse event (CVAE) reporting may impair the ability to capture CV safety data in ICI+VEGFI combination therapy trials; 2) to assess whether anthracycline exposure is associated with large artery inflammation, measured by [18F]FDGPETCT, in a retrospective analysis of a cohort of patients with lymphoma; 3) to compare current international recommendations for imaging protocols for arterial assessment by [18F]FDG-PETCT in comparison to a locally optimised protocol; 4) to make a prospective assessment of the effect of ICI on arterial inflammatory activity, and; 5) to compare arterial inflammatory effects in patients receiving ICI+VEGFI versus ICI monotherapy and VEGFI monotherapy.
Methods
A systematic review of randomised controlled trials of combination ICI+VEGFI therapy was performed. I assessed data relating to trial eligibility criteria and CVAE reporting. I subsequently performed a retrospective analysis of clinically indicated [18F]FDG-PETCT scans to compare large artery inflammation before and after completion of anthracycline-based chemotherapy. A locally optimised PET imaging protocol was designed and compared with EANM recommendations for arterial inflammation assessment in order to inform the design of my prospective PET-CT study. Novel metrics to quantifiably compare imaging protocols were used for assessment, such as mean contrast recovery (MCR), coefficient of variation (CoV), and error. A prospective observational study of patients with cancer receiving either VEGFI, ICI or ICI+VEGFI was performed. Arterial inflammation was assessed using [18F]FDG-PETCT before and after 24- weeks of therapy. The primary outcome was the change in TBRmax at 24-weeks from baseline in ICI+VEGFI vs monotherapy. Biomarker analyses were also performed.
Results
In the review of 17 trials with 10,313 participants, there was broad CV eligibility criteria using heterogenous definitions of CV disease. No trial published baseline CV characteristics of participants. Reporting of CVAE was inconsistent and subject to incidence thresholds. No trial reported the absence of CVAEs. In 16 trials, AEs were investigator reported without centralised adjudication.
I observed no change in arterial [18F]FDG uptake in patients with lymphoma treated with anthracycline chemotherapy, compared with pre-treatment scans.
Current international recommendations for arterial inflammation assessment by [18F]FDG-PETCT are not applicable to modern digital PETCT scanners. Fewer reconstruction parameters (iterations and subsets) are required for optimal imaging, than recommended by EANM.
In the first prospective study of ICI and large artery inflammation, 55 patients were enrolled (VEGF: n=15; ICI: n=20; VEGFI+ICI: n=20), mean age was 66±10 years, 29% female. CV risk factors were highly prevalent and comparable in all groups. Compared to pre-treatment, at 24 weeks TBRmax had not increased in any group (baseline vs 24 weeks, VEGFI: 1.72±0.2 vs 1.72+0.2; ICI: 1.71±0.1 vs 1.67±0.1; VEGFI+ICI: 1.74±0.2 vs 1.64±0.2). There was no difference in the change of TBRmax over time between groups (p=0.13). The results were consistent when accounting for potential heterogeneity, including clinical characteristics (such as pre-existing CV disease) and arterial characteristics (such as calcification vs none).
Conclusion
Arterial toxicity from anticancer therapies is poorly understood and limitations within oncological efficacy trials impairs accurate capture and quantification of CV toxicity in ICI+VEGFI regimens. The heterogeneity in defining and reporting CVAE, in a population where prevalence of CV disease is unknown, limits understanding of the incidence and severity of events relating to these combinations. [18F]FDG-PETCT analysis did not reveal an association between anthracycline exposure and large artery inflammation. If anthracyclines are associated with arterial injury, this could occur through a non-inflammatory process. Current international recommendations for assessment of large artery inflammation by [18F]FDG-PETCT are not applicable to modern digital PET scanners but metrics, such as MCR, CoV and error, are valuable methods to quantifiably compare imaging protocols. When assessed in a prospective study, ICI exposure was not associated with large artery inflammation, when assessed by [18F]FDG-PETCT, compared to baseline, when used alone or in combination with VEGFI.
Standardisation within the design and reporting of randomised clinical trials and mechanistic PET research are required to truly elucidate the potential association, between ICIs and atherothrombotic events before risk stratification and therapeutic strategies can be developed
SARS-CoV-2 seroepidemiology across urban and rural cohorts in Malawi: a longitudinal study.
No full textAbstract not currently available
Failing the herd: how resistance and counterfeit drugs undermine Trypanosomosis control
No full textAbstract not currently available
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