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Stealing metals like a pro(tozoan): ironing out metal acquisition and host manipulation in Toxoplasma gondii
Full text linkTransition metals, including iron and zinc, are indispensable metals for almost all life. They play essential roles as cofactors for enzymes involved in a range of biological processes, including DNA replication and metabolism. Toxoplasma gondii is a ubiquitous obligate intracellular apicomplexan parasite which requires iron and zinc for survival. However, in excess, these metals are toxic. Thus, T. gondii has to regulate the uptake of iron and zinc to maintain homeostasis and avoid metal toxicity. Many organisms acquire divalent metals, including iron and zinc, from the environment through an evolutionary conserved family of proteins; Zrt/Irt-like (ZIP) proteins. At the start of my PhD, the mechanisms by which T. gondii acquired these essential metals was not known. The main focus of this work is on the functional characterisation of TGME49_261720, one of the four ZIPdomain containing proteins predicted to be encoded by the T. gondii genome, which we called ZFT (Zn and Fe transporter).
In this thesis, I demonstrate that ZFT localises to the plasma membrane of the parasite and is essential for the replication of T. gondii. I found that the localisation and expression of ZFT is dynamic and dependent on iron and vacuolarstage. I show that overexpression of ZFT leads to a growth defect, and parasites become hypersensitive to excess iron and zinc although protected from iron chelation. I demonstrate that loss of growth upon ZFT knockdown cannot be rescued by either excess iron or zinc, suggesting that ZFT’s function is not redundant in the parasite. Loss of ZFT leads to altered morphology of the apicoplast - although function is maintained - and inhibits mitochondrial respiration, linked to decreased expression of the mitochondrial Fe-S cluster protein SDHB and activity of complex IV of the mitochondrial electron transport chain. ZFT knockdown triggers the partial differentiation of parasites to a more quiescent lifecycle stage. Importantly, I demonstrate that the expression of TgZFT in a yeast model complements the loss of zinc transporter activity, supporting the role of ZFT as a zinc transporter in T. gondii. Finally, I show that knocking down ZFT results in a decrease in parasite-associated iron and zinc, confirming ZFT transporter activity in Toxoplasma gondii.
However, as an intracellular pathogen, Toxoplasma acquires iron from its host cell. At the start of my PhD, little was known about the mechanisms by which T. gondii infection impacts host cell iron homeostasis. Thus, the second aim of my PhD project was to start to understand if and how T. gondii manipulates host cell iron homeostasis and trafficking by examining proteins involved in iron homeostasis in the host cell, in the context of infection.
Here, I found changes in expression of proteins involved in host iron acquisition (TfR and DMT1) upon infection in both human fibroblasts and murine macrophages, although no changes in iron storage (FTH1) were observed. I show that infected fibroblasts and macrophages take up significantly more transferrin following T. gondii infection. However, whether these changes are host- or parasite-driven is not yet known, and further work is required to elucidate this. In high iron conditions, I show that DMT1 expression levels are maintained in both cell types compared to uninfected/untreated. TfR expression levels are maintained in fibroblasts but are reduced in macrophages, suggesting differences in iron homeostasis between the two cell types. Finally, I demonstrate that the T. gondii zft 3’ UTR confers iron responsiveness in fibroblasts but not in macrophages, further suggesting differences in iron handling between the two cell types.
Overall, I have characterised the first iron and zinc uptake transporter in Toxoplasma gondii, identifying the major pathway for the acquisition of these metals by the parasite. Moreover, I demonstrated that infection with T. gondii leads to changes in the expression of iron-related proteins in fibroblasts and macrophages. This work emphasises the importance of both iron and zinc to Toxoplasma gondii and for their ability to survive and persist within the host
Contemporary material performance in Turkey and Lebanon: puppetry as a political-geographic tool
No full textAbstract not currently available
When accountability breaks down: socio-material assemblages in COVID-19 governance
Full text linkThis study investigates the enactment and reconfiguration of accountability in the context of everyday community governance during the COVID-19 pandemic in an urban Chinese community. Much of the existing literature conceptualises accountability in hierarchical, institutional, and human-centred terms, treating it as either a mechanism of control by the state or a compliance response by citizens. A critical engagement with these literatures reveals a gap: the complex ways in which accountability is dynamically produced through the entanglement of human and non-human actors, technologies, and affective forces are underexplored. To address this, the central research question guiding this study is: How is accountability enacted, distributed, and reassembled through socio-material networks during a public health emergency? Subsidiary questions further explore how technologies, legal devices, and community practices contribute to the formation and destabilisation of accountability relations, and what these processes reveal about the nature of governance under crisis conditions.
Actor–Network Theory (ANT) was adopted both as a theoretical lens and as a methodological strategy. ANT’s utility lies in its insistence that no single actor—whether state, law, technology, or community—possesses pre-given explanatory power. Instead, agency and accountability emerge from the associations between heterogeneous elements. This theoretical move is particularly productive for a pandemic context, where accountability was not simply a matter of state directives or citizen compliance, but of how mobile phone health codes, quarantine seals, WeChat groups, policy documents, community workers, and residents were assembled into shifting networks. By “following the actors,” ANT makes it possible to capture accountability not as a stable institutional arrangement but as a fragile and contingent socio-material accomplishment. ANT also enables a rethinking of responsibility beyond normative categories of duty or liability, showing how accountability is enacted performatively, through translations, negotiations, and displacements among diverse actors.
Methodologically, the study employs a qualitative case study design. Data were generated over the course of the pandemic through ethnographic observation, semi-structured interviews, digital ethnography, and inscription analysis. This multi-method approach was chosen to capture the temporal unfolding of accountability relations and the multiplicity of sites—physical and digital—where they were negotiated. Ethnographic observations traced the rhythms of community life and the mundane practices of surveillance, compliance, and care. Interviews with residents and community workers surfaced perceptions of fairness, responsibility, and trust. Digital ethnography followed the circulation of accountability discourses in WeChat groups and online forums, while inscription analysis mapped how policy documents, notices, and seals codified responsibilities. Together, these methods operationalised ANT’s methodological imperative to track associations and translations across time and space, producing a richly textured account of pandemic governance.
The findings show that accountability was not a fixed attribute of institutions or individuals but an emergent, performative achievement. Non-human actors—health codes, quarantine seals, and algorithmic rating systems—were not merely instruments but constitutive participants in accountability practices, shifting responsibility and visibility among different actors. Affective forces such as fear, fatigue, and care animated these networks, influencing their stability and transformations. For example, while fear initially reinforced compliance with surveillance technologies, over time care and solidarity among residents generated new grassroots practices of accountability that partially displaced formal structures. When official systems faltered, these localised practices—sharing food, mutual monitoring, and informal coordination—temporarily stabilised governance.
These findings directly address the research questions by demonstrating how accountability was enacted through socio-material networks rather than imposed from above. They highlight the relational and contingent character of accountability: it is made and remade through negotiations between technological artefacts, legal discourses, human actors, and affective intensities. The study thus challenges the assumption that accountability can be reduced to hierarchical command or institutional design. Instead, it shows how accountability in crises is co-produced through fragile networks that are always at risk of breakdown.
The contribution of this research is threefold. First, it advances critical accounting scholarship by foregrounding the mundane, affective, and material dimensions of accountability, moving beyond static or instrumental accounts. Second, it extends public sector governance studies by demonstrating how accountability emerges not simply from state–citizen binaries but from distributed networks that include digital infrastructures and non-human mediators. Third, it enriches ANT itself by illustrating its capacity to capture the temporal, affective, and socio-material processes of crisis governance, while also revealing its limitations in addressing normative concerns about justice and responsibility. Ultimately, the study argues that effective accountability in crises does not depend on perfect systems of surveillance or formal legal controls, but on adaptive, caring, and materially attentive practices. This has implications for both theory and policy: theorists are urged to reconceptualise accountability as a socio-material performance rather than an institutional arrangement, while policymakers should recognise that resilient governance depends on supporting flexible, community-based forms of accountability rather than relying solely on top-down mechanisms
Understanding the intersection of signalling pathways between apoptosis and cellular senescence
No full textAbstract not currently available
Investigating the effects of hypoxia on the sphingolipid system and adiponectin in adipocytes and perivascular adipose tissue
Full text linkPerivascular adipose tissue (PVAT) exerts important paracrine control over vascular tone, but how acute hypoxia impacts upon PVAT signalling and vascular reactivity remains incompletely understood. Hypoxia is central to adipose pathophysiology because as the volume of adipose depots expand, limited oxygen diffusion and inadequate angiogenesis create localised hypoxia that drives metabolic stress, inflammation, and altered secretion of adipokines and bioactive lipid mediators. Together with impaired perfusion responses in obesity, these changes indicate that the regulatory role of PVAT may change and hypoxia may be central to this. To address this, I combined wire myography with molecular and biochemical measurements in rat thoracic aorta and mesenteric arteries, 3T3-L1 adipocytes, and ex vivo PVAT depots exposed to normoxia and hypoxia.
Functionally, pre-exposure to hypoxia altered subsequent contractile responses to phenylephrine and relaxant responses to cromakalim in a manner dependent on vessel type, PVAT status, and endothelium; when hypoxia was applied acutely during sustained phenylephrine-induced tone, thoracic aorta relaxed robustly even without endothelium, and relaxation was significantly augmented by PVAT, supporting an endothelium-independent component mediated by PVAT-derived factors.
Adiponectin is an abundant adipocyte-derived hormone with insulin-sensitising and anti-inflammatory actions and has recognised roles in vascular homeostasis. Therefore, adiponectin content and release were measured in 3T3-L1 adipocytes and in thoracic and mesenteric PVAT to determine if acute hypoxia alters PVATderived adiponectin and whether these changes could account for hypoxiainduced vascular relaxation. Adiponectin studies showed that short-term hypoxia reduced adiponectin protein and Adipoq mRNA in 3T3-L1 adipocytes and lowered adiponectin in thoracic but not mesenteric PVAT; under normoxic conditions, thoracic PVAT exhibited higher basal adiponectin protein content than mesenteric PVAT, and a trend toward increased release during hypoxia. Pharmacological manipulation revealed that, with PVAT present, neither β3-adrenoceptor agonist nor AdipoR1 blockade altered hypoxic relaxation; in PVAT-removed endotheliumintact rings, β3-agonism (CL-316,243) attenuated relaxation, indicating an inhibitory endothelial β3 pathway unmasked by PVAT removal. An exploratory adipokine array indicated broader hypoxia-induced reductions in several factors secreted from thoracic PVAT.
Sphingosine-1-phosphate is a PVAT-derived bioactive lipid produced by SphK1 that regulates vascular tone and plays key roles in cardiovascular and immune function. Hence, after observing that acute hypoxia induces relaxation with PVAT present, S1P was investigated as a candidate mediator linking hypoxia to vessel responses. SphK/S1P experiments demonstrated that hypoxia selectively and transiently increased SphK1 mRNA and SphK1 phosphorylation in adipocytes, while a short exposure to gas hypoxia did not change SphK1 protein or tissue S1P in PVAT. Thoracic PVAT released less S1P under hypoxia. Inhibition of SphK1 with PF543 reduced S1P release under normoxia and further decreased it under hypoxia, consistent with SphK1-driven S1P export from PVAT. Conversely, mesenteric PVAT showed no effect of PF543 or hypoxia on SphK1 or S1P release. Thus, the hypoxic reduction in S1P release was depot specific. Exogenous S1P or selective S1P2 activation (CYM 5478) reduced hypoxic relaxation only when PVAT was absent, suggesting that S1P/S1P2 can limit relaxation of the vessel wall but this is masked by PVAT factors when PVAT is present.
Collectively, these data show that acute hypoxia induces a PVAT-enhanced, largely endothelium-independent vasorelaxation while rapidly altering adiponectin and S1P signals. When PVAT is present, adiponectin and β3 agonism are not the dominant acute mediators of hypoxic relaxation, and S1P/S1P2 opposes relaxation primarily when PVAT support is removed. These findings refine the mechanistic understanding of PVAT to vessel crosstalk under hypoxic stress and point to PVAT factors as key acute effectors
Assessment of the correlation between patients with a unilateral cleft lip and palate (UCLP) and non-cleft individuals regarding the duration and speed of maximum smile using 4d imaging
Full text linkIn a cleft lip and palate (CLP), the upper lip and palate fail to develop correctly during embryological development. CLP is managed by surgical interventions; cleft lip repairs, nasal reconstruction and revision procedures. Asymmetry is noted in the nasolabial region (Hallac et al., 2017), due to scarring, muscular pull and underdeveloped muscles around the cleft causing weakness or muscular imbalance which can cause profound psychosocial impact (Yezioro-Rubinsky et al., 2020).
Scar revision during childhood can minimise the psychosocial impact (Tan and Pigott, 1993) and restore function to facial muscles. The decision for revision surgery is currently based on subjective evaluation of limitations by a surgeon. Objective quantification of dynamic motion with 4D imaging could allow comparison of different treatments, monitor patients for worsening and guide future intervention. Each expression has specific muscle groups that undergo contraction and relaxation during different phases of movement. Some of these muscles are surgically corrected during repair and others are relatively untouched.
This study aims to objectively assess dynamic dysmorphology from rest to maximum smile with 4D imaging for individuals with a unilateral cleft lip and palate (UCLP) and unaffected individuals, to improve quality of care and treatment for patients with UCLP. The impact that residual scarring has on expression speed during the maximum smile was also investigated. Maximum smile for the two groups were compared, 31 UCLP patients (13-17yrs) and 34 control participants. Nine landmarks were used; 6 paired landmarks to analyse lip motion, cheilion, crista philtri and lower lip and 3 landmarks to minimize head motion. Different phases of the smile were assessed; onset, apex and offset and the speed for the individuals to reach maximum smile. Comparison allows differences between groups and intrapersonal differences between right and left to be identified.
Results show UCLP participants have longer onset and offset (contraction and relaxation) phases and a longer smile duration (2.02 secs) than unaffected individuals (1.33 secs). There was measurable asymmetry in philtrum magnitude and speeds between the two sides in UCLP participants with the cleft side significantly slower (7.24mm/s) than the unaffected side (8.22mm/s). Although the same pattern was seen for cheilion magnitude and speed, this did not reach statistical significance (cleft side 28.69 mm/s, non-cleft side 32.05 mm/s). In contrast the cleft side had significantly greater magnitude and speeds at the lower lip (20.98mm/s) than the non-affected side (19.22mm/s). Asymmetric movement on the lower lip is due to distorted muscle dynamics, secondary to the asymmetric upper lip muscles during expression phases. Less muscular development on the cleft side causes weakness, reduced control and tension from scarring limits upper lip movement, causing the lower lip to compensate for the deficit. Control participants had no significant speed or magnitude differences for the landmarks on opposing sides, indicating no discernible asymmetry.
During maximum smile, all landmarks on the cleft side exhibited slower speeds than control participants (cheilion 34.89 mm/s slower, philtrum 14.53 mm/s slower, lower lip 18.1 mm/s slower). This was also reflected for the UCLP participant’s unaffected side (Cheilion 37.71 mm/s slower, philtrum 12.21 mm/s slower, lower lip 21.14 mm/s slower) when compared to individuals without a cleft. Indicating restriction in muscular activity on both sides regardless of which side is affected by the cleft.
The odds of having reduced speeds at the cheilion are 87% higher when a cleft is present and it is 3 times more likely to have slower speeds at the philtrum on the cleft side than in an unaffected individual. Unlike other landmarks, the lower lip is faster on the side affected by the cleft than the unaffected individuals
"You need to have a break": exploring young people's experiences of wellbeing, leisure and creativity in the school holidays
Full text linkPrevious research on school holidays has focused predominantly on quantitatively measuring education and health outcomes, drawing conclusions that school holidays lead to ‘learning loss’ or negatively impact on health. However, there are significant limitations of this existing research and a lack of research engaging directly with young people or employing a qualitative approach. This research has therefore sought to qualitatively explore how young people experience these periods, how this affects their wellbeing, and how engagement in creative activities interacts with these experiences. By employing a theoretical framework combining Childhood Studies and the Capabilities Approach, it examined the substantive freedoms young people have to achieve what they value, and the role that school holidays play in them doing so.
Data were generated with young people aged 10-16 in Greater Glasgow through ‘enhanced’ interviews (artefact-elicitation and creative tasks), focus groups with young people engaged in community arts organisations and interviews with staff in these organisations. Data were analysed using reflexive thematic analysis. The analysis of the findings presented in this thesis argues that school holidays can benefit young people’s wellbeing primarily through the enhancement of their agency, and the subsequent choices young people can make to achieve the things they value both in the present, and for their futures. The findings highlight the importance of free, self-directed time, and balanced facilitation from adults who acknowledge and support young people’s agency. This research demonstrates the value of studying school holidays as a distinct period, rather than a comparator to school term, but also highlights some of the challenges young people face at school, and from which they value a break. Future school holidays research should aim to expand understanding of young people’s lived experiences in different social and geographical contexts and consider their impact not only in terms of future outcomes but on young people’s experience of the present. Similarly, provision of care during school holidays should seek to be informed more directly by the perspectives of young people and give consideration to what is of value to young people in the present, as well as for their future. Community arts organisations, and similar youth-centred organisations, are highlighted in this research as a valuable asset to supporting young people’s wellbeing in school holidays, and beyond
Spectral fluorescence lifetime imaging for the quantification of biomarkers in the retina
No full textAbstract not currently available
Development of spatio-temporal data fusion frameworks for point and gridded soil moisture data
Full text linkMonitoring soil moisture can play an important role in helping to inform researchers, regulators, and landowners about the available water content of the soil for agriculture and vegetation. However, the capacity to observe soil moisture is constrained by practical and financial limitations, making it challenging to observe continuously across space and time. We can only monitor soil moisture at a finite number of spatial locations and time points. One of the most accurate methods for measuring soil moisture is to use in-situ sensors. However, the high cost of deploying these sensors extensively means that soil moisture data tends to be collected from a sparse network of monitoring points.
Given the limited in-situ sensor data, it becomes essential to explore the benefits of utilising other data sources, such as satellite data, by developing and using data fusion techniques. Data fusion allows for the integration of different data sources, enhancing the ability to make informed decisions and understand environmental phenomena with more precision, despite the limited direct monitoring of soil moisture.
The research question is motivated by the in-situ soil-moisture data provided by SEPA in Elliot Water and the satellite images provided by Copernicus. It is necessary to develop a data-fusion method for point data and gridded data, so that the accuracy of the in-situ data can be combined with spatial and temporal information from satellite data to generate a fine-resolution map with uncertainty quantification.
This thesis introduces three INLA-based data-fusion methods in Chapter 3, 4, and 5, which include a spatio-temporal regression with misaligned covariates, a spatial data fusion method, and a spatio-temporal data fusion method. A comprehensive simulation study varies sensor density, grid resolution, percentages of missing grid data, and temporal window length k. Across scenarios, joint fusion consistently outperforms point-only and grid-only baselines in RMSE. This thesis also introduces an XGBoost-based constrained ensemble method with conformal prediction in Chapter 6, developed to merge in-situ point and satellite gridded data under different spatio-temporal supports.
This thesis presents the background, motivation, model development, and application of the novel data fusion methods, addressing the gap in the literature by accounting for spatio-temporal change-of-support problems. Results are presented throughout to demonstrate the use of the data fusion model in soil moisture data
At the frontier of immunology: exploring cellular crosstalk across time and space
Full text linkCellular interactions underpin all biological processes and offer unprecedented insight into mechanisms of action in steady state and disease. The advent of single-cell and spatial technologies has allowed us to resolve these interactions across time and space unveiling novel pathways in infectious and inflammatory disease, yet interpretation and visualisation remains challenging in these multi-faceted high-dimensional datasets. This thesis develops and applies computational and visual approaches to infer, prioritise, and validate cell–cell communication (CCI) in such contexts, demonstrating leveraging spatial information allows us to hone in on biological hypotheses and reduces false positives in ligand–receptor analyses. In Chapter 1, I analyse lethal COVID-19 in a Malawian cohort using histology, high-dimensional imaging, and single-cell transcriptomics from lung, blood, and nasal tissues, integrated with datasets from Northern Hemisphere cohorts. This cellular interaction analysis reveals distinct immune drivers in our cohort: an interferongamma programme in lung-resident alveolar macrophages in Malawi contrasted with type I/III interferon responses in blood-derived monocytes reported in USA/European cohorts. These results provide mechanistic insight into fatal disease in an under-represented population, and highlight the value of context-aware cellular inference and validation. In Chapter 2, I introduce cellXplore, a Flask–React interactive visualisation web tool that unifies widely used CCI packages and leverages single cell RNA sequencing with spatial transcriptomics to investigate computed cellular interactions. Through interactive, point-and-click workflows, cellXplore streamlines analysis, allowing customisable interactive plots, and prioritises spatially plausible interactions by overlaying ligand–receptor expression with co-localisation of spatial gene expression. I present three end-to-end user workflows using single cell and spatial transcriptomics data from a 10X Visium parasitic infection and a 10X Xenium breast cancer dataset to show indirect spatial validation of cellular interactions can be utilised in a user-friendly manner. Lastly in Chapter 3, I extend cellular communication inference to complex datasets, validating cellular interactions and key drivers of inflammation leveraging immunohistochemistry and spatial transcriptomics. A multifactor macrophage–fibroblast atlas spanning four tissues and inflammatory states reveals conserved tissue-resident myeloid–stromal circuits through a APOE+/SPARC+ - SPP1+ axis that underpins inflammation alongside tissue-specific crosstalk reflecting organ microenvironments. A second study applies 10X Visium to intestine ’gut-rolls’ across four time points of Heligmosomoides polygyrus infection. The analysis uncovers epithelial and immune programs associated with granuloma formation, stem-cell reprogramming, and parasite driven immunomodulation within a distorted tissue landscape, with cellular interactions validated in the spatial context. Together, these studies shine a spotlight on the power of spatially-aware cellular interaction inference providing insight into COVID-19, tissue-resident myeloid–stromal communication during inflammation, and helminth infection in addition to a novel visualisation tool to unlock new insights from cellular interaction data
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