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A holistic study of the effect of the murine microbiome on metabolism and systemic inflammation using integrated molecular imaging technologies
Get PDFInflammatory bowel disease (IBD) is a multifactorial disease involving genetic susceptibility, impaired barrier function, alterations in the microbiome, and a dysfunctional immune response. Current therapeutic treatments are aimed at controlling symptoms; however, symptoms recur, and patients can become susceptible to infection, increasing the need for new treatments. There has been a growing interest in the role host-microbe interactions play in the development of IBD and many studies have uncovered distinct shifts in small molecule classes in patients compared to healthy controls. Microbial and host small molecules are able to interact with host immune cells and polarize them towards either a pro- or anti-inflammatory phenotype. This immunometabolism/ immunomodulation is an emerging concept that plays an important role in human health and disease. Furthermore, IBD patients frequently experience extraintestinal manifestations, commonly affecting organs such as the liver, lung, eyes, kidney, and spleen, and often results in a loss of proper function. The cause of systemic inflammation is still poorly understood; however, studies have suggested that small molecules originating from the intestinal bacterial community may play a role. Firstly, we aimed to discover small molecular changes in the intestine (ileum and colon) and systemic sites (liver and eye) in a mouse model after infection with an IBD associated pathobiont, adherent-invasive Escherichia coli (AIEC). We applied a powerful analytical technique known as mass spectrometry imaging (MSI) to map the spatial distribution and relative abundance of molecules across a sample surface in a label-free manner. This allows the distribution of known and unknown molecules including proteins, metabolites, and lipids to be determined. Our infectious mouse model revealed specific molecular changes across the different organs that were either microbial or host derived, and many play a role in the onset or perpetuation of inflammation. Despite, producing informative host-microbe interaction data, results of this proof-of-concept study were not fully reflective of human IBD. Therefore, we investigated metabolomic adaptation in intestinal and systemic sites in a dextran sodium sulphate (DSS) mouse model. This model has been shown to reflect human disease, including disrupted barrier function, microbial dysbiosis and immune cell dysregulation. MSI revealed 30 molecules in the colon, 88 molecules in the ileum, 239 molecules in the liver, 65 molecules in the spleen and 16 molecules in the kidney differed in abundance between DSS colitis and uninflamed control mice. This study confirmed the identity of some intestinal molecules including creatine, docosahexaenoic acid (DHA), and 1- methylnicotinamide (1-MNA). However, identifying the location and abundance of specific molecules does not provide an overall assessment of the tissue environment that may lead to inflammation. Therefore, we applied imaging mass cytometry (IMC) to tissue regions of interest (ROI), where molecules of interest had been located. IMC found markers such as CD4 and major histocompatibility complex class II (MHCII) were decreased in the inflamed ileum, whereas CD4 and others (e.g. NKp46, granzyme B) were increased in the inflamed colon compared to the control. Hence, our study combined two imaging technologies to gain a better understanding of how region-specific molecules may be influencing the immunological profile in the ileum, colon, and liver. Rheumatoid arthritis (RA) is another inflammatory condition with a poorly understood aetiology and has been linked to IBD. We applied MSI and IMC to investigate metabolomic and immunological changes in a mouse model of RA, collagen induced arthritis (CIA). We found 9 molecules in the lung, 3 molecules in the kidney, 2 molecules in the liver, and 16 molecules in the spleen could differentiate between diseased and non-diseased mice. In the lung, only one molecule was increased in the diseased group compared to the control groups and was identified as lysophosphatidylcholine 18:0 (LysoPC 18:0). IMC revealed cells expressing the markers B220 and CD19 (B cells) were increased in the lung of CIA mice compared to controls. Therefore, LysoPC (18:0) may promote the recruitment of B cells in the lung. As microbes play an important role in immune priming and homeostasis, this study wanted to identify metabolomic and immune profile differences in mice with (specific pathogen free) and without (germ-free) a microbiome. MSI revealed 9 molecules in the colon, 1 molecule in the ileum, 255 molecules in the liver, 5 molecules in the spleen and kidney, and 6 molecules in the lung that discriminate between germ-free (GF) and specific pathogen free (SPF) mice. We were able to confirm the identity of two polyamine molecules, spermidine and spermine, that were decreased in the SPF liver compared to GF liver. In vitro experimentation showed that spermidine reduced the percentage of macrophages expressing MHCII in a dose dependent manner. Impaired macrophage MHCII expression has been linked to dysfunctional adaptive immune activation; thus, reducing spermidine might be a microbial adaptation to support the development of the adaptive immune response. This study highlights the usefulness of MSI and IMC as metabolomic and immunological discovery tools that can be used together to identify how molecules and cells within an environment may be interacting under different conditions. This allows us to hypothesise and test various host-microbe and immunometabolism mechanisms that may be implicated in inflammatory processes during IBD and RA
Atomic layer deposition for superconducting quantum detectors
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Galician colour semantics: An investigation of basic colour terms
Get PDFThis thesis explores the basic colour categories in Galician, a minority language spoken in the northwest of the Iberian Peninsula that has been increasingly impacted by diglossic language contact with Spanish over the last century.
This study collected data from two age groups: the oldest speakers available, who were generally less affected by language contact with Spanish, and young adults, who were bilingual and the first generation schooled in Standard Galician. All participants reported having Galician as their everyday language. Data was collected from 98 participants from 11 collection points across Galicia seeking a balanced sample of the Galician speaking population and their dialects.
Results were extremely heterogeneous across and within age and gender subgroups. Nevertheless, some general trends have been identified. Consensus was much lower among elderly participants. Elderly males showed diverse categorisation patterns which ranged from distributions with fewer and more comprehensive categories (e.g. RED+ORANGE, YELLOW+ORANGE, PINK+ORANGE and even BLUE+PURPLE) to systems with more categories and more restrictive denotations. Elderly females presented similar categorisation patterns but tended to be ahead in the process of developing unitary categories, especially ORANGE. Young males had the highest consensus by generally presenting the classic 11 basic colour categories. Although young females agreed, some were developing new partitions such as LILAC.
The categorisation patterns attested across the age groups generally align with the Universals and Evolution (UE) model’s premises of partition and a series of predictable trajectories. The data, however, reveals the existence of extreme variation: members of the same generation can be several evolutionary stages apart and present different partition strategies for the same hue. Moreover, this thesis has uncovered a new possibility for the development of ORANGE. Instead of partitioning unitary ORANGE directly from MACRORED, there may be an intermediary stage PINK+ORANGE.
The labelling strategies for these categories were highly variable, particularly for RED and PURPLE. This variation is not frequently attested in colour semantics and highlights the importance of factors such as a) lack of — or recent — standardisation, b) the impact of language contact and c) the instability of labels when partition is not complete (ORANGE) but also much later after the category is consolidated (PURPLE).
This thesis shows the relevance of sociolinguistics, linguistic background and repertoire when collecting, processing and analysing data. Moreover, a new methodology is proposed to deal with this complex data: a series of increasingly comprehensive levels that allows an operational analysis without reducing the rich phenomena the data reports
Multiphysics simulation of drug-coated balloon deployment and drug delivery
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Plume regolith interaction in lunar and martian conditions
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Repurposing legacy iron and steel slag: a resource potential
Get PDFThe reuse of legacy iron and steel wastes presents opportunities for resource recovery and atmospheric carbon dioxide (CO2) storage. Limited documentation of these anthropogenically derived rocks and the natural environmental processes altering slag deposits resulting in ecotoxic metal leaching pose challenges to repurposing. Increasing interest in integrating Circular Economic (CE) approaches into waste management requires a comprehensive understanding of the materials and developing innovative methods to resolve characterisation complexities. In this study, the opportunities for legacy slag are explored using the two Carnforth Iron Work deposits in Warton, South Lancashire, England that are located on the Morecambe Bay coast and ~ 435 meters (m) inland. The mineralogy and trace metal content are quantified and identified using a data-driven unsupervised learning approach from the inland deposit (A), and the lithification mechanisms and mineralogic features are identified from the coastal deposit (B).
From the inland setting deposit A, 23 sections spanning five stratigraphic horizons were analysed for microstructural compositional variation using scanning electron microscopyenergy dispersive X-ray spectrometry spectrometry (SEM-EDS). These large and highlydimensional datasets were quantified using a semi-automated approach leveraging nonnegative matrix factorisation (NMF) and Hierarchical Density-Based Spatial Clustering of Applications with Noise (HDBSCAN), the regions were segmented into mineral phases and the trace metal constitutes were quantified. The variable mineralogy and metal content between horizons reflects contemporaneous iron and steel production and possibly early iron pig production. While this approach is not fully automated, the automated dimensional reduction and clustering is a turnkey operation for processing numerous large datasets. Applying the approach on specific phases (iterative phase classification (IPC)) drove the analysis that confirmed and revealed both the microstructures and trace Ba, Fe, and Mn from the model outliers and more statistically representative phases.
At the coastal deposit B, X-Ray Diffraction (XRD) and EDS analysis of the slag and thermogravimetric analysis (TGA) of the cream-coloured material covering the slag shows lithification on the top surface and seaward side above the mean high-water mark (MHWM) is the result of carbonate mineralisation. This is driven by water and leached calcium from weathering slag minerals (i.e., gehlenite, åkermanite, pseudowollastonite) reacting with ingassed and hydroxylated atmospheric CO2, forming calcite with slightly to strongly depleted δ13C values (-6.4 ‰ to -22.7 ‰) following partial dissolved inorganic carbonate (DIC) equilibrium. Calcium-silicate-hydrate (CSH), a component in cement, precipitated and was responsible for lithifying the deposit where more frequent and abundant seawater washing prevents subsequent slag mineral dissolution and carbonate precipitation.
The trace Ba, Fe, and Mn quantified at deposit A and the carbonate and CSH precipitation identified at deposit B are evidence that legacy iron and steel slag deposits can be sources of critical raw materials (CRM) and are prone to lithification in coastal settings. The iterative approach utilising machine learning provides a tool for locating hidden and nonmajority component regions, enhancing microstructural analysis. This lithification can draw down atmospheric CO2 and the CSH precipitation could help to slow the release of toxic metals, reducing the environmental contamination risk of repurposing legacy slag for ‘hard’ protection and coastal defence. Considering how the environment affects industrial waste deposit evolution can elucidate the most appropriate and safest slag repurposing option between CRM recovery, atmospheric CO2 storage, and coastal defence
Electrochemical evaluation of organic semiconductors for device applications
No full textAbstract not currently available
A global policy in local context/a local policy in global context: investigating dual VET youth transitions in Coahuila, Mexico
Get PDFIn recent decades, a global agenda has developed to promote apprenticeships as an educational policy solution of near universal relevance. Among such models, dual vocational education and training (dVET) is often considered the ‘gold standard’. As such, there has been intense activity to ‘transfer’ dVET from DACH countries (Austria, Germany, Switzerland) to elsewhere, including many low- and middle-income country (LMIC) contexts. Mexico is one such LMIC to have adopted dVET, in a process explicitly brokered by German co-operation actors. In 2013, the Modelo Mexicano de Formación Dual (MMFD) was piloted in 11 states, expanding over the proceeding decade.
This thesis identifies and addresses important gaps in research knowledge about ‘transferred’ dVET models of this kind, advancing theory about how dVET functions in LMIC contexts based on empirical research that centres the experiences and insights of young policy participants. Three waves of qualitative longitudinal interviewing were conducted with 16 MMFD participants (n=48) in the state of Coahuila, Mexico between February 2020 and February 2022. The Grammars of Youth framework developed by Ana Miranda and colleagues at FLACSO Argentina is used to conceptualise and explain the structures and strategies that mediate MMFD youth transitions.
Theoretically, the thesis extends the Grammars of Youth framework to develop a typology of grammars – i.e. structures – that mediate youth transitions, namely: subjective, temporal, and locational grammars. Subjective grammars relate to the influence of young people’s intersecting social identities, temporal grammars relate to the specific time context in which youth transitions unfold, producing distinct cohort effects, and locational grammars relate to the multi-scalar sociospatial contexts in which young people construct their transitions. In addition, this thesis also explains how and why MMFD participants employ different youth pragmatics – i.e. strategies – in their transitions and, thus, how grammars and pragmatics co-construct one another over time.
This rich and contextualised understanding of MMFD youth transitions is used to analyse MMFD policy features and suggest future policy directions to make dual training more effective and equitable. Furthermore, the ‘local’ case of the MMFD is used to scrutinise the discursive claims of the ‘global apprenticeship agenda’. Theories and assumptions about how apprenticeships function are found to be troubled by the contextual realities in which policy participants live, particularly in LMICs. These inconsistencies contain important risks related to inequalities, exploitative practices, and programme ineffectiveness. Greater attention to the lives and desires of young people as the embodied protagonists of dVET is argued to be a crucial means of counteracting those risks and pursuing an expanded vision of what vocational education can achieve
Echoes of peace: Qatar’s manoeuvres in the Israeli–Palestinian conflict (1995–2013)
No full textAbstract not currently available
The Orpheus complex: Understanding cinema through Maurice Blanchot
Get PDFThis dissertation conceptualises the Orpheus complex as a way to understand the nature of the cinematic image and the pleasure of spectatorship. It uncovers the potential of Blanchot’s philosophy of literature to elucidate cinema, taking his exegesis of the myth of Orpheus as its point of departure. Blanchot’s philosophy of literature and his deconstruction of narcissism were unpacked to elucidate his notion of the Orphic gaze. This was, then, put into dialogue with two differing theories of the gaze in cinema, namely Mulvey’s theory of an identificatory male gaze and Derrida’s theory of the visor effect. This revealed that a misidentification lies at the heart of the theory of specular recognition, in cinema, and that a sense of haunting permeates the cinematic experience. This notion was then applied to the case study, Paris, Texas (1984), which contemplates identity and loss, through a storyline resembling the orphic myth. This offered a new way of understanding the film as a symptom and rumination on the Orpheus complex. Moreover, the film was shown to be a self-reflexive study of the cinematic image, which opened up for a consideration of the Orpheus complex within the cinematic image, at large. This led to the conclusion that spectatorship is characterised by a dissociated gaze and the desire to look at images is reflective of a compulsion toward fascination, which come together to form the Orpheus complex
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