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Appraising novel host and gut microbial interactions at Inflammatory Bowel Disease onset: Exploring the role of galectins and the microbiome
No full textInflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of increasing prevalence. Its aetiological basis is multifactorial, with interactions between the host immune system and gut microbiota, alongside genetic and environmental factors of key importance. Despite our increasing understanding, the consistent delivery of early diagnosis and the development of biomarkers that can predict disease course to facilitate timely personalised treatment both remain elusive.
In this thesis, I explore what is known about the gastrointestinal microbiome at IBD onset, alongside our current understanding of the immune functions of a group of proteins, beta-galactoside binding lectins, and how they relate to IBD. This is achieved via systematic review and meta-analysis relating to the microbiome, and a literature review concerning galectins.
I describe the cross-site implementation of a novel rapid-access pathway for IBD diagnosis in one of the largest NHS trusts in the UK and explore how current clinical tools can be better utilised for referral triage, resource allocation and more detailed baseline assessment. I present a comprehensive prospective analysis of how best to utilise the clinical history and tools such as Faecal Calprotectin (FCP) to optimally triage referrals. Furthermore, I introduce the first validation of the IBD Disk as a means of screening for significant psychological disturbance, whilst also identifying those at risk of adverse treatment outcomes.
Patients recruited to research from this clinical pathway provided faecal samples to allow the detailed evaluation of the treatment-naïve gut microbiome using both 16S ribosomal RNA (rRNA) sequencing and shotgun metagenomics. I have integrated this dataset with published pre-treatment IBD microbiome data to present the largest analysis of the role of microbiome at IBD onset in the literature to date. The longitudinal follow up and outcome data from our own Birmingham cohort has allowed us to build up on the findings from the pooled dataset and demonstrate novel microbial associations with disease activity, disability, and treatment outcomes.
In this same patient cohort, I have undertaken the first study of serum galectin levels in IBD patients prior to the initiation of treatment. This study has elucidated the close association of baseline galectin-9 levels to disease severity and subsequent treatment response, outperforming established clinical indices in this regard. I have, for the first time, integrated serum galectin expression with the gut microbiome at IBD onset, both in terms of overall diversity and enrichment or depletion of specific bacterial taxa. For example, serum galectin-9 levels positively correlate with the abundance of established pathobionts including Ruminococcus gnavus. I have developed models of this integrated data able to accurately predict the subsequent failure of conventional therapies in patients presenting with IBD.
The studies performed in this thesis contribute to the ongoing efforts to deliver earlier and personalised care to patients presenting with IBD. I aim to build upon the data presented through my ongoing research objectives, such as with targeting microbiome intervention, as I embark upon my consultant career
Re-classifying Iron Age marsh-forts
No full textMarsh-forts, as they currently stand, are a relatively poorly understood class of archaeological site. They have been consigned to a sub-category of hillfort using a descriptive criterion based on proximity to a generalising view of ‘wetland’. In doing so, we have lost sight of much of their nuance. Sites currently within this category often share little in common. This thesis re-examines these sites by integrating site morphology, landscape, and environmental analysis, causing us to rethink current classificatory models.
This research compiles a gazetteer of thirty-four sites previously classified as ‘marsh-forts’. Beginning with a re-examination of each site, this thesis reflects on our current understanding of each site, incorporating earlier investigations and building upon them by applying current archaeological theory, GIS analysis, and new field observations. The resulting summaries focus on the architecture of the enclosures and their relationship with the surrounding wetland and dryland environments, as well as commenting on the evidence for internal activity where it is available. In doing so, this research highlights the disparate levels of archaeological investigations across these sites, ranging from extensive excavations published in monographs to sites whose known existence is dependent on vague antiquarian commentary. These assessments identify thirteen sites where geoarchaeological investigations were required to develop our understanding of the sites. The subsequent borehole surveys determined the nature, extent, date and condition of any wetland deposits. The results of this work broaden our understanding of specific sites and, in some cases, call into question pre-existing and long-held beliefs about their environments.
This thesis concludes by addressing the two primary research aims: to refine and provide a detailed understanding of ‘marsh-forts’ and to reconsider the classificatory framework for archaeological sites. The study refines the initial thirty-four candidate sites, identifying sites which have been incorrectly attributed to this classification, recognising alternative landscape focuses besides wetland (e.g. river-associated enclosures) and producing a new framework for marsh-forts which reflects a range of site-landscape interaction and relationships. This culminates in the distinction of ‘marsh-forts’ and ‘forts in marshes’; the former referring to a more symbolic wetland-oriented category of site, the latter to a more functional interaction. In doing so, the culminating analysis identifies a range of social and environmental nuances, which allow us to better understand past people. Through this analysis, the thesis serves as an example of a new model of archaeological site classification based on interpretive rather than descriptive terminology. It proposes a new rationale based on features such as ‘directionality’, visibility, accessibility, connectivity and segregation. This new model integrates the natural environment within the cultural/historic as a fundamental part of our understanding. In realising this, we can improve our interpretation of heritage assets and develop new heritage management practices that recognise the importance of preserving natural and human environments as a single entity
A neo-Aristotelian theory of emulation: Implications for cultivating teacher character through role modelling
Full text linkThis thesis expounds a new theory of emulation qua moral role modelling and suggests how it could be applied as a method of virtuous character development in the professional context of teaching. Through a synthesis of reconstructed neo-Aristotelian virtue ethics, current developmental moral psychology and qualitative empirical insights, it builds upon work by eminent philosophers, psychologists and educationists to enhance the understanding of what emulation is, conceptually speaking, and how it works as a developmental process. My central argument addresses how the methodological tensions surrounding emulation are grounded in a category mistake: the misconceptualisation of emulation as merely an emotion, rather than, as I argue, a moral virtue in its own right. Predominantly composed of virtuous emotion and necessarily entailing virtuous action, I thus propose a componential account of the virtue of emulation, which I synthesise with Aristotle’s theory of causation: the four causes. Historically revered for their explanatory power, I argue that appeal to the four causes enables one to better understand emulation as a quadripartite causal process. Through doing so, I make visible the importance of phronesis to emulation and accordingly introduce a new concept – entangled phronesis – as the psycho-moral mechanism which underpins it. As entangled phronesis works differently according to a learner’s phase of virtuous character development, I also divide emulation into two types: pre-phronetic ‘habituated emulation’ and phronetically-informed ‘complete emulation’. In the naturalistic spirit of the thesis, I then refine and extend the main concepts pertaining to this philosophical argument by aligning them with insights from developmental moral psychology and neuroscience. The result: a philosophically discerning, psychologically realistic and developmentally adequate theory of emulation. Having expounded the moral philosophy and moral psychology of emulation, the thesis then takes a more applied turn into the professional ethics education of teachers. Here, I build a normative case for phronimoi teacher role models, i.e., experienced teachers as role models to more novice teachers, which I frame as a moral developmental solution to the threshold problem – the issue that many teachers do not meet the phronetic standard required to be role models to pupils. This then fuels an empirical case study on teachers who actually are moral role models to early carer teachers. The results of the study illuminate the salience of phronesis to the emulative process and motivate sustained interest in emulation qua role modelling as a method of moral virtue and phronesis development in teachers
Human Cardiac Age-OME. A multi-facet approach to understanding healthy ageing of the heart
No full textThe world’s population is ageing, expecting individuals over 65 to represent 38% of the total population by 2050705. As lifestyle and medical practices have improved and one’s life expectancy is longer, comorbidities associated with ageing are also expected to raise healthcare costs in the near future. This can limit access to appropriate medical treatments and introduce further disparities in healthcare accessibility due to one’s socio-economic background556. Older age is a strong risk factor for cardiac morbidity and cardiovascular diseases, including heart failure, one of the leading causes of death. Furthermore, those who survive cardiomyopathies can often be left with disabilities, which would exert financial and
socioeconomic impacts on themselves, family members and the community. The increase in cardiovascular diseases partially attributed to ageing has set a novel and challenging goal for the scientific community: understanding how cardiac tissues age. Although aged hearts might not develop cardiomyopathies, their functionality, shape, histology and molecular composition decrease over time. Frailty of the cardiac muscle is developed around the age of 50, where mortality for cardiovascular diseases arises for both genders. On the other hand, mortality due to non-congenital cardiovascular diseases is almost negligible for young individuals, usually aged between 12 and 25. Utilising a unique set of pre-mortem, cryopreserved, non-diseased human hearts, we analysed the molecular landscape (transcripts, proteins, metabolites and lipids) in young (≤ 25 years old) and old (≥ 50 years old) donors to characterise human cardiac ageing. Analysing all the molecules using multiple biostatistical and mathematical methods, including a novel framework for analysing biological networks and a newly engineered method for detecting dysregulated biological processes, we observed a downregulation of proteins involved in calcium signalling, such as SERCA, decreased abundance in key proteins of the contractile apparatus, like myosin heavy chain, in older hearts. In addition, we found a potential counteractive upregulation of central carbon metabolism, an increase of long-chain fatty acids, and possible dysregulation of the β-oxidation in older individuals. This is the first study on the molecular data set of normal human cardiac ageing, which, coupled with the innovative omics methods, enhances our understanding of the development of age-related heart diseases
Investigating the MADS-box protein family in the fern Ceratopteris richardii
No full textThe family of transcription factors known as MADS-box proteins is found across all land plants, with multiple MADS-box encoding genes per species. In flowering plants such as Arabidopsis thaliana a subset of MADS-box proteins regulates the development of flowers and seeds, binding to each other following the ‘ABCDE’ floral model to specify the identities of each organ type. These functions are thus important to food security because seeds are staple foods globally. MADS-box gene functions remain uncategorised in non-flowering plants, with no corresponding model to the ‘ABCDE’ found in flowering plants. How MADS-box floral functions evolved is largely unknown. This can be determined by studying MADS-box gene functions in nonflowering plants. The model fern Ceratopteris richardii falls into the sister clade of all seed-bearing plants and is an ideal candidate to investigate MADS-box genes in a non-flowering plant because gene functions can also now be tested directly in this species.
The phylogenetic data presented in this thesis suggests the MADS-box protein family present in C. richardii reflects the relationships observed by the MADS-box protein family of A. thaliana. The expression data shows differing expression between developmental stages, despite previous studies suggesting a ubiquitous expression of MADS-box proteins in non-seed plants. Protein-protein interactions within the MADS-box protein family in this thesis suggest no interaction contradicting the interactions observed in flowering plants and within the ‘ABCDE’ model. This thesis provides novel insights into the relationship, expression, and interactions of MADSbox proteins in C. richardii. The work in this thesis offers a starting point for future investigation into MADS-box proteins in non-seed plants
Microflora derived whey protein compared to dairy-derived whey protein on muscular adaptations to lower limb resistance training in healthy young adults
Full text linkBackground:
Individuals and athletes alike require a higher habitual protein intake to support muscular adaptations in response to resistance training (RT). Many non-animal protein alternatives are typically associated with reduced anabolic potential, compared to animal derived protein sources. With the rising popularity of animal-free diets, researchers are faced with the challenge of investigating novel protein alternatives that are more sustainable. Microflora derived whey protein has a similar composition to traditional dairy, promising a lower carbon footprint and more efficient production process, relative to traditional dairy derived whey. Research to date has not yet revealed whether a novel microflora derived whey protein alternative can comparatively support muscular adaptations to RT.
Aims:
This study aimed to compare muscular adaptations following the ingestion of microflora derived non animal whey protein, against an animal derived whey protein.
Methods:
In a randomised double blinded control trial, 23 healthy young adults (23 ± 5 yr), were allocated to receive either microflora derived whey or a dairy whey supplement. Participants completed a high load (>60% 1RM) lower body focussed resistance training program, three times a week, for 8 weeks. Ultrasonography to evaluate muscle architecture, and muscle strength (isokinetic knee extension and 1RM strength for each exercise) were recorded at baseline, week 5, and week 8 post intervention. Measures of 1-RM and ultrasound were analysed using 2 way repeated measures ANOVA in SPSS (version 29, IBM SPSS, Armonk, NY USA). Mean peak torque of MVC measures across both visits were analysed using a paired sample T test to evaluate statistically significant differences between test and retest values.
Results:
The results show that 1RM and MVC increased after the 8-week lower body focussed resistance training intervention. There was a statistically significant increase in MVC from baseline (389 ± 132 Nm) in group A, and (464 ± 147 Nm) in group B compared to week 8 (397 ± 101 Nm) and (484 ± 165 Nm; P<0.01) in group A and B respectively. Overall, measures of MVC demonstrated a greater increase in group B than group A. There was no significant difference in measures of muscle architecture from baseline to week 8. Measures of pennation angle showed no significant difference in group A (17 ± 3°) and group B (18 ± 3°) at week 8. Fascicle length decreased in both group A (91 ± 18mm), and group B (86 ± 7mm). Muscle thickness remained constant from baseline to week 8 in group A (27 ± 4mm), and group B (28 ± 5mm).
Conclusions:
Amongst a healthy young adult population, ingestion of microflora derived, and standard animal-based whey protein comparatively support increases in muscular strength, facilitating muscular adaptation in response to lower body focussed RT. Overall, there is evidence of a significant time effect on strength in both groups, shown by increases in MVC and 1-RM output following the training protocol for 8 weeks compared to baseline. However, no significant difference in measures of muscle architecture, as a marker of muscle hypertrophy suggests that the extent of muscular hypertrophy achieved during the study remains to be determined
Museum resilience: the impact of the Covid-19 pandemic on the independent museums in the UK
Full text linkSince the coronavirus swept across the globe, the cultural and creative sectors worldwide have faced unprecedented challenges in terms of financial revenue, public safety and staff wellbeing, and museums are no exception. Therefore, the impact of Covid-19 pandemic on the museums and strategies for navigating these institutions within such a shifting social environment has been the central concern within the UK museum sector. This thesis scrutinizes the impact of the Covid-19 pandemic on independent museums in the UK and explores how the independent museum sector has responded to these challenges in the light of museum resilience. This thesis delves into both the conceptual underpinnings and practical applications of the concept of museum resilience in the context of the independent museum sector during the Covid-19 pandemic from 2020 to 2023.
To capture data relating to the research question, this thesis has employed a multi-method qualitative research methodology, incorporating methods of secondary research, surveys, case studies, and semi- structured interviews. With the assistance of the Association of Independent Museums, this research received 207 survey responses from museum professionals across the independent museum sector in the UK. Additionally, thirteen distinctive independent museums participated as case study museums.
Inspired by the conceptual roots of resilience in ecological literature, this research adopts an ecosystem framework to analyse the research data. This ecosystem comprises diverse stakeholders such as independent museums, governmental bodies, professional organizations, and museum communities. This thesis evaluates the functioning of each stakeholder within this ecosystem during the Covid-19 pandemic, investigating their interconnections. As a result, it furnishes a comprehensive perspective for understanding the dynamics of the independent museum sector in the context of the Covid-19 pandemic.
In doing so, this research yields insights into the impact of the Covid-19 pandemic on independent museums and their responses, encompassing financial, institutional, and emotional dimensions. First, it details the impact of the Covid-19 pandemic on the financial stability of independent museums and then it explores the combined effect of financial pressure on institutional decision-making regarding operations, staffing, and long-term strategy. It also discerns the emotional impact of the Covid-19 pandemic on museum workers, such as worries, loneliness, and exhaustion. More importantly, this thesis provides numerous examples of efforts made by the independent museum sector to mitigate the impact of the pandemic, which involve a bundle of strategies to boost museum finances, re-engage museum audiences, and alleviate staff emotional stress. By analysing these responsive strategies, this thesis examines the notion of museum resilience within the context of the crisis induced by the Covid-19 pandemic, offering a more detailed interpretation of what it means for a museum to be resilient.
This thesis reveals that the lockdown caused by Covid-19 pandemic significantly reduced ticket sales, retail, and catering revenues for many independent museums in the UK. Although visitor numbers gradually recovered as museums reopened, these institutions continued to face financial pressure to enhance online services and ensure on-site safety in the post-pandemic era. Thanks to the function of public grants, the financial impact of the pandemic did not lead to widespread permanent closures of independent museums in the UK. However, the loss of volunteers, the gap of digitalization between different museums, and the dilemma between promoting staff welfare and navigating financial constraints could pose future survival risks for these museums. Additionally, the pandemic took a toll on museum staff’s mental health, leading to anxiety, loneliness, and fatigue, which may present potential challenges in the future. Moreover, external risks such as climate change, geopolitical instability, and inflation further exacerbate the challenges faced by the independent museum sector in the UK. Therefore, enhancing museum resilience has become more critical than ever.
This study, through analysing various cases, posits that museum resilience is a combination of the defensive ability to avoid destructive failure, consistency in upholding the museum’s core mission, the flexibility to mobilize resources, and the progressive power to achieve greater goals. This research provides a forward-looking perspective for future museum management studies, as the threat of the Covid-19 pandemic may have diminished, but potential museum crises have not disappeared. Beyond its focus on museology, this research presents successful crisis response strategies, serving as a resource for professionals in the cultural sector. These professionals can enhance their understanding and draw lessons from the experiences of independent museums
Constructive and predicative locale theory in univalent foundations
Full text linkWe develop locale theory constructively and predicatively in univalent foundations (also known as homotopy type theory or HoTT/UF), with a particular focus on the theory of spectral and Stone locales. The constructivity of our foundational setting means that we do not use any classical principles such as the axiom of choice (or any of its weaker forms), the law of excluded middle, or any form of the limited principle of omniscience. In the context of univalent foundations, predicativity refers specifically to the development of mathematics without the use of Voevodsky’s propositional resizing axioms. The traditional approach to the predicative development of point-free topology is to work with presentations of locales known as formal topologies. Here, we take a different approach: we work directly with frames and locales, keeping careful track of the universes involved and adopting certain size assumptions to ensure that the theory is amenable to predicative development. Although it initially appears that many fundamental constructions of locale theory rely on impredicativity, we show that these can be circumvented under rather natural size assumptions. Our development here is inspired by de Jong and Escardó’s constructive and predicative development of domain theory in univalent foundations.
We first lay the groundwork for the predicative development of locale theory. We then orient this towards an investigation of the theory of spectral and Stone locales, using the univalence axiom and the set replacement principle to ensure a predicatively well-behaved notion of spectral locale. We also develop Stone duality in the context of spectral locales, showing that there is a categorical equivalence between the type of large, locally small, and small-complete spectral locales and the type of small distributive lattices. Moreover, we exhibit the category of Stone locales as a coreflective subcategory of the category of spectral locales and spectral maps, using the construction known as the patch locale of a spectral locale (the localic manifestation of the so-called constructible topology). Finally, we investigate the topology of algebraic DCPOs and Scott domains in this constructive and predicative framework for locale theory. We develop the Scott locale of a Scott domain, show that it forms a spectral locale, and then proceed to investigate its patch. Using this, we obtain a topological characterization of de Jong’s notion of sharp element: we establish a correspondence between the sharp elements of a Scott domain and the points of the patch of its Scott locale.
Our development is completely formalized and has been machine-checked using the Agda proof assistant
Temperature controlled, single column, continuous hydrophobic interaction chromatography of proteins
Full text linkThe increasing clinical relevance of mAbs has necessitated a substantial scale-up in biopharmaceutical production. To address this rising demand, numerous biopharmaceutical companies have invested in large-scale manufacturing facilities employing standardised platform processes (Shulka and Gottschalk, 2013; Shukla et al., 2017). Despite the operational advantages of continuous downstream processing methods, their adoption within the industry has been limited. The primary impediments include the excessive generation of equilibration, wash, elution, and regeneration buffers, contributing to inefficiency and waste. Additionally, the mechanical and software complexities of existing continuous chromatography systems render them costly and challenging to implement. Thus, there is a clear demand for innovative technologies that can facilitate continuous processing while offering sustainable advantages, such as reduced buffer and salt consumption.
This thesis seeks to advance a continuous chromatography solution, specifically through the development and application of the TCZR system. Unlike conventional continuous chromatography approaches that typically rely on multiple columns and intricate control mechanisms, the TCZR offers a streamlined alternative, employing a single-column system with temperature modulation. Prior applications of this technology have focused
on thermo-responsive cation exchange chromatography (Müller et al., 2013; Cao, 2015), and a thermally responsive protein A mutant (Ketterer et al., 2019). In this work, we extend the utility of the TCZR to hydrophobic interaction chromatography (TCZR-HIC), broadening its application in bioprocessing.
Chapter 2 documents the materials, methods, and instrumentation used in the below results chapters. As the TCZR, chromatography methods, and analysis are closely related between these chapters, these have been documented in a stand-alone chapter to avoid redundancy.
Chapter 3 presents a new application of the TCZR using HIC. In this work, TCZR-HIC is employed to purify bovine serum albumin isocraticly, meaning that the salt concentration remains constant during both binding and elution, which contributes to the process's sustainability. A local temperature decreases of ΔΦ = 30 °C was used to facilitate protein desorption, effectively decoupling the elution process from the mobile phase composition. This setup enables continuous TCZR-HIC with a single column, offering a more sustainable and simplified alternative to traditional multi-column systems.
Chapter 4 builds upon the principles established in Chapter 3, exploring the application of TCZR-HIC to a thermally stable and commercially significant mAb, Rituximab. The feasibility of utilizing TCZR-HIC in a bioprocessing context is evaluated with Rituximab as a model system. While the technique demonstrates potential, optimal results necessitate a greater temperature deference than the current TCZR instrumentation can
achieve.
Chapter 5 summarises the findings from the preceding studies and outlines possible directions for this research. Recommendations for enhancing the TCZR system are discussed, with a focus on overcoming the limitations identified in the current setup. To conclude, this thesis aims to elucidate the capabilities of TCZR-HIC through the purification of two model proteins, BSA and Rituximab. The research expands upon the foundational work by Müller and Franzreb, demonstrating continuous single-column purification and exploring the applicability of TCZR-HIC in an industrial bioprocessing context. The findings offer promising insights into the future of sustainable continuous chromatography technologies for biopharmaceutical production
Novel metal-organic frameworks with naphthalene-diimide based linkers
Full text linkA naphthalene diimide-based ligand (DNNDI) was used to create novel lanthanide metal-organic frameworks (MOFs). The lanthanide metals used were Yb(III), Y(III), Lu(III), Er(III), and Sm(III). A simple solvothermal technique was used to create each MOF, and FTIR, SCXRD, PXRD, TGA, SEM, and UV-Vis spectroscopy were used to characterize them. All the frameworks crystalised in a similar tetragonal crystal system I41/a space group or monoclinic space group and are isostructural being built from similar rod SBUs linked by the naphthalene-diimide-based ligand. The secondary building units (SBUs) consist of M-O-C rods and MO8 polyhedra. The pyridyl nitrogen of the nicotinic acid moiety was found to be uncoordinated, providing opportunities for post-synthetic alteration of the MOFs. Host-guest studies encapsulating molecules of phenothiazine and ferrocene were synthesized, characterized and reported. Additionally, a mixed metal MOF with DNNDI linkers and the first, medium and last member of the lanthanide series (La(III), Gd(III) and Lu(III)) were synthesized and characterized by the same techniques as with the single metal lanthanide MOFs reported
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