Measuring and treating negative symptoms: developments and challenges

Abstract available at each chapter

Examining refugee educational inclusion in the UK: opportunities and challenges for Syrian students in Greater Glasgow

This thesis examines the educational inclusion of Syrian students in mainstream schools within the Greater Glasgow area, focusing on two critical aspects: (1) understanding the opportunities and challenges related to Syrian students’ educational inclusion, and (2) examining their inclusion in terms of presence, participation, and achievement. Syrian families and school educators in Greater Glasgow were invited to participate, and data was collected through semi-structured interviews with 11 parents and 15 children, as well as an online survey completed by 6 school educators. The Capability approach by Nussbaum, focusing on human development, provides the comprehensive philosophical framework for this study. Unterhalter’s concept of equity in education, which includes Equity from Below, Equity from the Middle, and Equity from Above, is also incorporated. In addition, this study utilizes the Index for Inclusion developed by Booth and Ainscow, alongside key documents from the UNESCO: ‘Reaching Out to All Learners: A Resource Pack for Supporting Inclusive Education’ and ‘A Guide for Ensuring Inclusion and Equity in Education’. Collectively, these concepts and documents form the framework for analysing the study's findings, demonstrating their relationship to or deviation from existing literature on inclusive education, the education of Syrian children, and refugee education. Qualitative data analysis was conducted using thematic analysis, guided by Braun and Clarke's methodology. The study's findings reveal a positive outlook on the educational experiences of Syrian students in Scotland. Syrian students enjoyed attending school and also harboured a genuine liking for both their schools and teachers. Parents expressed contentment with school offerings, affirming that schools effectively fulfilled their responsibilities. However, the English language barrier and insufficient measures to mitigate it pose significant challenges to the educational inclusion of Syrian students. Furthermore, disparities between the education systems of Scotland and Syria, alongside evident cultural distinctions, are apparent in the data. Analysis of the online survey data highlighted commendable efforts by educators to address diverse learner needs in classrooms, mitigating potential challenges. However, despite these positive efforts, significant barriers to inclusive education were identified, particularly for learners from refugee and asylum-seeking backgrounds. The lack of support and training for educators, coupled with insufficient resources and services in certain schools, emerged as significant obstacles to comprehensive educational inclusion

Efficient and scalable algorithms for bigraph matching

Bigraph reactive systems provide an established approach to modelling large and dynamic systems which contain both spatial and non-spatial relationships between entities, and have been used for modelling in a wide variety of research areas such as biology, networking, sensors and security. Bigraph state rewriting operations which represent temporal evolution rely upon an underlying NP-complete matching algorithm to identify pattern components to substitute, but this limits the scale and scope of bigraphs due to the computational cost and frequency of rewriting. The bigraph matching tool BigraphER relies on a Boolean satisfiability (SAT) encoding to do this, which generates an impractically large number of clauses for larger models which limits scalability and is difficult to adapt for extensions to the bigraph structure. We propose a novel and efficient algorithm for solving bigraph matching which encodes the problem as a subgraph isomorphism constraint satisfaction problem, applying additional constraints where required to model the added complexity of bigraph composition logic. This approach can be supported by any constraint programming toolkit as well as any graph solving tool which supports additional side-constraints. This approach also grants more flexibility in regards to modelling extensions to the bigraph formalism such as bigraphs with sharing and directed bigraphs. We adapt the state of the art constraint-based Glasgow Subgraph Solver tool to implement the encoded matching problem, where we observe a greater solve time of over two orders of magnitude on a variety of different real-world matching instances performed within mixed reality, protocol and conference models. We also integrate the subgraph solver into the BigraphER framework and provide further evaluation metrics when used as a component for building full-scale models. We build further upon this idea by proposing an adaptation for the McSplit algorithm for finding largest common subgraphs in order to obtain a maximum common bigraph between two agents, a novel definition which provides the means for supporting more rich and complex types of modelling in a bigraph toolkit such as performing contextual transitions for labelled transition systems and identifying bisimulations. This is implemented using a prototype solver to demonstrate the promise of this approach. These contributions substantially expand the scope of bigraph modelling tools and their applications for modeling large-scale systems

Investigating the roles of FOXO3 and FOXO4 in CLL proliferation and survival

Chronic lymphocytic leukaemia is a B-cell malignancy emanating from the aberrant growth and accumulation of monoclonal lymphocytes whose origins can be traced to naïve or mature B-cell clones. A groundbreaking study revealed a heavy reliance of CLL cells on interactions with accessory cells within a ‘tumour microenvironment’ niche that drive proliferation, survival and drug resistance. As such, a core theme in the development of novel therapies has been perturbing the activity of intrinsic signalling components that are pivotal in driving these events, such as BCR and CD40 signal inhibition with the advent of BTK inhibitors (e.g. ibrutinib). Current small molecule inhibitor therapy has revolutionised CLL treatment. Even still, patient responses and suitability for treatments are highly variable, reinforcing an unmet clinical need for tailored therapeutics to treat CLL on a patient-specific basis. Malignant cells often exploit proliferative and survival signalling components to aid their rapid, uncontrollable growth. A prime example is the PI3K-AKT-mTOR signalling axis, which is hyperactivated in most cancer contexts. This signalling axis can orchestrate proliferative and pro-survival events via downstream mTORC1/2 and AKT activity. mTOR components can promote cell growth and proliferation via a multitude of events including mTORC1-mediated translation initiation, as well as enhancing AKT activity. AKT itself can regulate the activity of several downstream substrates via phosphorylation, including FOXO transcription factors. Canonically, FOXO transcription factors mediate the expression of tumour-suppressive genes, and are negatively regulated by AKT-mediated phosphorylation and subsequent cytoplasmic sequestration. However, ever-emerging evidence (in B-cell malignancies and in the wider cancer context) suggests a bimodality to FOXO function, where they promote and/or suppress tumour progression in a context-dependent manner. Indeed, FOXO1’s tumour suppressive roles in CLL have been characterised as part of previous investigations within the group. In this work, we aimed to characterise the behaviours of the FOXO3 and FOXO4 isoforms to determine the suitability of targeting FOXO activity as a potential novel therapeutic approach in CLL. Initially, prominent FOXO3/4 expression was demonstrated in ex vivo patient samples and in MEC1 and HG3 CLL cell lines. Further investigation revealed that, while FOXO3/4 protein and gene expression were negatively regulated by TME-associated signals (BCR ligation or CD40 activation), FOXO3/4 expression persisted in CLL cell nuclear fractions, indicative of a reliance of CLL cells on constitutive FOXO3/4 activity. Furthermore, global transcriptomic analyses of primary patient samples revealed that FOXO4 is heavily regulated by mTORC1/2-mediated signals downstream of CD40 activation, demonstrating a notable association between FOXO4 and mTOR activity in CLL. This was evidenced by tight regulation of FOXO3/4 localisation by BTK and mTOR, as well as the expression of discrete FOXO target genes downstream of CD40 activation. These findings demonstrate the complexity of FOXO biology in proliferating CLL cell populations. To further characterise FOXO3/4 behaviour in CLL, we conducted shRNA-mediated knockdown of FOXO3 or FOXO4 in CLL cell lines (and primary patient samples: FOXO4). Here, we demonstrated an isoform-specific reliance of CLL cells on FOXO3/4; in both cases, viability and proliferative capacity were adversely affected. Cells lacking FOXO3 exhibited a loss of drug-mediated cell kill, while extensive investigation revealed that FOXO4 depletion sensitised CLL cells to multiple targeted agents including AZD8055, ibrutinib and venetoclax. Further investigation identified that FOXO4 depletion increased CLL cell susceptibility to DNA damage, coincident with the aberrant expression of GADD45A and BCL2 family members, as well as a dysregulation of mTORC1/2 signalling components; the latter perhaps due to a lack of FOXO4-mediated SESN3 expression. Together, these findings improve our understanding of the characteristics of FOXO transcription factors in CLL, demonstrating their ability to exhibit discrete behaviours and orchestrate distinct cellular functions. We argue that, while they are inextricably regulated by TME-associated signals and may facilitate tumour-suppressive effects, FOXO transcription factors are also required to promote CLL cell proliferation, survival and drug resistance in a context- and isoform-dependent manner. These data have the capacity to contribute to future pre-clinical investigation as well as the consideration of novel therapeutic strategies in CLL and in the wider context of malignancy

Investigating drug resistance in RAS-driven models of colon cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the world, accounting for more than 900,000 deaths in 2020. A disproportionate number of these deaths are due to KRAS-mutant CRCs, which account for ~40% of all CRC cases and are notoriously resistant to most therapies. Despite showing great promise in preclinical studies, targeted therapies have performed sub-optimally in clinical trials for KRAS mutant cancers. The mechanisms by which RAS pathway inhibitors have failed to reduce tumour progression remains poorly understood and presents a huge clinically unmet need. This research addresses the significant gap in effective treatments for KRAS-mutant CRC by delving into the mechanisms underlying drug resistance, using advanced CRC models. Several studies have reported that drug resistance is an emergent feature of genetically complex tumours. To capture tumour genome complexity, I used a diverse panel of CRC models reflecting multigenic and heterogeneous nature of tumours. Our patient-specific Drosophila avatars and transgenic mouse models are designed to explore how genome complexity impacts drug response. Our models comprise alterations in at least three primary pathways implicated in CRCs– APC, KRAS and TP53, providing a robust platform for studying the cellular and molecular dynamics driven by oncogenic Ras signalling. Key findings demonstrate that CRC tumour complexity significantly impacts the efficacy of RAS-pathway inhibitors, which have shown limited success clinically. By characterizing these models, this research has uncovered that different stages of tumour development exhibit varying dependencies on the MAPK pathway, offering insights into the failure of existing therapies. Additionally, the study identifies and validates the upregulation of the glucuronidation detoxification pathway as a novel resistance mechanism, showing that targeted combination therapies can enhance drug efficacy within tumours. This comprehensive study not only deepens the understanding of CRC pathogenesis and resistance mechanisms but also opens avenues for developing more effective targeted therapies

Inclusive Pedagogy: exploring faculty perceptions and professional development needs at a North American Catholic university

This interpretivist study examines the perceptions and practices of Inclusive Pedagogy among academic staff (faculty) at a North American Catholic university, as well as their professional development needs pertaining to Inclusive Pedagogy implementations. Theoretical interpretations and practical recommendations for Inclusive Pedagogy abound (Moriña, 2020a; Stentiford & Koutsouris, 2021), while many practitioners in higher education lack initial teacher preparation (a reality fourteen out of twenty-three participants described). Using a theoretically flexible heuristic and a conceptual framework of Beliefs, Knowledge, and Actions (Gale et al., 2017; Moriña, 2020a; Rouse, 2008), I conducted semi-structured interviews with the methodological aid of coaching techniques. I analysed the data using Reflective Thematic Analysis (Braun & Clarke, 2021b) supported by NVivo 14. The findings from the qualitative interviews were rich and complex. Participants shared a wealth of (often divergent) perspectives, some of which were consonant with Inclusive Pedagogy literature, and many that were novel. Participants expressed theoretical and normative frameworks, as well as personal convictions that add new complexity to possible conceptualisations of Inclusive Pedagogy. Despite unfamiliarity with the term “inclusive pedagogy” (13/23 participants), many described practices and pedagogical sensibilities that could be described as “inclusive.” Participants shared a range of professional development needs, though (a lack of) Pedagogical Fluency was the most pronounced theme. Finally, I found that the use of coaching techniques, specifically OARS of motivational interviewing (Rosengren, 2017), propelled participant ideation and enhanced my data collection method of semi-structured interviewing. Participant data can inform future conceptualisations of Inclusive Pedagogy and the degree to which the term is understood or even be useful in furthering its purpose. Based on the intersection of previous research and this study’s findings, I provide practical recommendations for educational developers, faculty, and institutions. Chief among these are: providing ongoing HE teacher development through general and discipline-specific support, organisational incentivisation of pedagogy, and a holistic, multi-layered approach to implementing Inclusive Pedagogy

Encountering windows and mirrors in the diaspora: using Young Adult literature to explore the stories and counterstories of Asian American and British ESEA young people

Historically, stories have often been used to marginalize and misrepresent the Other and to disseminate stereotypes in society (Said, 2003; Adichie, 2009; Ramdarshan Bold, 2019a). This is particularly harmful for BIPOC young people who rarely see themselves represented in stories, as the lack of representation creates a version of reality which excludes them entirely (Saha, 2021). Thus, it is crucial for stories to include both ‘windows’ and ‘mirrors’ which can truthfully capture the complexity and diversity of the world in which we live (Bishop, 1990). Young Adult literature can provide some of these necessary ‘windows’ and ‘mirrors,’ especially for young people who are seeking stories that are relevant, relatable, and can provide counterstories that work against the deficit messages of society (Alsup, 2003; Cart, 2008; Hughes-Hassell, 2013; Ramdarshan Bold and Phillips, 2019). However, the field of YA is still lacking when it comes to nuanced representation, especially regarding Asian American and British ESEA (East and Southeast Asian) stories. British ESEA stories are particularly invisible, even when compared to Asian American stories, with British Chinese stories making up only 0.3% of children’s fiction in 2020 and 2021 (Centre for Literacy in Primary Education, 2021, 2022). This is partly due to the historical differences between Asian American and British ESEA communities, as the Asian American community has a far longer tradition of community-building, political organising, and panethnic coalitions (Benton and Gomez, 2008; Lee, 2015). The impact of these historical divergences can not only be seen in YA but also in Asian American and British ESEA young people themselves, especially in their perceptions of their own diasporic, hybrid identities and the knowledge (or lack thereof) of their communal histories in the US and the UK. This thesis sits at the centre of these theoretical threads, pulling them together in the form of an asynchronous, online book club for Asian American and British ESEA young people where they discussed representative YA from the US and the UK. Several insights were generated over the course of the book club, as participants wrestled with difficult topics such as intergenerational and intercultural family relationships, feelings of ‘identity flux,’ ESEA stereotypes, the insidious ‘single story,’ and whether it is possible to create a better world. There were also striking differences between the US and the UK participants that became clear, which I attempted to contextualise within the disparate histories of each community. In the end, several important findings emerged from this study regarding the importance of representation (and the harm of misrepresentation) across the diaspora, as well as the power of YA to create a space for young people to explore and understand their identities and the identities of others. It is crucial to note that this book club did not reveal any absolute truths about Asian American and British ESEA young people; rather, it only provided a safe space for a multiplicity of opinions, identities, and stories to be honestly discussed and exchanged. Ultimately, this study has highlighted the need for more such spaces for Asian American and British ESEA young people, where they can negotiate their hybrid identities and have the chance to define themselves

Clara Schumann, concert programming and the formation of canons: An examination of the relationship between Clara Schumann’s concert programming and the formation of musical canons in Leipzig, Vienna and London

This thesis examines the public performing career of Clara Schumann in Leipzig, Vienna and London through her concert programmes and the critical response to her performances. The development of her programmes and the understanding of them by critics is used to inform our understanding of Clara Schumann’s particular influence on the development of musical canons in these three cities, and to examine the way in which canons developed differently in these locations. This thesis has been helped enormously by the generosity of Reinhard Kopiez, Andreas Lehmann and Janina Klassen, in allowing me access to their database of Clara Schumann’s playbills created for their 2009 article ‘Clara Schumann's collections of playbills: a historiometric analysis of life-span development, mobility, and repertoire canonization’

Local solubility of a family of quadric surfaces over a biprojective base

We prove an asymptotic formula for the number of everywhere locally soluble diagonal quadric surfaces 𝑦₀𝑥²₀+𝑦₁𝑥²₁+𝑦₂𝑥²₂+𝑦₃𝑥²₃=0 parametrised by points 𝑦 ∈ ℙ³ (ℚ) lying on the split quadric surface 𝑦₀𝑦₁ = 𝑦₂𝑦₃ which do not satisfy −𝑦₀𝑦₂ = □ nor −𝑦₀𝑦₃ = □. Our methods involve proving asymptotic formulae for character sums with a hyperbolic height condition and proving variations of large sieve inequalities for quadratic characters

Scores into Bodies: communication between audiovisuals and instrumentalist

Watching people play music together pulls one into the ensemble through their communicative gestures and social interaction. How can we preserve this sense of togetherness when one of the performers is computer generated and perhaps not a human form? This is a portfolio–based music composition research project that explores the design of non-human entities and how they communicate, proposes an initial conceptual understanding for ensemble performance, and creates a technical framework for the composition of multimedia interactive systems that prioritises relationships between sub– systems