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Characterising the role of Galectin-9 in platelet activation and thrombo-inflammatory disease.
No full textThrombosis and inflammation are two interrelated processes (termed thrombo-inflammation) that contribute to various pathologies, including infection, cardiovascular disease, autoimmune disorders, and cancer. Platelets have been proposed to be a major cellular mediator in thrombo-inflammation. Several members of galectins (Gal-1, -3, -8), a family of carbohydrate-binding proteins with a broad range of immunomodulatory actions, have been reported to activate platelets. Galectin-9 (Gal-9), an immunoregulatory protein, is rapidly emerging as a key inflammatory mediator and biomarker in numerous inflammatory diseases. In this thesis, we investigated the role of Gal-9 as a novel ligand for platelet glycoprotein VI (GPVI), C-type lectin-like receptor-2 (CLEC-2) and scavenger receptor CD36.
We have shown that Gal-9 binds to recombinant GPVI and CD36 in vitro. Soluble Gal-9 stimulates aggregation in human and mouse washed platelets dose-dependently. Platelets from both species adhere and spread on immobilised Gal-9 and express P-selectin. Gal-9 competitively inhibited the binding of human recombinant D1 and D2 domains of GPVI to collagen. Gal-9 stimulated tyrosine phosphorylation of CLEC-2 and proteins known to lie downstream of GPVI and CLEC-2 including spleen tyrosine kinase (Syk) and linker of activated T cells (LAT) in human platelets. Murine platelets with CD36, CLEC-2 and GPVI deficiency exhibited significantly impaired aggregation in response to Gal-9 which was further abrogated in GPVI and CLEC-2-double-deficient platelets.
We also demonstrated that Gal-9 downregulated CD36 expression on human platelets but upregulated the expression of membrane-bound TLR2/6 and S100A8/A9. Transgenic mice with Gal-9 deficiency exhibited attenuated thrombus formation in models of laser-induced thrombosis and intra vena cava (IVC)-stenosis, but had normal platelet counts and responses to collagen, collagen-related peptide (CRP), thrombin were observed when compared to wild-type littermates.
In conclusion, we have identified Gal-9 as a novel platelet agonist that induces activation through interaction with GPVI, CLEC-2 and CD36. Gal-9 is capable of initiating both the pro-thrombotic and pro-inflammatory phenotypes of platelets in vitro and supporting thrombosis in the microcirculation in vivo
Autonomous online hierarchical conformance refinement planning using answer set programming for general-purpose robots
Get PDFThis thesis proposes a novel approach to rapid online task and high-level action planning, called Hierarchical Conformance Refinement (HCR), which focuses on robotics applications. HCR planning is domain-independent, geared towards problems with many complex interacting constraints, and designed to minimise downtime and maximise productivity of robots. HCR is built in Answer Set Programming (ASP), a declarative knowledge representation and reasoning paradigm. ASP is highly effective for solving complex planning problems involving large amounts of descriptive domain knowledge. However, existing ASP planners perform poorly for problems with long minimal plan lengths. HCR tackles this weakness, by combining ASP with a novel mechanism for hierarchical refinement planning, and finds in the union of their complementary capabilities, the overcoming of their weaknesses and reinforcement of their strengths. The resulting technique enables a flexible divide-and-conquer method that exponentially reduces problem complexity and naturally supports online planning. This greatly improves speed and scalability to large problems with long plan lengths, whilst maintaining the high expressivity and generality of existing ASP planners.
Simulated experiments ran on a combined blocks world and navigation domain show that HCR planning significantly outperforms the classical approach to ASP based planning by exponentially reducing execution latency and total planning times in the minimum plan length of a problem. HCR planning reduced median execution latency by between 81 to 99% and total planning time by between 42 to 98%, over classical ASP based planning, for only between 0 to 11% reduction in plan quality, from the easiest to hardest problems tested. For the most complex problem tested, a robot equipped with the HCR algorithm can reduce total planning time from 607.0 to 14.1 seconds, and execution latency to less than 7 seconds. This makes ASP planning fast enough to be used for practical robotics applications
An exploration of the decision making of mainland Chinese undergraduates who have chosen to study in the United Kingdom
Get PDFThe study explored how Mainland Chinese undergraduate students made their study abroad decisions: their initial decision to study overseas; their choice of the United Kingdom as a destination country; and their ultimate subject and university choices. The investigation focused on who or what influenced these decisions, and the impact of the Covid-19 pandemic on all the above.
Individual, semi-structured interviews were conducted, face to face or online, with 34 participants who were all current Year One or Year Two Mainland Chinese undergraduates studying at UK universities.
The findings indicate two strong themes emerging from participants’ data: educational competition as a driver of decision making, and the complex and intersectional nature of the decision-making process. Specifically, Students’ initial study abroad decisions and subject and university choices appeared to be influenced by their awareness of educational competition when pursuing university status and navigating neijuan. Furthermore, these decision making processes reveal the multifactorial nature of choice making and the overlaps between different factors. There seemed to be no clear-cut phases in participants’ decision making processes. Both their initial study abroad decision making and their subject and university choices were shaped by participants’ pre-university educational pathways. Four distinct pre-university pathways appeared in the interview data: the foundation course route, the gaokao route, the A-Level route and the international school route. In addition, their access to information sources and parental advice both played an important role throughout their decision-making.
The findings of this study illuminate the processes entailed in Mainland Chinese students’ study abroad choice making and add to our understanding of how individual Mainland Chinese students weigh different factors in order to make their study abroad decisions
Mattering in Lambda-award nominated sapphic young adult fiction published from 1990-2020
Get PDFThis thesis explores the impact of mattering or not mattering on sapphic characters in young adult fiction in three key spaces in their lives: within the family, within the community, and within the wider world. Drawing from existing sociological research, including Meyer’s minority stress model, and close reading of nine award-nominated sapphic young adult texts published between 1990- 2020, this study looks at the ways sapphic protagonists are shown that they do or do not matter and the impact this has on their self-regard and well-being.
Chapter one looks at mattering within the family and discovers the link between not mattering and withdrawal from the family, depersonalisation, and suicidal ideation, while characters who are shown that they matter within their families are able to form deep bonds rooted in honesty and authenticity. Chapter two explores mattering within the community, focusing on the local community, the religious community, and friendships. This chapter highlights the link between not mattering and the development of internalised homophobia, while characters who are shown that they do matter to their communities are able to overcome this internalised homophobia. Chapter three examines mattering within the wider world, focusing on the impact national and statewide policies and attitudes have on spaces frequented by sapphic youth, including high school. This chapter uncovers the link between not mattering within the wider world and the sapphic protagonist’s concealment of her sexuality and withdrawal from community spaces, while characters who are shown that they do matter within the wider world have the confidence to engage in activism and fight back against injustice within their communities.
This thesis ultimately argues that sapphic teenage protagonists who are shown that they do not matter within their family, their communities, and within the wider world experience a negative impact on their identity formation as a result, whereas when characters are shown that they do matter within these spaces, they enjoy a positive impact on their self-regard
Adhesion and invasion dynamics of fusobacterium nucleatum in colorectal cancer
No full textABSTRACT
The role of microbial dysbiosis in colorectal cancer (CRC), which ranks amongst the top five deadliest cancers, has gained a lot of research interest recently. This study focused on the bacterium Fusobacterium nucleatum, which is often enriched in CRC patients compared to healthy controls. The overarching aim of the study was to investigate the adhesion and invasion dynamics of three F. nucleatum subspecies, namely subspecies (ssp.) nucleatum (FNN23), ssp. polymorphum (FNP) and ssp. animalis (FNA), to improve understanding of the mechanism of action of F. nucleatum in CRC. Adhesion and invasion assays were performed using a monolayer model of a CRC cell line, Caco-2. Subspecies-specific differences in the levels of adhesion to CRC cells were observed, with FNP having higher adhesion levels than the other two subspecies. The adhesins, FadA and Fap2 are important F. nucleatum virulence factors in CRC. Therefore, their contribution to adherence and invasion, in FNN23 was investigated using deletion mutants of the adhesins. The mutations resulted in decreased adherence and invasion of Caco-2 cells by FNN23. The decrease was greater with the Fap2 mutant than the FadA mutant strain. Additionally, this study determined the impact on adhesion and invasion of Tspan6, a protein belonging to the tetraspanin family of proteins which have been implicated in various aspects of cancer. While Tspan6 expression improved the adherence of FNN23 to Caco-2 cells, it decreased that of FNA and made no difference to FNP adherence. Interestingly, the invasion of FNN23 to Tspan6 expressing cells was decreased, but no significant impact on FNA and FNP invasion was observed. Furthermore, the impact of the bacterial growth phase on adhesion dynamics was also investigated. FNN23 and FNA samples experienced over 2-fold increases in their levels of adherence at the exponential compared to the stationary phase, while FNP adherence remained unaffected. Then, bacterial RNA sequencing was performed to establish whether there were differences in the expression of adhesins and other virulence factors resulting in the observed differences in adherence and invasion of the subspecies. Global gene expression differences between stationary and exponential-phase bacteria were observed. In addition, differences in the expression of adhesion genes at the exponential and stationary phases were discovered. This study also demonstrated differential induction of cytokine and chemokines by the F. nucleatum subspecies compared to controls using the Olink target 48 cytokine and chemokine assay service. Lastly, paired metagenomics and transcriptomics analyses were performed on 57 CRC samples and their controls to determine the impact of the metagenomic profile on gene expression. Metagenomic differences led to differences in immune cell composition and the expression of Hallmark pathways. Understanding the adherence and invasion dynamics of F. nucleatum subspecies is key to uncovering key mechanisms important in F. nucleatum virulence CRC, which can help inform diagnostics and therapeutic interventions
Song translation over time: a digital analysis of Italian-dubbed animated musical comedies 1959-2019
Get PDFTaking its cue from Susam-Sarajeva’s call (2008: 190) to focus on ‘why’ a specific song translation activity is ‘done in a certain way’, this study aims to provide the first empirical investigation into translation techniques used in Italian-dubbed animated musical comedies from 1959 to 2019. It compiles eleven selected song case studies from songs produced by major US film companies (Disney and DreamWorks), which (a) present features of multiple pop song genres (e.g. swing, gospel, stage musical) and (b) have been released in different language versions: ‘Once Upon a Dream’ (Sleeping Beauty, 1959), ‘Thomas O’ Malley Cat’ (The Aristocats, 1970), ‘Be Our Guest’ (Beauty and the Beast, 1991), ‘Arabian Nights’ (Aladdin, 1992), ‘Jack’s Lament’ (The Nightmare Before Christmas, 1993), ‘Be Prepared’ (The Lion King, 1994), ‘Zero to Hero’ (Hercules, 1997), ‘Deliver us’ (The Prince of Egypt, 1998), ‘Holding Out for a Hero’ (Shrek 2, 2004), ‘Love is an open door’ (Frozen, 2013), and ‘Into the Unknown’ (Frozen II, 2019).
Building on Abbott’s definition (2017) of song as a ‘conjoined work’, this research deploys a ‘thick’ method of song analysis (Abbott, 2021) combining contextual, schematic, statistical, and time-bound analysis via Sonic Visualiser (Cannam et al., 2010) to investigate complex and simultaneous interrelations between (translated) text, singing medium and visual performance. Through the transversal use of innovative digital humanities techniques, this study creates a set of quantitative and qualitative data for each song across six interconnected parameters: (1) word count/musical phrase duration; (2) rhyme/prosody; (3) linguistic, visual and/or musical culture-specific elements; (4) vocal interpretative nuances; (5) phonetic and visemic implications for lip-synch; (6) visual performance matching word meaning.
In so doing, this research interrogates the notion of representations of ‘cultural otherness’ (Di Giovanni, 2003) in Western animated film songs’ interplay of linguistic, visual and musical features, whilst looking at how ‘the same tune with a different set of words becomes a new song within a new context’ (Susam-Saraeva, 2019: 48). It provides detailed sets of both synchronic and diachronic screenshots of cultural interactions (Bassnett and Lefevere, 1998) through comparative analyses of song translations within the broader context of dubbed film products (Chaume, 2012). The study concludes with findings showing that translators and performers tension the competing linguistic, visual and musical aspects to varying degrees within a given song to produce coherent multi-semiotic representations of cultures. This suggests that over-simplified or reductive approaches are ill-suited to understanding the complex interplays at stake in dubbed songs in the context of animated musical comedies
Cognitive predictors of individual differences in language acquisition
Get PDFThere are vast individual differences in the way in which people acquire, process and use language. While most people learn their native language with ease, some people have difficulty with understanding and producing language in their day-to-day lives, a condition known as Developmental Language Disorder (DLD). Research to date has focused on cognitive and linguistic difficulties associated with DLD, but the underlying causes are not well-understood. A series of empirical studies were conducted with the objective of developing a deeper understanding regarding the interrelationship between cognitive abilities and language in children and adults, with and without DLD. There are two novel approaches to this research, firstly, the speed of automatization is explored using the Multiple-trial Tower of Hanoi paradigm, showing that automatization is relevant to language in children with DLD, and LT and DLD adults. Secondly, this thesis investigates the role of (foreign) language aptitude/analytic ability, with results suggesting that language aptitude is relevant to linguistic outcomes in language typical (LT) children and adults, with and without DLD. The overall results presented in this programme of research suggest that specific cognitive abilities are important for language. In children with DLD (study one), a cumulative risk model is presented, demonstrating the combinatory effects of nonverbal IQ, working memory, and speed of automatization. Study two investigates language and cognition in adulthood, showing that language aptitude is relevant to linguistic outcomes in adults with and without DLD. There are small to no differences in other cognitive abilities assessed in this study, yet the results show that adults with DLD require more time to process linguistic and non-linguistic tasks. Study three demonstrates that analogical reasoning is a key predictor of language in LT children and children with DLD. Lastly, a key relationship emerges between nonverbal intelligence and grammar, challenging the widely accepted view that grammar develops purely implicitly. Language difficulties have been studied since the 19th century, and although great strides have been made in gaining a deeper understanding of DLD, there is still much to learn. Collectively, the results from the studies detailed in this thesis provide evidence that individuals with DLD process language differently to their LT peers and show that certain cognitive abilities support language in DLD
How do nations control political finance and why do reforms occur? A nested mixed-method analysis of political finance reform in Canada, New Zealand, and Commonwealth Caribbean small states
Get PDFThis thesis aims to provide a greater understanding of how nations regulate political finance and why reforms occur. To compare models of regulation, the first stage of the thesis develops the ‘Regulation of Political Finance Indicator’ (RoPFI). Starting with the 2020 iteration of International IDEA’s ‘Political Finance Database’, Multiple Correspondence Analysis is used to construct a variable on which to measure levels of regulation across 180 nations. Subsequently, Model Based Clustering identifies the ‘Unregulated’, ‘Partially Regulated’ and ‘Strongly Regulated’ types of political finance system, and provides a statistical measure of the certainty of each nation’s classification. Using the RoPFI to assess global trends, findings indicate that small states of the Caribbean and Pacific have the fewest regulations on political finance, while nations of Central and Eastern Europe, the Middle East and North African (MENA) region, and the Americas employ the strictest controls in this area. The remainder of this thesis examines political finance reform in a group of Westminster democracies, namely Canada, New Zealand, and a sample of seven small states from the Commonwealth Caribbean (The Bahamas, Belize, Dominica, Grenada, St. Kitts & Nevis, St. Lucia, and St. Vincent & The Grenadines). Studies use Zim Nwokora’s ‘General Theory of Campaign Finance Reform’ as a foundation upon which to examine why reforms occur. Distinguishing between loosening and tightening reforms, the model suggests that the reform process is guided by shifts in party competition, party organization strength, and ideological factors. Scandals and changes in incumbency are also suggested as junctures that may prompt reform. To test the projections of this model, Hansard is used to document Parliamentary interactions on political finance, and operationalized indicators of party competition, organization, and ideology are used to trace the context within which discussions took place. Findings indicate that variations in levels of party competition and party organization strength are influential in shaping political finance reform, while ideological factors are much less so. Scandals are found to be influential in the passage of tightening reforms, while changes in incumbency are identified as a poor predictor in this area. Building on these observations, the final case study – focused on small states of the Commonwealth Caribbean – finds that the endurance of clientelism in the region continue to act as a barrier to political finance reform. This relationship is exemplified in a detailed case study of failed reform attempts in Saint Lucia and, subsequently, a link between practice in small and large states is identified. The differentiation between governance approaches – where small states are more likely to trend toward clientelism, relative to larger states – is identified as the causal mechanism that underpins this observation. Taking this into consideration, the thesis concludes with an updated theoretical model of political finance reform. To summarize, scandals are presented as critical junctures in the passage of tighter regulations. Beyond this, variations in governance model type, levels of competition, and the strength of party organizations are the main factors that influence the direction of the reform process. This thesis makes contributions in methodological, empirical, and theoretical terms. Methodologically, the development of the RoPFI provides a key resource for scholars of political finance. In empirical terms, the RoPFI represents one of the first global measures of political finance to consider all areas of regulation – both from the party and candidate perspectives – and also incorporates some of the least studied regions in this area, namely the Caribbean and the Pacific. Theoretical contributions span numerous areas of research. Primarily, the theoretical model developed in this thesis broadens understanding of the origins of political finance regulation, by addressing inconsistencies in prior literature. The identification of clientelism as a barrier to reform, particularly within the small state context, contributes to knowledge on the implications of clientelist governance models, as well as institutional development in small states
The political economy of the management of public expenditure in Britain: The introduction of cash limits under the 1974-79 Labour government
Get PDFThis thesis examines the political economy of the management of public expenditure during the 1974-79 Labour government in the UK. In particular, it examines the introduction of cash limit reforms to the control of public expenditure in the context of significant economic pressures which confronted state managers during the 1970s. Inflation, low economic growth, high public borrowing, stagnant productivity, and recurring sterling crises prompted a serious reappraisal of public expenditure governance in 1974-5. It is due to these pressures that cash limits were introduced, as a means of controlling expenditure. This thesis makes use of primary archival documentary evidence to shed new light on the motivations of state actors in introducing cash limits. Contrary to mainstream accounts which explain cash limits as a technical fix to an issue of control over spending, the thesis demonstrates how cash limit reform was in fact motivated by a series of political and economic concerns, primary amongst them being wage inflation. By way of a Marxist examination of the political economy of public spending, the thesis demonstrates the way cash limits were used to discipline the working class and to depoliticise decision-making vis-à-vis public expenditure
Design and analysis of isogeny-based static-key protocols
Get PDFThe advent of quantum computers renders most cryptographic protocols obsolete and urges for a quick transition to post-quantum solutions. Many valid techniques for quantum-secure encryption and digital signatures have been proposed, but more advanced primitives do not yet have efficient post-quantum replacements. Among these are primitives where multiple parties have long-term secrets; we refer to these protocols as static-key cryptography. Few post-quantum static-key protocols have been reported in the literature, and nearly all are based on isogenies. In this work, we focus on two fundamental static-key primitives: non-interactive key exchanges (NIKE) and oblivious pseudorandom functions (OPRF). We first study the security of existing constructions with long-term static keys, and then we develop new protocols that outperform the existing ones.
In particular, we first assess the security of the isogeny-based NIKE based on k-SIDH proposed by Jao and Urbanik. Compared to the original k-SIDH, the protocol relies on non-trivial automorphisms to improve its efficiency. However, we show the protocol is vulnerable to an attack that exploits the additional automorphism structure. While the attack does not fully break the proposed parameters, it shows that the k-SIDH variant by Jao and Urbanik reduces the security level more so than it increases efficiency, making it less preferable over the standard k-SIDH.
We also analyze a validation method proposed by Fouotsa and Petit that checks the correctness of SIDH public keys. If the method were secure, it could be translated into an efficient NIKE. However, we demonstrate an efficient attack that allows a malicious party to provide dishonest public keys and satisfy the validation check. As part of this work, we also discuss possible improvements to the countermeasures but show that they are similarly vulnerable to an extension of our attack. We then conclude with a discussion on the possibilities and the requirements of future validation techniques.
Beyond NIKEs, we analyze the security of the isogeny-based OPRF proposed by Boneh, Kogan, and Woo at Asiacrypt 2021. We introduce a polynomial-time attack on the one more unpredictability property of the OPRF, which allows a malicious user to evaluate the PRF independently after some interactions. We show that a simple countermeasure can prevent the attack; we also propose a second attack that achieves the same goals but cannot be easily defended against. The second attack, however, has subexponential complexity. To demonstrate its feasibility, we develop a proof-of-concept implementation that can efficiently carry out the attack.
In follow-up work, we develop an efficient countermeasure against the previously introduced attack. We also integrate the countermeasures against the SIDH attacks into the OPRF protocol, and we propose a new proof of isogeny knowledge that can work with the countermeasures. Moreover, we introduce a novel zero-knowledge proof of parallel isogeny that provides non-interactive verifiability. By combining everything together, we obtain an OPRF protocol that is post-quantum secure, verifiable, round-optimal, and moderately compact.
Lastly, we study the problem of generating supersingular elliptic curves with unknown endomorphism ring. Such curves are often needed as starting parameters in many isogeny-based protocols, including the OPRF protocol we have developed. To generate curves of unknown endomorphism ring, we propose a distributed trusted-setup protocol that relies on a new statistical zero-knowledge proof; we prove its security in the general universally composable framework.
These works, both constructive and cryptanalytic, provide a better understanding of the limitations and the possibilities of isogeny-based cryptography in developing static-key protocols, and they are an important stepping stone towards fully practical post-quantum NIKEs and OPRFs
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