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Neural characteristics of reward and punishment learning for optimising decision-making
Get PDFAvoiding aversive or punishing outcomes is integral to the survival and function of an organism, and yet this specific dimension of learning has received comparatively little attention in comparison to its rewarding counterpart. There are a number of mechanistic theories and pathways implicated in each dimension, but as of yet there is limited consensus on a holistic model of punishment processing. They key contributions of this thesis are three-fold. First, I offer a novel insight into the role of a motivational salience signal in modulating different behaviours in rewarding and punishing contexts and make the claim that this is compatible with prominent existing mechanistic accounts of punishment learning. Second, I frame this effect with a prominent individual-difference focus, highlighting the importance of considering subject-specific sensitivities to reward and punishment when attempting to model this dichotomy. Third, I use the insights from the first two contributions to show the viability of using this paradigm as a potential means to improve task performance through a closed-loop brain-computer interface (BCI).
These contributions are made primarily from data from a reversal learning task conducted across rewarding and punishing blocks, with EEG and pupillometry as the primary measures of interest. In Chapter 2, I replicate a two-component paradigm from Philiastides et al., (2010) and Fouragnan et al. (2015) with the extension of a punishment condition. I show broad similarities in the EEG signatures, with some notable insights from pupillometry as to promising temporal signals to focus on for further investigation. In Chapter 3, I use these insights to test a motivational salience hypothesis, targeting specifically the earlier component in this two-component hypothesis. I show that individual differences in the sensitivity of this component to context can reliably track task performance. In Chapter 4, I delve further into these individual differences, focusing more specifically on reinforcement learning parameters and psychometric personality measures to better characterise performance effects from Chapter 3. In Chapter 5, I apply all of these findings in a tentative pseudo-BCI analysis, where I retroactively estimate performance and predict whether dynamic context switching might have led to improved behavioural outcomes.
Together, these findings offer new insights into the spatiotemporal characterisation of reward punishment differences and propose some tentative yet exciting future directions for the application of this in the performance optimisation domain
Development of optical suspensions and laser technology for a cryogenic interferometer prototype
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Characterising Plasmodium falciparum cyclin dependent like kinase 1 (PfCLK1) as a potential antimalarial target
Get PDFThe widespread and indiscriminate use of antimalarial drugs has contributed to recurring parasite resistance that threatens a global resurgence of malaria with increasing morbidity and mortality rate towards the verge of endemicity. The dual specificity protein kinase family, CLKs, play crucial roles in the regulation of transcript splicing by phosphorylating SR proteins. Global phospho-proteomic studies of the Plasmodium kinome have shown such splicing events to be an essential process across developmental stages of the parasite life cycle. Thus, members of the CLK family have been considered as potential therapeutic targets in present antimalarial drug development pipelines for new molecules which demonstrate the required efficacy and selective toxicity to the parasite without the propensity to induce parasite resistance. A member kinase PfCLK3 was validated as a cross species multistage drug target in a previous study by our group using a selective and specific small drug like inhibitor TCMDC-135051. However, to achieve poly-pharmacology or develop drugs for combination therapy as an approach to circumvent potential drug resistance, a second target PfCLK1 with similar therapeutic potential was identified. This thesis aimed to extend the previous study by characterising potent selective inhibitors for PfCLK1 and explore the role of the kinase in Plasmodium falciparum. The primary screen at GlaxoSmithKline from the previous study yielded four distinct chemical series of small molecule inhibitors with specific nanomolar activity towards PfCLK1. In this study, two potent members JZ208105-178D1 and HGC-0017530023-NX-1 were further characterised through enzymatic and cellular analyses to investigate their mode of inhibition and determine their interaction with the target kinase.
First, the enzymatic parameters of the biochemical assays were determined using recombinant PfCLK3 and kinase domain PfCLK1 proteins. In addition, a robust assay measuring ATP consumption was developed that proved suitable for high throughput screening. Substrates that were recognised and efficiently phosphorylated by both kinases were identified and used to establish optimal concentrations of protein and ATP for inhibition assay conditions. Second, a detailed analysis of the inhibition mechanism, target specificity, timing of peak activity during life cycle and the rate of parasite reduction was completed to identify the most potent inhibitor that could be optimised to the status of lead compound through further in vitro and in vivo studies. In vitro inhibition results showed that both compounds displayed low nanomolar inhibition of kinase domain PfCLK1 and further demonstrated selective inhibition towards PfCLK3 suggestive of an affinity for the highly conserved domain between both kinases. Additionally, JZ208105-178D1 demonstrated a mode of binding suggestive of ATP competitive inhibition, in contrast to the non-ATP competitive inhibition observed for HGC-0017530023-NX-1. Both inhibitors emerged effective at high nanomolar to low micromolar concentrations against asexual blood stages of P. falciparum 3D7 wild type. For chemical validation, a PfCLK1-like PfCLK3 mutant parasite, G449P demonstrated the same sensitivity as wild type parasites to both inhibitors suggesting PfCLK1 inhibition is linked to their parasitical activity.
Susceptibility profiling of P. falciparum 3D7 asexual blood stages to both inhibitors revealed a variety of stage-specific profiles that differentiated the modes of action including TCMDC-135051 and identified trophozoite-specific peak activity for JZ208105-178D1 and TCMDC-135051. Given that JZ208105- 178D1 conferred higher inhibitory effect in vitro and in vivo, further investigations were carried without HGC-0017530023-NX-1. The morphological analysis of asexual blood stages following treatment with JZ208105-178D1 confirmed that parasite development was completely arrested at the early trophozoite stage. This contrasted with the progression of untreated parasites to late trophozoites at comparable time points. In addition, JZ208105-178D1 impaired the maturation of P. falciparum NF54 gametocytes, stages responsible for transmission, by an ~11-fold reduction in gametocyte number at 1x EC50 concentration.
The parasite reduction rate assay was used to quantify the speed of therapeutic capacity, JZ208105-178D1 demonstrated activity levels similarly to TCMDC-135051 and standard antimalarial artemisinin. The combined data in this study suggests the malaria parasite's response to JZ208105-178D1 inhibition are PfCLK1 dependent and corroborate previous functional characterisation studies relating to PfCLK1 expression in the parasites. Thus, pointing to the PfCLK1 kinase as a promising target for antimalarial and transmission blocking chemotherapy strategies
A multi-phenotypic GWA screen for renal function in Drosophila
No full textRenal function plays a critical role in maintaining water-salt homeostasis and survival of most animal species. Impaired renal function has been associated with kidney stone disease, with evidence linking compromised tubular secretion to the progression of renal dysfunction in humans. Moreover, substantial genetic contributions have been identified in both kidney stone formation and tubular transport of endogenous solutes and xenobiotics. Therefore, understanding the genetic basis of nephrolithiasis and tubular transport may provide valuable insights into the mechanisms underlying nephrolithiasis, impaired tubular secretion, and their contributions to renal function decline. Genome-wide association studies in humans have reported several sequence variants associated with kidney function and kidney stone disease. Calcium-based urinary stones account for more than 80% of all kidney stones, and tubular transport represents another important renal functional parameter apart from glomerular
filtration. Despite this, only a handful of genes implicated in calcium nephrolithiasis and tubular transport have been identified. The genetic basis of variation in susceptibility to kidney stones and renal tubular secretion remains largely unclear. While association studies are powerful and unbiased tools for identifying risk loci, several challenges persist in human studies.
The Malpighian tubules of Drosophila, functional analogues of human kidneys, have been demonstrated to be an excellent model for studying human renal function and disease. The Drosophila melanogaster genetic reference panel serves as a valuable genetic resource for investigating the genetic basis of complex traits. In this study, we utilized inbred, fully sequenced lines from the panel to identify genetic variants influencing kidney stone formation and the secretion capacity of renal tubules. Calcium crystals were quantified in the renal tubules of fly lines subjected to a lithogenic diet, and the fluid secretion capacity of the dissected tubules was measured. Furthermore, the genetic basis of neuroendocrine regulation of secretion was explored using two neuropeptides targeting distinct cell types. We found considerable and reproducible phenotypic variation in both crystal formation and fluid secretion ability. Interestingly, no correlation was observed between the development of renal crystals and basal fluid secretion rates, despite low urine volume being a recognized risk factor for kidney stone disease.
Association studies were conducted to identify genetic variants associated with the observed phenotypic variation. A total of 68 polymorphisms corresponding to 41 genes were associated with crystal formation, while 155 polymorphisms corresponding to 92 genes were linked to basal secretion rate. Candidate genes harbouring these polymorphisms were functionally validated through RNAimediated knockdown. Interactions between candidate genes and their physically and genetically interacting genes were extracted from curated databases. Functional enrichment analysis of the clustered gene networks revealed that biological processes, including the Wnt signalling pathway and extracellular acidification, were associated with the gene networks identified in the analysis of stone formation. Additionally, processes such as the electron transport chain, aerobic respiration, and mitochondrial ATP synthesis were linked to variation in basal secretion rate.
In conclusion, this study presents the first genome-wide association analysis of renal crystal formation and tubular fluid secretion in Drosophila, identifies multiple candidate loci and pathways, and helps to prioritise human genes and pathways as potential therapeutic targets for kidney stone disease and impaired tubular transport. This study has thus demonstrated the utility of a systematic, unbiased screen in identifying genes of interest in renal function in both insects and humans
A characterisation of the materials and methods in oil paintings by Glasgow Boy artist David Young Cameron (1865-1945)
Get PDFThis research addresses David Young Cameron’s (1865-1945) disputed position as one of the Glasgow Boys through the characterisation of the materials and methods he employed in his oil paintings and through evaluation of the development of his style and subject matter. Cameron is not as well known for his work in oil as he is for his printmaking; being ignored and forgotten in discussions on Scottish painting and the Glasgow Boys. Using a technical art history methodology combining art historical and archival research with detailed technical examination of six oil paintings; and visual examination of a wider range of works from throughout his career - this thesis argues that Cameron should be reinstated as a Glasgow Boy. Paintings not previously studied from the early period of Cameron’s artistic career highlight the similarities between the development of his ideology, style and subject matter with that of the Glasgow Boys during the late nineteenth and early twentieth century. Technical examination reveals that the shift towards a brighter tonality observed in his paintings after 1900 coincides with a change in his use of pigment: throughout his career Cameron made use of a combination of traditional and modern pigments, but where he mixed black in his paints to create a reduced tonality in his early works, he mixed bright colours or used them unadulterated in his later works. Additionally, a change in paint application can be observed around this time. In earlier works, the paint is applied smoother and with little to no impasto. In contrast, later works show experimentation with surface texture, alternatively applying paint thickly to hide the canvas weave or thinning it and rubbing it in to reveal the canvas weave. The use of preparatory drawing directly onto the preparatory layers in architectural works and underpainting in his landscapes allowed him to create the sharp outlines and clean pictures typical of his paintings. This first technical study of Cameron, one of the Glasgow Boys, opens the discussion on this group and highlights the need for further technical analysis of their materials and methods to gain a deeper understanding of this diverse group
Deep learning calibration framework for detecting asset price bubbles from option prices
Get PDFAsset price bubbles are associated with exuberant trading and unsustainable price increases, eventually culminating in abrupt collapses, causing widespread socioeconomic and financial devastation. Such phenomena have become increasingly frequent across various asset classes in recent times, and given the interconnectedness of global markets, the potential damage from bubbles bursts has significantly amplified. This is evidenced by the enduring repercussions of the Global Financial Crisis from nearly two decades ago.
This research is motivated to enhancing efficiency of bubble detection from option prices by employing neural networks, such that exuberance in the underlying asset is examined more comprehensively. Following an exhaustive overview of historical occurrences and detection methods, a three-step approach under the framework of the local martingale theory of bubbles was preferred. It captures forward looking expectations of market participants, and overcomes joint-hypothesis related issues, as opposed to traditional methods. The three-step approach relies on calibrating a sophisticated stochastic volatility jump diffusion model to market put observations, prior to testing for exuberance in call option prices. However, computational inefficiencies during calibration, limit its ability in extracting crucial information from option prices.
To overcome this roadblock, a deep calibration framework is constructed such that an optimally trained neural network is employed as a numerical solver for the desired stochastic process. This framework boosts computational efficiency by orders of magnitude, without sacrificing accuracy. It enables the extraction of crucial information regarding the formation of bubbles from the entire surface of option prices, without any compromises. Such calibrations further allow for exploration of bubbles within different maturity groups, and even across the lifetime of call options. At first, the deep calibration framework is applied to observe bubbles in the S&P 500 index, and then for a more recent case study on selected technology stocks. Finally, factors influencing the formation exuberance are examined, which also doubles down as a robustness test for the methodology.
Construction of the deep calibration framework, improves tractability of the three-step
approach, making it more attractive for practitioners. Typically, despite possessing greater sophistication, inefficient stochastic processes are overlooked due to their computationally cumbersome nature, creating a trade-off between accuracy and efficiency. This trade-off is overcome with the application of neural networks, allowing for a deeper exploration and subsequently, greater comprehension of call option and underlying price bubbles. The significant boost in efficiency ensures that practitioners are able to extract real-time information regarding bubble formations, repeatedly, at superior speeds. The contributions of this research are important for policymakers and institutions seeking to properly manage risk and adjust positions in abidance with the ever-fluctuating essence of financial markets
The application of the Delphi methodology in intervention development for social withdrawal and Hikikomori
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Chances or choices? The influences on subject choices in the Curriculum for Excellence
Get PDFOver the past two decades, the education system in Scotland has been – and still is – in a state of deep structural reform. Considerations over equity, curriculum design, opportunity, and the post-school pathways of young people, have long remained at the forefront of considerations for both policy and practice (e.g. Cryrie, Furst & Lauder, 1979; Scottish Government 2008, 2009a, 2011a&b; Priestly & Minty, 2013). The subjects that young people have the option to study, and subjects they then choose to study, are profoundly important to them, their communities, and ultimately the economic skills pipeline of the country. What has often been missing during these considerations are the perspectives, perceptions, and experiences of young people regarding their potential pathways and factors underlying the learning decisions they make.
The aims of this research were to explore the internal and external influences upon the subject choices of young people, under the Curriculum for Excellence (CfE), and explore the impact of social background and policy structures on these learning decisions. It highlighted the voice of pupils in an environment which has seen increasing politicisation since the implementation of the CfE. The present research employed a multi-method qualitative design of interviews and documents, comprised of N=79 semi-structured interviews; N=72 of these with pupils in S4-S6 within four participating schools, and N=7 interviews with invited expert stakeholders. These experts were selected for their knowledge in a range of key areas of the policy of subject choices and classroom practice, including individuals with significant influence in Government, policy, and practice. Thematic analysis was applied to make sense of the data and draw meaning and conclusions from it. The research also used a form of content analysis on the choices forms in each participating school. The focus of the analysis was to identify similarities and differences in the characterisation of schools’ curriculum structures in a systematic manner, setting the context of the choices that young people had in each school.
Findings revealed that schools have employed different processes for subject choices and different curriculum structures, with varying width (the maximum number of qualifications a young person could take), breadth (the range of subjects a young person could choose from), and intent (the curriculum experiences and type of pathways the school was predominately focused on facilitating towards). Indeed, the analysis of the school choices forms, and interviews with staff reveals four distinct approaches to curriculum across the four schools: Diverse Breadth Mandatory Width, Collaborative Depth, and Flexible Facilitation. The research suggests that post-school aspirations were a key driver of subject choices, because aspiration becomes the frame within which choices are made. Aspirations were overwhelmingly related to direct and indirect family influence. Exposure to the job market through employer engagement also played a key role in shaping aspirations. Social background played a further role in shaping the perception of what was possible, proliferating a ‘perception gap’ amongst more and less deprived pupils; i.e., where less deprived pupils had less exposure to types of post-school pathways open, and less knowledge of how to access such pathways.
Pupil interviews revealed a strong interrelation between the internal and external influence and the extent to which they operate is impacted by factors such as age and stage, and social background. The research established the main internal influences over young people’s aspirations and subject choices were perceived as; enjoyment of subjects, usefulness towards attaining their aspirations, and importance of subjects to general development, knowledge, or their future. In addition, it pointed to five ‘spheres’ of external influence: family, teachers, media, employers, and peers. These insights have important implications for education policy and practice, in Scotland and internationally. If Scotland’s secondary education system is to reduce inequalities in subject choice, including concluding that there is a need for greater flexibility within the curriculum, a need for enhanced guidance provision relating to choices, and policies that challenge rather than reinforce socio-economic disparities
Investigating the innate immune barriers that constrain the transmission of coronaviruses
Get PDFSince the turn of the century, the emergence of three highly pathogenic coronaviruses highlights the importance of understanding coronavirus-host interactions. If sufficient cellular factors are available for a virus to complete its life cycle, genome-encoded post-entry blocks to replication may determine whether virus replication is successful. One such barrier is the interferon response, a signalling pathway upregulating hundreds of interferon-stimulated genes (ISGs), many of which encode proteins with specific and potent antiviral activity. The presence and timing of a functional interferon response is important in controlling coronavirus infection. Thus, identifying ISGs with antiviral activity can provide insights into genetic risk factors associated with coronavirus disease severity and the barriers to coronavirus zoonosis. To identify ISGs that inhibit unmodified coronaviruses, I optimised an arrayed ISG expression screening protocol that utilises immunostaining of the dsRNA replication intermediate and quantification of virus infection by plate-based image cytometry. I screened the endemic coronavirus HCoV-OC43 against multiple ISG libraries encoded into lentiviral vectors, including three published species libraries (human, macaque, bovine) and two newly generated libraries (mouse, bat). This revealed ISGs with known and novel antiviral activity against coronaviruses, including 2’-5’-oligoadenylate synthetase 2 (OAS2). OAS proteins classically activate RNase L via the synthesis of 2’-5’-oligoadenylates, resulting in the degradation of cellular and viral RNA. Alternative splicing generates two OAS2 isoforms, p69 and p71, exhibiting differential antiviral activity. I show that the p69 isoform restricts HCoV-OC43,while the p71 isoform restricts the unrelated picornavirus Cardiovirus A (EMCV) via different mechanisms. The OAS gene family thus enhances antiviral breadth in the host genome by both gene duplication and alternative splicing. This research has provided insights into how coronaviruses interact with the innate immune system
The transformation of classics teaching in Scotland, c.1960-c.2000: the decline of Latin and Greek and the rise of classical civilisation
Get PDFIn this thesis, the author charts the history of Classics teaching in Scotland between 1960-2000. The second half of the 20th century was a time of extraordinary change, not solely for Latin and Greek, but for the education system at large. It was a period of shifting attitudes towards Classics and its place in the curriculum. Particularly at school level, moreover, the form and purpose of education itself was under debate. A rebalancing was under way, with a move away from language-learning towards an increasing emphasis on the sciences. As this subject has been underexplored to date, the author looks to supplement the existing literature via archival research and through oral testimony gathered from a broad range of educators.
In the years following the 1963 Robbins Report – a landmark publication that would transform the tertiary education sector – Classics occupied a precarious position. Tracing the stories of Classics teaching at Scotland’s four Ancient Universities, the author compares the distinct approaches taken and the different outcomes reached. The University of Aberdeen is utilised as a case study to explore the institutional failures that led to the demise of Classics there. In contrast, the Universities of Glasgow, Edinburgh, and St Andrews all managed to retain their Classics provision. Greek at the University of Glasgow is taken as an additional case study – one that demonstrates how a department with university support was able to adapt to the significant changes that took place from the 1960s onwards. Although each university adapted to survive in different ways, common threads emerged over the period under investigation in the form of non-linguistic modules and the rise of Classical Civilisation programmes. Whilst the decline of language-focused courses may be lamented, the development and proliferation of popular non-linguistic programmes of study would ultimately open up the classical world to students for whom it would have otherwise remained inaccessible
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