VictorJuiz/thesis huggingface dataset:
Characterising the transcriptional profile of CACNA1C expression in rodents

Introduction: The CACNA1C gene, which codes for the ɑ1-subunit of the voltage-gated calcium channel Cav1.2, has been repeatedly associated with psychiatric disease in genome-wide studies. Cavv1.2 can be expressed in a number of isoforms produced through alternative splicing of pre-mRNA. Splice variants in CACNA1C have been shown to be spatially and temporally regulated, many variants being tissue specific or changing expression during development. Moreover, CACNA1C splice variants are known to have differing electrophysiological properties as well as differences in expression. With the advent of long-read sequencing technologies, it has become possible to reliably identify and characterise mRNA splice variants, and recent evidence from human post-mortem brains suggests that the transcriptional profile of CACNA1C may be under-characterised in rodents. In this project, we have set out to fully characterise the full range of mRNA splice variants in mice and rats across neural and cardiovascular tissues.
Methods: We extracted whole-tissue RNA from aorta, heart, cerebellum, and frontal cortex of 8 mice and 8 rats. Full-length CACNA1C cDNA was isolated from each tissue using RT and PCR amplification of transcripts starting with exon1a, exon1b, or exon1c. Sequencing libraries were prepared as per the Nanopore 1D Ligation Sequencing protocol, and sequenced on the Nanopore MinION. Transcripts were then translated using the online ExPaSy tool and aligned on UniProt to annotate and predict functional significance of individual splice variants.
Results: Principal component analysis (PCA) of sequencing reads reveals a clear segregation of transcript isoforms enriched in the brain compared to isoforms enriched in the heart and isoforms enriched in smooth muscle tissue. Across all samples, reads showed 53 different transcript variants, out of which 45 novel splice variants, among which 37 are predicted to be coding, and 3 which contain novel previously uncharacterised exons.
Conclusion: The transcriptional profile of CACNA1C in rodents has been under-characterised. Although our results need to be validated at the proteomic level, we reveal 45 novel mRNA splice variants. Further study of these may reveal insights to the pathophysiology of psychiatric disorders associated with CACNA1C, and potentially lead to novel therapeutic targets.

Keywords: bipolar disorder
mRNA
schizophrenia
rodent
CACNA1C
transcription
splicing
Advisor: Tunbridge, E
Non-reductive geometric invariant theory and its applications to Higgs bundles

Geometric Invariant Theory (GIT) is a powerful theory for constructing and studying the geometry of moduli spaces in algebraic geometry, as quotients of a parameter space by a linear group action. However GIT only applies to classification problems involving reductive group actions, and only produces a moduli space for the subclass of "stable" objects. Non-Reductive GIT was developed over the last ten years to overcome these limitations.
The aim of this thesis is firstly to describe a systematic way of constructing and studying the geometry of quotients using both classical and Non-Reductive GIT, and secondly to show how these methods can be applied to the classification problem for Higgs bundles.
In the first part we describe an algorithm which, given the linear action of a linear algebraic group with so-called "internally graded unipotent radical" on a projective variety, uses classical and Non-Reductive GIT to produce a non-empty open subset of the variety admitting a quasi-projective geometric quotient, together with an explicit projective completion of this quotient. Assuming the initial variety is smooth, we describe a procedure for calculating the Poincaré series of the resulting projective completion, which first requires showing that it can have at worst finite quotient singularities. We then obtain as a result a formula which can be viewed as the non-reductive analogue of the formula for the Poincaré series of the partial desingularisation of classical GIT quotients.
In the second part we show how Non-Reductive GIT can be used to refine two instability stratifications of the stack of Higgs bundles: the Higgs Harder-Narasimhan and the Harder-Narasimhan stratifications. These refined stratifications satisfy the property that each stratum admits a quasi-projective coarse moduli space with an explicit projective completion. In the rank 2 case we provide a complete moduli-theoretic interpretation of these refined stratifications and study the geometry of the corresponding moduli spaces.

Keywords: Moduli spaces
Non-Reductive Geometric Invariant Theory
Quotients by group actions
Cohomology of quotients
Higgs bundles
Advisor: Kirwan, F
Ziegler, P
On the uses of confidence judgements to guide behaviour

The ability to reflect upon our own thoughts and actions is a defining feature of human cognition. People can evaluate the quality of their own performance and report levels of confidence that are correlated with objective accuracy. As such, the subjective sense of confidence that accompanies our decisions and beliefs could potentially be a useful tool that can guide adaptive behaviour. The research presented in this thesis explores this idea to examine the functional role of confidence and the scope of its influence on our behaviour.
Across three lines of work, the role of confidence is studied in the context of carefully-controlled perceptual decision making tasks. In the first part of this work, I examine the role of confidence in guiding task selections, acting as a valuable indicator of likely success. I present data showing that people exhibit a preference for tasks in which they report higher confidence. Furthermore, I show that confidence guides task choices in a more nuanced way than binary error detection, and that this preference is evident even when external feedback is available.
In the second part, I examine the proposal that people can use their confidence flexibly, depending on the specific context. Using an advice seeking task, I show that when advice quality is unknown, people select advice more often when their confidence is high, presumably using their confidence as a feedback proxy to learn about advisor quality. A contrasting pattern is observed when advice quality is known, with people requesting more advice when confidence is low, consistent with the idea that confidence is used as a self-monitoring tool that signals that external help is needed. Together, the results indicate that people use confidence in a way that is directed towards achieving their current goals.
The third part explores how confidence also modulates attention and, through this, influences lower-level processing of information. I present behavioural and electrophysiological data indicating that high confidence in the informativeness of task-relevant information is associated with greater attention towards it.
Overall, the three lines of work provide converging support for the view that confidence plays an important role in guiding behaviour in a flexible, goal-directed way, and suggest that it influences a wide range of both high-level and low-level processes.

Keywords: confidence
decision making
metacognition
cognitive control
Advisor: Yeung, N
Southern African synoptic climate dynamics and future change: tropical lows and the Congo Air Boundary

Southern Africa's development and economy is dependent on a rainfall resource that is projected to decline in coming decades as a result of anthropogenic climate change. This rainfall decline has been attributed to a half month delay in the onset of the wet season by the end of the \nth{21} century based on RCP8.5 projections, shortening the growing season and reducing the agricultural viability of the region. Yet many aspects of the basic climatological state of the southern African atmosphere remain chronically understudied. Rainfall onset and regional rainfall climate depend on the behaviour of day-to-day weather systems along the southern margin of the African rain belt. However, the dynamics of these systems are not well understood. This thesis addresses this problem by characterising the frequencies, spatial distributions, dynamics, interannual variability and future change of two classes of weather systems: tropical lows and the Congo Air Boundary (CAB).
A vortex tracking algorithm is optimised to detect tropical lows in sub-daily reanalysis data and climate model output. It is found that tropical lows aggregate to form the synoptic expression of the summer Angola Low. Tropical lows are shown to exhibit a unique anchoring behaviour in Angola due to interactions with nocturnal low-level jets associated with differential surface heating. 70% of rainfall in south-east Angola and 31% of summer rainfall across the southern African tropical margin is attributed to tropical lows. Meanwhile, the majority of interannual rainfall variability in Angola, northern Namibia and western Zambia derives largely from tropical lows. Climate model projections indicate that tropical lows will become 15% less frequent by the end of the 21st century. Future change in the spatial distribution of tropical lows contributes to model disagreement over the spatial pattern of rainfall change in the summer season.
Computational edge detection is applied to identify surface drylines and convergence lines associated with the CAB, a forgotten feature of the southern African climatology. The CAB is shown to be a sharp discontinuity which marks the southern edge of the African rain belt, and is detected on at least 80\% of days from August to October. Its seasonal southward progression over southern Africa is presented, and a close dynamic link between the CAB and the Angola Heat Low is demonstrated. Seasonal rainfall variability is closely linked to the CAB, since tropical rainfall does not occur to the south of the CAB, with CAB variability explaining at least 55% of local monthly rainfall variability. The projected delayed wet season onset is shown to be related to a projected 0.7° CAB latitude increase and a 13% CAB frequency increase from October to December, with inter-model CAB variability explaining 46% of inter-model variance in projected rainfall change.

Keywords: Congo Air Boundary
Regional Climate
Tropical Lows
Climate Change
Southern Africa
Advisor: Washington, R
Internationalism as an organisational practice: the League of Nations Secretary-General, 1918-1946

This thesis analyses the development of the League of Nations secretary-generalship as an independent office through the perspective of internationalism, making two key arguments. First, that the secretary-generalship is unjustly overlooked in International Relations: it was crucial for international organisational development, leading (and to a considerable extent creating) the first international civil service, meant to represent the international organisation rather than states. Second, that analysing that office through internationalism, a concept regarding which scholarship often overlooks practice in favour of intellectual history, enriches our understanding of the office and international organisation. It grounds internationalism in organisational practice, analysing it in three dimensions; practice itself (how secretaries-general sought to shape their office through bureaucratic and diplomatic precedents); politics (how that practice related to political strategies); and authority (how they sought to legitimise their practices and politics by mediating between law and power).
The thesis draws on primary and secondary research, bringing into International Relations historical scholarship insights about the nature and multiplicity of internationalisms, charting the practice of the League’s secretary-generalship from its creation in 1918-1919, through the administrations of its secretaries-general (Eric Drummond (1919-1933), Joseph Avenol (1933-1940), and Sean Lester (1940-1946)), to the transfer of its duties to the UN in 1945-1946. It analyses each official’s practice, politics, and how they perceived their office’s claim to authority in different ways, representing distinct internationalisms. This shows that, contrary to traditional narratives, the secretary-generalship was an independent, innovative, and precedent-setting institution. Studying it through the lens of internationalism reveals the interwar period as a time of tension not between nationalism and internationalism, but between competing internationalisms. Analysing how these internationalisms inter-related through practice within an institution contributes to our understanding of diplomatic practice as a constitutive process of international development, and of the multiplicity of internationalisms animating international relations, historically and today.

Keywords: international law
Secretary-General
United Nations
international organisations
executive leadership
Sean Lester
diplomacy
Joseph Avenol
international history
League of Nations
Eric Drummond
Advisor: Keene, E
Hurrell, A
Measurements of the associated production of a Higgs boson decaying into two beauty quarks with a weak vector boson

For more than four decades, the Higgs boson has been the most sought-after particle in Particle Physics. Its observation, by the ATLAS and CMS collaborations in 2012, has confirmed the existence of the Higgs field, which is responsible for the spontaneous symmetry breaking mechanism in the electroweak sector and the mass generation of fermions through the Yukawa interaction. Since then, many measurements have been performed, with increasing accuracy, to check whether its properties matched the Standard Model predictions.
The measurement of the Higgs boson decay to beauty quarks is the first test of the Yukawa coupling to bottom-type quarks. Although this decay channel has the largest branching ratio, it has been difficult to observe it at the LHC due to the presence of the large multi-jet background. In this regard, the associated production of a Higgs boson with a leptonically decaying vector boson offers an excellent leverage to reject this background. Furthermore, this production mode is particularly sensitive to Beyond Standard Model physics in the form of Effective Field Theories operators.
This thesis presents inclusive and differential measurements of the associated production of a Higgs boson decaying into two beauty quarks with a weak vector boson using the full Run 2 ATLAS dataset. The inclusive measured signal strength is μbbVH = 1.02+0.18-0.17 = 1.02 +0.12-0.11 (stat.) +0.14-0.13(syst.) , which corresponds to a rejection of the background-only hypothesis with a significance of 6.7 standard deviations, when 6.7 standard deviations are also expected. The differential measurements are reported in five bins of Simplified Template Cross Sections, defined with respect to the transverse momentum of the vector boson. The total uncertainties on each bin range from 85% to 30%. These analyses represent some of the first steps towards the era of precision measurements in Higgs physics, which will characterize the future physics programme of the LHC and the high-luminosity LHC.

Keywords: LHC
ATLAS
Higgs
Advisor: Bortoletto, D
Hegel's hidden history of the Fall

This thesis argues that Hegel’s claim that the coming of Christ is the central axis of history, entails a twofold punctuation of history by the Christ-Event. As Benedetto Croce recognised, Christianity inaugurates for Hegel a ‘new’ history, which he called the ‘history of Truth’. I argue that this history of Truth is preceded, on the other side of the Christ-Event, by a hidden, ‘history of the Fall’. I identify this ‘history of the Fall’ with Hegel’s developmental narrative of religious history, which plots the movement from Naturreligion to the emergence of Christianity. The ‘history of the Fall’ is, accordingly, the history of the emergence of revelation from the immediacy of natural life. For Hegel, this life is historically ‘lapsarian’, having emerged with the breakdown of the Zweck of history into sin and slavery. The Jewish (and later Christian) religion represents this historical catastrophe as a ‘Fall’ of Adam, whom Hegel reads typologically as Christ. The Christ-Event is therefore both the goal and the starting point of history. It is the goal of the ‘history of the Fall’, and the starting point of the ‘history of Truth’, whose ‘first man’ is Christ, the second Adam. However, while this ‘history of Truth’ coincides with Christianity as ‘revelation’, the ‘history of the Fall’ is ‘hidden’ from the merely ‘natural consciousness’ of Naturreligion, just as sin is, for Christian theology, known only under grace. The emergence of the Genesis Fall narrative is therefore linked by Hegel to the possibility of understanding history because it is necessary for the possibility of human self-understanding (as unfree and, therefore, as not yet Geist). The development of consciousness leading up to the Christ-Event, which I refer to as the ‘history of the Fall’, designates the concretisation of its self-understanding as ‘fallen’, from the ‘pictorial’ form of the Genesis narrative as ‘story’, to the revelation of human ‘fallenness’ in polemical antithesis to the life and teaching of Christ as ‘history’. In this way, I argue that the Christ-Event constitutes humanity as a historical ‘unity’ in its rejection of the offer for the kingdom, and therefore constitutes the historical past as a ‘history of the Fall’. I argue that highlighting the role of the Fall narrative in this way, allows us to understand Hegel’s philosophy of history as formulating a developmental narrative of the origins of human life as emerging from historical failure, without giving up on its essence as a Christian Heilsgeschichte (as is common with secularising readers, from Hyppolite and Kojève, to Žižek).

Keywords: historical time
Christology
sin
dialectics
Hegel
Marxism
the Fall
Advisor: Ward, G
Catalytic reductive cyclisations of amides using Vaska's complex

Chapter 1 introduces tertiary amines, and the main strategies available for their synthesis. Vaska’s complex is introduced, and its recent use for the reduction of tertiary amides and lactams is exhaustively described.
Chapter 2 details the development of a spirocyclisation methodology from indole-tethered tertiary amides and lactams. The selectivity observed and the broad substrate scope make it a method of choice for the synthesis of spirocyclic indolines.
Chapter 3 describes the development of a cycloaddition methodology, based on accessing azomethine ylides from tertiary amides and lactams, and reacting these 1,3-dipoles with a range of dipolarophiles, generating polycyclic amines. It is of value for the synthesis of polysubstituted pyrrolidine ring-containing amines.
Chapter 4 details the investigations towards the design and application of a synthetic sequence leading to the total synthesis of a pentacyclic alkaloid, catharanthine. Previous syntheses are described, before model studies establish the feasibility of an IMDA cascade sequence triggered with Vaska’s complex. The natural product synthesis is then described.
Chapter 5 details our efforts towards making the previously described methodologies amenable to large scale, and why they should be particularly attractive for industrial applications. Finally, preliminary results for the synthesis of new Vaska-type Iridium complexes for the reduction of non-tertiary amides functional groups are described.

Keywords: Vaska's complex - tertiary amide - reduction - cyclisation - cycloaddition - tertiary amine synthesis - catharanthine - grignard - indole - spirocyclisation - 3+2 - 4+2 - Diels-Alder - dienamine - secondary amide reduction
Advisor: Dixon, DJ
Piecewise-deterministic Markov chain Monte Carlo

Recent interest in a class of Markov chain Monte Carlo schemes based on continuous-time piecewise-deterministic Markov processes has led to several new and promising algorithmic developments. Prominent examples include the zig-zag process and the bouncy particle sampler. We explore this class of algorithms, proposing extensions and drawing connections to existing literature.
Two key aspects of a continuous-time piecewise-deterministic process are the flow and the event kernel. We discuss conditions on these sufficient to design a process targeting a distribution of interest. Based on these conditions, we show how the flow can be extended to Hamiltonian dynamics when exactly computable. For the event kernel, we demonstrate that a simple factorization of the invariant distribution subsumes all existing kernels and allows new kernels to be easily derived.
Next, we explore the idea of piecewise-deterministic processes in discrete time. These algorithms have many close connections with pre-existing algorithms. The simultaneous simulation of multiple event rates may be connected to the discrete-time delayed acceptance algorithm. We demonstrate that the flow and event kernels used in the bouncy particle sampler bear strong resemblance to the reflective slice sampler. A class of discrete-time event kernels which we call here tunnelling algorithms also prove to be a special case of this framework.
Applying this framework to the setting of large datasets with many observations, we describe how both the continuous-time and discrete-time algorithms can be adapted to this setting. We explore the use of approximations to bound the effects of individual observations. Methods of simulating from discrete distributions based on Poisson processes are used to efficiently subsample the data. Finally, we show how these methods can be used to extend and improve upon the existing firefly Monte Carlo algorithm.
A second application is found in the setting where interaction between parameters is limited and forms a sparse graph, for which the continuous-time local bouncy particle sampler algorithm has been developed. A discrete-time extension mimicking the local properties of this algorithm is proposed, unveiling a close connection to the random cluster algorithm of Swendsen-Wang.

Keywords: big data
simulation
Markov chain Monte Carlo
random cluster methods
piecewise-deterministic Markov processes
Monte Carlo
Bayesian statistics
Swendsen-Wang
logistic regression
Advisor: Doucet, A