VictorJuiz/thesis huggingface dataset:
Human-based computational investigations into cardiac electromechanical alterations caused by drugs and hypertrophic cardiomyopathy

The assessment of drug safety and efficacy remains one of the biggest challenges in preclinical and clinical drug development. The prediction of drug action on cardiac contraction and electrophysiology is especially complex and diseased cardiac substrates are at a higher risk of developing potentially lethal reactions to pharmacological therapy. A deep mechanistic understanding of drug action in the context of specific cardiac pathophysiology is needed to guide the development and administration of effective and safe patient-specific therapies. These mechanistic understandings are still unknown for many cardiac diseases in particular cardiomyopathies. Most cardiomyopathy treatments focus on symptom relief, which do not specifically target disease pathophysiology. Therefore, defining key mechanisms in inherited cardiomyopathies due to specific genetic mutations is needed to develop novel effective pharmacological interventions that are patient specific.
Human-based modelling and simulation can accelerate the mechanistic understanding of cardiac pathophysiology and the development and evaluation of therapeutic interventions through human in-silico trials. Thus, the overall goal of this thesis is to develop computational methodologies integrated with experimental and clinical data to investigate the mechanisms explaining the cardiac safety and efficacy of pharmacological therapies in health and hypertrophic cardiomyopathy.
To achieve this goal a novel in-silico human electromechanical ventricular modelling and simulation framework was developed, and mechanistic simulations conducted to assess drug-induced pro-arrhythmia and inotropic risk in healthy cardiac function. Next, a novel software tool was developed to provide automated high-throughput analysis of calcium transients in cardiomyocytes. This was used to phenotype primary and induced pluripotent stem cell-derived cardiomyocytes under pharmacological action and hypertrophic cardiomyopathy variants. Analysed data was used to inform a computational investigation into the pathophysiology of three different hypertrophic cardiomyopathy-causing mutations and their response to the novel pharmacological compound Mavacamten. To conduct in-silico trials of Mavacamten, the cellular electromechanical model was extended to include representation of myosin sequestration and release from the energy-conserving state SRX.
Overall, this thesis contributes towards a better understanding of how cardiac electromechanical substrates are affected by disease and pharmacological action and holds both preclinical and translational potential for precision medicine in inherited cardiomyopathies.

Advisor: Rodriguez, B
Bueno Orovio, A
Toepfer, C
The unwritten constitution in Britain and China

This thesis is about the unwritten constitutions of Britain and China. Britain has no written constitution. China’s written constitution is a small part of its unwritten constitution. By comparing these two unusual constitutional orders, the thesis sheds light on the nature of the constitution, the way that written and unwritten constitutions interact and the relationship between the unwritten constitution and a theory of the state.
There is a strict sense in which we can describe the rules of a written constitution as constitutional. In contrast, when we describe unwritten rules as constitutional, we need to specify what we mean by ‘constitutional’. In this way, an inquiry into the unwritten constitution leads us to a substantive account of the constitution. This thesis considers how these two states develop that substantive account. In doing so, it reveals contrasting, unwritten theories of the state and of the constitution, which pose questions of general importance for constitutional theory.

Keywords: UK
unwritten constitution
China
Advisor: Barber, N
Modulation of T-regulatory cells by small molecules: potential therapy for GvHD

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is often curative for patients suffering from blood cancers. Nonetheless, significant morbidity and mortality are still prevalent. One major complication is graft versus host disease (GvHD) which occurs in 30-70% of patients. In this disease donor T-cells recognise the host as foreign and subsequently expand and attack the host’s tissues and organs. T-regulatory cells (Tregs) are a subpopulation of T-cells which promote anti-inflammatory immune responses and suppress T-cell activation and proliferation. It has been demonstrated that a high proportion of Tregs in the donor graft significantly reduce the occurrence of acute GvHD and increases overall survival. However, modern techniques have failed so far to routinely expand Tregs in the clinic due to many reasons including lineage instability and cost. This thesis explores the repurposing of two drugs, Atorvastatin and Vitamin D, which have an excellent safety profile, are cheap and easy to use, to boost Treg numbers and modulate distinct immune cell populations. The drug combination efficiently elevates Treg numbers, inhibits pathogenic CD4+ T-cells and suppresses Tcell proliferation. In addition, it induces a tolerogenic phenotype, at the transcriptional and translational level, in monocyte-derived dendritic cells. Atorvastatin and Vitamin D treatments are a viable approach to boost Treg numbers in the donor as well as combating GvHD in the recipient.

Advisor: Roberts, D
Are moral beliefs ideological? A reconstruction and assessment of Karl Marx's critique of morality

The question of whether moral beliefs are ideological has important implications for philosophy and society. Since the publication of John Rawls’s A Theory of Justice in 1971, much political theory has attempted to develop moral principles to guide state action. Similarly, a prominent concern of ethicists has been to deduce the requirements moral principles impose on individuals. More broadly, moral beliefs pervade the life of every person. They determine how we view the world and situate ourselves within it.
This thesis answers this question through a reconstruction and assessment of Karl Marx’s critique of morality. In Chapters 2 and 3, I construct Marxian conceptions of morality and moral ideology. In Chapter 4, I construct and defend a Marxian thesis about the development of moral beliefs I call the dominant moral norm thesis. The thesis states that an economically dominant class will likely have disproportionate influence in determining the content of any dominant moral norm and that the dominant moral norm often has the function of sustaining the existing status quo. In Chapter 5, I argue that some moral beliefs are ideological owing to the plausibility of the dominant moral norm thesis. I conclude that not all moral beliefs are ideological, but that beliefs justified solely through intuition are at particular risk of being ideological. I offer several concluding thoughts in Chapter 6, including on a possible objection to my approach and on the implications of my thesis.

Keywords: political theory
Advisor: Leopold, D
China, AI, robots, taxation: essays in applied microeconomics

This thesis consists of four self-contained essays in applied microeconomics. The first exploits China’s accession to the WTO to investigate the impact on Indian manufacturing firms of improved access to intermediate inputs, and finds a persistent quality-upgrading effect which ripples out across the production network. The second examines the impact of artificial intelligence on hiring and wages in the Indian service sector, using a novel dataset of 15 million online vacancy posts, and finds evidence of direct negative effects within incumbent firms. The third paper explores the impacts on developing countries of robot adoption at home and abroad, drawing on industry- and firm-level robot data from a wide range of countries, and outlines the groups most likely to benefit – and those most likely to lose out. Finally, the fourth paper investigates the sources of observed heterogeneity in VAT pass-through, using reforms across 14 Eurozone countries between 1999 and 2013, and finds important roles for product market regulation and product quality.

Keywords: Artificial intelligence
International trade
Microeconomics
Value-added tax
Industrial robotics
Advisor: Woodruff, C
The politics of judicial review in inter-war Europe

Why do some politicians choose to tie their own hands by empowering courts to review the constitutionality of legislation? This is a persistent question in judicial politics. According to a popular rational choice theory, politicians accept judicial constraints on their power because they seek “insurance” against costs they might incur during future periods in opposition. Hence, the key variable favouring support for judicial review is electoral alternation.
This theory fails to explain some cases where politicians oppose judicial review despite a competitive, democratic political system. I argue that some of these cases are explained by the expectation of a slant of judicial review against the policy agenda of a part of the political spectrum. Such a slant is more likely where judicial review primarily safeguards policy-interactive legal provisions, such as rights, rather than policy-indifferent provisions, such as the provisions demarcating the powers of different levels of government in federations. Hence, judicial review is more likely to find broad political support where it is expected to safeguard primarily the boundaries between state and federal powers, rather than rights.
Using secondary and primary sources, I test this argument in case studies of three inter-war democracies – Norway, Weimar Germany, and the First Austrian Republic. In the first two countries, left-wing politicians, especially socialists, opposed judicial review for at least some time, whereas Austrian Social Democrats supported judicial review throughout the First Republic. My argument partly explains these differences: In Norway and Germany, judicial review emphasised safeguarding rights, raising concerns that the courts would obstruct progressive social policies. In Austria, judicial review hardly protected rights against the legislature; its purpose was primarily the adjudication of federalism-related conflicts. Hence, Austrian Social Democrats did not expect it to obstruct their policy agenda. Instead, they benefited from judicial safeguards of their control over the state of Vienna.

Keywords: Weimar Germany
inter-war Norway
judicial review
judicial politics
inter-war Europe
First Austrian Republic
constitutional courts
constitutional rights
constitutional history
constitutionalism
Advisor: Gonzalez Ocantos, E
Rueda, F
Non-smooth optimisation applied to improving steam turbine designs

This project is motivated by Siemens’ desire to improve the efficiency of their steam turbines. Siemens has developed a software called 3dv1d which tests a theoretical steam turbine design both for efficiency and practicality. By using 3dv1d to define black box objective and constraint functions, we can find optimal steam turbine designs by applying mathematical optimisation software.
We begin by investigating the optimisation algorithm currently used by Siemens, which is known to yield good steam turbine designs for Siemens even though it does not converge to a point which satisfies optimality conditions. This investigation reveals that this algorithm fails because the efficiency function is not continuously differentiable. Since the algorithm currently used is a smooth optimisation algorithm, this means its failure follows from the fact that it is not suitable to the problem.
Next we explore the literature for existing non-smooth optimisation (NSO) algorithms which may be suitable for solving the problem. We identify one of these as being most applicable, and test its effectiveness only to find that it runs too slowly to be useful in practice.
Our continued exploration of the topic of non-smooth optimisation led us to the particular topic of exact line search for non-smooth optimisation, and more specifically non-smooth 1D optimisation. Here we have noted that many of the objections to using ELS do not apply in the context of NSO. Moreover, while the topic of 1D optimisation has been well developed, there is a surprising absence of any algorithm capable of robust super-linear convergence when applied to 1D NS functions. Our main contribution to mathematics through this project has been to construct a new algorithm to fill this void.
In addition to this, we have also addressed the larger problem motivated by Siemens: to robustly locate local optima for functions like that implied by 3dv1d. While not being as rigorous as in 1D optimisation, we have constructed a heuristic for the purpose of solving problems like Siemens’ which we demonstrate both to perform robustly and often find the best known solution.

Keywords: non-smooth optimisation
exact linesearch
Advisor: Hauser, R
Ruehle, T
Welsh mythology and folklore in the novels of Arthur Machen, John Cowper Powys and Alan Garner

This thesis traces a line of engagement with Welsh mythology and folklore in British fiction from the fin de siècle Celtic Revival through to the 1960s and beyond. It argues that the three writers Arthur Machen, John Cowper Powys and Alan Garner, each attuned to the importance of local place and region, turn to Wales – or in various senses back to Wales – as a country whose traditions could be used to revive or reinvent aspects of life in Britain which they considered lost or in the process of disappearing. To varying extents, all three writers negotiate a relationship with Wales and ‘Welshness’ in their fiction and within this explore questions of ancestry, personal identity and what they view as the wider spiritual crises of an increasingly rational and industrialised society. Their conceptions of Wales as an alternative imaginative space in which their individual spiritualities and philosophies could more easily take shape than in England suggests that for these writers Wales exists as a place of transformation, liminality and magic, intimately connected to its mythological past. Their collected works of fiction are unique in this way; informed by, and at times working against, modern constructions of a romantic Celtic mysticism, this thesis demonstrates how the mythology and folktales of Wales are developing influences across Machen, Powys and Garner’s work, and provide the narratives and symbols necessary for exploring questions of spirituality, inherited tradition and the immaterial in the rationalised world of late nineteenth and twentieth-century Britain.

Keywords: Cheshire
John Cowper Powys
comparative mythology
Celtic mythology
folklore
Alan Garner
Arthur Machen
welsh mythology
The Mabinogion
Mysticism
Owen Glendower
Wales
romanticism
occultism
John Rhys
Alderley Edge
Jungian
The redox chemistry of oxygen in cathode materials for rechargeable alkali-ion batteries

There is a clear and urgent need for rechargeable batteries of higher energy density. Alkali-ion batteries based on Li-ions are the state-of-the-art, although Na-ion may offer a cheaper alternative. In both cases the cathode imposes the biggest limitation on overall energy density.
Alkali-rich cathode materials can store alkali-ions and electrons densely by invoking redox chemistry of both the transition metal (TM) and oxide ions in the lattice. However, O-redox is accompanied by voltage hysteresis, irreversible O-loss and complex structural changes. In this thesis, model Na-ion materials have been investigated to isolate and examine these phenomena.
Firstly, Na0.67[Mg0.28Mn0.72]O2, with Mg2+ ions occupying the TM layer rather than alkali-ions, is studied and shown to exhibit O-redox. This reveals that ionic interactions between the TM layer substituent and O are the necessary precondition for O-redox.
Secondly, by comparing the O-loss behaviours of Na0.67[Mg0.28Mn0.72]O2 and Na0.75[Li0.25Mn0.75]O2, the critical role of the TM layer substituent is revealed; when removed from the structure, the co-ordination number around O can drop below three and O-loss is triggered. Unlike Li+, Mg2+ is retained within the structure preventing O-loss.
Thirdly, O-redox materials Na0.75[Li0.25Mn0.75]O2 and Na0.6[Li0.2Mn0.8]O2 are studied in parallel to understand why the former exhibits voltage hysteresis and the latter not. The preservation of the TM layer ordering scheme is shown to prevent hysteresis maintaining stable electron holes on O2- in Na0.6[Li0.2Mn0.8]O2. For Na0.75[Li0.25Mn0.75]O2, severe in-plane TM migration destroys the ordering scheme, triggered by formation of molecular O2 gas which is directly evidenced for the first time in the bulk. Reduction of O2 occurs on discharge at low voltage giving rise to hysteresis.
Finally, a new Li-rich oxyfluoride, Li2MnO2F, with a stable disordered rocksalt structure is presented. Li2MnO2F stores charge utilising both Mn and O-redox with negligible O-loss demonstrating the potential of disordered rocksalts to deliver high energy densities.

Keywords: Disordered Rosksalts
Anion Redox
Cathode Materials
Oxygen Redox
Na-ion Batteries
Li-ion Batteries
Resonant Inelastic X-ray Scattering
Advisor: Bruce, P
Prolegomena to an internalist meta-ethics

A classic split in meta-ethics concerns whether there are mind-independent normative truths. Those like Derek Parfit and T. M. Scanlon maintain that there are such truths; others like Christine Korsgaard and Sharon Street reject that claim. This BPhil dissertation takes the latter approach to meta-ethics, which it calls an internalist meta-ethics, as its starting point. It then develops such an internalist meta-ethics in several ways. In Chapter 1, it discusses the difference between externalist and internalist accounts of the normative domain, and it motivates an exploration of the prospects of an internalist account. In Chapter 2, it asks which normative attitudes should be taken to ground normative truths for the internalist. It contends that much of the existing literature is mistaken in thinking that we must find one attitude that exhaustively grounds normative truths, and it argues that the broader notions of normative endorsement and rejection, which can run through different attitudes, are the proper grounds of normative truths. Finally, in Chapter 3, it asks whether internalism has the resources to meet prominent substantive objections that concern prudential goodness. Advancing two new internalist arguments, it contends that all rational agents, in virtue of continuing to make endorsements and rejections in the present, are committed to the conclusion that they have reason to pursue their strongest counterfactual endorsements – a result which can provide the internalist a promising rejoinder to the substantive objections in question. The conclusion of these explorations will be a cautious optimism about the prospects of internalism.

Keywords: internalism
meta-ethics
antirealism
moral philosophy
Advisor: Crisp, R
Rising seas and sinking islands: the geopolitics of climate change in Tuvalu and Kiribati 

Anthropogenic climate change is predicted to accelerate throughout the 21st century, with transformative impacts for biophysical and social systems. Due to their vulnerability to sea level rise and because of fears that they may be fully inundated, low-lying atoll states have been framed as spaces at the forefront of climate change. Questions have been raised over the future sovereignty, territorial integrity and identity of these states in a warmer and wetter world. This thesis explores climate change in relation to small island states from a critical geopolitics perspective by focusing on two Pacific atoll states: Tuvalu and Kiribati. It examines how space and time are influencing understandings of climate change within these states in relation to geopolitics, adaptation and diplomacy. Whilst geomorphologically similar, the perceived threat from climate change has been constructed, and responded to, differently in Tuvalu and Kiribati.
Employing a mixed-methods approach, this thesis draws upon fieldwork conducted in Tuvalu and Fiji as well as at the 2018 United Nations Climate Change Conference (COP24) held in Poland, consisting of elite interviews, participant observation and analysis of secondary sources. Through three substantive chapters, this thesis examines different aspects of the geopolitics of climate change. Firstly, it unpacks the construction of atoll states as “sinking islands” by drawing upon bodies of literature discussing vertical geopolitics and geographies of the ocean. It offers an insight into how scientific knowledge is co-opted, contested and propagated within climate geopolitics by considering the recent geomorphological and diplomatic dispute over the future of Tuvalu’s islands. Secondly, it argues that these debates are key in understanding how climate change adaptation is framed within island imaginaries. Resultantly, this research explores the spatialities and temporalities which underpin the geopolitics of adaptation in atolls. Finally, it is argued that the relationship between bodies, emotion and performance is a core component of Tuvalu and Kiribati’s diplomacy. Particular bodies are enrolled in emotional diplomatic performances to make climate change visible.
Overall, this thesis advocates that emotions are used to disrupt the privileged position of science within climate diplomacy, and scholars should be more attentive to the spatiality of emotions in order to better understand the power relations in diplomacy. It contends that spatial imaginaries, temporalities and emotions are intertwined within topographic anxieties of climate change that disrupt the process of territorialisation. This thesis argues that climate change adaptation is both performative and prefigurative and a key process for states to resist hegemonic climate narratives. Finally, it asserts the importance of methodological approaches that amplify and take seriously the voices of those affected by climate change.

Keywords: Tuvalu
climate change
Kiribati
adaptation
geopolitics
diplomacy
Advisor: McConnell, F
Klinke, I
Trade and protectionism in interwar Germany

Germany’s trade policy underwent many paradigm shifts throughout its modern history, but none were as dramatic as the year 1930 when, at the height of the Great Depression, the German government abandoned a policy of moderate free trade and re-integration in the world economy to set Germany on a path towards autarky. This dissertation takes advantage of newly transcribed, highly disaggregated data on the structure of German interwar trade to investigate questions related to the causes and consequences of this paradigm shift.
I first use socioeconomic data at the district level combined with electoral data to show that Germans’ voting intentions were well-aligned with their trade policy preferences. The correlation between trade exposure and votes for protectionist parties became stronger over time, both within the agricultural sector and between different industries.
I then use data on the universe of German trade to investigate the structure of the interwar trade collapse and find parallels to the 2009 Great Trade Collapse and the British trade crash during the Great Depression. The decline occurred primarily at the intensive margin. Industrial goods were hit harder in the early years than consumer goods, but this correlation is reversed in later years. Trade in non-differentiated goods fell more than trade in differentiated goods. Deflation played a much bigger role in the decline of trade values than in 2009 and the crash was less geographically balanced.
Finally, I construct a computable general equilibrium model to test the impact of trade policy on imports. I find that the shift towards protectionism alone caused a decline in trade as big as the entire 2008/09 trade collapse in Germany. This shift was concentrated in three sectors: fuel, consumer goods, and food. However, trade policy mattered very little for the geographical shift towards the Reichsmark Bloc in the 1930s.

Keywords: Great Depression
trade
Germany
protectionism
20th century
economic history
interwar period
Advisor: O'Rourke, K
Broadberry, S