VictorJuiz/thesis huggingface dataset:
Adult height and the risk of cardiovascular diseases: investigating causality using genetic associations in two ethnically diverse populations

Background: Taller adult height has been associated with lower risk of most vascular and respiratory diseases, but higher risk of other diseases (cancer and some vascular diseases) in studies predominantly from European populations. The causal relevance of height for different cardiovascular diseases remains unclear.
Methods: Instrumental variables for height were constructed from up to 3200 genetic variants having genome-wide significant association with height in published European ancestry based sources. Conventional observational and causal genetic associations (Mendelian randomisation analyses) of 1 SD (~6.5 cm) taller height with cardiovascular diseases and risk factors were assessed in 1M participants from the UK Biobank (UKB) and the China Kadoorie Biobank (CKB) studies, supplemented with data from CARDIoGRAMplusC4D and METASTROKE consortia.
Results: The genetic instruments selected explained 16.9% of the variance of height in UKB but only 10.5% in CKB. The association of genetically elevated height was inversely associated with coronary artery disease (odds ratio [OR] per 1 SD taller height: 0.87; 95% CI: 0.84, 0.89; n=78 960 cases), systolic blood pressure and LDL cholesterol, positively with atrial fibrillation (1.32; 95% CI: 1.27, 1.38; n=13 365) and lean body mass, but null with ischaemic stroke overall. However, for ischaemic strokes subtypes available in METASTROKE, the association was inverse with large-vessel stroke (OR: 0.91; 95% CI: 0.84, 0.99; n=2167) and positive with cardioembolic stroke (1.13; 95% CI: 1.05, 1.22; n=2365). Genetically elevated height was also positively associated with all ischaemic stroke among UKB and CKB participants with atrial fibrillation. Observational and genetic associations with diseases were directionally consistent, and were inverse with haemorrhagic stroke (n=7819, mostly from CKB).
Conclusions: Genetically elevated height is inversely associated with occlusive cardiovascular diseases, potentially mediated by blood lipids and blood pressure, but also positively associated with atrial fibrillation and cardioembolic stroke, potentially through its association with lean body mass.

Keywords: height
Mendelian randomisation
cardiovascular diseases
Advisor: Parish, S
Clarke, R
Improvements in electron cryo-tomography towards understanding virus surfing

Electron cryo-tomography (cET), in combination with sub‑volume averaging (SVA), is a powerful technique for determining the structure of complex biological specimens that are not amenable to more traditional structure determination methods. In Chapter 1, SVA was used to achieve a sub-nanometre resolution structure of Herpes simplex virus 1 glycoprotein B in its pre-fusion conformation. Nevertheless, several challenges still undermine the routine use of cET for structural cell biology. Imaging with an electron beam damages specimens, leading to localised warping of tomograms and reduced resolution of SVA maps if not compensated for. Using densities of biological structures within tomograms as fiducial markers is one solution to this problem. A software implementation of this concept, termed ‘Flexo’ and its application is demonstrated in Chapter 2. While this improves tomogram quality, other issues persist. The lack of a specific labelling technique for cET often limits the use of SVA to large and recognisable structures; correlation with super‑resolution cryo-fluorescence microscopy (cryo‑FM) is a promising solution. The primary drawback of this technique has been devitrification induced by the high laser intensities typically required. Chapter 3 describes Cryo-SOFI as a general solution to this problem, enabling substantial resolution improvement in cryo‑FM, and allowing cET to be performed in a correlative fashion. Chapter 4, explores the avenues of combining live-cell FM imaging with cET to study the transport of virus particles along cellular protrusions, called virus surfing. Events of surfing and static viruses can look alike in cET snapshots, making it necessary to link these high-resolution observations with their dynamic history. This led to the development of techniques towards live-CLEM: correlative live‑cell light and electron microscopy, which also revealed that cells undergo major structural changes during the preparation for cryogenic preservation. Overall, the work presented in this thesis presents a number of promising solutions to overcome some major obstacles for cET to fulfil its full potential for in situ structural cell biology.

Keywords: Virus surfing
Cryogenic specimen warping
Flexo
CryoET
Membrane fusion protein
Cryo-SOFI
MLV
Cryo-FM
HSV gB
Herpes Simplex Virus
sub-tomogram averaging
HSV glycoprotein B
Super-resolution cryo-fluorescence microscopy
Murine Leukemia Virus
CryoEM
sub-volume averaging
Electron Cryo-Tomography
Advisor: Grünewald, K
Modal ethics: the role of counterfactuals in stoicism

This paper argues that interpreting Stoic compatibilism through the lens of Chrysippus’ modal logic (specifically his account of counterfactual possibility) reveals a broader understanding of moral responsibility than is typically discussed. Moreover, this understanding suits the school’s emphasis on human nature and moral improvement. To the Stoics, the moral agent is considered responsible for all acts of assent (and thus all impulses, beliefs and thoughts) but modal responsibility goes beyond this. If the agent is considered responsible in the presence of a counterfactual opportunity to act otherwise - even in circumstances that she was not immediately able to control – then she is forced to consider the notion of internal consistency and temporalised understanding of external hindrance employed by Chrysippean possibility. Thus, moral responsibility understood this way encompasses an understanding of the agent’s nature as a being that is teleologically capable of virtue and a consideration of her future moral development. The paper attempts to consider the interweaving system of logic, physics and ethics in a holistic manner to reveal the full scope of Stoic responsibility.

Keywords: Stoic Logic
Ethics
Ancient Logic
Logic
Determinism
Compatibilism
Modal Logic
Ancient Philosophy
Stoicism
Advisor: Durand, M
Adaptation and genetic conflict

Genes that increase organism fitness can come to prominence as a result of natural selection, leading to the appearance of organismal design, or ‘adaptation’. However, genes that compromise organism fitness can also come to prominence if they are able to secure a selfish propagation advantage from doing so. Such genes are called ‘selfish genetic elements’. I consider the consequences of selfish genetic elements for organismal design (adaptation). First, I consider a fungus in which – strikingly – different nuclei in the same individual may be genetically different from each other (‘chimera’). I show how such diversity could be maintained by natural selection, and what consequences this has on the organism. Second, I consider, in general and in a range of specific biological scenarios, whether selfish genetic elements might be expected to gain control of organism traits. I show that the ‘parliament of genes’ is generally effective in suppressing selfish genetic elements, meaning organism design is generally preserved. Third, I ask whether animals can, in principle, evolve to recognise kin via genetic cues. I show they often can, as long as genetic kin discrimination is favoured, over indiscriminate cooperation and indiscriminate defection, at the individual level (it maximises individual fitness).

Keywords: Genetic Conflict
Adaptation
Advisor: West, S
Optimising the outcomes of the Oxford unicompartmental knee replacement

The two main surgical options for knee arthritis are total knee replacement (TKR) and unicompartmental knee replacement (UKR). UKR has advantages over TKR but has higher revision rates. As a result, UKR only forms 10% of all primary knee replacements. The broad aims of this thesis were to determine; the long term implant survival of the Oxford UKR and to assess current and develop new evidence based strategies to reduce revision rates.
A systematic review investigating the long term outcomes of 8,658 Oxford UKRs found the 10 year implant survival was 93% with leading revision causes including aseptic loosening, pain and bearing dislocation. There was a lack of cementless studies.
A large prospective cementless Oxford UKR cohort study (n=1000) in Oxford allowed the assessment of long term clinical outcomes using various endpoints; reoperation, revision and revision to TKR. The respective 10 year survivals were 96.6%, 97.5% and 98.9%.
A retrospective observational study from the National Joint Registry (NJR) was used to compare the long term outcomes of 14,814 matched cemented and cementless UKRs. The cementless group has significantly reduced revision rates (HR=0.76) given rates of revision for aseptic loosening, pain and lysis decreased. However the revision rate for peri-prosthetic tibial fracture increased. These results were mirrored by a systematic review comparing fixation types for all UKR types (n=10,736).
Other retrospective observational studies from the NJR were used to investigate the effect on revision rates of (1) increasing surgeon caseload, (2) Microplasty (new guiding surgical instrumentation) and (3) adding a second femoral peg on revision rates. All three were associated with lower revision rates.
A radiostereometric study of polyethylene wear was undertaken to determine why an increased rate of bearing fracture has been observed. The wear rate for the current bearings are 57 μm/year which is substantially higher than in previous studies. Although moulded bearings were found to have less wear than machined, no factors studied including recent changes to the bearing resin or manufacture accounted for the increased wear.
An experimental study found that new wider surgical saw blades halved the force required to seat the tibial component whilst maintaining fixation achieved. This should reduce the risk of periprosthetic fractures and is now used clinically.
This thesis has characterised the performance of the Oxford UKR and has highlighted strategies to lower UKR revision rates, to levels similar of TKR. If this is achieved the only real disadvantage of UKR compared to TKR will have been addressed.

Keywords: Clinical outcomes
Unicompartmental knee replacement
Advisor: Mellon, S
Murray, D
Judge, A
Valued: A participatory ethnography of the gender lens investing movement

Research in socially responsible investing (SRI), corporate social responsibility (CSR), environmental, social, and governance (ESG) factors, and social impact investing focuses on how social issues are introduced into finance after an organization, institution or investor has accepted the integration of the social issue (post-acceptance perspective). However, advocates start the introduction of these issues into finance decades before a post-acceptance perspective can be studied. Through a case study of investing in women or gender lens investing, this study explores the process, motivations and resistance experienced by advocates introducing social issues into finance. A multi-method approach was used to triangulate findings through participatory ethnography, desk research, attendance at public conferences, roles in intimate gatherings of advocates, participation in projects, and a series of 42 formal interviews with advocates, both men and women, in Australia, Canada, the UK, and the US. Findings show that the process for introducing social issues into finance from an early advocate perspective is challenging, non-linear, fraught with resistance, and requires an understanding and acceptance of different frames of reference and subgroups amongst individual advocates. In the case of investing in women it was found that individuals advocate from three distinct frames of reference: a development champion perspective focused on measures, impacts and counts; an integrated financial risk perspective focused on financial indices and alpha returns; and a visionary value perspective focused on experimentation, innovation, paradigm-shifts, and seeing value or worth in things previously undervalued or not valued. Study findings provide an understanding of the motivations and process that is used by early advocates to introduce social issues into finance and provides a framework for future research of gender lens investing (or the introduction of gender issues into finance).

Keywords: Impact Investing
Socially Responsible Investment
Resistance
Investing in Women
Advocate
Gender Lens Investing
Finance for Social Change
Advisor: Scott, L
Global legal institutions in local contexts: the making of commercial arbitration in China

The study to be presented here examines the practical processes and outcomes of commercial arbitration in China. It aims to provide an anthropological account that illustrates and explains how a transnational legal institution such as commercial arbitration is implemented in the contexts of Chinese arbitral organs and local bureaucratic sectors. Specifically, this thesis takes on two tasks. The first is to identify and present some of the Chinese arbitral practices that can be described as “vernacularized” due to their deviance from the “best practices” of international arbitration law. In particular, I am concerned with practices that pertain to aspects of institution-building and dispute-processing. The second is to analyze what may be the “local factors” – in both institutional and sociocultural terms – that contribute to these practical results of vernacularization. Drawing on my twelve-months ethnographic fieldwork in China, I show that opposed to the Euro-American model that it borrows, Chinese commercial arbitration has become highly bureaucratized and mediatory. I argue that these drifts towards state bureaucracy and mediation can be explained by a distinct mode of “reasoning” in which the aspiration to state authority operates as a presumptive constraint on how local actors consider their compliance or other forms of engagement with legal rules. For participants observed, this constraint is not necessarily absolute, but it does have a presumptively decisive force that tends to undermine other competing reasons for engaging with law. By foregrounding the deliberative aspect of transnational legal practices in their local settings, what I attempt to achieve is to better identify and explain its relationship with the broader “sociocultural” conditions with which local actors are entangled. In so doing, it is my hope that this study would not only help better explain China’s frequent deviance from its commitment to the rule of law but also break fresh ground in studying legal phenomena anthropologically in the Chinese society and beyond.

Keywords: commercial arbitration in China
legal anthropology
Chinese arbitration
Advisor: Clarke, M
An ecological approach to Aristotle’s theories of light and vision

Scholarship on Aristotle’s theory of visual perception has traditionally held that Aristotle had a single, static conception of light and that he believed that illumination occurs prior to and independent of the actions of colours. I contend that this view precludes the medium from becoming actually transparent, thus making vision impossible. I offer an alternative to the traditional interpretation, using contemporary conceptual tools to make good philosophical sense of Aristotle’s position. I call my view the ‘ecological’ interpretation. It postulates two conceptions of light: non-visible mobile propagated light and visible static illumination, produced by the interaction of propagated light with the environment’s coloured textured surfaces. I argue that these contemporary conceptual tools can find a foothold in and consistently enrich Aristotle’s extant position and that, with their aid, we can restore coherence to his theories of light and vision.

Keywords: perception
light
illumination
vision
Aristotle
Evaluating inquiries

How should we go about collecting evidence when we’re looking to settle some question? In this thesis, I develop and defend an account of the evaluative and normative epistemic dimensions intrinsic to the practice of evidence-gathering. Chapter 1 introduces the topic. Chapter 2 is devoted to laying out the positive proposal, which makes use of the notions of accuracy and competence to spell out the conditions under which an act of evidence-gathering is successful, rational, and skillful. It also shows how the account can be applied to the simple case of inquiry into polar questions as well as to the more complex cases of inquiry into wh-questions and subject matters. Chapters 3 and 4 provide arguments for accepting the account. Chapter 3 zooms in on the central notion of the proposed account, accuracy gain, and argues that such a notion independently provides the best available measure of information value, namely the usefulness of a certain piece of information given the aim of settling a certain question. This is done by showing that accuracy gain fares better than competing measures from information theory, Bayesian statistics, and decision theory on a number of fronts. Chapter 4 first looks at how the proposed account fares vis-à-vis three main competing views about the aim of inquiry, arguing that it emerges as superior in several respects. Then, the Chapter considers three objections that may be raised against the proposed account, and argues that these can be met. Chapter 5 concludes by looking at potential avenues for future research.

Keywords: Inquiry
Accuracy Gain
Information Value
Evidence-gathering
Advisor: Williamson, T
Investigating the links between the nuclear RNA exosome and RNA export in fission yeast

Production of the correct amount of functional RNA molecules is vital for cell survival. This can be achieved at different times during the life of an RNA molecule, starting with RNA synthesis and ending at RNA degradation, whilst passing through maturation and transport inside the cell. In eukaryotes, an important player in RNA regulation is the essential multi-protein 3’ to 5’ RNA exosome complex. This molecular scissor monitors the correct maturation and levels of a diverse variety of protein-coding and non-coding RNA transcripts as well as plays a role in the export of RNAs from the nucleus to the cytoplasm. However, the molecular mechanism underpinning various functions of the exosome in RNA regulation are not well understood. The work presented here explores the possible links between a predicted export protein Sbp1, component of Ran GTPase complex and the nuclear RNA exosome. This study characterises Sbp1 and links Sbp1 to Dis3, the main catalytic RNase of the exosome, accentuating the relation between RNA export and decay. Secondly, this study uses the data collected from the poly(A)+ interactome to investigate possible mechanisms involved in substrate recognition by the nuclear RNA exosome. These results propose a two-step mechanism of RNA substrate recognition in which a specific ribonucleoparticle is assembled and then targeted by the nuclear exosome, which is coordinated by the essential helicase Mtl1/Mtr4.

Advisor: Vasilieva, L
Patents and fundamental rights in U.S. law: Excessive drug pricing as an instance of Unfair Competition

The United States suffers from a “resource curse” of essential medicines. It has great industrial and commercial capacity to meet the essential medicine needs of its citizens, yet by and large, average consumers struggle to obtain the drugs on which they depend to maintain a subsistence level of health due to the exorbitant drug pricing. As a result, they face a dilemma between paying the prices charged for access to the drugs or continued ill health. I believe that denying access to essential medicines on reasonable terms constitutes a form of injury to them. This thesis conceives of restrictive access’s injurious effects on consumers as a legal harm and sees its lack of recognition in law as an explanation for the problem’s continued existence. Traditional legal restrictions on patentee conduct, based on principles of patent misuse and antitrust, are unable to properly address this injury. While this might suggest a need for legal reform, there exists another solution almost entirely overlooked by commentators. This solution is the law of unfair competition, specifically its Unfairness Doctrine. In this thesis, I argue that the Unfairness Doctrine supports a tort-based cause of action against those who rely on patent rights to exclude consumers from access to essential medicines on reasonable terms. As such exclusion causes harm to consumers’ autonomy and bodily integrity, I further argue that even if the Unfairness Doctrine does not apply, the nature of this harm, combined with the duty of the state to protect the fundamental rights of its citizens, supports legal intervention to prevent the excessive pricing of essential medicines.

Advisor: Pila, J
Investigating the links between transcription and mRNA 3' end processing

RNA Polymerase II (Pol II) is responsible for transcribing all protein coding genes and some non-coding genes. Protein-coding mRNAs undergo extensive processing during Pol II transcription in order to become functional molecules. This includes 5’capping, splicing and 3’end cleavage and polyadenylation. mRNA processing is coordinated by the phosphorylation of the Pol II carboxy-terminal domain (CTD) and has been shown to be affected by transcription rate. However, the molecular mechanisms underpinning regulation of mRNA processing by transcription are not well understood. Here, I aim to address this by establishing an in vitro system which allows to the study of processes linked to transcription such as mRNA 3’ end processing. The work presented here contains detailed studies of Pol II Rpb1 mutants that show opposite effects in RNA processivity and transcription rate using an in vitro transcription system and state-of-the-art in vivo approaches such as PRO-seq (in collaboration with the postdoctoral visitor), studying how transcription rate contributes to the ability of Pol II to interact with factors and reconstitution of the 3’ mRNA processing machinery that is involved in cleavage and polyadenylation.

Keywords: CPF
transcription rate
RNA Polymerase II
Seb1
in vitro
mRNA 3' end processing
Advisor: Vasilieva, L
Optimization for and by machine learning

Optimization and machine learning are both extremely active research topics. In this thesis, we explore problems at the intersection of the two fields. In particular, we will develop two main ideas.
First, optimization can be used to improve machine learning. We illustrate this idea by considering computer vision tasks that are modelled with dense conditional random fields. Existing solvers for these models are either slow or inaccurate. We show that, by introducing a specialized solver based on proximal minimization and fast filtering, these models can be solved both quickly and accurately. Similarly, we introduce a specialized linear programming solver for block bounded problems, a common class of problems encountered in machine learning. This solver is efficient, easy to tune and simple to integrate inside larger machine learning algorithms.
Second, machine learning can be used to improve optimization, in particular for NP-hard problems. For problems solved by using hand-tuned heuristics, machine learning can be used to discover and improve these heuristics. We show that, for the problem of super-optimization, a better heuristic to explore the space of programs can be learnt using reinforcement learning. For problems where no such heuristics exist, machine learning can be used to get an approximate solution of the original problem. We use this idea to tackle the problem of program synthesis by reformulating it as the problem of learning a program that performs the required task. We introduce a new differentiable formulation of the execution and show that the fastest programs can be recovered for simple tasks.

Keywords: Conditional Random Field
Continuous relaxations
Machine Learning
Optimization
Linear Programming
Advisor: Torr, PHS
Kumar, MP