VictorJuiz/thesis huggingface dataset:
Statistical models of gene-environment interactions
Keywords: Bayesian statistics

Despite longstanding interest in gene-by-environment (GxE) interactions, the contribution of GxE interactions to complex disease in humans remains poorly characterised. Studies of GxE interaction are statistically challenging due to the inherent high dimensionality of environmental exposures, the increased sample size required to robustly detect GxE effects and the historic lack of large datasets that combine genetic and environmental data. In this thesis I introduce a new approach for GxE interactions with multiple environmental variables on biobank scale datasets called LEMMA (Linear Environment Mixed Model Analysis). LEMMA uses a Bayesian whole genome approach to jointly model SNP marginal effects and SNP GxE interaction effects with an Environmental Score (ES). The ES is a linear combination of multiple environmental variables, and 'interaction weights' used to construct the ES are learnt in the same Bayesian framework. The ES can subsequently be interpreted directly, used in single SNP hypothesis or used for heritability estimation. Using variational inference to fit the model and a distributed computational architecture allows LEMMA to be computationally tractable on Biobank scale datasets.
LEMMA is compared to existing single-SNP approaches that jointly model the effects of multiple environmental variables at each locus. Results suggest that LEMMA has substantially greater power to detect GxE effects when the underlying model assumptions hold.
I have applied LEMMA to model GxE interactions in body mass index, systolic, diastolic and pulse pressure, using 42 environmental variables and approximately 280,000 white British individuals from the UK Biobank. LEMMA uncovered 3 loci with GxE interactions at genome wide significance levels, and estimated that 9.3%, 3.9%, 1.6% and 12.5% of phenotypic variance is explained by GxE interactions, and that rare variants explain most of this variance.
In my final chapter I suggest a new model, referred to as RHE-NLS, that promises to achieve many of the same objectives as LEMMA with improved computational complexity.
Structural basis of positive modulation of type-A GABA receptors
Keywords: structural biology
nanobody
GABAA receptor
cryo-electron microscopy

The GABAARs is the main inhibitory neurotransmitter receptor in the brain, and is primarily responsible for maintaining the excitatory-inhibitory balance in neurons on which normal function of the nervous system depends. This receptor is subject to modulation by several endogenous and pharmacological agents, which can have dramatic effects on the brain and behaviour. Common examples of drugs acting GABAARs include anaesthetics, anxiolytics and sedatives. In particular, there has been great interest in developing drugs against the α2- and α3-containing GABAARs because of their roles in pain and anxiety. The aim of the work described in this thesis was to investigate modulation of GABAARs by positive modulators. In particular, because nanobodies raised against GABAARs have previously been shown to positively modulate the α1β3γ2L receptor, new nanobodies were raised against the α2β3 and α3β3 GABAARs, in the hope of obtaining specific modulators. These were characterised for affinity and modulatory activity at their respective GABAARs, and several high-affinity nanobodies that act as positive allosteric modulators were identified. In order to investigate the structural effect of these nanobodies, methods for expression and purification of full-length heteromeric GABAARs were then investigated. A comparison of transient transfection, BacMam and stable cell lines indicated that the highest expression was obtained from HEK293 cells stably transduced with triheteromeric GABAARs. After developing a method for purification of these receptors, the interaction of the α3β3γ2L GABAAR with one nanobody, α3β3nb173, was investigated by single-particle cryo-EM. Several datasets were collected, and the best map had a nominal resolution of 3.8 Å. This map revealed a novel modulatory site on the GABAAR, at the top of the β+/α- interfaces and above the GABA binding site. These findings have implications for the discovery of novel drugs against the GABAAR, potentially of major clinical importance, either by using nanobodies directly or developing compounds to mimic their activity at this novel site.
The role of vigilance and alarm calling in the red junglefowl, Gallus gallus
Keywords: junglefowl
vigilance
sexual selection
alarm calling
anti-predation

Vigilance and alarm calling are considered exclusively anti-predator behaviours. However recent work suggests they may have other functions. My thesis explores the role of vigilance and alarm calling in red junglefowl, Gallus gallus. Male fowl are more vigilant than females and produce male-specific alarm calls for aerial predators. Chapter 2 tested hypotheses for male vigilance and aerial alarm calling by manipulating group size and sex ratio. Vigilance and alarm calling generally increased as groups became more female-biased, potentially reflecting compensation for reduced female vigilance. Chapter 3 explored how male vigilance and aerial alarm calling correlated with measures of male pre- and post-copulatory mating success; finding that more vigilant males and males that produced more alarm calls had higher mating success. One explanation for the link between male vigilance and alarm calling and mating success is that males invest more to protect their sexual partners to increase the survival of offspring that they may have sired. Chapter 4 tested this by experimentally manipulating male paternity confidence and mating success by allowing or preventing sexual access to a female in the presence or absence of male competitors. Males invested more in vigilance and alarm calling when they had sexual access to a female, regardless of the level of competition, which suggests that male investment is related to mating success per se. Finally, Chapter 5 considered the role of vigilance in females using two approaches. First, in mixed-sex groups females were three times less vigilant than males. Second, I examined whether female vigilance could play a role in foraging by allowing an individual to gather information on food location by watching a conspecific. I found no evidence that vigilance enables foraging females to gather information. Collectively, these results suggest that vigilance and alarm calling are linked to mating behaviour in male fowl.
Migration status and violence against women: four legal responses evaluated
Keywords: discrimination
trafficking
Istanbul Convention
domestic violence
domestic violence rule
migration status
violence against women (VAW)
EU Citizens' Directive
Trafficking Convention
compounded disadvantage

Violence against women (VAW) is constitutive of patriarchal dominance and a distinctive human rights violation. This thesis explores VAW in the context of migration, focussing on the main laws governing migration to the UK and within the EU. To do so, it develops a conceptual account of VAW, one that is grounded in international law and which establishes what is at the core of this wrong: interpersonal, discriminatory violence.
Part 1 of this thesis demonstrates that British immigration law disadvantages women, granting them migration statuses which make them dependent on others and which bestow few rights. Some of the rules that create this disadvantage are properly characterised as involving unlawful discrimination. This State-created disadvantage interacts with the extant risks and consequences of VAW in particular ways, including by granting its perpetrators access to the coercive power of the State. Not only does the State increase migrant women’s vulnerability to VAW, it compounds their experience of it.
States and others, including the EU, have recognised that some migrant women’s experience of VAW warrants an immigration law response. This has, however, been achieved in a piecemeal fashion, by establishing what this thesis characterises as ‘regimes of exception’. Part 2 evaluates four of these regimes. Chapter 4 examines two sets of rules which determine the migration status of some domestic violence victims. Chapter 5 analyses the European trafficking regime, whilst Chapter 6 focuses on the Istanbul Convention. Contrary to the obligations identified in Part 1, Part 2 demonstrates that the domestic violence and trafficking regimes provide a migration status which is reparative of the compounded disadvantage migrant women experience in only a minority of cases. Accordingly, this thesis argues for States’ and the EU’s full ratification of the Istanbul Convention, and for comprehensive migration status reform, including the abolition of dependent migration statuses.
An investigation of age-period-cohort models for individual-level data
Keywords: age-period-cohort
BMI
cohort
obesity
collinearity
identification

When dealing with temporal effects, there is a well-known identification problem that arises as a result of the linear relationship between age, period, and cohort. Kuang, Nielsen, and Nielsen (Kuang et al., 2008) approach this problem in the context of aggregate data by examining estimable functions of the parameters of the standard model of temporal effects. These functions are both uniquely identified from data and invariant to transformations of the parameters of the original model. This thesis extends their approach to study the standard model applied to individual-level data. A new test of fit for models of inter-temporal variation in individual-level data is developed, along with an algorithm for the test's implementation. These extensions are demonstrated in an application to BMI data from the Health Survey for England from 1995-2013, which yields suggestive evidence that age and period effects are of primary importance in this data.
Novel approaches to pancreas allograft surveillance
Keywords: Pancreas
Transplantation

Pancreas transplantation is a successful treatment option for selected patients with advanced complications of diabetes. It offers insulin independence, stabilisation of diabetic complications, and improved survival. However, these are largely conditional on long term pancreas allograft survival. Pancreas graft survival is poorer than that of other transplanted organs and this is mainly due to the absence of accurate and reliable techniques for monitoring the pancreas allograft. Irreversible damage has usually occurred to the pancreas before rejection is diagnosed, such that treatment which would otherwise have been effective, brings no benefit.
This thesis describes a number of novel approaches to pancreas allograft surveillance, aiming to identify graft injury early enough that treatment can be initiated before permanent damage occurs.
• The Homeostatic Model Assessment (HOMA) model has been modified to allow for systemic venous drainage of the endocrine pancreas. HOMAtx has been validated in a cohort of pancreas transplant patients with insulin secretion and sensitivity correlating well with the HOMAtx-derived outputs of %B and %S respectively. A lower threshold for beta cell function (%B) was identified that had a 100% sensitivity and 84.1% specificity for detecting diabetic glucose tolerance during oral glucose tolerance testing.
• Urinary C-peptide creatinine ratio (UCPCR) has been assessed as a marker of pancreas allograft function. Good correlation with serum C-peptide has been confirmed and the use of patient-directed remote monitoring via home UCPCR samples has been shown to be a potential tool for future allograft surveillance.
• The use of a donor-specific vascularised composite allograft or ‘sentinel skin flap’ to detect rejection in pancreas transplantation has been evaluated. Although isolated skin rejection was observed in 10% of patients, there was no associated rejection of the primary visceral allografts, suggesting that the SSF might be identifying an early alloimmune response and allowing treatment before clinical rejection has occurred.
Together, these studies represent novel approaches to pancreas allograft surveillance that may deliver incremental improvements that are required to advance overall outcomes.
Synthesis and biology of resolvins D3, E1 and hybrids and synthesis of bridge-substituted bicyclo[1.1.1]pentanes
Keywords: Bicyclo[1.1.1]pentane
Resolvin

This thesis consists of two projects, the first describes the development of a modular and enantioselective total synthesis of resolvins D3 and E1 using cyclic dimethyl alkenylsiloxanes. These potent anti-inflammatory polyenes are an integral part of the mammalian immune response, yet their structure-activity relationship remains poorly understood, a short coming that this work sought to address. The molecules were split into three fragments and three strategies have been examined for their unification. First, leveraging the different rate of transmetallation between 5- and 6-membered cyclic dimethyl alkenylsiloxanes; second, leveraging the different rate of transmetallation between 5-membered cyclic dimethyl alkenylsiloxanes and acyclic benzyldimethylsilanes and third, using the different rate of oxidative insertion into C-Br and C-I bonds. Ultimately, the latter strategy proved successful and was applied to the synthesis of resolvins D3 and E1 and hybrids.
The second project describes a novel synthesis of bridge-substituted bicyclo[1.1.1]pentanes (BCPs). Bridge-substituted BCPs offer unique opportunities in drug design and molecular engineering, as the bridge-substituents are placed at a dihedral angle relative to the linear 1,3-substituents, that cannot be achieved by current molecular scaffolds. Bridge-substituted BCPs were thought to arise from carbene insertion into 2-substituted bicyclo[1.1.0]butanes. These molecules are poorly precedented and three strategies were examined for their synthesis. First, via the synthesis or 2,3-disubstituted cyclobutanones; second, through a novel bis 3-exo-tet alkylation strategy and third, via the sequential synthesis of the respective cyclopropane, followed by a ring-closing alkylation. The last strategy proved successful and the examined 2-substituted bicyclo[1.1.0]butane was indeed a viable substrate for dichlorocarbene insertion which resulted in a proof of concept of the described strategy.
The movement for a society of peace:  Islamism and political sense-making in post-conflict Algeria
Keywords: MSP
Algeria
Islamism

This thesis seeks to broadly understand the role of social meaning-making in the formation, practices, and discourses of political challengers. Focusing on the case of Islamism in Algeria, I highlight how collective efforts to make sense of the 1989 political opening and the 1990s civil conflict have re-introduced into public contestation: the meaning of Islamist moderation, the role of religion in politics, Algerianness/nationalism, and the viability of political parties. Using ethnographic research focused on Algeria’s Muslim Brotherhood affiliate, the Movement for a Society of Peace (MSP) party, I show that such contested concepts factor prominently in how movement identity is negotiated and political platforms are articulated, both by the leadership in order to position itself as a viable political actor, and by the movement base so they may reconcile their multiple subjectivities. I argue that Algerian Islamists do not reject the wider political culture that disavows their brand of politics or the attendant hegemonic frames used to cast them out of the body politic; instead, they work to make their positions and their activism legible, palatable, and even meaningful through these very frames. This argument interrogates the assumption common in academic literature that Islamism is at odds with local and nationalist articulations of subjecthood.
This responds to two literatures. First is the literature on Islamist parties in authoritarian contexts, which tends to view parties as unidimensional: either as votemaximizing parties seeking to alternate ‘power’ with the regime, as ‘contentious’ social movements, or as piety-driven religious revivalists. An ethnography of the MSP reveals a case where what animates members are not fixed or neatly classifiable. Rather, their goals and identities as a movement are formed more through interaction with those of the wider body politic, than with some grander, disembodied imperatives. Second is the literature on Algerian post-conflict politics, which has tended to take popular characterizations of a moribund partisan sphere and generally meaningless Algerian politics at face value, rather than analyzing them as the values, priorities, narratives and social labels through which sense-making processes manifest, and decoding their function in Algerian political culture. Instead, this thesis deconstructs the prevailing discursive patterns as means through which power, social order, and legitimacy are (re)negotiated.
Functional characterization of ankylosing spondylitis genetic risk variants
Keywords: Ankylosing spondylitis
CRISPR/Cas9
iPS cells

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis characterized by inflammation and osteoproliferation in the lower spine and sacroiliac joints. This dysregulated bone growth leads to the fusion of affected joints, resulting in chronic pain and disability. It is considered a complex genetic disorder, with a heritability of around 90%, and has over 100 genetic loci associated through genome-wide association studies (GWAS). An inherent challenge with GWAS is that many of the associated genetic variants lie within the non-coding genome and exhibit linkage disequilibrium (LD). Therefore determining their function, and the genes and pathways they modulate, and thus identify the disease causal variant and its mechanism of action is a major roadblock to progress in this field. Functional genomic approaches are emerging to interpret the non-coding genome and its relationship with disease. This thesis aimed to utilize functional genomic approaches to advance the understanding of the genetic aetiology of AS.
CRISPR/Cas9 modulated genome editing was utilized for the functional characterization of two putative enhancers within the ASGWAS associated locus, TNFRSF1A. The generation of large deletions using CRISPR/Cas9 presented unanticipated challenges, including the issue of mosaic cellular clones post CRISPR/Cas9 editing. The methodological issues and how these can be addressed for generating homozygous CRISPR/Cas9 edited cells, harbouring deletions of interest, are discussed. Despite unforeseen complications with CRISPR/Cas9 editing, the two putative enhancers were deleted in induced pluripotent stem cells (iPSCs), which were then differentiated in macrophages. The edited cells then underwent assays to map regions of open chromatin, histone modifications, physical chromatin interactions, and gene expression changes in edited and unedited cells. One of the predicted regulatory regions was found to be an enhancer for TNFRSF1A, and the other was discovered not to be enhancer, but a potential repressor for NCAPD2, located approximately 150kb away.
In addition to functional experiments in a model system, this thesis also examined the genome-wide epigenetic differences between AS patients and healthy controls in primary human immune cells. Assay for Transposase Accessible Chromatin Sequencing (ATAC-seq) was used to define regions of chromatin that were differentially open in AS patients. Chromatin Immunoprecipitation Sequencing (ChIP-Seq) was performed to identify differential regions of H3K27ac, denoting active enhancers, and H3K4me3, denoting active promoters. This data was combined with gene expression data to define putative regulatory regions associated with AS and annotate GWAS variants for future functional studies.
Rethinking resistance
Keywords: Defensive ethics
Resistance
Political resistance
Commemoration
Conscience
Political duties
Conviction
Civil disobedience
Vandalism

This thesis is a collection of four discrete essays on the topic of political resistance. While the contents of the individual essays are disparate, they are nonetheless connected by substantive and methodological themes. I discuss these issues, and the broader framing of the thesis, in the Introduction.
The first essay, Clarifying Our Duties to Resist, examines a prominent argument according to which the moral principles that ground individuals’ duties to comply in just conditions also ground their duties to resist injustice in unjust conditions. I argue that this argument does not apply to conditions where injustice is entrenched and normalised.
The second essay, Differentiating Disobedients, considers the question of the ways in which morally motivated individuals should differentiate themselves from criminals when they engage in political resistance or disobedience. I argue that the category of morally motivated disobedients is potentially more inclusive than has been commonly assumed.
The third essay, The Legitimate Targets of Political Disobedience, address the question of what individuals can legitimately target during their acts of political disobedience. I defend a novel principle that allows us to make fine-grained differentiation between legitimate and illegitimate targets.
The fourth essay, Vandalising Tainted Commemorations, adjudicates a contemporary disagreement about what we should do about commemorations of people or events implicated in injustice. I offer a qualified defence of vandalising tainted commemorations, as a strategy that adjudicates the demands of the two dominant yet opposing views on the issue.
In a final note, In Lieu of A Conclusion, I review the work that has been done, and identify several areas for future work.
Visible light-mediated cyclizations of cyclic enones
Keywords: Triplet Energy Transfer
Visible Light

The work outlined in this thesis covers the development of visible light-mediated cyclizations of cyclic enones. Chapter one provides an overview of photochemical cyclizations, focusing on visible light-mediated cyclizations using triplet energy transfer from a suitable sensitizer, as well as an overview of the photochemical cyclizations of cyclic enones. Chapter two discusses the development of a visible light-mediated intramolecular arylation of cyclic 2-arylheteroenones to generate a wide range of cis-fused heterocycles.
Chapter three details efforts into the photochemical synthesis of spirocyclic compounds via intramolecular hydrogen atom abstraction using a cyclic enone chromophore. Chapter four discusses the development of a visible light-mediated spirocyclization of cyclic 2-amidoenones. After initial optimization, the scope and scalability of the reaction was explored, and derivatization of the products investigated. Subsequent mechanistic experiments provided insight into the high diastereoselectivity of the reaction.
Chapter five looks at applications of the previously developed reactions to acyclic chromophore systems, and the challenges present in this modification