VictorJuiz/thesis huggingface dataset:
Structural basis of positive modulation of type-A GABA receptors

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.

Keywords: structural biology
nanobody
GABAA receptor
cryo-electron microscopy
Advisor: Aricescu, AR
Kohl, MM
The role of vigilance and alarm calling in the red junglefowl, Gallus gallus

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.

Keywords: junglefowl
vigilance
sexual selection
alarm calling
anti-predation
Advisor: Pizzari, T
Migration status and violence against women: four legal responses evaluated

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.

Keywords: discrimination
trafficking
Istanbul Convention
domestic violence
domestic violence rule
migration status
violence against women (VAW)
EU Citizens' Directive
Trafficking Convention
compounded disadvantage
Advisor: Costello, C
An investigation of age-period-cohort models for individual-level data

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.

Keywords: age-period-cohort
BMI
cohort
obesity
collinearity
identification
Advisor: Nielsen, B
Compensated compactness methods in the study of compressible fluid flow

This thesis comprises an introduction and three subsequent chapters; each focusing on a particular problem, and containing novel results that complement the existing theory. Throughout, we are concerned with the existence of solutions of the governing equations of inviscid compressible fluid mechanics; the Euler equations. As these equations form an archetypal system of conservation laws, we study them using approaches from the theory of hyperbolic differential equations. Specifically, we implement methods of compensated compactness developed by Tartar and Murat.
To begin with, in Chapter 2, we prove the existence of a finite relative energy entropy solution of the one-dimensional compressible Euler equations under the assumption of an approximately isothermal pressure law. In particular, we obtain this solution as the vanishing viscosity limit of solutions of the one-dimensional compressible Navier–Stokes equations. This procedure can in fact be carried out for a more general class of pressure laws, which we call asymptotically isothermal. This is the subject of Chapter 3, where we show the existence of a finite relative energy entropy solution of the Euler equations in this new setting.
The focus of Chapter 4 is a related two-dimensional stationary problem. Therein, we consider the existence of bounded entropy solutions of the steady compressible potential flow equations in two dimensions; the Morawetz problem for transonic flow. We provide partial results for a γ-law gas of index γ ∈ [3,∞). This involves a detailed analysis of the singular ordinary differential equations that arise when considering the Lax entropy pairs of the system in the presence of a vacuum, which had yet to be performed.

Advisor: Chen, G
Novel approaches to pancreas allograft surveillance

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.

Keywords: Pancreas
Transplantation
Advisor: Friend, P
Sharples, E
Synthesis and biology of resolvins D3, E1 and hybrids and synthesis of bridge-substituted bicyclo[1.1.1]pentanes

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.

Keywords: Bicyclo[1.1.1]pentane
Resolvin
Advisor: Anderson, E
Approximation algorithms and inapproximability of partition functions of spin systems

Over the past 30 years, the study of counting problems has become an interesting and important work. The framework of counting problems can capture applications in diverse fields, such as graph colouring and homomorphism in graph theory, and the Ising and Potts model from statistical physics. In this thesis, we will discuss my recent research work focusing on this area.
In Chapter 1, the basic notions and definitions of counting problems will be introduced. Because of the hardness result of computation complexity for counting problems, we will mainly consider whether we have efficient approximation algorithms for counting problems.
In the algorithmic part, one of the most exciting research is to establish the connection between the uniqueness phase transition of spin systems and the approximability phase transition of computing partition functions. In Chapter 2, we first discuss some basic methods of designing approximation algorithms, including the connection between sampling and counting and the correlation decay approach. These methods will be used in Chapter 4 and 5. In Chapter 3, we will discuss the uniqueness threshold for the antiferromagnetic Potts model on d-ary trees and introduce our results for small q. Chapter 4 and 5 contain two examples of counting and sampling in the uniqueness regime. We designed approximation algorithms for counting the number of 4-colourings on cubic graphs and sampling from the Potts model on random regular graphs in the uniqueness regime.
In the complexity part, a classification result for the complexity of approximate counting Boolean Constraint Satisfaction Problems on bounded-degree instances will be introduced in Chapter 6. We focused on whether, for all Boolean constraint languages Γ, there is a “barrier” value ∆0 such that for all ∆ > ∆0, the counting problem of Boolean CSP is computationally hard to approximate, and completely classified the complexity of this problem.

Advisor: Goldberg, LA
Galanis, A
The movement for a society of peace:  Islamism and political sense-making in post-conflict Algeria

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.

Keywords: MSP
Algeria
Islamism
Advisor: Willis, MJ
Functional characterization of ankylosing spondylitis genetic risk variants

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.

Keywords: Ankylosing spondylitis
CRISPR/Cas9
iPS cells
Advisor: Knight, J
Davies, B
Cowley, S
Monopile response to scour and scour protection

Scour of seabed sediments can occur around offshore structures, the resultant reduction in strength and stiffness of the structure’s foundations presents operational challenges for monopile-supported offshore wind turbine structures. Turbines are at risk of reduced operation or even premature decommissioning if scour causes the natural frequency of a wind turbine to drop too close to the loading frequency, or if the foundation capacity is compromised. In practice scour protection systems are used to mitigate the development of scour itself. Scour protection may also have a restorative influence on the natural frequencies of the structure and capacity of the foundation. This portfolio presents the results of a DEng research project exploring the interactions between scour development, scour protection, foundation stiffness and strength, and structural dynamics of offshore wind turbine structures.
Flume experiments were performed, where a scale monopile – tower system exposed to realistic scour development in the Fast Flow Facility flume at HR Wallingford was subjected to structural dynamics testing and lateral loading. Three scour protection systems were modelled in the experiments: pre-installed rock-armour, remedial rock fill, and remedial tyre-filled net options.
Numerical modelling is presented, using a one-dimensional (1D) finite element model developed for the analysis of natural frequencies for monopile-supported turbines with scour and scour protection. A 1D finite element approach was also used to explore the results of the lateral loading experiments. The numerical modelling produces results that are consistent with data from the flume experiments and from a case study of field data from a high scour offshore wind farm.
The research confirms that there is potential for scour protection systems to enhance the stiffness and capacity of monopile foundations. These gains are negligible for tyre-filled net scour protection systems due to the low stiffness and density of the tyres. The stiffness contribution of rock-type scour protection systems is further enhanced if sand accumulates in the scour protection matrix, but these positive contributions become diminished if extreme global scour causes the scour protection to become unstable. Pre-installed rock armour scour protection systems provide the most reliable solution in terms of seabed stability and foundation response.

Advisor: Byrne, B
Burd, H
McAdam, R