VictorJuiz/thesis huggingface dataset:
The functional analysis of rare genetic variants in a familial neurodegenerative spectrum disorder
Keywords: Genetics
Neuroscience

Whole genome sequencing can enable an unbiased approach to the diagnosis and to the understanding of genetic aetiology of neurodegenerative diseases, which are a clinically and genetically heterogeneous group of disorders. Two brothers, originally diagnosed with primary progressive multiple sclerosis (PPMS), displayed an atypical disease progression over a 30-year period with a clinical picture of paresis, ataxia, mental impairment and dysarthria. Late stage fasciculations, absence of sensory symptoms and a follow-up magnetic resonance imaging (MRI) scan showing severe atrophy of the cerebrum, cerebellum and brainstem, but no white matter lesions, called the original diagnosis into question. Given the familial nature and the rarity of this very similar clinical profile, we hypothesised that a rare variant could be contributing to disease. Whole genome sequencing identified three rare variants segregating with disease: a homozygous non-frameshift deletion in the fatty acid 2-hydroxylase (FA2H) gene, an X-bound non-synonymous single nucleotide variant in the adaptor protein-1 complex subunit sigma-2 (AP1S2) gene, and a homozygous frameshift deletion in the mixed lineage kinase domain-like protein (MLKL) gene. Lipidomic analysis using liquid chromatography-tandem mass spectrometry of FA2H variant-expressing cell lines demonstrated no detrimental impact of the deletion in FA2H on protein function. Bioinformatic and computational structural analysis suggested the variant in AP1S2 to be benign. In contrast, the frameshift deletion in MLKL prevents expression of MLKL protein as demonstrated in patient-derived primary cells. The absence of MLKL was shown ex vivo to cause complete deficiency in necroptosis, a recently identified form of programmed cell death that is involved in a spectrum of neurodegenerative diseases. This thesis provides the first clinical case report implicating MLKL and necroptosis deficiency in a neurodegenerative spectrum disorder. The results suggest that current strategies to pursue MLKL inhibition for human therapy should be approached with caution.
Verifying concurrent systems by approximation
Keywords: SMT solving
Symbolic verification
CSP
Static properties
Reachability analysis
Concurrent systems
Refinement checking
SAT solving
Deadlock analysis
Transition systems

Approximate verification frameworks are an approach to combat the well-known state-space explosion problem. For properties formulated as "no bad state can be reached", an approximate framework can be simply obtained by replacing exact reachability by some over-approximation. These frameworks look for a bad state in this over-approximation. If no bad states are found, the system satisfies the original property; the framework is sound. If a bad state is found, we have an inconclusive result: this bad state might be reachable or not. This permitted incompleteness is a cornerstone of such methods and it is a means to obtain efficiency.
In this thesis, we propose three techniques to approximate reachability. The first analyses small subsystems to capture locally provable relationships between component states. The second and third complement the first by capturing some global system invariants. While the second combines component invariants to estimate whether components can cooperate to reach a system state, the third technique detects token mechanisms and deduces token invariants that approximate reachability.
Moreover, we show how our approximations can give rise to useful frameworks that check deadlock freedom, static properties -- a class of state-based properties we propose -- and CSP's traces and failures refinement expressions. Our evaluation of these frameworks seems to suggest that they can efficiently prove a large spectrum of properties for a variety of systems.
Despite tackling NP-hard problems, our frameworks can be efficiently powered by SAT/SMT solvers. The unsuccessful attempts at using symbolic exploration to precisely check concurrent systems, combined with the success of our frameworks, suggest that the approximations we study are a key factor in harnessing the verification power of these solvers.
Translational development of MyD88 as a biomarker for selecting patients with lymphoma responsive to histone deacetylase inhibitors
Keywords: histone deacetylase inhibitors
cancer biomarkers
MyD88

Histone deacetylase inhibitors (HDIs) are promising new agents for the treatment of haematological malignancy including lymphoma. MyD88 expression and secretion of pro-inflammatory cytokines may contribute to the sensitization of cancer cells to HDI. Moreover, MyD88 may be a direct target for HDAC- and BRD- inhibitors. Therefore, both expression level of MyD88 and MyD88 mutation status could serve as potential biomarkers for HDI sensitivity in patient selection.
‘Teeth and tongue jammed together’: Violence in relationships and its mediation in Freetown, Sierra Leone
Keywords: Gender and Generation
Punishment and Confinement
Violence
West Africa
(Human) Rights and Personal Autonomy
Legal Pluralism
Love
Law

Based on 13 months of fieldwork in households, communities, police stations, courts and the prison in Freetown, this thesis extends the classic model of gender complementarity by demonstrating how competing gender ideologies of household, community and state impact on partnerships in urban Sierra Leone that are interlaced with friction and violence.
I utilise the metaphor of ‘teeth and tongue’, to show how love and violence can be coconstitutive. Within various relationship forms, violence is perceived as part of a functional partnership, however, carefully differentiated according to a moral economy of relationships. Legitimated or ‘acceptable’ violence is constitutive of affection and love, whereas transgressive or ‘unacceptable’ violence is reported to household, community or the police.
The thesis argues that to households and communities, violence constitutes a relationship between people which must be cooperatively mediated to maintain social bonds. For state institutions, violence is an act executed by individuals. Here, punishment and imprisonment ruptures relationships and dissolves social bonds.
The thesis is set against the post-conflict and post-TRC watershed where laws were passed to rebuild the state, and to prevent rape, teenage pregnancy and domestic violence. It shows that these laws were inspired by human rights and development discourses but led to the criminalising of young people’s sexual behaviour. By raising the age for sexual consent from 14 to 18, boys now receive prison sentences of up to 15 years for sleeping with underage girlfriends.
The thesis explores how rigid laws rub against contingent social categories and how the criminalisation of sexual relationships clashes with normalisations of violence in speech, acts and relationships. It uncovers that these tensions are based upon different ideals of gender relations and gendered perceptions of violence. The thesis thus offers an ethnographic critique of concepts like love and violence that are often used by academics in ways that fail to capture the vernacular resonances and connotations of the terms in West African popular culture and social life. Based on the framework of competing gender ideologies, the thesis fosters new understandings of the anthropology of violence, love and law.
Magnetic order in functional iron oxides
Keywords: Photoemission Electron Microscopy
Hematite
Magnetoelectrics
Resonant X-ray Diffraction
Hexaferrite
Magnetism
Diffraction
X-ray Diffraction
Multiferroics

Developing our understanding of the magnetic order of iron oxides is essential if we are to devise novel, functional magnetic memory devices and sensors. In this thesis we report on the magnetic order of the newly synthesised Y-type hexaferrite Ba0.5Sr1.5Mg2Fe12O22 (BSMFO) and on the remarkable domain morphology of the archetypal iron oxide Fe2O3.
The magnetic phase diagram of BSMFO is studied by lab based characterisation methods and synchrotron techniques. We reveal a series of metastable magnetic structures, characterised by a period commensurate with the crystallographic lattice. We confirm this system is polar below 100 K and exhibits the worlds largest magnetoelectric effect. We perform a Resonant X-ray Diffraction (RXD) experiment to study this effect and show that RXD is sensitive to the magnetic polarity of BSMFO, the order parameter which drives the large magnetoelectric effect observed in this system. Using RXD microdiffraction, we spatially resolve the magnetic polarity domain configuration of BSMFO for the first time. When complemented by dynamic polarisation analysis of the scattered X-ray beam, these results allow us to propose a microscopic mechanism describing the large magnetoelectric effect observed in BSMFO. The RXD techniques demonstrated in this thesis open up a previously unexplored avenue for effectively studying the field-induced phases of the Y-type hexaferrites.
The coupled domain structure of a α-Fe2O3/Co heterostructure is imaged using vector-mapped X-ray PhotoEmission Electron Microscopy. Our measurements reveal an unprecedented network of vortices in the antiferromagnetically ordered α-Fe2O3 layer which imprint, by exchange proximity, into the adjacent Co layer. This work represents the first observation of antiferromagnetic spin vortices in a laterally unconstrained system. These vortices are consistent with the Kibble-Zurek mechanism, originally conceived in the context of cosmology, which describes the formation (and preservation) of topological defects when cooling through a symmetry breaking phase transition. The topological nature of these vortices is exploited to control the domain configuration of our heterostructure by inducing mass vortex-antivortex annihilation. As well as being a suitable system to test the universality of the Kibble-Zurek mechanism, the network of vortices observed in this work have the potential to be incorporated into novel, highly efficient magnetic memory devices.
Thermodynamic Anomalies in Network-Forming Materials
Keywords: Thermodynamic anomalies
Molecular dynamics
Density anomaly
Stillinger-Weber potential
Polarisable ion model

The density maximum observed in water at 4oC at ambient pressure is perhaps the most famous of the thermodynamic anomalies. However, anomalous behaviour in liquids is more widespread, spanning not only water, but systems such as silicon, germanium, silica and beryllium fluoride. A link between these systems is the dominance of local tetrahedral geometries. It is widely believed that the existence of a liquid-liquid critical point is the source of the anomalous behaviour in water. However, alternative scenarios of the anomalous behaviour exist but are either of little more than theoretical significance or are limiting cases of the so-called liquid-liquid critical point scenario. Recent studies have focused on establishing connections between liquid structure and the observed anomalous behaviour.
This work systematically explores the influence of the structure on the thermodynamic anomalies of systems modelled with both a Stillinger-Weber (SW) potential and a polarisable ion model (PIM). These are chosen as models conventionally associated with "covalent" and "ionic" interactions respectively. The liquid structure is changed continuously by varying specific structure-related parameters in either model; the magnitude of the three-body interactions in the SW potential and the anion polarisation in the PIM. The progression of the anomalous behaviour is observed as a function of these parameters and an explanation is given in terms of the evolution of the local environments. The bounds for the emergence of anomalous behaviour are also observed and have been correlated with the polymorphism of the crystalline phase diagram. The relationships between different anomalies are derived from thermodynamic relations and all the reported scenarios were successfully reproduced. Enhanced sampling methods were used to further study SW liquids and a new scenario describing the anomalous behaviour is detected. The progression of this scenario as a function of the model parameter and liquid structure is studied.
Finite element methods for Monge–Ampère type equations
Keywords: Partial differential equations
Finite element methods
Numerical analysis

This thesis focuses on the numerical analysis of partial differential equations (PDEs), the main goal being the development and analysis of finite element methods (FEMs) for fully nonlinear elliptic PDEs, particularly Monge-Ampère (MA) and Hamilton-Jacobi-Bellman (HJB) equations.
There are two clear distinctions in the approaches that are undertaken in this thesis: firstly, for the approximation of solutions to the MA problem, we implement and analyse a continuous Galerkin (CG) FEM; secondly, to numerically solve the HJB equation, we employ a discontinuous Galerkin (DG) FEM.
Though the chosen approaches (CG vs. DG) applied to the MA and HJB type equations are distinct, the equations themselves are related. A longstanding result, proven by N. Krylov in 1987, allows one to characterise the MA equation as a HJB equation.
Another important theme of this thesis, motivated by domain assumptions, necessary for the well-posedness of MA type problems, and oblique boundary-value problems is the implementation and analysis of FEMs on domains with curved boundaries. In the case of DG methods, where the consistency of the method plays a key role in obtaining a priori error estimates for the numerical solution, this quantitative consideration requires new techniques to extend the existing DG framework.
he main contributions of this thesis are new results concerning the existence and uniqueness of numerical solutions to CG and DG finite element methods on curved domains, for both fully nonlinear elliptic equations, and linear elliptic equations in nondivergence form, with Dirichlet and oblique derivative boundary conditions, as well as optimal a priori error estimates. Furthermore, we prove several key results from the theory of finite elements in the context of curved finite elements, that do not appear to be available in the literature.
Frontiers in protein-lipid interactions studied by native mass spectrometry
Keywords: GPCR
protein-lipid interactions
MS
nanodisc

Coordination between membrane proteins and their surrounding lipid environment dictates the function of biological membranes. While the study of membrane protein-lipid interactions is challenging for well-established techniques due to their transient and dynamic nature, recent developments in native mass spectrometry (MS) enables interrogation of membrane protein-lipid interactions in a label-free and high-resolution manner. This thesis presents two major developments in the study of membrane protein-lipid interactions via native MS: (1) the development of suitable MS methods for the transfer and characterization of nanodisc assemblies, promising membrane mimetics alternative to classical detergent micelles; and (2) the characterization of the lipid interactions with class A GPCRs.
Nanodiscs were transmitted into the gas-phase and collisionally activated to produce mass spectra, which were highly complex. To interpret these spectra, a dual Fourier transform method (Chapter 2) and a mass defect analysis (Chapter 3) were developed, allowing the determination of the lipid composition and the stoichiometries of the lipid/protein components of the nanodiscs. Analysis of the spectral results revealed that nanodisc-based MS provides novel insights into annular lipid interactions. In addition, the dissociation behavior of nanodiscs upon collisional activation was explored to understand how best to characterize nanodiscs in the gas-phase.
In the second part of this thesis, the lipid interactions of class A G protein-coupled receptors (GPCRs) were carefully characterized by native MS and coarse-grained molecular dynamics simulations. Class A GPCRs were shown to preferentially bind phosphatidylinositol bisphosphate (PIP2) over related lipids and potential PIP2-binding hotspots were identified. The effects of PIP2 on GPCR-G protein coupling were then investigated employing a Gα protein mimetic. Together, this information leads to a hypothesis that PIP2 binding modulates GPCR-G protein coupling and identifies a potential lipid-binding motif. Overall, therefore this thesis develops two novel methodologies, the native MS of nanodiscs and G protein coupling, both of which facilitate studies of protein-lipid interactions in challenging systems.
'Giving the worker his house': intervention, interaction, and inaction in three French cities, c. 1840-80
Keywords: Lyon
Roubaix
Comparative
France
Second Empire
Logements insalubres
Housing
Mulhouse

The history of working-class housing in nineteenth-century France is dominated by narratives of isolated successes, legislation at the end of the century, and the experience of housing in Paris above all other cities. Because of this, the significance and diversity of provincial French experiences have been overlooked. This obscures the very real and important role that different local elite strategies concerning the 'housing problem' played in provincial cities through the century, regardless of whether they impacted national housing policy. Just as important as direct interventions – which sought to improve legislation or build new houses – were strategies of interaction, which focused on working-class families impacted by poor housing without necessarily improving conditions, and self-conscious strategies of inaction, whereby provincial elites consciously chose not to intervene in the domain of workers housing because of what they judged more pressing economic, social, or political concerns.
By comparing the strategies employed by industrial and municipal elites in the three textile cities of Roubaix, Mulhouse, and Lyon between c. 1840-80, this thesis explores the multifaceted nature of the 'housing question' and responses to it. In this thesis, I reveal the diversity of elite strategies regarding housing, which were driven by a distinct combination of different local, regional, national, and international conditions. Through incorporating both failure and inaction alongside successful intervention and distinctive interactions, I not only overcome the dominant narratives in histories of housing, but I also offer a fresh interpretation of the social history of the heterogeneous, overlapping, and occasionally conflicting different elites that existed in nineteenth-century provincial France. The ways local industrial and municipal elites chose or chose not to tackle their specifically local housing situations reveal to us the different ways that interactions with workers and their domestic milieu shaped the construction of identities in nineteenth-century France.
Radiofrequency safety modelling of parallel transmit magnetic resonance imaging
Keywords: MRI RF safety
RF heating test
Personalised SAR modeling
Electro-magnetic simulation
Parallel Transmission

Radio-frequency (RF) safety plays an important role in Magnetic Resonance Imaging (MRI) with the goal of assuring patient safety and preventing excessive RF heating. Historically, RF safety in MRI has been monitored using pre-calculated specific absorption rate (SAR) limits which indicate the amount of energy that can be delivered safely to the subject. Electromagnetic (EM) simulations have usually been performed to assess the electric field and RF energy levels that are experienced by the subject. In order to validate these EM simulations, the distribution of radiofrequency (B1) field can be measured experimentally, and compared with simulation results. Also, the measurement of temperature in phantom and animal models has been used to assess RF heating directly and validate the EM simulations.
Well-characterized phantom models are needed to assess RF heating experimentally. Meat phantoms can be used for RF heating tests, but these are difficult to store and challenging for their shape to be well described. Agar-gel phantoms can also be used for RF heating tests, in which one can control their dielectric properties with use of carefully controlled ingredients, such as NaCl and polyethylene powder to achieve specific conductivity and permittivity values. Once a phantom is made, the dielectric properties can be verified experimentally using an open-ended coaxial cable.
A number of EM simulation methods have been proposed, which help one understand EM field phenomena in high-field MRI. But there are still many questions remaining which need to be further studied, including better characterization of thermal behaviours. In Chapter 3, three simulation methods are compared against experimental thermal elevation measures.
A framework of validating EM simulations using Proton Resonance Frequency Shift (PRF) based MR thermometry in the context of parallel transmit (pTx) MRI is described in Chapter 4. Also described in this chapter is a 3D gradient-echo sequence used to monitor temperature-induced phase shifts, as well as the required image reconstruction techniques and field-stabilisation methods.
The need for personalised SAR models has arisen quickly, especially in ultra-highfield pTx studies. Use of a safety margin of 1.5 (150%) to account for morphometric differences across the population has been reported previously. To reduce the need for overestimation, the development of a personalized SAR models using non-linear registration is described in Chapter 5 and assessed for robustness using three 'standard' models.
Finally, the practical advantages of using the personalised model in pTx MRI are discussed in Chapter 6. With the aid of high computing capacity the personalised model approach could help MRI users reduce safety margins, so that the scanners can operate closer to the true SAR limits representing the subject in the scanner.