VictorJuiz/thesis huggingface dataset:
Assessing the effect of tissue structural changes during cardiac deformation using magnetic resonance imaging techniques

Global assessment of the myocardial tissue wall motion from cine MRI (Magnetic Resonance Imaging) is widely used in clinical practice, however, the estimation is done, in the majority of cases, visually rather than quantitatively. This doctoral thesis proposes steps forward in the local assessment of the left ventricular (LV) function in order to provide a better estimation of the damage post acute myocardial infarction (MI). Accurate post acute MI tissue damage estimation from cine MR tracking might help clinicians to perform, better, more personalised, revascu larisation treatments. This thesis makes three technical contributions.
The first technical contribution focuses on LV scar segmentation from Late Gadolium Enhancement (LGE) using supervoxels. LGE represents the gold standard for assessing the viability of the heart muscle. However, considerable user input is needed in order to correctly segment the scar. A global intensity threshold is used, and a further, remote, area of "healthy myocardium" also needs to be segmented. Furthermore, an additional number of corrections are required to remove false positive areas of enhancement. We found that by using a strong regulariser such as a modified version of the Single Linear Iterative Clustering (SLIC) supervoxels, we can eliminate the false positive enhancement areas. Furthermore, there is no need for a remote "healthy myocardium" area to be contoured.
The second technical contribution is to provide a 4D map of supervoxels (voxels clustered together based on local similarity) computed using similarity in strain curves. Our study found that while LGE performs extremely well in highlighting the area where scarring occurs, at the same time it underestimates the area of affected myocardium when compared with strain analysis. Here we investigated various registration methods, based on optical flow deformable registration, in order to evaluate the accuracy of computing the displacement curves, and subsequently validated the registration method against manually placed landmarks in the LV. The third technical contribution is a modification to the maskSLIC algorithm to generate six cluster centers in each short axis, basal and mid-ventricular slice, equally distributed at 60◦ from each other in order to mimic the AHA 16 segments model used in clinical practice.
Considering clinical perspectives centered approach, these technical advances will contribute to the field of regional assessment of the cardiac function, therefore potentially improving patient outcome.

Keywords: wall motion assessment
patient specific
late gadolinium assessment
SLIC supervoxels
tissue parcellation
LGE
medical image registration
cardiac MR
maskSLIC
Advisor: Grau Colomer, V
Assessment and evaluation of visual function measurement in inherited retinal degeneration; focusing on optimisation

Photoreceptors at the back of the eye are the first step in producing our sense of vision, able to capture photons of light of differing wavelength. These connect to retinal circuits, which feed into visual pathways and networks in the brain, where the responses from the eye are processed to provide rich visual perception. Loss of these photoreceptors leads to severe visual impairment, as light can no longer be detected. While degeneration has a direct effect on the photoreceptors, there are also secondary effects on retinal circuits, in addition to the pathways processing visual information in the brain.
Recently there has been an increase in the development of novel interventions for the treatment of inherited retinal degenerations, with the first retinal gene therapy approved as an NHS treatment in 2019. Yet little work has been conducted on establishing the most appropriate outcome measures to quantify success. In this thesis I probe the practical impact of visual field loss on the conduct of visual function tests such as visual acuity and colour vision. I discuss factors affecting test reliability and propose solutions to improve measurement. I place emphasis on providing an understanding of the basis of the measurements to allow the appropriate measures to be chosen in trials, including for the first time a comprehensive assessment of local and global scotopic function. Beyond the retina, I show that the secondary changes in the inner retina can be detected with the use of ocular coherence tomography imaging and have an impact on visual function testing with microperimetry. I show changes in the integrity of the white matter in the visual brain pathways as a result of retinal disease. This could potentially pose a limiting factor in reversing visual deficits by treating the retina alone.
Vision is a result of interconnecting circuits between the eye and the brain and therefore, changes from retinal disease must be considered in terms of their wider effects along the visual system.

Keywords: visual cortex
retina
microperimetry
OCT
RP
choroideremia
visual acuity
retinitis pigmentosa
rods
genetic eye disease
photoreceptors
vision
inherited retinal degemeration
scotopic
ocular coherence tomography
colour vision
retinal therapy
dark adaptation
visual pathway
gene therapy
optic radiation
outcome measures
visual function
retinal remodelling
visual brain
RPGR
photopic
MRI
cones
Advisor: Maclaren, R
Bridge, H
The role of the ciliary protein IFT88 in post-natal joint development, homeostasis and disease

More than 50% of the UK population over 75 suffers from the degenerative cartilage disease osteoarthritis, but the mechanisms of pathogenesis remain elusive. While it is appreciated that joint mechanics are hugely influential to osteoarthritis and fundamental for cartilage development and homeostasis, the chondrocyte/cartilage ‘mechanostat’ is unknown. Chondrocytes assemble a primary cilium, a microtubule-based organelle reliant on intraflagellar transport (IFT). Mutations to ciliary genes alter the chondrocyte’s anabolic matrix response to compression in vitro. Perturbations to IFT in vivo alter embryonic and early post-natal skeletal development, but little is known of its cartilaginous influence in adulthood. The main aim of this thesis was to explore whether the core ciliary gene IFT88, and therefore likely the primary cilium itself, maintains influence beyond development in the contexts of adolescent and adult cartilage. A sub-aim preliminarily explored a role of IFT88 in cartilage matrix catabolism in vitro.
Experiments in vitro identified putative, novel regulation of aggrecaneolysis by IFT88, through control of the endocytic clearance of proteases. Establishment and validation of a cartilage-specific, inducible knockout mouse model (cKO) enabled the deletion of IFT88. Deletion during adolescence, resulted in longer growth plates, with large bilateral cartilaginous holes where the normal ossification programme associated with growth plate closure was inhibited. Thinner articular cartilage in cKO mice was exhibited throughout adolescence and adulthood and its progressive calcification was inhibited. The effects on cartilage thickness were most pronounced in plateaus that experience the highest compressive loads. Following deletion at skeletal maturity, some joints exhibited total loss of cartilage, associated with features of osteoarthritis 28- weeks later. Experimental osteoarthritis, instigated by destabilisation of the joint, was exacerbated in cKO animals.
These studies demonstrate that IFT88, and by extension the primary cilium, has a critical role in cartilaginous tissues, sustained throughout adolescence into adulthood. The results in this thesis suggest that in the growth plate and articular cartilage, IFT88 could be an integrator and dampener of extrinsic, physiological, mechanical cues and intrinsic ciliary signalling pathways such as hedgehog signalling, and thus critical to the maturation, homeostasis and health of the post-natal joint.

Keywords: IFT88
mechanics
osteoarthritis
disease
primary cilium
cartilage
Advisor: Wann, A
Vincent, T
Mood instability: its cognitive and neural correlates and the effects of L-type calcium channel antagonism

Mood instability is commonly experienced in the general population. It is associated with risk for subsequent diagnosis of bipolar disorder (BD) and is a prominent feature of several other psychiatric disorders. Despite the significance of mood instability in psychopathology, there is little research examining its potential underlying mechanisms. In a study measuring mood, cognitive function and resting-state magnetoencephalography (MEG) over 10-weeks, the first part of this thesis aimed to characterise mood instability and explore its cognitive and neural correlates in healthy individuals at low and high risk of BD as indicated on the Mood Disorder Questionnaire (MDQ). Findings demonstrated that instability in negative mood was significantly different between individuals scoring low and high on the MDQ. Individuals with high MDQ scores demonstrated deficits in learning context-based regularities across days, and higher levels of negative mood instability in this group were also associated with changes in neural activity such as reduced switching between brain states, and reduced time spent in a fronto-limbic state thought to be necessary for mood regulation.
The second part of this thesis aimed to explore the candidacy of L-type calcium channel (LTCC) antagonism as a potential treatment for mood instability. Healthy individuals with high MDQ scores participated in a double-blind, placebo-controlled, experimental medicine study. For two weeks in the absence of any intervention, measures of mood and neural activity were assessed. This was followed by a 2-week randomisation phase to either nicardipine SR or placebo, during which all measures were repeated. Compared to placebo, LTCC antagonism was not found to reduce mood instability or significantly affect resting-state MEG measures of spectral power, alpha peak frequency, or characteristics of fast transient brain states.
Overall, these findings provide insights into the potential mechanisms that might underlie mood instability, highlighting areas for future investigation. While the candidacy of LTCC antagonism in mood instability was not confirmed, this work demonstrates the feasibility of multimodal, high-intensity studies to investigate transdiagnostic constructs and the potential of new treatments.

Keywords: Mood instability
Transdiagnostic
Remote monitoring
Calcium channel antagonism
Cognitive function
Randomised control trial
Magnetoencephalography
Advisor: Nobre, A
Harrison, P
Essays in the ethics of distribution

This thesis is about the allocation of benefits under scarcity constraints. In five standalone papers, it provides answers to some aspects of the following central question of distributive ethics: Out of a set of distributions of well-being over a group of individuals, which distribution should we choose?
The first of the five papers draws a connection between the moral notions of interpersonal aggregation and equality. It argues that aggregation sceptics should be egalitarians. The second paper puts forward a novel model of “limited aggregation” that is not subject to the same objections that have recently been raised against other such models. The third paper criticizes one of the most influential views of cashing out non-aggregative ethics under conditions of risk, “ex ante contractualism.” The fourth paper defends an ex post approach as an alternative to ex ante contractualism. The fifth and final paper tries to incorporate some of our common-sense moral intuitions into a coherent theory of variable population ethics. It does so by combining reasons stemming from an impersonal axiology with reasons stemming from the complaints people can raise against our choices.

Advisor: Greaves, H
Bader, R
Component separation for cosmic microwave background studies

The detection of primordial B-mode polarization in the cosmic microwave background (CMB) remains the major outstanding goal of CMB cosmology. However, current upper limits on the strength of the primordial signal mean that it will be sub-dominant to astrophysical foreground emission at all frequencies, over the entire sky. Detecting primordial B-modes therefore becomes a problem in component separation.
In this thesis I address this problem from two angles. First, I present my work analysing data from the C-Band All-Sky Survey (C-BASS), a 4.76 GHz survey covering the whole sky in total intensity and polarization. I describe the point-source detection algorithm developed for C-BASS, and the northern sky point-source catalogue that has been produced using it. This catalogue has allowed us to confirm the accuracy of the C-BASS pointing and flux-density scale, and will form the basis of any C-BASS point source masks. I also present an analysis of the synchrotron power spectra, using C-BASS, WMAP and Planck data. From this it is found the minimum synchrotron contamination to CMB B-modes corresponds to a tensor-to-scalar ratio of r~0.001, with a typical contamination at the level of r~0.01.
Alongside the analysis of C-BASS data, I present a novel implementation of Bayesian parametric component separation. This uses the No-U-Turn Sampler (NUTS) to explore the posterior distribution. NUTS is a gradient-based sampling algorithm with excellent scaling to high dimensions, and also contains important self-diagnostics of potential failures in geometric ergodicity. This is particularly important for the hierarchical foreground model introduced here, which can exhibit highly complex posterior geometries. The hierarchical foreground model fits for hyper-distributions over large sky regions, from which foreground spectral parameters are drawn. This is compared to a complete pooling model, where foreground spectral parameters are assumed to be constant in each sky region. The hierarchical model is able to remove artefacts from the recovered CMB maps without inflating parameter uncertainties, translating through to reduced biases on cosmological parameters.

Advisor: Taylor, A
Alonso, D
Jones, M
Polymerisation catalysts to make polyesters and copolymers

The world needs more sustainable polymers and although there are some promising frontrunners, the range of degradable and renewably sourced plastics remains narrow. One issue to address is to improve the efficiency of production of aliphatic polyesters and to expand the range and properties of easily accessible degradable materials. This thesis describes new In(III), Sn(II), Ti(IV), and Zr(IV) polymerisation catalysts used to make aliphatic polyesters and copolymers. The overall objective is to develop efficient catalysis to improve upon the structures, scope and range of degradable polyesters. This is achieved by stereoselective lactide ring-opening polymerisation, by epoxide/anhydride ring-opening copolymerisation and by switch catalysis using mixtures of lactide/lactone, epoxide and anhydride.
Chapter 3 presents a series of phosphasalen In(III) complexes, with different diamine linkers and phosphorous substituents, which are highly active and iso-selective in the ring-opening polymerisation of racemic lactide. The highest performing catalyst produces isotactic polylactide (up to 92 %), via a chain-end control mechanism. Additionally, the complexes polymerise a range of other lactones with the activity depending strongly on both the catalyst and lactone structures.
Chapter 4 describes a series of phosphasalen Ti(IV) and Zr(IV) complexes which are active and, in some cases, highly selective for epoxide and anhydride ring-opening copolymerisations without any co-catalyst. Phosphasalen complexes show superior activity and selectivity over their salen and salalen analogues, highlighting the importance of the iminophosphorane backbone. A polymerisation mechanism is proposed, based on kinetic experiments and the polymerisation propagating intermediate isolation.
Chapter 5 describes the first report of an industrially relevant catalyst, Sn(OMe)2, for both epoxide/anhydride ring-opening copolymerisation and ‘Switch’ catalysis using lactone, epoxide and anhydride mixtures. The switch catalysis yields new polyester-ethers with microstructures including block-, tapered-, and gradient-copolymers. Selected copolymers are efficient toughening additives, at just 2 wt. % loading, for polylactide increasing toughness values by 400 %.

Advisor: Williams, C
Adequacy of damages

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease whose molecular pathogenesis serves as a useful model for understanding other chronic inflammatory conditions. Activated macrophages are critical for RA pathogenesis, since they promote the inflammation that causes cartilage damage, bone remodelling, pain and irreversible disability. Macrophages are activated by stimuli in their environment, and responses to these stimuli are fine-tuned by their interactions with highly sulfated heparan sulfate (HS) glycosaminoglycans. HS is sulfated in complex patterns, but 6-O-sulfation of HS glucosamine subunits is known to be particularly important for regulating activity of many cytokines, chemokines and growth factors. 6-O-sulfation is hence tightly regulated, and it is the only HS sulfation motif that can be post-synthetically removed by the extracellular sulfatases SULF1 and SULF2. Although extensively studied in cancer and development, the effect of 6-O-sulfation on inflammation and macrophage function is unknown.
In this thesis I showed that Sulf2 is mainly expressed by macrophages, monocytes and dendritic cells. Sulf2 is particularly highly expressed by protective resident alveolar macrophages in the lung and resident synovial macrophages in the joint, indicating that Sulf2 is likely to be important for maintaining homeostasis and suppressing inflammation. Moreover, Sulf2 is downregulated by many inflammatory stimuli, suggesting that downregulation of Sulf2 may enable macrophages to convert from a protective phenotype to an activated inflammatory phenotype. Phagocytosis was increased in Sulf2-deficient macrophages, while macrophage polarisation was inhibited.
Sulf2-deficient bone marrow chimeras were generated to investigate the role of Sulf2 in immune function during antigen-induced arthritis (AIA) as an example of a chronic inflammatory disease. These Sulf2-deficient mice developed increased knee swelling, which was associated with an increase in pro-arthritic Th17 cells.
In conclusion, SULF2 is important for maintaining homeostasis by suppressing macrophage activation, indicating that therapies reducing 6-O sulfation of HS might be effective for the treatment of RA and other chronic inflammatory diseases.

Keywords: private law theory
commercial remedies
private law
judicial discretion
injunctions
equity
specific remedies
specific performance
Advisor: Stevens, R
A Bayesian account of learning and generalising representations in the brain

Without learning we would be limited to a set of preprogrammed behaviours. While that may be acceptable for flies, it does not provide the basis for adaptive or intelligent behaviours familiar to humans. Learning, then, is one of the crucial components of brain operation. Learning, however, takes time. Thus, the key to adaptive behaviour is learning to systematically generalise; that is, have learned knowledge that can be flexibly recombined to understand any world in front of you. This thesis attempts to make inroads on two questions - how can brain networks learn, and what are the principles behind representations of knowledge that allow generalisation. Though bound by a common framework of Bayesian thinking, this thesis considers the questions in two separate parts.
In the first part of the thesis, we investigate algorithms the brain may use to update connection strengths. While learning attempts to optimise a global function of the brain state, each connection only has access to local information. This is in contrast to artificial networks, where global information is easily conveyed to each synapse via the back-propagation algorithm. We show that, contrary to decades old beliefs, an analogous algorithm to back-propagation could be implemented in the local dynamics and learning rules of brain networks. We show an exact equivalence between the two algorithms and demonstrate that they perform identically on a standard machine learning benchmark. These results are the first to show that an algorithm as efficient as those used in machine learning could be implemented in the brain.
In the second part of the thesis, we investigate frameworks for learning and generalising neural representations. It is proposed that a cognitive map encoding the relationships between entities in the world supports flexible behaviour. This map is traditionally associated with the hippocampal formation, due to its beautiful representations mapping space. This cognitive map, though, seems at odds with the other well-characterised aspect of the hippocampus: relational memory. Here we unify spatial cognition and relational memory within the framework of generalising relational knowledge. Using this framework, we build a machine that learns and generalises knowledge in both spatial and non-spatial tasks, while also displaying representations that mirror those in the brain. Finally, we confirm model predictions in neural data. Together, these results provide a computational framework for a systematic organisation of knowledge spanning all domains of behaviour.

Keywords: entorhinal cortex
representation learning
hippocampus
biological backprop
non-spatial reasoning
generative models
Bayesian
artificial neural networks
predictive coding
Advisor: Bogacz, R
Behrens, T
The role of extracellular sulfatase-2 in inflammation

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease whose molecular pathogenesis serves as a useful model for understanding other chronic inflammatory conditions. Activated macrophages are critical for RA pathogenesis, since they promote the inflammation that causes cartilage damage, bone remodelling, pain and irreversible disability. Macrophages are activated by stimuli in their environment, and responses to these stimuli are fine-tuned by their interactions with highly sulfated heparan sulfate (HS) glycosaminoglycans. HS is sulfated in complex patterns, but 6-O-sulfation of HS glucosamine subunits is known to be particularly important for regulating activity of many cytokines, chemokines and growth factors. 6-O-sulfation is hence tightly regulated, and it is the only HS sulfation motif that can be post-synthetically removed by the extracellular sulfatases SULF1 and SULF2. Although extensively studied in cancer and development, the effect of 6-O-sulfation on inflammation and macrophage function is unknown.
In this thesis I showed that Sulf2 is mainly expressed by macrophages, monocytes and dendritic cells. Sulf2 is particularly highly expressed by protective resident alveolar macrophages in the lung and resident synovial macrophages in the joint, indicating that Sulf2 is likely to be important for maintaining homeostasis and suppressing inflammation. Moreover, Sulf2 is downregulated by many inflammatory stimuli, suggesting that downregulation of Sulf2 may enable macrophages to convert from a protective phenotype to an activated inflammatory phenotype. Phagocytosis was increased in Sulf2-deficient macrophages, while macrophage polarisation was inhibited.
Sulf2-deficient bone marrow chimeras were generated to investigate the role of Sulf2 in immune function during antigen-induced arthritis (AIA) as an example of a chronic inflammatory disease. These Sulf2-deficient mice developed increased knee swelling, which was associated with an increase in pro-arthritic Th17 cells.
In conclusion, SULF2 is important for maintaining homeostasis by suppressing macrophage activation, indicating that therapies reducing 6-O sulfation of HS might be effective for the treatment of RA and other chronic inflammatory diseases.

Keywords: heparan sulfate
sulfatase
inflammation
rheumatoid arthritis
macrophage
Advisor: Troeberg, L
Monaco, C
Williams, R