VictorJuiz/thesis huggingface dataset:
Mouse models for the investigation of MAPT and its role in neurodegenerative disease

Microtubule-associated protein tau plays an important role in many neurodegenerative diseases. By using and creating various novel mouse models, the role of tau and its relationship with other amyloidogenic proteins was investigated.
Behavioural and molecular characterization of novel mouse models expressing all six isoforms of human wild-type (H1) or N296H mutant (N51) tau protein was carried out to study the age-related emergence of phenotypes commonly associated with tauopathies. Mutant animals displayed no degenerative cognitive or motor phenotype. However, a possible mood phenotype was observed even at a young age. No formation of intracellular tau inclusions was observed. Using acute slice cultures, I further investigated phosphorylation of N296H mutant tau. Relative tau hypophosphorylation was observed in a N296H mutant compared to the wild-type tau expressing animals. In the hippocampus, exposure to Abeta led to an increase in tau phosphorylation at S202/T205 in H1, but not N51 mice. Electrophysiological studies by M. Vargas-Caballero showed that H1, but not N51 animals are susceptible to Abeta-induced LTP impairment. Taken together, these results suggest that tau phosphorylation could mediate the effects of Abeta on LTP. N51 mice also showed a trend towards increased fyn expression. Fyn relocalization into the soma was not detected either in N51 or tau knockout animals.
The functional relationship between tau and α-synuclein was investigated in several novel models. Neither acute exposure of acute slices to α-synuclein oligomers nor α-synuclein overexpression induced tau hyperphosphorylation. A novel mouse model lacking both tau and α-synuclein was generated, but revealed no remarkable behavioural changes. Finally, a new mouse model was created overexpressing human wild-type α-synuclein on a tau knockout background to investigate whether tau is required for α-synuclein-induced dopamine release deficits previously observed in α-synuclein overexpressors.

Keywords: tau protein
neurodegeneration
frontotemporal dementia
Advisor: Wade-Martins, R
Cragg, S
Elementary states, supergeometry and twistor theory

It is shown that Hp-1 (P+, 0 (-m-p)) is a Fréchet space, and its dual is Hq-1(P-, 0 (m-q)), where P+ and P- are the projectivizations of subsets of generalized twistor space (≌ ℂp-q) on which the hermitian form (of signature (p,q)) is positive and negative definite respectively, and 0(-m-p) denotes the sheaf of germs of holomorphic functions homogeneous of degree -m-p. It is then proven, for p = 2 and q = 2, that the subspace consisting of all twistor elementary states is dense in Hp-1(P+, 0(-m-p)).
A supermanifold is a ringed space consisting of an underlying classical manifold and an augmented sheaf of Z2-graded algebras locally isomorphic to an exterior algebra. The subcategory of the category of ringed spaces generated by such supermanifolds is referred to as the super category. A mathematical framework suitable for describing the generalization of Yang-Mills theory to the super category is given. This includes explicit examples of supercoordinate changes, superline bundles, and superconnections. Within this framework, a definition of the full super Yang-Mills equations is given and the simplest case is studied in detail. A comprehensive account of the generalization of twistor theory to the super category is presented, and it is used in an attempt to formulate a complete description of the super Yang-Mills equations. New concepts are introduced, and several ideas which have previously appeared in the literature at the level of formal calculations are expanded and explained within a consistent framework.

Advisor: Penrose, R
Eastwood, M
Category-theoretic quantitative compositional distributional models of natural language semantics

This thesis is about the problem of compositionality in distributional semantics. Distributional semantics presupposes that the meanings of words are a function of their occurrences in textual contexts. It models words as distributions over these contexts and represents them as vectors in high dimensional spaces. The problem of compositionality for such models concerns itself with how to produce distributional representations for larger units of text (such as a verb and its arguments) by composing the distributional representations of smaller units of text (such as individual words).
This thesis focuses on a particular approach to this compositionality problem, namely using the categorical framework developed by Coecke, Sadrzadeh, and Clark, which combines syntactic analysis formalisms with distributional semantic representations of meaning to produce syntactically motivated composition operations. This thesis shows how this approach can be theoretically extended and practically implemented to produce concrete compositional distributional models of natural language semantics. It furthermore demonstrates that such models can perform on par with, or better than, other competing approaches in the field of natural language processing.
There are three principal contributions to computational linguistics in this thesis. The first is to extend the DisCoCat framework on the syntactic front and semantic front, incorporating a number of syntactic analysis formalisms and providing learning procedures allowing for the generation of concrete compositional distributional models. The second contribution is to evaluate the models developed from the procedures presented here, showing that they outperform other compositional distributional models present in the literature. The third contribution is to show how using category theory to solve linguistic problems forms a sound basis for research, illustrated by examples of work on this topic, that also suggest directions for future research.

Keywords: vector space models
category theory
distributional semantics
semantics
Advisor: Pulman, S
Coecke, B
Sadrzadeh, M
Investigating the ecology, diversity and distribution of cord-forming fungi in Great Britain

Cord-forming fungi (CFF) are an assemblage of saprotrophic fungi which can use complex foraging organs of longitudinally arranged hyphae to join up disparate substrates in a patchy resource environment. Their importance to woodlands lies, mainly, in their ability to modify nutrient cycling and soil structure. Therefore, in order to enable woodlands to continue to thrive in terms of their health and ecosystem function, it is necessary to understand the factors contributing to the establishment, success and diversity of this group. Whilst work to date on CFF has focussed on their physiology and interactions in laboratory conditions, little work has been carried out on their taxonomy and establishment/presence in the field. The work in this thesis begins to address these crucial unanswered questions in CFF ecology.
By carrying out investigations at a range of scales, from phylogenetic analysis to UK wide Species Distribution Modelling, this thesis reaches a number of surprising results with potentially important implications for woodland management. This is most evident in Chapter 3 where our hypothesis that fungal communities develop over time in plantations of different woodland ages was disproved, illustrating that even 13 years after planting, fungal communities in plantations on ex-agricultural land had not begun to reach those in established ASNW. These unexpected results continue into Chapter 4, where the thesis demonstrates that dominant canopy species has a greater impact on community composition than any other woodland factor. Chapter 5 continues this theme, by showing that removal of invasive species is not always beneficial for the cord-forming fungal communities, especially if it involves removing the woody substrate.
The work described, detailed and analysed in this thesis has initiated further investigations, proposed changes to woodland management practices and laid the foundations for future work relating to CFF and their role and function in British woodlands.

Keywords: Phylogenetics
ecology
forest ecology
species distribution modelling
restoration
regeneration
cord-forming fungi
Advisor: Brown, N
Hemery, G
Changes in functional connectivity due to modulation by task and disease

Soon after the advent of signal-recording techniques in the brain, functional connectivity (FC), a measure of interregional neural interactions, became an important tool to assess brain function and its relation to structure. It was discovered that certain groups of regions in the brain corresponding to behavioural domains are organized into intrinsic networks of connectivity (ICNs). These networks were shown to exhibit high FC during rest, and also during task. ICNs are not only delineated by areas which correspond to various behaviours, but can be modulated in the long and short-term in their connectivity by disease conditions, learning, and task performance. The significance of changes in FC, permanent and transient, is poorly understood with respect to even the simplest ICNs corresponding to motor and visual regions. A better grasp on how to interpret these changes could elucidate the mechanisms and implications of patterns in FC changes during therapy and basic tasks. The aim of this work is to examine long-term changes in the connectivity of several ICNs as a result of modulation by stroke and rehabilitation, and to assess short term changes due to simple, continuous task performance in healthy volunteers.
To explore long-term changes in ICN connectivity, fifteen hemiparetic stroke patients underwent resting state scanning and behavioural testing before and after a two-week session of Constraint Induced Movement Therapy (CIMT). It was found that therapy led to localized increases in FC within the sensorimotor ICN.
To assess transient changes in FC with task, sixteen healthy volunteers underwent a series of scans during rest, continuous performance of a non-demanding finger-tapping task, viewing of a continuous visual stimulus, and a combined (but uncoupled) visual and motor task. Group Independent Component Analysis (ICA) revealed that canonical ICNs remained robustly connected during task conditions as well as during rest, and dual regression/seed analyses showed that visual and sensorimotor ICNs showed divergent patterns of changes in FC, with the former showing increased intra-network connectivity and the latter decreased intra-network connectivity. Additionally, it was found that task activation within ICNs has a relationship to these changes in FC.
Overall, these results suggest that modulation of functional connectivity is a valuable and informative tool in the study of disease recovery and task performance.

Keywords: functional connectivity
fMRI
stroke
resting state networks
task modulation
Advisor: Johansen-Berg, H
Makin, T
Duff, E
Spatiotemporal dynamics of cytoskeletal and chemosensory proteins in the bacterium Rhodobacter sphaeroides

The discovery of the prokaryotic cytoskeleton has revolutionized our thinking about spatial organisation in prokaryotes. However, the roles different bacterial cytoskeletal proteins play in the localisations of diverse biomolecules are controversial. Bacterial chemotaxis depends on signalling through large protein clusters and each cell must inherit a cluster on cytokinesis. In Escherichia coli the membrane chemosensory clusters are polar and new static clusters form at pre-cytokinetic sites, ensuring positioning at new poles after cytokinesis and suggesting a role for the bacterial FtsZ and MreB cytoskeletons. Rhodobacter sphaeroides has both polar, membrane-associated and cytoplasmic, chromosome-associated chemosensory clusters. This study sought to investigate the roles of FtsZ and MreB in the partitioning of the two chemosensory clusters in R. sphaeroides. The relative positioning between the two chemosensory systems, FtsZ and MreB in R. sphaeroides cells during the cell cycle was monitored using fluorescence microscopy. FtsZ forms polar spots after cytokinesis, which redistribute to the midcell forming nodes from which gradients of FtsZ extend circumferentially to form the Z-ring. The proposed node-precursor model might represent a common mechanism for the formation of cytokinetic rings. The MreB cytoskeleton continuously reorganizes between patchy and filamentous structures, and colocalises with FtsZ at midcell. Membrane chemosensory proteins form individual dynamic unit-clusters with mature clusters containing about 1000 CheW3 proteins. These unit-clusters diffuse randomly within the membrane but have a higher propensity for curved regions like cell poles. Membrane clusters do not colocalise with FtsZ and MreB and appear excluded from the Z-ring vicinity. The bipolar localisation of membrane clusters is established after cell division via random diffusion and polar trapping of clusters. The cytoplasmic chemosensory clusters colocalise with FtsZ at midcell in new-born cells. Before cytokinesis one cluster moves to a daughter cell, followed by the second moving to the other cell. FtsZ and MreB do not participate in the positioning of cytoplasmic clusters. Therefore the two homologous chemosensory clusters use different mechanisms to ensure partitioning, and neither system utilizes FtsZ or MreB for positioning.

Keywords: chemotaxis
cytokinesis
spatial organisation
Rhodobacter sphaeroides
prokaryotic cytoskeleton
polar localisation
FtsZ
fluorescence microscopy
bacterial cell division
MreB
chemosensory clusters
Advisor: Armitage, J
Leake, M
The role of HLA-B27 in the pathogenesis of spondyloarthritis

The Human Leukocyte Antigen (HLA)-B27 is a Major Histocompability Complex (MHC) class I antigen that is strongly associated with development of a group of closely related arthritic diseases, collectively known as the spondyloarthropathies (SpA). However, the mechanism by which HLA-B27 confers this susceptibility is unclear. Studies have shown that HLA-B27 heavy chains can form classical heterotrimers associated with peptide and β2-microglobulin (B27HT), and also non-classical heavy chain homodimers (B27₂). B27₂ assemble intracellularly during maturation and are also expressed at the cell surface following endosomal recycling of B27HT. A pathogenic role for B27₂ has been proposed in two of the current theories of pathogenesis: the B27 homodimer theory and the B27 misfolding and UPR theory. Yet, determinations of the extent, distribution, and triggers of B27₂ expression, as well as the functional consequences of its receptor interactions in AS pathogenesis, have been hampered by the lack of a specific detection reagent. Therefore, to investigate the role of B27₂ in AS, we generated a novel antibody to B27₂ – HD6 – using phage display technology, which binds to in vitro refolded B27₂ but not B27HT complexes by ELISA. This thesis provides evidence that HD6-reactive molecules, which include B27₂, are expressed at the cell surface in both cell lines and in the context of a disease setting. Recognition is B27-specific and strongly correlated with the magnitude of B27 expression, which could account for the lack of staining in some cell subsets. Moreover, staining was comparable in cell lines expressing the disease-associated B*27:05 and the less disease-associated subtype B*27:09. In addition, I have shown cells expressing physiologic levels of B27, including EBV-transformed BCLs and AS patient PBMCs, are capable of expressing the HD6 epitope upon low pH treatment. Interestingly, these ‘acid-inducible HD6’ molecules were absent from cells lacking a functional PLC. Finally, I have shown that HD6-reactive molecules can derive from pre-existing folding B27 molecules at the cell surface, which may be inhibited by the addition of exogenous B27-binding peptides. These findings are consistent with a mechanism of pathogenesis involving the surface expression and recognition of B27₂ and/or other aberrantly folded forms of B27, as proposed in the homodimer theory. HD6 will be a powerful tool to address the potential pathogenic role of B27₂ in SpA and may additionally have therapeutic potential.

Keywords: HLA-B27
major histocompatibility complex
spondyloarthropathies
arthritis
ankylosing spondylitis
pathogenesis
Advisor: Bowness, P
Topics in general and set-theoretic topology: slice sets, rigid subsets of the reals, Toronto spaces, cleavability, and neight

I explore five topics in topology using set-theoretic techniques. The first of these is a generalization of 2-point sets called slice sets. I show that, for any small-in-cardinality subset A of the real line, there is a subset of the plane meeting every line in a topological copy of A. Under Martin's Axiom, I show how to improve this result to any totally disconnected A. Secondly, I show that it is consistent with and independent of ZFC to have a topologically rigid subset of the real line that is smaller than the continuum. Thirdly, I define and examine a new cardinal function related to cleavability. Fourthly, I explore the Toronto Problem and prove that any uncountable, Hausdorff, non-discrete Toronto space that is not regular falls into one of two strictly-defined classes. I also prove that for every infinite cardinality there are precisely 3 non-T1 Toronto spaces up to homeomorphism. Lastly, I examine a notion of dimension called the "neight", and prove several theorems that give a lower bound for this cardinal function.

Keywords: rigid
forcing
homogeneity
slice set
real line
cleavage
2-point set
Toronto problem
neight
cleavability
Toronto space
Advisor: Knight, R
Pericyclic and related rearrangements for the synthesis of nitrogen heterocyclic ring systems

The thesis describes synthesis and reactions of allene azides tethered to various functional groups and the application of the discovered cascade transformations towards the synthesis of radianspene J model system.
Chapter 1 covers reactions of simple allene azides containing alkyl and cycloalkyl substituents. Thermal rearrangements of these substrates delivered isocyanides and azadienes via the proposed azatrimethylenemethane (ATMM) intermediates.
On the other hand, vinylidenecyclopropanes (VDCPs) gave dramatically different products, as described in Chapter 2. A phenyl-substituted VDCP was transformed into an unstable polycyclic compound by a divinylcyclopropane rearrangement. Chapter 3 discusses allene azides tethered to furan, N-substituted pyrroles, and E- and Z-dienes. Depending on the structure of the starting material, products of formal (3+4)- or (2+3)-cycloaddition were formed.
Finally, an application of the discovered cyclisation cascade towards total synthesis is described in Chapter 4. A model system of radianspene J was assembled using a key transannular cycloaddition of a macrocyclic allene.

Keywords: total synthesis
pericyclic reactions
azides
allenes
rearrangement
cycloadditions
azatrimethylenemethane
ene reaction
Radianspene J
Advisor: Robertson, J
Scalable reasoning for description logics

Description logics (DLs) are knowledge representation formalisms with well-understood model-theoretic semantics and computational properties. The DL SROIQ provides the logical underpinning for the semantic web language OWL 2, which is quickly becoming the standard for knowledge representation on the web.
A central component of most DL applications is an efficient and scalable reasoner, which provides services such as consistency testing and classification. Despite major advances in DL reasoning algorithms over the last decade, however, ontologies are still encountered in practice that cannot be handled by existing DL reasoners.
We present a novel reasoning calculus for the description logic SROIQ which addresses two of the major sources of inefficiency present in the tableau-based reasoning calculi used in state-of-the-art reasoners: unnecessary nondeterminism and unnecessarily large model sizes. Further, we describe a new approach to classification which exploits partial information about the subsumption relation between concept names to reduce both the number of individual subsumption tests performed and the cost of working with large ontologies; our algorithm is applicable to the general problem of deducing a quasi-ordering from a sequence of binary comparisons. We also present techniques for extracting partial information about the subsumption relation from the models generated by constructive DL reasoning methods, such as our hypertableau calculus.
Empirical results from a prototypical implementation demonstrate substantial performance improvements compared to existing algorithms and implementations.

Keywords: automated reasoning
classification
description logics
Advisor: Horrocks, I
Motik, B
The syntax of adverbs: an LFG approach

This article proposes an LFG treatment of predicational adverbs in English. We argue that each adverb contains in its lexical entry a typological designation, or disjunction of multiple typological designations, which interact with lexical entries to produce c- and f-structures. ADVPs are adjoined to either I' or VP, depending on this typological designation, and provide all necessary readings from these two adjunction sites. Functional precedence is used to resolve ordering restrictions in cases of multiple adverb occurrence within a sentence.

Keywords: General Linguistics
Phonetics
Comparative Philology
Advisor: Dalrymple, M
Towards a small molecule inhibitor of Lactate Dehydrogenase-A

Lactate Dehydrogenase-A (LDH-A) is up-regulated in a broad array of cancers and is associated with poor prognosis. Involved in the hypoxic response, LDH-A is a HIF-1 target and is responsible for the enzymatic reduction of pyruvate to lactate. This is important for several reasons, chiefly (1) the regeneration of NAD+ which feeds back into earlier glycolytic stages and (2) the depletion of intracellular pyruvate concentrations. High intracellular pyruvate is known to inhibit HDACs and is associated with increased apoptosis. LDH-A is also known to be controlled by oncogenes such as c-Myc suggesting an oncogenic role. Studies have shown that the knock-out of LDH-A reduces proliferation and tumourgenicity, and stimulates the mitochondria. This thesis therefore had three aims: firstly, to validate LDH-A inhibition and elucidate its full nature in terms of the implications for tumour survival; secondly, to ascertain the role of LDH-B in order to determine whether selectivity towards LDH-A would be a necessary feature of any small molecule; lastly, to recapitulate siRNA mediated LDH-A inhibition with small molecule inhibitors that had the potential for clinical application. The thesis examined both clinical data and a broad panel of cultured cancer cell types in order to select appropriate model in which to validate siRNA mediated inhibition of LDH-A and LDH-B. After it was demonstrated that LDH-A inhibition reduced the growth of cultured cells, a range of techniques were used to quantify this reduced growth in terms of cell death and changes in metabolism. Further to this, literature studies had proposed a role for LDH-B in maintaining lactate fuelled tumour growth; however, this thesis shows that in the cell lines studied, lactate-fuelled tumour growth was an LDH-A dependent phenomenon. Finally, a high throughput assay system was designed and validated and a library of small molecules was selected, synthesized, and screened in order to identify selective inhibitors of LDH-A.

Keywords: synthesis
Warburg effect
tumour metabolism
rational drug design
breast cancer
Advisor: Harris, A
Russell, A