VictorJuiz/thesis huggingface dataset:
The role of adenosine A2A receptor signalling in cardiac fibrosis

Myocardial fibrosis contributes to the pathogenesis of diverse forms of cardiac hypertrophy. Recent evidence suggests a crucial role for purinergic signalling in the formation of tissue fibrosis. In particular, inhibition of adenosine A2A receptors (A2AR) in animal models for hepatic and skin fibrosis resulted in a reduction of fibrosis formation. The specific hypothesis of this investigation was that myocardial stress results in increased interstitial levels of adenosine, which activate cardiac fibroblasts via adenosine A2AR. Accordingly, the specific objective of this investigation was to delineate the role of adenosine A2AR signalling in the development of myocardial fibrosis.
In vitro, isolated cardiac fibroblasts demonstrated a significant increase in collagen secretion into CCM upon specific A2AR stimulation. This stimulatory effect was inhibited by the addition of a specific A2AR inhibitor.
In vivo, models for cardiac hypertrophy including the transgenic cardiac actin E99K hypertrophic cardiomyopathy model, and a transverse aortic constriction (TAC) model of pressure overload, were investigated as murine models for myocardial fibrosis (MF). In cardiac actin E99K hearts the occurrence of cardiac fibrosis was associated with ventricular dysfunction, as well as energetic perturbations. In addition, a direct linear correlation between myocardial collagen content and interstitial adenosine levels was found in actin E99K hearts upon microdialysis experiments. Crossbreeding of actin E99K and A2AR knock-out (KO) mice resulted in a significant reduction of myocardial collagen content and fibrosis in E99K heterozygous A2AR KO animals compared to E99K heterozygous A2AR wild-type (WT) animals.
Further, adenosine A2AR KO mice undergoing transverse aortic constriction demonstrated significantly less fibrosis formation compared to constricted WT mice. This was associated with a significant rescue of cardiac function. In addition, pharmacologic adenosine A2AR inhibition using the antagonist ZM241385 demonstrated a partial rescue of myocardial fibrosis in both TAC and E99K animals.
These data suggest that adenosine the A2AR plays a crucial role in the formation of myocardial fibrosis in a variety of cardiac pathologies and that this pathway is susceptible to pharmacologic modulation. A2AR manipulation may contribute to further understanding of pathophysiological pathways in the development and progression of cardiac disease and represents an excellent therapeutic target for clinically available A2AR antagonists.
Clustering genes by function to understand disease phenotypes

Developmental disorders including: autism, intellectual disability, and congenital abnormalities are present in 3-8% of live births and display a huge amount of phenotypic and genetic heterogeneity. Traditionally, geneticists have identified individual monogenic diseases among these patients but a majority of patients fail to receive a clinical diagnosis. However, the genomes of these patients frequently harbour large copynumber variants (CNVs) but their interpretation remains challenging. Using pathway analysis I found significant functional associations for 329 individual phenotypes and show that 39% of these could explain the patients’ multiple co-morbid phenotypes; and multiple associated genes clustered within individual CNVs. I showed there was significantly more such clustering than expected by chance. In addition, the presence of a multiple functionally-related genes is a significant predictor of CNV pathogenicity beyond the presence of known disease genes and size of the CNV. This clustering of functionally-related genes was part of a broader pattern of functional clusters across the human genome. These genome-wide functional clusters showed tissuespecific expression and some evidence of chromatin-domain level regulation. Furthermore, many genome-wide functional clusters were enriched in segmental duplications making them prone to CNV-causing mutations and were frequently seen disrupted in healthy individuals. However, the majority of the time a pathogenic CNV affected the entire functional cluster, where as benign CNVs tended to affect only one or two genes. I also showed that patients with CNVs affecting the same functional cluster are significantly more phenotypically similar to each other than expected even if their CNVs do not affect any of the same genes. Lastly, I considered one of the major limitations in pathway analysis, namely ascertainment biases in functional information due to the prioritization of genes linked to human disease, and show how the modular nature of gene-networks can be used to identify and prioritize understudied genes.

Keywords: biological networks
protein-protein interactions
copy number variation
Advisor: Webber, C
Ponting, C
On the standing of states : Latin America in nineteenth-century international society

The present dissertation offers a critical examination of the place accorded to Latin American states in the English School account of the expansion of international society. It pursues two aims. First, the study contributes to understanding the nature and scope of international order, and its historical transformation over the course of the ‘long nineteenth century’. Because of the profound impact that European colonization had on the region, the English School has conventionally treated the entry of Latin American states into international society as an unproblematic historical fact achieved with diplomatic recognition in the 1820s. The crucial cases of Argentina, Brazil, and Mexico, however, indicate that more attention needs to the paid to the hierarchical nature of the international order. The central argument of this historical-comparative study posits that the three Latin American states were recognized diplomatically, but they were not regarded as fully-fledged members of the community of ‘civilized’ states.
Second, the dissertation examines the implications of hierarchy in international politics. Building on a critique of the legal-formalist conception of ‘standing’ in English School theorizing, three ideal-typical dimensions of international stratification are identified: the distribution of material capabilities (stature), the function states perform in international society (role), and estimations of honour and prestige (status) among states. The interpretative framework sheds light on how agents understand international society, and the way in which they deal with its hierarchical nature. The study analyzes how Latin American elites perceived the standing of their state, and how these perceptions shaped politics through their corresponding ‘logics of social action’. The study finds that nineteenth-century elites in Argentina, Mexico, and Brazil conceived of the standing of their states predominantly in terms of status, and demonstrates how these perceptions informed politics.

Keywords: English School
Recognition
Expansion of International Society
Status
Standing
Latin America
Advisor: Fawcett, L
PAGOdA: Pay-as-you-go ontology query answering using a datalog reasoner

Answering conjunctive queries over ontology-enriched datasets is a core reasoning task for many applications of semantic technologies. Conjunctive query answering is, however, computationally very expensive, which has led to the development of query answering procedures that sacrifice either the expressive power of ontology languages, or the completeness of query answers in order to improve scalability. This thesis describes a hybrid approach to query answering over OWL 2 ontologies that combines a datalog reasoner with a fully-fledged OWL 2 reasoner in order to provide scalable "pay-as-you-go" performance. The key feature of this hybrid approach is that it delegates the bulk of the computation to the datalog reasoner and resorts to expensive OWL 2 reasoning only as necessary to fully answer the query. Although the main goal of this thesis is to efficiently answer queries over OWL 2 ontologies, the technical results are more general and the approach is applicable to first-order knowledge representation languages that can be captured by rules allowing for existential quantification and disjunction in the head; the only assumption is the availability of a datalog reasoner and a fully-fledged reasoner for the language of interest, both of which are used as "black boxes". All techniques proposed in this thesis are implemented in the PAGOdA system, which combines the datalog reasoner RDFox and the OWL 2 reasoner HermiT. An extensive evaluation shows that PAGOdA succeeds in providing scalable pay-as-you-go query answering for a wide range of OWL 2 ontologies, datasets and queries.

Keywords: query
knowledge representation
description logic
Advisor: Horrocks, I
Grau, B
RNA-based therapeutics for Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised pathologically by the accumulation of amyloid-β plaques and neurofibrillary tangles within the brain. Currently, there are no disease-modifying therapeutic interventions available. This thesis describes the development and delivery of novel RNA-based therapeutics for AD.
Recently, significant advances have occurred in the field of RNA interference (RNAi)-based therapeutics, allowing targeted silencing of disease-relevant genes through the use of short interfering RNAs (siRNAs) or microRNAs (miRNAs). However, development has been impeded by poor penetrance of the blood-brain-barrier (BBB) in vivo. Exosomes, as secreted extracellular vesicles (EVs), may overcome this problem as they naturally deliver RNA between cells and cross the BBB. Furthermore, recent evidence suggests that they may be loaded with exogenous RNA and preferentially targeted to neuronal tissue. Thus, this study investigated EV-mediated delivery of RNAi-based therapeutics shown to regulate AD-relevant genes. A comparison of EV-loading methods revealed that electroporation was confounded by the formation of large siRNA aggregates and indicated that endogenous loading strategies may be preferable. Endogenous loading of RNAi molecules was shown to be enhanced by co-expression with RNA-binding proteins, particularly following inclusion of an acylation domain. These findings highlight the potential for EV-mediated delivery of RNAi-based therapeutics.
A combinatorial therapeutic approach is increasingly recognised to hold the most promise for the future of AD. Thus, this study also focused upon the development of novel multi-gene targeting locked nucleic acid-modified antisense oligonucleotides (LNA-ASOs) as a combinatorial approach towards AD therapy. Two multi-gene LNA-ASOs each produced potent silencing of two separate target genes simultaneously, resulting in a significant reduction in amyloid-β production in vitro. A murine-specific multi-gene LNA-ASO was also identified, paving the way for future in vivo studies. These findings suggest that multi-gene targeting LNA-ASOs may represent a promising novel therapeutic strategy for AD.
In summary, this thesis has investigated novel strategies for both RNA delivery and multi-gene targeting, demonstrating the potential of RNA-based therapeutics for the treatment of AD.

Keywords: neurodegenerative disease
Alzheimer's disease
exosomes
Advisor: Wood, M
Mäger, I
Halogen- and hydrogen-bonding cyclic and interlocked hosts for anion recognition and sensing

This thesis describes the synthesis of macrocyclic and interlocked receptors which exploit halogen- and hydrogen-bonding intermolecular interactions for anion recognition.
Chapter One introduces the field of supramolecular chemistry, with particular focus on applications of host–guest chemistry to anion coordination and anion templation in the construction of mechanically interlocked molecules.
Chapter Two details the synthesis of a series of cyclic and cage-like porphyrin-based receptors which bind anions through halogen- and hydrogen-bonding interactions. The ability of these receptor systems to bind and sense anionic guest species is investigated and comparisons between hydrogen- and halogen-bonding are discussed.
Chapter Three reports anion-templated pseudorotaxane assemblies stabilised by both halogen- and hydrogen-bonding. The related catenanes are also prepared and their affinity for anions is investigated. The first examples of interpenetrated and interlocked architectures constructed by a single charge-assisted halogen bond are also reported.
Chapter Four describes the synthesis of a 1,3-dialkyl-1,2,3-triazolium-containing threading component, whose anion binding properties are studied and compared with other threading molecules. The ability of this novel thread to form pseudorotaxanes is investigated and the preparation of the related rotaxane species is outlined.
Chapter Five discusses attempts to prepare rotaxanes with improved anion binding affinities through increasing the lipophilicity of the anion binding clefts. Several novel rotaxanes are described and their anion binding properties are probed.
Chapter Six describes the experimental procedures used in this work and the characterisation of compounds presented in chapters two to five.
Chapter Seven summarises the conclusions of this thesis.
Electrochemistry of silver nanoparticles

This thesis presents findings realising two main objectives. The first aim is to investigate the electrochemical detection of nanomaterials with an emphasis on silver nanoparticles. The second goal is to employ silver nanoparticles in electroanalysis to aid in the detection of other analytes.
First, the detection of silver nanoparticles was demostrated through two different electrochemical methods, stripping voltammetry and 'nano-impacts'. For stripping voltammetry, the potential of metallic nanoparticles oxidation was quantified by various new analytical expressions for peak potential. For the novel method of 'nano-impacts', individual silver nanoparticles were successfully detected in an optically opaque suspension. Then, a comparison between the two techniques was achieved via the oxidation of silver nanoparticles with different capping agents. Strong capping agent effects was found for stripping voltammetry and one may markedly underestimate the amount of silver nanoparticle present on the electrode surface. The electrochemical sizing of nanoparticles via 'nano-impacts' remained unaffected by the capping agent effect. Amidst the study on the various types of capping agent, it was discovered that cetyltrimethylammonium bromide (CTAB) is electroactive due to the oxidation of its bromide content. This inspired the use of 'nano-impacts' to detect the presence of large CTAB micelles which self-assembled at concentrations above the critical micelle concentration.
Next, various types of silver nanoparticles were applied to different electroanalytical systems to aid in the measurement of other analytes. (a) Small silver nuclei, remaining after the oxidative stripping of an electrode modified by silver nanoparticle suspension drop casting, allowed subsequent signal enhancement (at least a factor of three) in anodic stripping voltammetry of silver ions. (b) The thermodynamic favourable formation of silver halide complexes allowed the silver nanoparticle modified electrode to analyse the halide content of a solution. Hence, a proof-of-concept for an electrochemical sensor based on silver nanoparticle modified electrode for chloride ions was established. This might be applied to the pre-screening of cystic fibrosis, a genetic disease detrimental to many infants' lives. (c) Another key halide in human body, iodide ions, was also measured using a related concept. The level of iodide ions in synthetic human urine was determined.
Last, the strong affinity of silver to thiol groups also warranted a study devoted to their interaction through electrochemical and spectroscopic measurements. It was found that there is no general mechanism for silver-thiol interaction and each thiol must be treated as a separate entity.

Keywords: Silver Nanoparticles
Nano-impacts
Advisor: Compton, R
Spatio-temporal registration of dynamic PET data

Medical imaging plays an essential role in current clinical research and practice. Among the wealth of available imaging modalities, Positron Tomography Emission (PET) reveals functional processes in vivo by providing information on the interaction between a biological target and its tracer at the molecular level. A time series of PET images obtained from a dynamic scan depicts the spatio-temporal distribution of the PET tracer. Analysing the dynamic PET data then enables the quantification of the functional processes of interest for disease understanding and drug development. Given the time duration of a dynamic PET scan, which is usually 1-2 hours, any subject motion inevitably corrupts the tissue-tovoxel mapping during PET imaging, resulting in an unreliable analysis of the data for clinical decision making. Image registration has been applied to perform motion correction on misaligned dynamic PET frames, however, the current methods are solely based on spatial similarity. By ignoring the temporal changes due to PET tracer kinetics they can lead to inaccurate registration. In this thesis, a spatio-temporal registration framework of dynamic PET data is developed to overcome such limits. There are three scientific contributions made in this thesis. Firstly, the likelihood of dynamic PET data is formulated based on the generative model with both tracer kinetics and subject motion, providing a novel objective function. Secondly, the solution to the optimisation based on the generic plasma-input model is given, leading to the availability of a variety of biological targets. Thirdly, reference-input models are also incorporated to avoid blood sampling and thus extend the coverage of PET studies of the proposed framework. In the simulation-based validation, the proposed method achieves sub-voxel accuracy and its impact on clinical studies is evaluated on dopamine receptor data from an occupancy study, as well as breast cancer data from a reproducibility study. By successfully eliminating the motion artifacts as shown by visual inspection, the proposed method reduces the variability in clinical PET data and improves the confidence of deriving outcome measures on a study level. The motion correction algorithms developed in this thesis do not require any additional computational resources for a PET research centre, and they facilitate cost reduction by eliminating the need of acquiring extra PET scans in cases of motion corruption.

Advisor: Schnabel, J
Gunn, R
Flow boiling near the critical heat flux

An experimental investigation of the flow boiling of water at atmospheric pressure was undertaken, including a high—speed cine photographic study of the flow structure near the Critical Heat Flux (CHF). Experimental tests from single-phase forced convection to burnout were conducted at different flow velocities and inlet subcoolings for water flowing upwards through a vertical channel of rectangular cross—section electrically heated on one wall with a glass window forming the opposite wall. The test surfaces were stainless steel strips of constant dimensions, except that wall thickness ranged from 0.08 mm to 0.20 mm.
Quantitative measurements of the bubble parameters for the same heating surface under the same operating conditions with varying levels of heat flux (70% to 95% of CHF) were carried out. A nucleation site deactivation/reactivation process was observed with increasing heat flux. A proposed site deactivation mechanism explained this behaviour. A nucleate boiling heat transfer model was proposed for the fully— developed nucleate boiling region, with allowance made for the overlapping areas of bubble influence. It compared favourably with the experimental data.
The effect of wall thickness on CHF was investigated: increases in CHF as between the 0.08 mm and the 0.20 mm wall thickness ranging from 38% to 57% were observed. An empirical expression for CHF, including wall thickness as a parameter was developed, correlating the experimental data to within 15% and indicating a limiting value for wall thickness affecting CHF. The flow regimes near burnout were identified as bubbly and slug, these being independent of wall thickness.
Other models proposed for the CHF mechanism were tested against the detailed experimental observations at high subcoolings. They were found to be inconsistent with the experimental evidence. A possible alternative for the CHF mechanism points towards stabilisation/ growth of a vapour patch following bubble coalescence as a most likely cause for burnout.

Keywords: heat
water
flux
ebullition
transmission
thermography
boiling
flow
Advisor: Kenning, D
Evaluating conjunctive and graph queries over the EL profile of OWL 2

OWL 2 EL is a popular ontology language that is based on the EL family of description logics and supports regular role inclusions,axioms that can capture compositional properties of roles such as role transitivity and reflexivity. In this thesis, we present several novel complexity results and algorithms for answering expressive queries over OWL 2 EL knowledge bases (KBs) with regular role inclusions.
We first focus on the complexity of conjunctive query (CQ) answering in OWL 2 EL and show that the problem is PSpace-complete in combined complexity, the complexity measured in the total size of the input. All the previously known approaches encode the regular role inclusions using finite automata that can be worst-case exponential in size, and thus are not optimal. In our PSpace procedure, we address this problem by using a novel, succinct encoding of regular role inclusions based on pushdown automata with a bounded stack. Moreover, we strengthen the known PSpace lower complexity bound and show that the problem is PSpace-hard even if we consider only the regular role inclusions as part of the input and the query is acyclic; thus, our algorithm is optimal in knowledge base complexity, the complexity measured in the size of the KB, as well as for acyclic queries.
We then study graph queries for OWL 2 EL and show that answering positive, converse- free conjunctive graph queries is PSpace-complete. Thus, from a theoretical perspective, we can add navigational features to CQs over OWL 2 EL without an increase in complexity.
Finally, we present a practicable algorithm for answering CQs over OWL 2 EL KBs with only transitive and reflexive composite roles. None of the previously known approaches target transitive and reflexive roles specifically, and so they all run in PSpace and do not provide a tight upper complexity bound. In contrast, our algorithm is optimal: it runs in NP in combined complexity and in PTime in KB complexity. We also show that answering CQs is NP-hard in combined complexity if the query is acyclic and the KB contains one transitive role, one reflexive role, or nominals—concepts containing precisely one individual.

Keywords: OWL 2
Query Answering
Description Logics
Ontologies
Advisor: Motik, B
Horrocks, I