VictorJuiz/thesis huggingface dataset:
Conservation, error and dynamics in protein interaction networks.
Keywords: network alignment
protein interactions

The availability of large scale protein interaction networks for several species has motivated many comparative studies in recent years. These studies typically employ network alignment algorithms for the task and use the sequence similarity of proteins to aid the alignment process. In this thesis I use a quantitative measure of protein functional similarity and show that the results are superior to sequence based network alignment. I present a method for module detection that combines results from network alignments with clustering measures to achieve superior results over several existing methods. Next, I address the issue of generally low conservation detected by alignments of interaction networks from model organisms. By explicitly modelling evolutionary mechanisms on pairs of networks I test the hypothesis that divergent evolution alone may be the cause. I use a distance metric based on graph summary statistics to assess the fit between experimental and simulated network alignments. Our results indicate that network evolution alone is unlikely to account for the poor quality alignments given by real data. We also find that false positives appear to affect network alignments little compared to false negatives indicating that incompleteness, not spurious links, is the major challenge for interactome-level comparisons. Finally, I focus on the comparative analysis of a subset of the interaction network related to mitosis in Yeast, Human and Fly. Manual ordering of mitosis-related functional annotations allows the study of temporal aspects of the network. I also use a Markov random field approach to infer temporal labels for unlabelled proteins. Sequence based network alignment of the mitotic networks in the three species finds little conservation despite the proteins being functionally very similar. Further investigation suggests a fuzzy relationship between protein sequence and function that may have implications for future network alignment studies.
Juglans regia L: genetic variation and provenance performance
Keywords: forestry
provenance
Juglans
walnut
genetic variations

A range-wide collection of Juglans regia seeds was undertaken in autumn 1997 from 12 countries, including 25 provenances and 375 half-sib progenies. 2200 seedlings were produced using innovative nursery techniques. The seedlings were planted in three provenance trials in southern England in 1999, the largest of which acted as a combined provenance/progeny trial. After one growing season, survival was 98.9 %, mean height growth 35 cm, and mean stem diameter increment 5 mm. Provenance differences for both height and stem diameter increment were highly significant (p<0.001). There were no significant genotype × environment interactions. Flushing assessments revealed few significant differences between provenances and flushing was complete by early April. Family heritability for tree height was 0.19 at one site and, with combined selection, genetic gain was estimated at 8 %. The effects of three types of treeshelter and a stumping treatment on walnut establishment were tested over three growing seasons. Treeshelters were found beneficial to height increment. However, 120 cm tall shelters promoted early flushing, and consequent risk of increased frost damage, and caused more stem die-back than 75 cm shelters. Stumping promoted rapid early height increment but gave no longer-term benefit. The crown (cd) and stem (dbh) diameter at breast height relationship of open growing trees in Britain was assessed and was highly significant (r2 = 0.96, p<0.001). The regression equation (cd = 2.71 + 17.6dbh) permitted the estimation of suitable planting densities for the provenance trials and the calculation of a thinning regime. Isozyme analysis of the 375 genotypes identified 20 loci in 15 enzyme systems with seed embryo extracts. Using young leaf extracts, the polymorphic locus Pgm-1 indicated low expected heterozygosity of 0.06 both within populations and at the species level. FST and GST estimates, both 0.05, indicated high uniformity among populations. Genetic distance estimates did not identify significant clustering consistent with geographic origin.
Confusing credentials: the cross-nationally comparable measurement of educational attainment
Keywords: survey research
education
ISCED
measurement
comparability

The quality of educational attainment measures lies at the heart of many cross-national micro-sociological research projects and international education statistics. This study aims at validating cross-nationally comparable measures of educational attainment, among which are the International Standard Classification of Education 1997 (ISCED 97), the CASMIN education scheme and years of education. Following a conceptual discussion of what educational attainment means, the most common ways of measuring educational attainment cross-nationally as well as previous evaluations thereof are reviewed. Then, the implementation of ISCED 97 in cross-national surveys is examined by looking at both the resulting educational attainment distributions in three European surveys as well as the data generation and harmonisation processes. Finally, a number of cross-national measures of educational attainment are compared with country-specific measures with respect to their information content by firstly examining the dispersion of educational attainment, and secondly the predictive power when explaining two core social stratification outcomes, occupational status and social class attainment, by educational attainment. The main results of the study are that the measurement of educational attainment in cross-national surveys is affected by a number of avoidable weaknesses which adversely affect the validity of claims based on analyses of these data: 1. Countries and surveys are inconsistent in the way they measure educational attainment and apply ISCED 97 to national data; and 2. actual years of education and the one-digit version of ISCED 97 distort measures of association to differing degrees in different countries. Both make cross-national comparisons using these measures highly problematic. Therefore, some amendments to the implementation of ISCED 97 in cross-national surveys and coding for statistical analyses are proposed. As part of the latter, an alternative simplification of ISCED 97, optimised for European survey research, is developed and validated. Moreover, suggestions for data collection procedures are made to improve the measurement of educational attainment nationally and cross-nationally.
The Padang, the Sahib and the Sepoy - The role of the Indian Army in Malaya, 1945 to 1946 
Keywords: history
Britain
Singapore
Malaya
Malaysia
Commonwealth
India
Indian Army

This thesis analyses the nation-building work that the Indian Army undertook during the military administration of Malaya, 1945-6. This was a two-part process, taking in military-led relief work and a political reform scheme. Historians have conducted little work on the Indian Army’s role in the British return to empire in Malaya, thus the army’s crucial and nuanced role has been overlooked. This limits the understanding of the army’s institutional development and role in Malayan nation-building between 1945-6. This thesis redresses this. It argues that the military administration of Malaya encapsulated the culmination of wartime changes to the role of the Indian Army fighting soldier. Whereas before the war the Indian Army found it expedient to keep its soldiers isolated from current affairs, British experience during the Second World War instead suggested that soldiers educated in current affairs could be very effective. Concurrently, British military leaders began to think on the role of the Indian Army and its men after the war. They concluded that the Indian Army’s soldiers could become catalysts of national political and social development, and initially identified this as a role for the army in post-war India. Furthermore, it was felt that the Indian Army could contribute both to the Commonwealth and United Nations ideals. The return to Malaya encapsulated these changes to the conception of the Indian Army soldier and was a practical expression and measure of these. The soldiers became agents of political change, imperial re-entrenchment and administration – which this thesis terms ‘soldier-administrators’. The Indian Army, it is argued, was deployed consciously as a nation-building force, using the new thinking on the role of Indian Army soldiers. In so doing, the Indian Army partook in targeted schemes for military relief, political reform and nation-building to try to build the new Malayan nation.
The universality and demarcation of lexical categories cross-linguistically
Keywords: linguistic categories
Wakashan languages
Prototype theory
functional linguistics
fuzzy grammar
Salish languages
cognitive linguistics
typology
lexical categories
categorization
Michif

Drawing data from a variety of sources, this thesis compares functional evidence regarding lexical categories from a number of Salish and Wakashan languages, as well as from the Michif language. It then applies Prototype Theory to examine the structure of the lexicons of these languages. They are described in terms of prototype categories that overlap to varying extents, with each category and each area of overlap defined by a central set of prototypical features. A high degree of gradience appears to exist between categories in Salish and Wakashan languages, with no clear boundary between categories or areas of overlap, indicating that lexical categories in these languages, rather than being clearly demarcated, are instead fuzzy categories with very little distinguishing them. Categories in Michif, on the other hand, exhibit far less overlap. This variation is compared to variation in conceptual categories across languages, and challenges the notions of the universality of clearly demarcated lexical categories and the existence of separately stored language module in the human mind. In spite of the variation in lexical category demarcation observed across the languages studied, it is possible to demarcate the categories of Noun and Verb to at least some extent in all languages, as well as a category of Adjective in some languages. This supports the proposed universality of the categories of Noun and Verb, as well as the implicational universals proposed in the Amsterdam Model of Parts of Speech (Hengeveld 1992a, b). It is also possible to identify a number of defining characteristics for each lexical category that appear to hold across languages. Since similar characteristics can be identified across languages for all categories, but the categories themselves display varying degrees of overlap in individual languages, this research supports the proposal that language universals, rather than consisting of structures, rules, and categories that are identical in all languages, are rather collections of prototypical characteristics for grammatical categories that are similar across languages (Croft 2000).
Characterisation of AEBP2: a polycomb repressive complex 2 component
Keywords: Developmental biology
polycomb
embryonic stem cells
epigenetics

Polycomb complexes act as repressors of transcription at many developmentally important genes. Repression by polycomb-repressive complex 2 (PRC2) is mediated by the deposition of a tri-methylation mark on lysine 27 of the histone H3 tail (H3K27me3). The PRC2 complex consists of three core proteins: EED, SUZ12, and one of either EZH2 or EZH1, which contain the enzymatic activity. The zinc finger containing protein AEBP2 (AE1 binding protein 2) has been co-purified with the PRC2 complex. The aim of this thesis was to study the function of AEBP2. Chromatin immunoprecipitation experiments indicate that AEBP2 is enriched at the same genomic locations as H3K27me3 genomewide. Using an X inactivation model, I found that AEBP2 and H3K27me3 also co-localise by immunofluorescence upon Xist induction.
Large scale immunoprecipitation followed by mass spectrometry confirmed the interaction of AEBP2 with PRC2 complex members. Interestingly, I did not detect any peptides of the Polycomblike (PCL) family proteins. These proteins have previously been shown to interact with the PRC2 complex. Their absence in the AEBP2 immunoprecipitation, together with published work demonstrating an absence of AEBP2 in PCL purifications, suggests that AEBP2 and PCL family proteins might be mutually exclusive in PRC2 complexes.
I have created an embryonic stem cell line in which both alleles of Aebp2 contain a gene-trap. This cell line was used to address the suggestion that AEBP2 might use its zinc finger domain to act as a sequence-specific PRC2 recruitment factor. AEBP2-depleted cells do not show diminished recruitment of PRC2. Additionally, electromobility shift assays failed to show that AEBP2 could bind DNA. Furthermore, recruitment of AEBP2 to genomic targets depended on the presence of the core PRC2 protein EED. Together, this makes it unlikely that AEBP2 acts as a sequence-specific PRC2 recruitment factor.
In keeping with the lack of effect on PRC2 enrichment, preliminary experiments have shown that AEBP2 depletion does not greatly affect levels of H3K27me3, or the expression of PRC2 target genes. The Aebp2 gene-trapped cell line will be used to investigate further functions of AEBP2. Additionally, these cells have been used for blastocyst injection to create an Aebp2 gene-trapped mouse. Future work will show the effect of AEBP2 depletion on development.
Stereoselective cyclopropanations of allylic amines and derivatives
Keywords: Shi's carbenoid
cyclopropanation
allylic amines

This thesis is concerned with the development and application of methods for the stereoselective cyclopropanation of allylic amines and derivatives. Firstly, a highly chemo- and stereoselective cyclopropanation of N,N-dibenzyl-protected allylic amines was developed using the highly reactive Shi’s carbenoid [CF₃CO₂ZnCH₂I]. Subsequent mechanistic studies revealed that the high diastereoselectivity of the reaction was likely to be due to coordination of the amine to the zinc carbenoid reagent. It is then shown that the reaction is general for a wide range of both cyclic and acyclic substrates giving the corresponding cyclopropanes in high yields and diastereoselectivities. Secondly, a novel stereodivergent cyclopropanation of allylic carbamates and amides was developed. It was found that reaction of cyclic allylic carbamates with the Wittig-Furukawa reagent [Zn(CH₂I)₂] typically gives the syn-diastereoisomer in high yields and diastereoselectivities, whilst treatment of the same substrates with Shi’s carbenoid [CF₃CO₂ZnCH₂I] gives the corresponding anti-diastereoisomers in high yields and diastereoselectivities. Mechanistic investigations suggested that reactions with the Wittig-Furukawa reagent proceed via a N-directed intramolecular cyclopropanation step whilst those with Shi’s carbenoid proceed via a sterically directed intermolecular cyclopropanation step. Unsuccessful investigations into an asymmetric variant of the cyclopropanation reaction utilising chiral carbamate protecting groups are then described. Finally, studies towards the total synthesis of the potential anti-obesity therapeutic trans-SCH-A and its epimer cis-SCH-A are described. A stereodivergent route towards the epimeric products was developed through the cyclopropanation of a common allylic carbamate intermediate with either the Wittig-Furukawa reagent or Shi’s carbenoid to give the corresponding trans-2-amino-5-arylbicyclo[3.10]hexane or cis-2-amino-5-arylbicyclo-[3.10]hexane intermediates respectively.
Functionalised polymers by surface modification using diaryl carbenes
Keywords: modification.
Polymer
surface

This thesis is concerned with the synthesis of diazo compounds for the introduction of various functional groups on the surface of polymers by means of carbene insertion and diazonium coupling. Characterisation and investigation of their properties were conducted.
A library of functionalised polystyrene beads containing pyridine rings has been established for the coordination of metal ions and metal complexes. The pyridyl system on the surface has demonstrated its capability to bind with zinc complexes of bis(thiosemicarbazones) and release the corresponding copper complexes upon transmetallation.
A spiropyran derivative has been introduced onto the surface of polystyrene and polyethylene terephthalate. The chromophore on both polymers exhibited photoswitchability as determined from colour change and wettability.
Polystyrenes with either pyridine or spiropyran units have been investigated for reversible immobilisation of bioactive species. Materials coated with penicillin V gave significant inhibition zones in antibacterial assays, showing efficacy in drug delivery.
Finally, a range of diazo compounds with different substituents has been synthesised and their thermal stabilities have been assessed by differential scanning calorimetry technique.
A critique of the decision of the European Court of Human Rights in Ireland v United Kingdom, and its effect on Article 3 jurisprudence
Keywords: human rights
non-refoulement
inhuman and degrading treatment or punishment
extradition
cruel
torture

Article 3 of the European Convention on Human Rights ostensibly provides absolute protection against torture and inhuman or degrading treatment or punishment. Despite what the Court says, this protection is not unqualified. Article 3 now embodies a two-tiered protection, with torture alone attracting a ‘special stigma’. This hierarchical approach is traceable to the seminal decision of Ireland v United Kingdom, and Part A of this thesis demonstrates that it is deeply flawed. The hierarchy between torture and other forms of ill-treatment (the Ireland hierarchy) has become entrenched in the Court’s case law. It continues to manifest in the Court’s narrow definition of torture, and its expansive interpretation of inhuman and degrading treatment. This thesis argues that the growing breadth of the latter concept has occurred in tandem with, and may partly explain, the rapid increase in the number of Article 3 violations found by the Court each year. These developments have carried important consequences. There have been policy consequences for the member states in areas such as national security (where deportation of terrorist suspects is sought to be used as a policy tool) and prisoners’ rights (where the proportionality of sentences, conditions of detention and administrative penalties within prisons, are all now subject to European supervision). In addition to the policy consequences, the expanding second tier of the Ireland hierarchy has carried legal consequences for the Court’s conception of Article 3. It has compelled the Court to introduce limiting devices into its case law on inhuman and degrading treatment. The introduction of these limiting devices, into what is an ostensibly unqualified domain, challenges the position of Article 3 as an absolute right.
The development and application of new hyperpolarized magnetic resonance spectroscopy techniques for the non-invasive assessment of metabolism in the rodent heart
Keywords: metabolism
MRS
MRI
cardiovascular
hyperpolarized

The aim of this thesis was to develop and apply new hyperpolarized magnetic resonance spectroscopy techniques, to assess in vivo metabolism in the rodent heart. Initial work using rat models of heart disease has provided key findings, such as significant increases in pyruvate dehydrogenase flux in the hypertensive rat heart and metabolic alterations in the TCA cycle during the progression into heart failure. Both could provide future non-invasive markers for the metabolic alterations associated with hypertrophy and heart failure in patients. Whilst both of these models provided useful information regarding the metabolic abnormalities of the diseased heart there is also a need to better characterize the individual metabolic pathways that are modified during heart disease. This requires the study of genetically modified animals, namely transgenic mouse models. However, the translation of the hyperpolarized technique from rat to mouse is particularly challenging, mainly due to the mouse heart being a tenth of the size of the rat heart and with a heart rate at least twice as fast. Work in this thesis details the development of mouse cardiac dynamic nuclear polarization (DNP). The development of this technique allowed interesting insights in to differences in the in vivo metabolic phenotype of commonly used “control” mouse strains, and of mouse models of defects associated with β-oxidation. This work also demonstrated that hyperpolarized [1-13C]pyruvate could be used to monitor anaplerotic pathways in the stressed mouse heart, potentially increasing its power for clinical use. In combination with cine-MRI and 31P MRS, this work has highlighted that DNP could play an important role in the diagnosis and prognosis of cardiovascular diseases.
Evaluation of new therapies in Niemann-Pick type C disease
Keywords: Lysosomal storage disease
Niemann-Pick type C
Inflammatory bowel disease

Niemann Pick type C (NPC) disease is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by a mutation in the NPC1 or NPC2 genes. The functions of the proteins these genes encode are not fully understood, but are thought to be involved in free cholesterol egress from the acidic compartment. The pathogenic cascade in proposed to begin with sphingosine accumulation followed by reduction of acidic store calcium levels. This results in impairing intracellular trafficking and storage of multiple lipid substrates in the late endosome/lysosomal compartment.
In this thesis, multiple potential therapies have been tested in a mouse model of NPC1 disease including neuroprotective compounds. Positive effects were observed with some compounds, as reflected by increased life span and/or improved neurological function. In the course of these studies, I discovered another factor that affects the outcome of treatment with liver metabolised drugs. In the NPC1 mouse the cytochrome P450 system is impaired as is the case in the NPC1 cats and in patients. This thesis therefore sheds light on the impairment of this system at the genetic and functional level and presents data on why this aspect of pathology must be considered when designing therapeutics for this fatal neurodegenerative disease. This defect was partially corrected with bile acid supplementation, resulting in an unexpected functional improvement suggesting benefit in the CNS. Another aspect of NPC disease investigated was Crohn's-like intestinal inflammation that occurs in some NPC patients. This has been investigated in the Npc1-/- mouse model using two colitis models showing a partial protection by the Npc1 mutation with different infection kinetics and secretory cytokine profiles. Taken together, this thesis therefore provides insights into two novel aspects of pathogenesis (Crohn's-like intestinal inflammation and a drug metabolism defect) and provides new leads on treatments that target unique aspects of the pathogenic cascade.