VictorJuiz/thesis huggingface dataset:
Genome-wide mapping of the hypoxic response

Hypoxia regulates many hundreds of genes with important roles in ischemic and neoplastic disorders. Central to this response are the hypoxia inducible transcription factors (HIF). This work aimed to better understand the direct transcriptional response to HIF by mapping HIF-binding sites across the genome using chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-seq). ChIP-seq for HIF in MCF-7 breast cancer cells under hypoxic conditions revealed more than 400 high-stringency HIF-binding sites genome-wide. Each member of the HIF heterodimer was present with near complete concordance. Binding of the two principle isoforms revealed a high degree of overlap with no differences in the DNA-binding motif. HIF-binding was associated with upregulation, but not downregulation of genes indicating that it functions as a transcriptional activator but not as a repressor. HIF-binding occurred preferentially at gene promoters, but was also present at promoter-distant sites, which were also associated with gene regulation, implicating long-range interactions in hypoxic gene activation. HIF-binding was associated with markers of open chromatin and active enhancers that were present in normoxia, indicating that HIF-binding sites are already “prepared” to bind HIF before the hypoxic stimulus. Analysis of normoxic and hypoxic RNA pol2 and H3K4me3 signals revealed distinctive hypoxia-inducible changes unique to HIF-binding genes. Comparable numbers of HIF-binding sites were observed in a second cell line (von Hippel-Lindau defective 786-O renal cancer cells) as in MCF-7 breast cancer cells, although approximately 65% were unique to 786-O cells. These unique sites were more frequently promoter-distant. Correlation with expression analyses from renal tumours indicated that many HIF-binding genes were upregulated in renal cancer. One such RCC unique promoter-distant HIF-binding site was identified at an intergenic locus on chromosome 11q13.3 that has been associated with renal cancer in Genome-Wide Association Studies. The HIF-binding site was in high linkage disequilibrium with the disease associated SNP and had the epigenetic hallmarks of an enhancer. Analysis of pan-genomic expression analyses identified the cell-cycle regulator cyclin D1 as highly HIF-regulated, and a physical association between the HIF-binding site and the CCND1 promoter could be determined. Furthermore, in a renal cancer cell line heterozygous at this locus, the RCC-protective allele disrupted HIF-binding leading to an allelic imbalance in cyclin D1 expression.

Keywords: ChIP-seq
RNA-seq
Hypoxia
Hypoxia inducible transcription factors
Renal cancer
Advisor: Ratcliffe, P
Mole, D
Schofield, C
Kinetics of radical reactions of tropospheric importance

The object of the research described in this thesis is to provide, by means of laboratory experiments, data required to understand the atmospheric chemistry of the nitrate radical, from both a mechanistic and kinetic point of view.
The low pressure discharge-flow kinetic technique coupled detection of the NO3 radical by optical absorption was used to measure the temperature-dependent rate coefficients for the reaction of NO3 with 1-butene, 1-chloro-l-butene, 2-chloro-2-butene, 3-chloro-l-butene, 1-chloro-2-butene, 2-chloro-2-butene, 1-chloromethylpropene, 3-chloromethylpropene, 3-bromo-1-butene, 4-bromo-l-butene and 2-bromo-2-butene. The atmospheric implications for the reaction of NO3 with these compounds are discussed.
In order to understand the patterns of reactivity towards NO3 exhibited by these compounds, a number of approaches were adopted. First, a non-quantitative approach employing the simple ideas of inductive and mesomeric effects. Secondly the observed reactivity of NO3 towards these compounds was discussed, quantitatively, in terms of the relative energies of the interacting orbitals. This quantitative analysis required an extensive set of molecular orbital calculations were undertaken at various levels of sophistication. A good correlation was found, for compounds not containing vinylic halogen atoms, between -E(HOMO) and the measured rate constant; the data were used also to calculate "group-reactivity factors". In an extension to this work a new empirical correlation is presented that takes account of the contribution, in terms of the atomic orbital coefficients, of vinylic halogen atoms to the observed rate constant. To provide support for these calculations, work was undertaken using photoelectron spectroscopy to characterise experimentally the individual molecular orbitals. A correlation between the inverse of the molecular polarisability and the activation energy of the reaction is also described.
Complementary work was undertaken in a unconventional flash-photolysis system to look at the kinetics of the reaction NO3 + NO3 andlongrightarrow; 2 NO2 + O2 over a pressure range of 2 to 100 Torr in helium. The measured rate coefficient was found to be pressure independent and to have a value of (2.2±1.0) x 10-16 cm3 molecule-1 s-1.
The experimental work on the nitrate radical was extended to look at the laser-induced fluorescence (LIF) spectrum and at the quenching of the excited state of the nitrate radical.

Advisor: Wayne, R
Numerical modelling of building response to tunnelling

The construction of underground tunnels in soft ground in urban areas involves the potential for ground movements caused by the tunnelling to affect existing surface structures. Masonry structures are at particular risk of crack damage. Conventional empirical building assessments do not fully capture all aspects of this soil-structure interaction situation. Numerical methods are increasingly used for such problems. It is common practice in empirical and numerical methods to model a building as an elastic beam in 2D. The objective of this thesis is the development of a new approach to the numerical modelling of masonry buildings using surface beams in 3D. In phase one of this project, finite element analyses of elastic and masonry facades are undertaken and the traditional beam method of modelling them is assessed. New equivalent elastic surface beams are developed, the properties of which account for the dimensions and openings in facades which were found to influence the response to settlements. Equivalent masonry beams are also developed which have a constitutive model that accounts for the different response of masonry buildings in hogging and sagging. Timoshenko beams are chosen to model the facades and these beams were implemented into the OXFEM finite element program with full 3D capability along with the new constitutive beam models. Example masonry structures were modelled in 3D using the new surface beams in phase two. Tunnel construction was simulated under the buildings and the response of the beams compared to a full masonry building model. Example analyses included buildings both symmetric and oblique to the tunnel. Results showed that the equivalent elastic beams accurately simulate full masonry building response in sagging regions. Parametric studies confirmed the choice of equivalent beam parameters and the impact of different relative stiffnesses. The equivalent masonry beams displayed the same good agreement in sagging but were less accurate in hogging. In phase three, finite element models are used to compare ground movements and structural response of buildings using the 3D equivalent masonry beam method and observed data from the construction of the London Underground Jubilee Line Extension. The surface beams showed good agreement with the observed building responses in both sagging, where the building response was essentially rigid and in hogging where a more flexible response was observed.

Keywords: tunnelling
settlement
Advisor: Burd, H
Houlsby, G
The evolution of social systems in human and non-human primates

From a Darwinian perspective, both history and environment are causal factors for change in animal social behaviour. Because behaviour leaves no fossil evidence researchers have focused on how social systems help animals and humans adapt to their current environments and have only been able to make tentative suggestions about how such systems may have evolved. However, a new theoretical framework, based on Darwin’s insights, allows phylogenetic relatedness to be incorporated into comparative analyses to discover the ancestral states of social behaviour and the ultimate drivers of change in human and primate societies.
This thesis uses these new methods to investigate the history and drivers of change in human and primate sociality and proposes a new model of primate social evolution. Analyses of mating systems suggest that social monogamy in humans and other primates is the result of infanticide risk brought about by life history changes. These methods were also able to reveal how changes in inheritance rules to matriliny among Bantu-speaking societies, contributed to a switch to matrilocal residence, which in turn contributed to a change from polygynous marriage to monogamy. Cultural history effects change in both descent and residence patterns, while geographical proximity also affects descent, but residence and environmental factors drive changes in marriage. This approach may provide a way for the various schools for the study of human and primate social behaviour to collaborate more closely and provide ultimate answers to the drivers of change in human society.

Keywords: Evolution
Language
Bantu
Primates
Kinship
Marriage
Bayesian Phylogenetics
Monogamy
Sociality
Advisor: Shultz, S
A study of tyrosine hydroxylase activity in nonadrenergic neurones in the rat brain

This abstract sent to supervisor 5/4/12 Tyrosine hydroxylase is the enzyme which controls the ratelimiting step in the synthesis of noradrenaline. In order to discover whether the activity of tyrosine hydroxylase might serve as an indicator of noradrenergic function in the brain, two preparations for the direct measurement of TH activity in rat brain regions by a tritium-release method were employed: synaptosomal suspensions prepared from pinchedoff nerve terminals, and partially solubilised enzyme preparations prepared from frozen homogenates or synaptosomal suspensions and assayed at saturating concentrations of cofactor and tyrosine. There was evidence of an increase in tyrosine hydroxylase activity in hippocampal synaptosomes of rats killed immediately after a mild electrical footshock. Activation of synaptosomal enzyme activity was also found after single doses of clonidine and parachloroamphetamine, and after repeated handling; and single doses of morphine and of yohimbine appeared to lower tyrosine hydroxylase activity. Repeated administration of drugs such as clonidine, desipramine and 2-deoxyglucose, however, did not affect tyrosine hydroxylation rate. A preliminary finding , suggesting differences in synaptosomal tyrosine hydroxylase activity related to experience with different reinforcement schedules (continuous reward vs. partial reward) in a runway experiment, was not substantiated in later experiments; nor was there any difference between the synaptosomal tyrosine hydroxylase activity of naive controls and rats given repeated daily shocks for a week. The saturated TH assay performed on solubilised enzyme was, as predicted, unresponsive to the short term stimulation effects detected with the synaptosomal assay. However, other changes, such as a reduced maximal hydroxylation rate after repeated desipramine administration, and an increased rate several weeks after a course of electrical stimulation of the septal area, were established with the saturated assay. Although the changes in stimulated rats were associated with increased behavioural tolerance to stress, e.g. resistance to extinction of a running response in a runway, other experiments in which the behavioural stress-tolerance was induced by behavioural methods alone showed no accompanying changes in TH activity. Measures of synaptosomal and saturated soluble TH activity appear to constitute independent indicators of noradrenergic function. It seems that synaptosomal tyrosine hydroxylase activity is not, as anticipated, controlled by the firing rate of locus coeruleus neurones; but it may be subject to local regulation in noradrenergic terminals. The results are discussed in the context of theoretical aspects of the regulation of noradrenaline synthesis in the brain, and the mechanisms underlying physiological responses to stress and behavioural tolerance to stress.

Advisor: Fillenz, M
Gray, J
A hyperplasticity model for clay behaviour: an application to Bangkok clay 

The main purpose of this thesis is the development of a new constitutive soil model emphasising the use of thermodynamic principles. This new approach to plasticity modelling, termed ‘hyperplasticity’, was first developed by Collins and Houlsby (1997) and Houlsby and Puzrin (2000). This idea has been further extended to continuous hyperplasticity in which smooth transitions between elastic and plastic behaviour can be modelled (Puzrin and Houlsby, 2001b). Applying hyperplasticity to this research, a kinematic hardening model specified by means of two scalar functionals is used to accommodate the effect of stress history on stiffness. A rate-dependent calculation for an approximation of the incremental stress-strain response is introduced. The model developed in the research is named ‘kinematic hardening modified Cam-clay (KHMCC) model’ and requires eight parameters (plus an extra parameter for rate-dependent analysis). Triaxial test results from the Asian Institute of Technology (AIT) and cyclic undrained triaxial data from Chulalongkorn University are employed to establish the soil parameters for the new model. The model is initially developed in terms of triaxial stress-strain parameters for the purpose of comparison with the experimental data on Bangkok clay. The model is expressed in FORTRAN code for implementation into the OXFEM finite element program. Two examples of real geotechnical projects in Bangkok (a road embankment and tunnelling in soft ground) are analysed under plane strain conditions. Comparisons of the numerical analysis results with field data are made. In addition, factors affecting the results of the analysis such as stress history and K0, are investigated.

Keywords: hyperplasticity
clay
Advisor: Houlsby, G
The construction nominative + infinitive in Russian

The construction "Nominative + Infinitive" is that in which the direct object of an infinitive verb appears in the nominative case. It is used widely in written Russian up to the early eighteenth century and survives in certain dialects. The main questions examined in this thesis concern: the origin of the construction in Russian; its syntactic and morphological limits; the levels of language in which it is used; the geographical distribution of the construction within the East Slavonic area; the development of the construction and its disappearance from the written language of Moscow.
Although the evidence on the first question is contradictory, it is suggested that the construction may have appeared in Russian shortly before the date of the earliest texts and may be due to a combination of factors. The nominative replaces only direct objects in the accusative, and in the original form of the construction the nominative-object is used only with independent infinitive verbs. Only feminine singular -a type and -i type nouns appear as nominative-objects Except where the language is strongly influenced by Old Church Slavonic, the use of the construction appears to be independent of the level of language used.
Examples of the construction are found in Old Ukrainian documents and in modern South Russian dialects, and, although these are few and their usage differs from that found in North Russian sources (where the construction is well documented), it cannot be said that the construction has always been restricted to northern and central dialects. In almost every text both nominative and accusative are used for the direct object of independent infinitives, and often the choice of case seems to be random. From the sixteenth century, however, the accusative gradually becomes more frequent until it displaces the nominative from the written language.
Compression behaviour and shear strength characteristics of a natural silty clay sedimented in the laboratory

The compression behaviour, shear strength characteristics, and material properties of dense slurries and soft settled beds of natural fine-grained sediments were studied experimentally. Slurries of varying initial density, initial height, and pore fluid salinity were settled one-dimensionally, by self-weight, in the laboratory. Settling behaviour was studied in terms of slurry appearance, particle segregation, height of surface versus time, sediment surface and element settlement rates, and the redistribution of sediment with respect to height and time. Consolidation behaviour was studied in terms of sediment compressibility and pore fluid flow. Shear strength was examined 'in situ' and related to the parameters effective stress and specific volume.
Instruments and techniques were developed to facilitate the measurement of low effective stresses, low strengths, and high specific volumes. A small- scale sediment sampler was developed and used in an attempt to study the arrangement of particles within soft sensitive beds.
The experimental results revealed numerous fundamental reasons why theoretical models of settling and consolidation are unsatisfactory when applied to dense flocculated slurries and beds of high specific volume, respectively. For the sediment studied, well-defined compressibility and shear strength relationships were observed. Pore fluid flow relationships were non-unique at high specific volumes.
The compression behaviour of slurries was found to have a rational basis in terms of electrochemical forces and degrees of particle association. The experimental results are relevant to engineering practice. Recommendations are made regarding future research.
What to do when there isn't enough: the fair distribution of scarce goods

My DPhil submission consists of a series of papers on related topics on the moral philosophy of scarce benefit distribution. It focuses on two types of scarce benefit distribution case.
The first type occurs when which all potential beneficiaries of a good each have an equally strong moral claim on an equal benefit from the resource but scarcity or indivisibility prevents us from benefiting all potential beneficiaries. Call these cases equal conflict cases. In 'Anti-Majoritarianism', I argue against the view defended by both utilitarians and non-utilitarians that in equal conflict cases you always ought to give the benefit to as many people as possible. I argue that doing so is neither morally right nor fair. In 'Weighing Up Weighted Lotteries', I argue that the philosophical debate between unweighted and weighted lottery benefit distribution procedures has been misconceived and that fairness requires us to use a new kind of weighted lottery that I call the exclusive composition-sensitive lottery. In 'Can't Get No Satisfaction', I defend a new view that I call the dual-structure view about how lotteries satisfy potential beneficiaries' claims in equal conflict cases and highlight the implications of that view for the distribution of donor corneas to those who have suffered corneal degeneration.
The second type of this distributional problem occurs when we can either benefit a very large number of potential beneficiaries with a very small benefit (call these the many) or a very small number of potential beneficiaries with a very major benefit (call these the few). In "Valuing the Few Over the Many" I argue that there are cases where not only ought we to benefit the few over the many no matter how numerous the many are, but it is also better to do so. However, this conclusion can be shown to conflict with a number of widely held tenets of value theory. I evaluate different ways of accommodating these intuitions and argue that in some contexts, benefits are not of finite value. The view I defend in 'Valuing the Few Over the Many', combined with some intuitively plausible axiological claims, is inconsistent with the transitivity of the 'better than' relation. In 'Making Betterness Behave' I argue that for what I call the conditional non-coextensive thesis: if 'better than' is not transitive, one ought to take the position that 'more reason to bring about rather than' is transitive. I argue that one can generate a transitive 'more reason to bring about rather than' deontic ordering from a non-transitive axiological ordering in a principled way. This deontic ordering avoids the major practical objections (money pumps, moral dilemmas and threats to practical reasoning) to non-transitivity of the 'better than' relation.

Keywords: lotteries
scarcity
distributive ethics
value theory
fairness
Advisor: Broome, J
Parfit, D
Essays in industrial organisation

This thesis presents four largely independent essays on industrial organisation. The first three essays examine how search and switching costs distort competitive markets, whilst the fourth essay studies how firms themselves might eliminate competition by agreeing to fix the market price. The key insight from the first two essays is that by choosing to pay a search cost, a consumer reveals to a retailer some private information about their product valuations. In this context the first essay re-examines the well-known theoretical Diamond Paradox in which markets completely break down if firms sell only a single product. I demonstrate that multiproduct retailers offer an elegant and realistic way of overcoming this Paradox, and then apply the model to supermarkets. In particular, this essay provides new insights into why convenience stores charge high prices and why grocery stores use selected loss-leaders. The second essay looks at internet search and therefore focuses on the special case in which search frictions become very small. It seeks to explain why retailers pay so much for online advertising, when consumers can easily click on whichever links they like. I show that if consumers have prior information about products, their search behaviour is limited but very informative about their preferences. This places prominent firms in a privileged position, and makes them substantially more profitable. The third essay provides a simple model in which small switching costs are pro-competitive and beneficial to consumers. This challenges the conventional wisdom, but also argues that switching costs should be less of a policy priority than search costs. The final essay examines a game in which two firms bargain over a collusive price. It is shown that entry into such a market may make collusion easier, and may increase price.

Keywords: switching
multiproduct search
Advisor: Klemperer, P