VictorJuiz/thesis huggingface dataset:
Understanding the role of the TOPBP1 and BLM interaction in promoting genome stability

The ability to sense, respond to and repair DNA damage is essential in normal development and survival of an organism. A number of human congenital syndromes are associated with mutations in pathways involved in the DNA damage response, including Seckel and Bloom syndromes. Such diseases are often characterised by developmental abnormalities and cancer, emphasising the importance of gaining a deeper understanding of the mechanisms underlying these pathways. The protein kinase ATR, mutated in Seckel syndrome, is a critical mediator of the intra S-phase checkpoint in response to replicative stress. ATR activation is a multistep process that requires its interaction with TOPBP1. Recently published data identified an interaction between TOPBP1 and the BLM helicase. This interaction is dependent on the phosphorylation of the conserved serine 304 of BLM and mutation of this residue results in genome instability. However, exactly how TOPBP1-BLM interaction protects the genome remains unclear.
The findings presented in this thesis demonstrate that DT40 cells expressing the BLM S251A mutant are defective in activation of the ATR kinase upon DNA damage. In line with this, these cells display reduced CHK1 phosphorylation, increased origin firing and unreliable replication fork restart. Importantly, these phenotypes could be rescued by fusing the ATR activating domain of TOPBP1 to the mutated BLM. Furthermore, results from BLM-deficient human cell lines demonstrate similar phenotypes. Thus, this data establishes a non-enzymatic role for the BLM helicase in promoting genome stability via activation of the ATR kinase. This may help in explaining why many Bloom syndrome patients display many of the same symptoms as ATR-Seckel patients, including short stature and microcephaly.

Advisor: Niedzwiedz, W
McHugh, P
Heterodinuclear catalysts for CO2/epoxide copolymerisations

This thesis describes the preparation of new heterodinuclear catalysts for the selective copolymerisation of epoxides with CO2 or anhydrides. The catalysts are based on a symmetrical diphenol-tetraamine macrocycle to prepare heterocomplexes coordinated to zinc and magnesium. The coordination sphere is completed by co-ligands derived from carboxylates. Optimisation of the synthesis is carried out to enable a straightforward route to new catalysts through the metathesis of a dibromide complex using a range of potassium salts. The characterisation of these complexes is explored using multinuclear NMR spectroscopy, mass spectrometry, infrared spectroscopy and elemental analysis.
The heterodinuclear complexes are highly active for the copolymerisation of cyclohexene oxide and CO2, under atmospheric pressures [TOF = 645 h-1, 120 °C, 0.1 mol%, 1 bar]. At higher temperatures (120 °C), excellent selectivity for poly(cyclohexene carbonate) formation (&GT; 99 %) is maintained. The catalysts are highly active under low catalyst loadings, with excellent activities [TOF = 8830 h-1, 120 °C, 0.01 mol%, 20 bar]. Telechelic polymers are produced upon addition of chain transfer agents, and the system is stable under aerobic conditions. A linear increase in molar mass with conversion shows the polymerisation is controlled. The copolymerisation of CO2 with a range of epoxides is explored, allowing formation of poly(propylene carbonate), albeit with low selectivity [25 %, 60 °C, 0.01 mol%, 20 bar], and high molar mass poly(cyclopentene carbonate) in excellent (&GT; 99 %) selectivity [TOF = 76 h-1, 80 °C, 0.01 mol%, 20 bar].
The catalysts are also tested in the copolymerisation of phthalic anhydride with cyclohexene oxide to yield polyesters in excellent (&GT; 99 %) selectivity. These catalysts are also highly active and well controlled [TOF = 289 h-1, 100 °C, 0.13 mol%]. A range of anhydrides were tested, including succinic anhydride, glutaric anhydride and diphenic anhydride, which generally show high selectivity, although a variation in catalytic activity is observed.
Kinetic studies are carried out to probe the rate equation for the copolymerisations of CO2 and phthalic anhydride, each with cyclohexene oxide. For the copolymerisation of phthalic anhydride and cyclohexene oxide, the data suggests a zero order dependence on anhydride and first order dependence on catalyst and epoxide. The rate equation determined for the copolymerisation of CO2 and cyclohexene oxide suggests a first order dependence on catalyst and epoxide, with a zero order dependence on CO2 pressure, and is in line with previous studies on similar systems. Computational analysis, applying density functional theory, shows that the previously hypothesised homodinuclear ‘chain-shuttling’ mechanism could be plausible for the analogous heterodinuclear systems.

Advisor: Williams, C
Integrating palaeontological and neontological perspectives to unravel the secrets of a third of vertebrate diversity

There are over 18,500 living species of acanthomorph (spiny-rayed fishes), and they represent half of all living fish species and a third of extant vertebrates. They inhabit countless ecological niches, they are incredibly diverse, and they have developed a number of specialised morphological innovations. The earliest acanthomorphs are known from the Cenomanian, but they were neither diverse not abundant during the Cretaceous period. Following the end-Cretaceous extinction event, the acanthomorphs radiated, and by the Eocene they were anatomically modern. However, our understanding of the relationships between most fossil and living acanthomorphs, and the macroevolutionary processes behind their rise to dominance in the Recent, are poorly known. In this thesis, I aimed to develop our understanding of the evolution of the acanthomorphs by combining palaeontological and neontological data. I undertook three separate projects to accomplish this. First, I studied the anatomy two fossil representatives (†Aipichthys pretiosus and †'Aipichthys' nuchalis) of a primitive acanthomorph lineage, the lampridomorphs. I then placed these taxa in a phylogenetic analysis to reveal the pattern of character evolution leading to the crown-group. Second, I aimed to understand the morpho- logical condition at the base of the acanthomorph tree by studying the relationships between two extinct groups (†Ctenothrissiformes and †Pattersonichthyiformes) that may have branched from the acanthomorph stem. Phylogenetic analyses utilising morphological and molecular data support a stem ctenosquamate placement for these taxa. Third, using a timescaled supertree, I studied the evolution of one of the major acanthomorph innovations, the protrusile upper jaw. The combination of palaeontological and neontological data provided deep insight into the evolution of the acanthomorphs, and allowed for the identification of patterns and processes that could not be identified from studying extant taxa in isolation.

Keywords: Palaeontology
Acanthomorpha
Evolution
Evolutionary biology
Fish
Palaeobiology
Phylogenetics
Advisor: Friedman, M
Giles, S
Lattice Boltzmann study of evaporation phenomena

Evaporation phenomena are having a resurgent interest in the recent years thanks to new techniques that allow for better flow visualization and microfabrication techniques of surfaces with interesting wetting properties. From the theoretical point of view the development of simulation techniques for evaporation phenomena is a challenging work due to the presence of moving interfaces and multiphase flows.
Thanks to its mesoscopic nature, the Lattice Boltzmann method is an ideal candidate for the simulation of evaporation phenomena. Here we present a Lattice Boltzmann algorithm capable to correctly reproduce the diffusion-limited evaporation dynamics.
We apply this numerical method to study the dynamics of multiple droplets evaporating together and we compare the results with experimental measures. We show that the presence of other droplets can dramatically increase the evaporation lifetime compared to the single droplet case; we also investigate the competition between convection and collective effects.
We then develop a theory to predict the instability behaviour of liquid fronts in two dimensional confined geometries and we consider the interplay between capillary forces, wettability gradients and phase changes. We use LB simulations to investigate the effect of a three dimensional geometry that cannot be taken into account in the analytical theory.
Finally we investigate the effect of flows on droplet evaporation. We consider both buoyancy induced and external flows. We show that even when diffusion is the dominant mechanism, flow effects are not negligible.

Advisor: Yeomans, J
The use and misuse of rhetoric by Don Quixote

This work of research aims to elucidate the structure and meaning of the "Quixotic rhetoric", that is, persistent patterns in the protagonist’s delivery of discourses. Through a close reading of select episodes in the novel, the study explores their style, structure, with a particular attention devoted both to their connections to the rhetorical thought of Renaissance Spain and departures from the rhetorical tenets of the time.
This thesis is focused on the following questions:
1) How exactly do Don Quixote’s discourses function (and/or fail to function)? What are the mechanisms used by Cervantes to create an impression of the protagonist’s rhetorical competence (or lack thereof)? How do the audience’s reaction, narrator’s comments, and further developments show that a particular speech is effective (ineffective)? Are there any discernible patterns in Don Quixote’s discourses that consistently lead him to rhetorical triumph or failure?
2) How does Don Quixote depart from the rhetorical rules and expectations of the Spanish Golden Age? What do the subject and style of his discourses have in common with the rhetorical thought of of his day, and “specialised” forms of rhetoric in particular (forensic, courtly, religious, etc.)? How does moving beyond the typical confines of rhetorical discourse affect the audience’s (and the reader’s) perception?
3) To what extent does the nature of Don Quixote as a work of fiction, and a putative originator of the novelistic genre, affect its representation of rhetorical discourse? Is the mad hidalgo’s mishandling of rhetorical rules a satire of rhetoric as a whole? What is the meaning of the protagonist’s use (and misuse) of rhetoric for the relationship between rhetoric and the novel?

Keywords: Bakhtin
Cervantes
Don Quixote
rhetoric
novel
Early Modern
Advisor: Williamson, E
Investigating the oncolytic properties of a group B adenovirus on cancer cells and its effects on the local  immune response

Oncolytic viruses are characterised by their ability to selectively infect and kill tumour cells. Recently it has emerged that they can exert an additional anticancer mechanism stimulating adaptive immune-mediated cancer cell killing. Enadenotucirev (EnAd, formerly known as ColoAd1), is a chimeric Ad11p/Ad3 virus group B oncolytic adenovirus that binds CD46 and is under development for the systemic treatment of metastatic carcinomas. The central aim of this thesis was to to assess whether EnAd provides an adjuvant effect on tumour-associated antigen presenting cells (APCs) that could drive TH1 polarisation for an effective anti-tumour immune response.
This thesis describes the potent oncolytic properties, fast replication and high numbers of virus progeny production by EnAd in cancer cells. Recombinant EnAd variants were engineered to investigate the roles of the mutant regions in the genome of EnAd, and how these influence the modified phenotype. A chemical drug panel was used to identify pathways and cellular factors involved in cellular production of EnAd, finding that several mTOR inhibitors and microtubule inhibitors could improve virus replication.
An ,em>in vitro system using partially matured human monocyte-derived dendritic cells (DCs), which displayed a similar phenotype to tumour-infiltrating DCs, was used to explore the effect of EnAd on APC responses. EnAd induced a strong adjuvant effect on these cells by up-regulating surface markers and secretion of pro-inflammatory factors. Further mechanistic experiments, alongside a CAR-binding group C adenovirus 5, indicated these adjuvant effects were virus particle-mediated and dependent on CD46 binding. To understand the functional implications downstream of these interactions, T cell activation and phenotype was assessed using a mixed lymphocyte reaction approach. The data indicated EnAd was a good candidate compared to other adenoviruses, that may steer the response of activated T-cells towards a TH1 phenotype, for an effective immune response.
In conclusion, the potent oncolytic properties of EnAd virus may provide an adjuvant effect on tumour-associated APCs, helping to harness an adaptive immune response.

Keywords: Oncolytic virus
Immunotherapy
Cancer
Advisor: Seymour, L
Abnormal combustion in spark ignition engines

Emissions from internal combustion engines are a major contributor to anthropogenic climate change. In order to decrease the amount of emissions, car manufacturers are investing in increasing the efficiency of spark ignition engines. Means for this include downsizing and turbocharging which come with an exacerbated risk of abnormal and harmful combustion phenomena, notably autoignition, knock and pre-ignition and thus pose a limit to the efficiency of the engines.
Abnormal combustion depends on the engine geometry, the operating conditions and the fuel. Industrial standard classification systems are outlined to be insufficient, misleading or non-existent for modern engines and fuels. This thesis aims to improve the understanding of the abnormal combustion phenomena through an experimental project which can be utilised for improved classification systems.
The vast majority of the experiments were conducted on a variable compression ratio engine which was fitted with modern control, measurement and data acquisition equipment to resemble an industrially-used test engine.
In a first study, methods of finding the ideal engine operating point were investigated. Knock was induced in the engine, and knock indicators and limitations of knock are discussed here. Enhanced humidity was passed into the heated air-inlet stream by means of a custom-built humidifying unit. Results showed that both the power output of the engine and the severity of knock were reduced with increased humidity. This was explained by the exclusion of combustible air. A fuel-vaporization unit allowed for experiments with fully vaporized fuel. It could be shown that this had an adverse effect on knock as the cooling effect of the enthalpy of vaporization was removed.
A second study employed a temperature-controlled glow plug to induce surface pre-ignition. A range of analysis techniques were tested and discussed which ranged from flame ionization detection to several in-cylinder pressure based methods. A cycle-by-cycle analysis with a maximum pressure method revealed an unexpected trend of surface pre-ignition tendency in sweeps of stoichiometry and fuels, with slightly weak of stoichiometric mixtures being the most susceptible to pre-ignition. Enhanced humidity had a negligible effect on surface pre-ignition under real world conditions.
A third study concerned itself with the analysis of knock-induced heat flux, which is both a major cause for damage to the engine and trigger for surface pre-ignition. A heat flux probe was fitted to the engine and results linking heat flux to knock could be obtained on cycle-by-cycle basis and cycleaveraged basis. A linear trend between heat flux and knock intensity was found.

Advisor: Stone, R
Situations beyond human control in the Zhuangzi

In this project, I reexamine the idea of acceptance in the Zhuangzi and develop it by reconstructing an 安 (contentment) as a fundamental element in dealing with 'human limitations', and accordingly, with things beyond human control. I argue that the question of how to deal with human limitations is central to ideas in the Zhuangzi of how one should live in the mundane world. That is to say, the idea of an is seen as an important part of self-cultivation for living a good life. In other words, the reason for the discussions on human limitations in the Zhuangzi is to arrive at a way of dealing with these limitations, rather than to try to escape from them.
To be specific, this project not only examines debates and discussions regarding human limitations through different terms and stories, but also focuses on actions and attitudes that can be adopted to deal with these limitations. It discusses the following aspects: how the Zhuangzi justifies the attitude of an (安) as a conscious and active choice through which one can willingly accept human limitations, namely ming (命) and nature xing (性), and accordingly lead a safe, efficient, and peaceful life; how the idea of contentment allows one to be a filial (xiao 孝) child when confronted with a problematic relationship with one's parents; how the idea of an is justified in the Zhuangzi as a form of courageous (yong 勇) behaviour; how and why the Zhuangzian sages chose singing (ge 歌) as a means of expressing their contentment towards situations that are beyond human control; and how laughing (xiao 笑) at the uncontrollable can be transformed into a form of self-control.
With a thorough analysis of contentment in the Zhuangzi, this project makes the following contributions. First, the Zhuangzian idea of contentment is re-evaluated by relating it to other questions of philosophical concern, therefore bringing new significance to it. Second, this work opens up a new discussion on how and why one can affirm and willingly accept the human limitations within the field of Chinese philosophy, so that one can engage in a topic that is also of concern in religious studies and Western philosophy. Third, through this project, we will be able to appreciate more fully the ways in which Zhuangzian philosophy is related to other works in early China.

Advisor: Meyer, D
New methods for new data: developing techniques for analysing alternative social science data

In social science research, methodology matters. Seemingly arcane issues of measurement are not trivial but can have profound inﬂuences on how we view the social world.This thesis seeks to fill methodological gaps that have opened up as new research techniques become available. This thesis consists of five chapters covering three projects.
The first project analyses whether Google Trends data can be used as proxies for issue salience. A methodology for validating Google Trends data against survey data is developed, with searches validated in the United States, the United Kingdom and Spain. The dangers of not testing the validity and reliability of Internet derived data is discussed.
The second project examines the translation equivalence of survey instruments into diﬀerent languages by using corpus linguistic on Internet corpora in 10 languages. Using these corpora, dissimilarity measures are constructed, allowing clusters of meaning to be identifed quantitatively and examined qualitatively. This method is illustrated using a postmaterialism item from the World Values Survey. This item is found to suffer from important translation problems, as the translations of the word ideas have clearly nonequivalent meanings across languages. These differences predict the item's correlations with other variables within the World Values Survey.
The third project looks at the role of information processing within the US State Department’s foreign policy analysis using social network analysis (SNA). First, the predictors of information ﬂow are identifed, showing diplomats focus most strongly on trade. Next, a new type of relational event model is developed to account for specifc communication features communication within this bureaucracy: a relational event conversation history actor initiated network model (RECHAIN). Using this model, we fnd the importance of trade is set by the Bureaus, with Embassies adopting this agenda against their preferences. Finally, we examine the evidence behind diﬀerent mechanisms of communication agenda setting.

Keywords: state department
world values survey
Internet search
diplomacy
survey translation
foreign policy
diplomatic networks
incidentally collected data
survey methodology
Social science methodology
social network analysis
Advisor: Fisher, S
Understanding the growth and convective instability of mushy layers, with application to young sea ice

Sea ice is salt-water ice which forms at the poles when the oceans solidify, and it plays a vital role in polar climate and ecosystems. In particular, the salt fluxes from growing sea ice are a major contributor to the cold halocline in the Arctic, and to the Arctic and Southern Ocean circulations more generally. Sea ice is not a pure solid - it has a microstructure of solid ice crystals and concentrated brine, known as a mushy layer. Segregation occurring during solidification means that the colder interstitial fluid closer to the ice surface also has a larger salinity than the warmer, fresher, underlying ocean. This creates a tendency for convection which drives the observed salt fluxes from growing ice, and provides nutrients fluxes for algae within the sea ice.
This thesis aims to characterise the early growth and convective onset in sea ice through a broad investigation of the relevant parameters. The study makes use of the mushy layer equations which describe the transport of mass, energy, salinity, and momentum through a reactive, porous medium. Whilst motivated by sea ice, the results are presented generally, and may have implications for convection problems in Earth sciences and engineering. I investigate the dependence on the dimensionless parameters that characterise the system; with particular focus on the (dimensionless) liquidus gradient and the Biot number. The liquidus gradient describes the ratio of salinity to thermal scales, while the Biot number measures the rate of effective thermal conduction by the surface boundary. This is an aspect which has not previously been considered in growing mushy layers.
I identify two clear limiting regimes for growth. When salinity variations are relatively large compared to thermal variations the mushy layer has a high porosity. A second regime, referred to as the Stefan regime, features comparatively smaller salinity variation and substantial internal solidification, with high porosity confined to a narrow region at the mush base. Most sea ice systems straddle the transition between these regimes. Inefficient cooling, as modelled by the Biot number delays the mushy layer growth and slows internal solidification. Regions of high porosity play a key role in convective dynamics due to their high permeability, reducing the requirements for convective onset but also leading to localisation of convective flow near the base of sea ice. Imperfect conduction is also shown to delay convective onset in a pure porous medium, which has geophysical implications, including for carbon sequestration.

Advisor: Wells, A