VictorJuiz/thesis huggingface dataset:
Investigating the contribution of alternative polyadenylation to the regulation of gene expression

Around 70% of human genes have been found to contain multiple cleavage and polyadenylation (pA) sites. The alternative usage of these different pA sites is referred to as alternative cleavage and polyadenylation (APA). A wide range of studies have described switches in APA profiles when comparing different cell types and different cell states, notably general shifts to shorter APA isoforms upon the onset of cancer. These shifts have been described at both the individual gene and transcriptome levels. However, the extent to which these changes in APA profiles are contributing to changes in gene expression, and thereby altering the observed phenotype, is still under debate.
This thesis develops a novel subcellular fractionation approach to isolate those genes where the alternative use of different pA sites results in APA isoforms that differ in either the cytoplasmic stability or nuclear export rates. These differences would materialise as a differential representation of the resulting APA isoforms in the cytoplasmic and nuclear RNA fractions. This approach was applied to 12 human cell lines using a combination of publicly available generic poly-A+ RNA-sequencing data and 3'end sequencing performed here. Eleven out of twelve of these cell lines showed a significant bias towards an overrepresentation of the shorter, proximal APA isoform in the cytoplasm, which fits with the general model that 3’untranslated regions (3'UTRs) are mainly repressive and promote cytoplasmic instability. Comparisons of the isolated genes for each cell line show that differential regulation of APA isoforms tends to be largely cell type specific.
Application of this subcellular fractionation approach to a cell-line based model for colorectal cancer progression highlights a small cohort of genes where APA is likely to have an impact on gene expression, potentially contributing to colorectal cancer progression. This analysis provides an ideal starting point to study these APA events at the individual gene level to elucidate fully whether APA is having a significant impact on gene expression.
Furthermore, post-transcriptional regulatory pathways governing these differential regulation events were investigated, including the contribution of micro-RNAs (miRNAs) to the differential regulation of APA isoforms. Unexpectedly, depletion of the endoribonuclease III, DICER1, reveals that it does not only shape the steady-state cytoplasmic APA profile through its well-known function in miRNA biogenesis, but also influences pA site choice in the nucleus.

Advisor: Furger, A
How international courts promote compliance: strategies beyond adjudication

In recent decades, international courts have proliferated the international system—a trend often referred to as the "judicialization" of international law and politics. States create international courts to promote greater compliance with international law, and have increasingly embedded these actors within various international regimes. Scholars have primarily analyzed the consequences of the judicialization trend based on international judges' authority for interpreting and applying international law, adjudicating international disputes, and rendering binding rulings. However, international courts, especially when conceptualized as international organizations, also perform a variety of activities beyond adjudication. This study theorizes international courts’ agency, in both its judicial and non-judicial dimensions, to explain how international courts aim to influence actors’ behaviour and promote greater compliance within their international legal regimes.
As a foundation, it conceptualizes the various approaches through which international courts can promote compliance with international law, showing how international courts can appeal to actors’ logics of consequences and appropriateness, either through their own agency or through using intermediary actors. An original dataset on the prevalence of these approaches across all twenty-three permanent international courts reveals significant variation in whether and how international courts have expanded their approaches for promoting compliance. International courts' level of autonomy influences their capacity for entrepreneurship and developing their approaches. Furthermore, their levels of acceptance and accessibility affect their adoption of particular approaches. Drawing on archival and interview research, ten case studies of a range of global and regional international courts, operating in a variety of issue areas and contexts, elucidate international courts' variable expansion of approaches based on these core variables. The study shows that international courts are dynamic and strategic actors, which address challenges and exploit opportunities to increase their influence and promote compliance within their international regimes.

Keywords: Compliance
Autonomy
International Law
Legitimacy
Entrepreneurship
Judicialization
International Courts
Advisor: Snidal, D
Evidence for a 5-HT6 receptor-mediated control of midbrain 5-HT neurons

The dorsal raphe nucleus (DRN) contains the majority of 5-hydroxytryptamine (5-HT)-producing neurons, whose firing is influenced by homeostatic feedback pathways. Dysfunction of 5-HT neurons is implicated in the pathophysiology of diseases such as depression. Thus, pathways regulating 5-HT neuron activity represent potential therapeutic targets. Negative feedback pathways influencing 5-HT neurons include 5-HT1A autoreceptors located in the DRN, and feedback from 5-HT1A, 5-HT2A and 5-HT2C receptors on postsynaptic neurons in forebrain regions. One pathway, mediated by 5-HT4 receptors on medial prefrontal cortex (mPFC) neurons, positively regulates 5-HT neuron activity. Preliminary findings in the Sharp Laboratory suggested that 5-HT6 receptors may also positively regulate 5-HT neuron activity. Using in vivo electrophysiological recordings in combination with drug tools, this thesis investigated the 5-HT6 receptor control of 5-HT neurons, a proportion of which were identified as 5-HT-containing using a juxtacellular labelling technique.
Electrophysiological recordings in anaesthetised rats found that 5-HT6 receptor agonists WAY-181187 and WAY-208466 increased 5-HT neuron firing to 58% and 47% above pre-drug firing, respectively. By contrast 5-HT6 receptor antagonist SB-399886 reduced 5-HT neuron firing to 56% below pre-drug firing. Four other 5-HT6 ligands, agonist ST-1936, and antagonists AE-58054, SB-258585, and SB-271046, had no significant effect on 5-HT neuron firing. Simultaneous electroencephalogram (EEG) recordings found that WAY-181187 and WAY-208466 reduced frontal cortex slow wave (SW) oscillation power to 62% and 60% below pre-drug values, respectively. It was considered that the frontal cortex may be involved in the effect of these agonists on 5-HT neuron firing. Subsequent experiments investigated the influence of 5-HT6 receptors over mPFC neural activity.
WAY-181187 reduced mPFC SW oscillation power maximally to 54% below pre-drug values. This occurred in a putatively 5-HT6 receptor-dependent manner since the effect was blocked by SB-399885 and AE-58054. WAY-181187 also modulated the firing of mPFC pyramidal neurons, including those projecting to the DRN. Specifically, one population of neurons was excited by WAY-181187, with a maximum increase in firing of 161% above pre-drug firing, whereas another population was inhibited by WAY-181187, with a maximum decrease to 73% below pre-drug firing.
In a final set of experiments neurotoxic mPFC lesion attenuated the excitatory effect of WAY-181187 on 5-HT neuron firing. Thus the effect of WAY-181187 at 2mg/kg was significantly reduced in lesioned rats compared to sham controls.
Experiments in this thesis provide evidence to support a role of 5-HT6 receptor-mediated excitatory control of DRN 5-HT neurons via an mPFC-dependent mechanism. This control may act with previously reported feedback mechanisms to balance inhibitory and excitatory input to 5-HT neurons. Finally, 5-HT6 receptor-mediated feedback may be a useful target for modulating the 5-HT-system, such as in depression therapy.

Advisor: Sharp, T
Space, monuments, and religion: the Christianisation of urban space in the late antique Levant

This thesis investigates the relationship between Christianity and urban monumental space in the late antique Levant. Through the analysis of both textual and archaeological evidence it seeks to clarify both the motives and the stages of the process of Christian takeover of the urban space of Levantine cities from the 4th to the 7th century AD. In doing so Christians were in essence both projecting their growth as the predominant religion and, at the same time, creating an entirely new monumental landscape.
The case studies are presented in three separate groups, selected on the basis of the principal strategy that was chosen in the process of Christianisation of urban space. The first section analyses the cases of Gerasa, Jerusalem, Heliopolis, and Petra to illustrate the first of these strategies: the main method for occupying the symbolic space of the city was the construction of a contrast between the surviving ruins of the earlier, Hellenic, temples and the new Christian churches. The second group of case studies includes Scythopolis, Caesarea Maritima, Gaza, and to a certain extent Heliopolis. This section deals with those cities where the main strategy was the physical demolition of all or at least the most pre-eminent Hellenic buildings and their direct replacement with a new, and often grand, church. The third group, and the last, consists of the cities of Bostra, Gadara, Apamea, where rather than having to engage with a major Hellenic monument the main competitor was the secular state whether local or imperial. This is found to have resulted in a search for integration into the landscape rather than active competition.

Advisor: Ward-Perkins, B
Neolithic Anatolia and Central Europe: disentangling environmental impacts from diet isotope studies

The aim of this thesis was to reconstruct dietary choices for Neolithic populations in Anatolia and Poland using stable isotope analysis, and to examine the extent to which local environmental factors in these regions affected the isotope values recorded from skeletal collagen. In total 278 new δ13C and δ15N values were obtained from human and animal bone collagen for this project (161 from the site of Osłonki 1, 59 from Barçin Höyük, and 58 from the site of Aktopraklık). From an environmental perspective, the multi-level statistical modelling highlighted a clear relationship with δ13C and δ15N and moisture availability, which was most evident through the proxy of mean annual precipitation (MAP). The modelling highlighted a 0.4‰ decrease in δ13C for every 100mm decrease of MAP, and a 0.5‰ decrease in δ15N for every 100mm decrease between sites.
The δ13C and δ15N values for the North-West Anatolian sites are the first dietary isotopic studies for the Neolithic period in the region. The values are largely commensurate with the dietary isotope studies from Neolithic sites located on the Central Anatolian plateau, with the caveat that the North-West sites perhaps had a greater reliance on herbivore protein (instead of plant protein) than their plateau counterparts. The dietary reconstruction of Osłonki 1 uncovered a rather unexpected outcome – namely that status exerted a degree of control over human diet. If this is indeed true it will be the earliest evidence in Europe of a distinct relationship between the socioeconomic status and diet of an individual.

Keywords: Turkey
Prehistory
Carbon and nitrogen isotopes
Neolithic
Human Diet
Advisor: Schulting, R
Lateral buckling of on-bottom pipelines in sand

Recent oil and gas developments in remote offshore locations require the construction of long seabed pipelines that operate under high temperature and pressure. Stress induced by thermal expansion of unburied seabed pipelines causes buckling and lateral deformation of the pipeline, which can damage the pipe and affect its overall integrity. A cost-effective design is to relieve the stress through controlled lateral buckling, which requires accurate and reliable assessment of the lateral resistance of pipe-soil interface.
Previous investigating of pipe-soil interface behaviour refers to the following 4 aspects: 1) the initial embedment of pipeline at installation, 2) breakout resistance during buckle formation, 3) Large amplitude displacement as buckle takes place; and 4) reduction effect in stability due to cyclic loading. This study aims at developing a better understanding of the pipe-soil interaction system in terms of lateral stability. To analyse and predict the pipe-soil response, a series of laboratory tests were conducted on a loose dry sand bed. Three types of load-controlled/displacement-controlled tests, namely 1) penetration test, 2) side swipe test and 3) probe test were designed and conducted to estimate the influence of the key parameters on the lateral buckling resistance of a shallowly embedded pipe in sand.

Advisor: Byrne, B
Estimation of conditional auto-regressive models

Conditional auto-regressive (CAR) models are frequently used with spatial data. However, the likelihood of such a model is expensive to compute even for a moderately sized data set of around 1000 sites. For models involving latent variables, the likelihood is not usually available in closed form.
In this thesis we use a Monte Carlo approximation to the likelihood (extending the approach of Geyer and Thompson (1992)), and develop two strategies for maximising this. One strategy is to limit the step size by defining an experimental region using a Monte Carlo approximation to the variance of the estimates. The other is to use response surface methodology. The iterative procedures are fully automatic, with user-specified options to control the simulation and convergence criteria. Both strategies are implemented in our R package mclcar.
We demonstrate aspects of the algorithms on simulated data on a torus, and achieve similar results to others in a short computational time on two datasets from the literature. We then use the methods on a challenging problem concerning forest restoration with data from around 7000 trees arranged in transects within study plots. We modelled the growth rate of the trees by a linear mixed effects model with CAR spatial error and CAR random e ects for study plots in an acceptable computational time.
Our proposed methods can be used for similar models to provide a clearly defined framework for maximising Monte Carlo approximations to likelihoods and reconstructing likelihood surfaces near the maximum.

Keywords: MCMC
RSM
CAR models
Spatial Statistics
Advisor: Ripley, B
Finding time in the geographies of food: how heritage food discourses shape notions of place

This thesis presents a multi-sited and multi-scalar ethnography of the processes and practices through which producers attempt to designate food as heritage. Grounded in cultural geography, it adopts a cultural economy approach to addressing concerns within agro-food studies by joining in conversation notions of heritage, place-making and time. By underlining the intrinsic relation between articulations of time and constructions of place, this thesis further maps the alternative geographies of food. It engages with three overarching questions, drawing on research conducted within two heritage-based food initiatives in Mexico and Scotland, both linked to the Slow Food movement. These produce, respectively, a traditional sweet called pinole and 'real' bread. The thesis asks: what objectives are pursued through the heritagisation of food whereby various actors strategically coin foods as heritage? How is time articulated in the discourse of heritage food, and how do heritage food networks and producers understand time as a component of food quality? Finally, what senses of place emerge from the various uses of time as a quality in global, translocal and local heritage food discourses?
This thesis explores Slow Food's heritage qualification scheme and the ensuing commodification of heritage food, as well as translocal networks, and practices of 'slow' production. Through empirical engagements it argues that the qualification of heritage foods is multifunctional and that various articulations of time enable small-scale producers to engage with a plethora of socio-economic and political issues. Numerous and at times conflicting constructions of place surface from the discourses woven around these two heritage products and problematise identity formation and narratives of the past linked to producers and communities. This thesis concludes that the constructions of place associated with heritage foods depend not only upon the authority and circumstances of actors articulating a heritage discourse, but also on the scale of the dissemination of that discourse, and on the notions and understandings of time associated with heritage and place.

Advisor: Lorimer, J
What's in a story? Children's learning of new written words via reading experience

Over the course of reading development, children are able to recognise an increasingly large number of words by sight, a process termed orthographic learning, as they move from effortful decoding to fast, efficient word recognition. Phonological decoding has been shown to account for some, but not all variance in orthographic learning. While it is clear that reading experience plays a crucial role, the mechanisms underlying orthographic learning require further investigation. The research presented in this thesis had two overarching objectives: first, to establish a novel, sensitive measure of orthographic learning, using the prime-lexicality effect in lexical decision to index the lexicalisation of novel words, and second, to investigate the effects of specific parameters of reading experience on the learning of novel words. In particular, the experiments focussed on incidental, non-directed learning of unfamiliar English words via story reading. Learning was assessed in terms of knowledge of the novel word spellings and meanings themselves, and their engagement with existing words in the lexicon, indexed by the prime-lexicality effect. Five experiments manipulated directed vs. incidental learning, number of exposures, the availability of semantics, and the variability of the story contexts. Across experiments, children showed good learning of the novel words, and a prime-lexicality effect emerged, validating this novel measure. Number of exposures affected lexicalisation of the novel words, as a prime-lexicality effect was evident after twelve exposures, but not after four. Performance was otherwise unaffected by the experimental manipulations, revealing robust orthographic learning in children aged 9 to 11.

Advisor: Nation, K
Methanol conversion to hydrocarbons via acidic catalysts

Methanol has long been advanced as a high-energy-density, widely-obtained (from non-oil sources such as coal, and biomass) material with potential as a replacement for the limitedly-distributed, finite-in-current-storage oil resources.
Given the fact that effective methanol conversion has been observed over the acidic, zeolite based catalytic materials, e.g. H-ZSM-5, since the 1970s, it is almost certain that extra catalytic properties, such as an enhanced C-H bond activation, govern by the introduced non-zeolitic promoters, e.g. metal oxide species, could further modify the reaction pathways, with potentially-achievable, lower energy costs, higher selectivity (or yields) to many valuable hydrocarbon products (e.g. olefins) and other benefits. On the other hand, a big step is to successful convert the laboratory achievements, e.g. a selected good performance zeolite sample, into the larger-scale applications. Such a process requires the involvement of catalyst binders, and when zeolite particle comes to the nano-scale, the corporation of binder phases, e.g. Al2O3, with the parent nano zeolite plays the most important role in determining the following methanol conversion. Another critical issue is the binder-incorporated, shaped zeolite catalysts would be better tested in larger reactors which are not often seen in the regular laboratory, and the scale-up also increases the research budgets. It should be mentioned that catalyst deactivation is another crucial limitation in this research area; particularly, the reaction formed cokes especially the higher-density, and deeply dehydrogenated graphitized compounds deopsiting deeply inside the zeolite cavities/channels give many difficulties not only in the effective methanol conversion but also in detecting and measuring their quantity and compositions.
This thesis aims to help in solving the above mentioned challenges in an effective methanol catalytic conversion, and can be accordingly divided into 3 aspects: 1) a method to further improve the C-H bond activations for higher olefin and aromatic yields, via modification of H-ZSM-5 (Si/Al=25, industrial) with MoO3 promoters, prepared at a lower-than-usual temperature of 400 °C (routinely 500 °C or higher temperatures are employed for the calcination of metal oxide modified zeolites); 2) an attempt to scale up the laboratory methanol-to-hydrocarbon reaction, obtained over Al2O3 incorporated nano H-ZSM-5 samples (the parent nano zeolites have Si/Al ratios of 20, 60 and 120), with a customized larger fixed-bed reactor that allows catalyst loadings of 20g packed in the shaped forms; 3) a technique based on microwave perturbation measurements in a resonant cavity, inside which coked zeolite samples are analyzed, and different coking levels as well as coke compositions are evaluated based on the sample dielectric loss values that can be calculated from the measured perturbation data.
Our efforts herein are made for the soul of "Science should be applied", for a sustainable future, in a great certain to be sparked by the utilization of methanol in the industries.

Advisor: Edwards, P