VictorJuiz/thesis huggingface dataset:
The role of DNA polymerase eta in determining cellular responses to chemo-radiation treatment
Keywords: oxaliplatin
radiation
DNA polymerase

DNA polymerase η (pol η), a crucial component of the cellular translesion synthesis pathway, allows cells to bypass and thereby temporarily tolerate DNA damage. Inherited deficiency of pol η, as reported in the variant form of xeroderma pigmentosum, predisposes to UV light-induced skin cancers. To date, pol η is the only DNA polymerase shown to exhibit a causal link to the formation of cancers in humans. However, the role of pol η in the cellular response to forms of DNA damage other than UV-induced lesions is largely unknown.
In the first part of this thesis, it is shown that cells deficient in pol η are resistant to ionising radiation. Deficiency in the polymerase was associated with accumulation of cells in S phase of the cell cycle. Cells deficient in pol η demonstrated increased homologous recombination-directed repair of DNA double-strand breaks created by ionising radiation, and depletion of the homologous recombination protein X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells compared to pol η-complemented cells. These findings suggest that homologous recombination mediates S phase-dependent radioresistance associated with pol η-deficiency.
In the second part of this thesis, it is shown that pol η-deficient cells have increased sensitivity to the chemotherapeutic compound, oxaliplatin, compared to pol η-deficient expressing cells, but not to the drug 5-fluorouracil that is usually administered in combination with oxaliplatin in the clinical setting. Despite the importance of pol η for cellular survival following exposure to oxaliplatin, the drug did not upregulate the enzyme after either short-term or long-term exposure. Inhibition of pol η activity by siRNA-mediated knockdown of the protein sensitised cells to oxaliplatin treatment, and partially reversed acquired resistance in oxaliplatin-resistant tumour cell lines. These data suggest that pol η is an interesting target whose function can potentially be interfered with to optimise oxaliplatin-based chemotherapy.
In the third part of this thesis, clinical samples obtained from oesophageal cancer patients before and after treatment with oxaliplatin-containing chemotherapy were analysed for POLH mRNA levels encoding pol η protein. Malignant tissue specimens obtained before treatment demonstrated a significantly higher level of POLH mRNA than matched normal oesophageal tissue samples. Contrary to the preclinical data, high POLH mRNA expression before therapy was shown to correlate with increased overall and disease-free survival of the patient cohort in the clinical trial. Additionally, patients with high POLH mRNA-expressing cancers had better therapeutic responses (measured by PET-CT) to oxaliplatin-based treatment than those with low levels. These data suggest that POLH mRNA expression should be tested as a biomarker to predict survival and therapeutic responses in oesophageal cancer patients treated with oxaliplatin-containing chemotherapy.
Essays in credence goods and repeated games
Keywords: overlapping generations
competition
partnerships
welfare
asymmetric information
credence goods
repeated games
search

This thesis presents two chapters on credence goods and one on ongoing partnerships in an infinitely repeated game. The chapters on credence goods focus on the welfare and efficiency of equilibria in overcharging models of credence goods, something which has not been explicitly addressed before. The chapter on partnerships presents a theory explaining ongoing partnerships as solving a commitment problem for clients. There is a small literature on partnerships, and this chapter represents a novel but complimentary approach to that literature. At core, chapters 2, 3 and 4 of this thesis ask the following questions respectively:
Do competition and information increase welfare in credence goods markets?
How do customers in credence goods markets discipline experts from committing fraud? Can these strategies be welfare ranked?
Why do ongoing partnerships exist? What problem do they solve?
Investigating tendon mechanobiology and the potential of high frequency low magnitude loads for tendon repair and remodelling using an novel in vitro loading system
Keywords: novel
mechanical load
Biomedical Engineering
in vitro
High Frequency
Biophysics
tissue
Medicine
repair
Tendon

Tendon injuries are ubiquitous in the sporting and occupational environment. Clinically they present a challenge to Orthopaedic surgeons as they account for up to half of all sports injuries and almost half of reported work related ailments. The capacity for tendons to heal subsequent to injury is restricted due to their poor blood supply. Moreover, healed tendon tissue may be inferior to the intact tendon, having diminished biochemical and biomechanical properties and this brings about an ever increasing need for optimized treatment methods for tendon repair.
Mechanobiology is concerned with how mechanical forces influence physiological and pathological aspects of the living tissue. However, the complex and poorly controlled loading environment in living organisms prevent the establishment of direct relationships between mechanical stimuli and tissue response.
By developing a novel in vitro loading system (IVLS), the work in this thesis investigates the potential of a new and exciting biophysical loading intervention, High Frequency Low Magnitude (HFLM) mechanical loading, for stimulation of tendon repair and remodelling.
Following a pre-defined stimulation period, healthy rat tail tendon fascicles (RTTFs) were evaluated for tissue viability and metabolism, Glycosaminoglycan (GAG) content, collagen arrangement and tangent modulus, using staining and biochemical assays, together with microscopy techniques, and mechanical testing.
HFLM mechanically loaded tendons showed a trend for a higher tangent modulus than fresh tissue, and significantly higher modulus than unloaded. Further, when varying mechanical loading parameters of frequencies and dosages over clinically relevant ranges, a frequency dependent response was observed with increased tangent modulus and GAG content with increasing frequency. An association between high tendon crimp pattern and elevated tendon modulus as a result of HFLM mechanical loading was also demonstrated.
Concomitantly, an injury model was developed to evaluate the effects of in vitro static, low frequency cyclic and HFLM mechanical loading conditions on the biochemical and biomechanical properties of in vitro damaged tendons. HFLM mechanically loaded damaged tendons again demonstrated significantly higher modulus and metabolism than unloaded tissue, although these were reduced below those of fresh damaged tissue.
The findings in this thesis together with the newly developed IVLS reveal the potential for an exciting and unique biophysical therapeutic loading intervention for treatment of tendon injuries, and provide a scientific platform for further investigation of the effects of HFLM mechanical loads, potentially leading to an application within the clinic for enhanced connective tissue repair and remodelling.
Interplay between chromatin conformation and transcription in eukaryotes
Keywords: chromatin
cohesin
molecular biology
transcription

The three-dimensional organization of the genome is important for various processes such as transcription, replication, and repair. Several studies have shown that the genome is organized into long-range and short-range chromatin loops. Gene loops represent a short-range chromatin loop, synonymous with the juxtaposition of promoter and terminator regions of a gene. In Chapter III, I investigate the mechanism of gene-loop formation in a constitutively expressed gene, mouse serum albumin (Alb). The Alb locus appears to exist in a clover-leaf structure, with the promoter in close physical proximity with an upstream enhancer and downstream genic sequences. Furthermore, Alb forms a promoter-terminator gene loop that is dependent on serine 2 phosphorylation of RNA polymerase C-terminal domain. I also investigate the presence of gene loop conformation at the human Nuclear factor NF-kappa-B (NFκB1) gene. In response to cytokine stimulation, NFκB1 transcription proceeds as a wave, with nascent RNA appearing as RNA polymerase traverses along the gene length. This coincides with formation of transient contacts between NFκB1 promoter and genic regions.
The cohesin complex is a key mediator of chromatin loops and sister chromatid cohesion. The association of cohesin with chromatin is dependent on the loading complex, Mis4/Ssl3. In Chapter IV, I provide direct evidence for two functionally different populations of cohesin is Schizosaccharomyces pombe. Cohesin that co-localizes with Mis4 represents "cohesive" cohesin. In contrast, cohesin alone is unable to maintain stable sister chromatid cohesion, therefore, "less-cohesive" cohesin. Cohesive cohesin ensures stable cohesion because it is acetylated by the Eso1 acetyltransferase, which preferentially interacts with Mis4. In contrast, less-cohesive cohesin may function in recombination/repair. In Chapter V, I have identified a novel interplay between cohesin loading and transcription by RNA polymerase II. Inhibition of transcription initiation results in loss of Mis4 and consequently, cohesin binding on chromosomal arms regions. Furthermore, cohesin and Mis4 physically interact with RNA polymerase II. In Chapter VI, I summarize the above findings and propose a model that describes the stepwise loading of cohesin onto chromosomal arms during the fission yeast cell cycle. To conclude, I discuss the importance of understanding cohesin and its functions in health and diseases.
Phenomenology of dark radiation and string compactifications
Keywords: string theory
axions
cosmology
particle physics

In this Thesis I explore aspects of dark radiation and its role in String Phenomenology. Dark radiation is any additional hidden type of relativistic matter present in the Universe today, conventionally labelled as an "excess effective number of neutrino species", Δ Neff. It provides a powerful test of hitherto untested theoretical models based on fundamental theories such as String Theory.
I begin by considering dark radiation in the LARGE Volume Scenario, a phenomenologically viable class of string compactifications. First I review how the minimal setup slightly overproduces axionic dark radiation via modulus decay. I then demonstrate that loop corrections to the main competing visible-sector decay process have a negligible effect and are unable to alleviate the tension with observations.
In the following chapter I explore fibred extensions of the LARGE Volume Scenario. The predictions for Δ Neff are qualitatively different: in particular, models with a sequestered visible sector on D3 branes at a singularity are swamped by massless axions and decisively ruled out. I then consider TeV-scale supersymmetry in a model with anisotropic modulus stabilisation. If the Standard Model is realised on D7 branes wrapping the small volume cycle a hierarchy of soft terms is generated, which may have applications to natural supersymmetry.
The final chapter takes a different approach and investigates the proposition that dark radiation, in the form of a Cosmic Axion Background, could explain the long-standing soft X-ray excess from galaxy clusters. I show for the Coma cluster that the morphology of the excess can be reproduced by axion-photon conversion in the intracluster magnetic field, provided the field is allowed to have more structure on smaller scales than typically assumed based on Faraday rotation data. This explanation requires an inverse axion-photon coupling M ∼ 1011 - 1012 GeV and a mean axion energy (ECAB) ∼ 50 - 250 eV.
The logic of ballistic missile defence procurement in Japan (1994-2007): from hedging through self-imposed restraints toward hedging from the position of military strength
Keywords: Northeast Asia
BMD
China
neoclassical realism
security strategy
North Korea
Japan
elite networks
military procurement
defence policy
US-Japan relations
Japanese politics
missile defence

This thesis asks why Japan decided to procure BMD if it meant building an infrastructure which, because of its technological nature, had the potential to disrupt Japan’s preferred security strategy of hedging, that is, maintaining ambiguity of commitment, vis-à-vis China and the US.
The investigation was divided into three parts dealing with the following questions – Why did Japan's BMD procurement matter? Who mattered? Why were the BMD and related decisions made? Such a structure of research was informed by “neoclassical realism,” according to which the relative material power of a country sets the parameters of its foreign policy, but the policy choices within these international constraints are made by political elites.
A range of policymaking heuristics were used to investigate the domestic element of the approach. In addition to the conventionally specified policymaking actors such as MOD, MOFA, Prime Ministers, an original attempt was made to identify the possible influences of several elite networks.
On the basis of the notes from the Japan-US Security Strategy Conference, two elite networks were analysed, namely the Japan’s Congressional National Security Research Group and Japan-US Centre for Peace and Cultural Exchange. It was concluded that they have probably had some influence on shaping Japan's BMD decisions.
The conclusion of this research is that BMD was procured despite its disruptive potential because it was a tool of shifting Japanese policy from one hedging policy to another, that is, from one based on self-imposed restraints toward one exercised from the position of military strength. An analysis of international relations in East Asia in 1994-2007 and an analysis of the views of the security elites make Japan's transition toward a military strength-based hedging appear rational and confirm BMD's utility as a tool in this transition. Some negative consequences of a possible disruption to hedging, induced by BMD, can be contained exactly because of such a reformatting of hedging.
Uranium, zirconium and hafnium eta8-permethylpentalene chemistry
Keywords: permethylpentalene
zirconium
metallocycle
pentalene
hafnium
uranium

The purpose of this project has been to expand the η8 binding mode of the permethylpentalene ligand into uranium, zirconium and hafnium chemistry. All three of these elements have shown intriguing, high-hapticity carbocyclic chemistry and, because of their relatively large size, are excellent candidates for the development of organometallic permethylpentalene chemistry. Chapter one of this thesis will review previous work on ηn carbocyclic ring chemistry of these elements, where n = 6 - 8. This introduction will include the unsaturated rings systems where all the carbons are bonded to the metal centre, specifically η6 arene systems, η7 cycloheptatriene systems, and ~8 cyclooctatetraene and pentalene systems. Species of lower hapticity (e.g. the η6 binding mode of cycloheptatriene) will not be covered but reviews, where available, will be referenced.
Chapter two documents the successful synthesis and characterisation of η8 permethylpentalene uranium (IV) species. Initially, the uranocene equivalent, UPn*2 was synthesised and characterised structurally, magnetically and electrochemically. From here, a half-sandwich synthon [UPn*Cl4][Li(TMEDA)]2 was synthesised which was used for further salt metathesis chemistry in order to make a number of mixed sandwich complexes.
Chapter three is an account of the synthesis and characterisation of zirconium and hafnium η8 permethylpentalene species. Initial work focused on the synthesis of a suitable synthon analogous to that used for the previously synthesised titanium species. However, this route was unsuccessful and an alternative species was formed, [MPn*(&nm;-Cl)3/2]2(&nm;-Cl)2[Li(THF)x (Et2O)y ]. This species could be made on a multi-gram scale and proved to be a suitable synthon for further synthesis. Salt metathesis reactions were undertaken and a number of new species were synthesised and characterised including mixed-sandwich, alkyl, aryl and allyl species.
Chapter four reports the results of polymerisation testing that was undertaken for selected synthesised compounds. All compounds catalysed the formation of poly(ethylene), with the group 4 mixed sandwich species being particularly active catalysts. Two of the zirconium species, ZrPn*CpCl and ZrPn*Cp2 were therefore used for further optimisation experiments which were somewhat limited due to the high activity of the compounds. These were useful in gaining insight into conditions that should be investigated on a larger reaction scale.
Chapter five gives the full experimental details for all the syntheses described in chapters two and three as well as details of instrumentation used for characterisation, and also gives the respective loadings of catalyst and co-catalyst employed in the polymerisation testing reported in chapter four. Chapter six presents the full characterisation data obtained for the compounds synthesised and the electronic appendix attached as a CD at the back of the thesis contains the crystal data .cif files and the DFT output files (.out).
Investigations into an archaeal RNA polymerase: structure to function analysis 
Keywords: Rpo13
RNA polymerase
archaea
RPC34

The archaeal RNA polymerase (RNAP) is similar to the eukaryotic RNAP-II in terms of subunit composition and overall protein structure. Despite its similarity, a new archaeal-speciﬁc Rpo13 subunit has been identiﬁed. Rpo13 occupies a position in the enzyme which, in RNAP-II, is ﬁlled by the eukaryotic-speciﬁc Rpb5 jaw domain. It has therefore been proposed to contact DNA, where the positively charged C-terminal tail might mediate protein-DNA interactions. Furthermore, analysis of archaeal genomes has identiﬁed a homologue of the eukaryotic RNAP-III-speciﬁc RPC34 subunit. RPC34 may associate with the single archaeal RNAP, modulating the speciﬁcity of the archaeal RNAP and re-directing it to a subset of genes such as non-coding genes, in analogy to the RNAP-III/RPC34 eukaryotic system involved in the transcription of 5S rRNA, tRNAs and other small RNAs. More importantly, the association of RPC34 with the single archaeal RNAP would deﬁne an archaeal enzyme which acts as a precursor of the eukaryotic RNAP-III. Electrophoretic mobility shift assay (EMSA) analysis of puriﬁed Rpo13 protein by recombinant means subsequently incubated with a double-stranded (ds)DNA sequence reveals the formation of protein-DNA complexes, where Rpo13’s binding to DNA is non-sequence speciﬁc but discriminatory to dsDNA, as no binding is observed in the presence of single-stranded (ss)DNA. Also, it is found that the ma jor determinant of DNA binding is the Rpo13’s positively charged C-terminal tail, since DNA binding is abolished with a Rpo13 mutant deﬁcient in this tail. Furthermore, neither ma jor groove nor minor groove interacting compounds have a major impact on Rpo13’s binding to DNA, suggesting that Rpo13 may associate with the negatively charged DNA phosphate backbone. Moreover, in vitro transcription assays indicate that a transcription product is observed upon RNAP incubation with a bubble DNA oligo shown to make Rpo13 contacts in the RNAP-DNA crystal structure. In addition, while a GST-pulldown experiment suggests the existence of an interaction between the archaeal RNAP and RCP34 in vitro, co-immunoprecipitation assays argue against the existence of such interaction from an in vivo point of view. Finally, a chromatin immunoprecipitation (ChIP)-sequencing approach to analyse Rpo13’s genomic distribution versus the one of the bulk RNAP was undertaken. While the gel ﬁltration elution proﬁle analysis of Rpo13 in the S. acidocaldarius cell extract versus the one of recombinant Rpo13 suggests that there is a free Rpo13 pool in the cell extract, indicating that Rpo13 may be acting as a transiently-associated RNAP subunit displaying a factor-like function, the ChIP-sequencing approach reveals that Rpo13 is a bona ﬁde RNAP subunit since it co-localises from a genomic point of view with the bulk RNAP.
Colouring, centrality and core-periphery structure in graphs
Keywords: colouring
core-periphery
random
brain
combinatorics
graphs
networks
centrality
probability
algorithms

Krivelevich and Patkós conjectured in 2009 that χ(G(n, p)) ∼ χ=(G(n, p)) ∼ χ∗=(G(n, p)) for C/n < p < 1 − ε, where ε > 0. We prove this conjecture for n−1+ε1 < p < 1 − ε2 where ε1, ε2 > 0.
We investigate several measures that have been proposed to indicate centrality of nodes in networks, and find examples of networks where they fail to distinguish any of the vertices nodes from one another. We develop a new method to investigate core-periphery structure, which entails identifying densely-connected core nodes and sparsely-connected periphery nodes.
Finally, we present an experiment and an analysis of empirical networks, functional human brain networks. We found that reconfiguration patterns of dynamic communities can be used to classify nodes into a stiff core, a flexible periphery, and a bulk. The separation between this stiff core and flexible periphery changes as a person learns a simple motor skill and, importantly, it is a good predictor of how successful the person is at learning the skill. This temporally defined core-periphery organisation corresponds well with the core- periphery detected by the method that we proposed earlier the static networks created by averaging over the subjects dynamic functional brain networks.
Delay-tolerant data collection in sensor networks with mobile sinks
Keywords: delay tolerant data collection
distributed networks
wireless sensor networks

Collecting data from sensor nodes to designated sinks is a common and challenging task in a wide variety of wireless sensor network (WSN) applications, ranging from animal monitoring to security surveillance. A number of approaches exploiting sink mobility have been proposed in recent years: some are proactive, in that sensor nodes push their read- ings to storage nodes from where they are collected by roaming mobile sinks, whereas others are reactive, in that mobile sinks pull readings from nearby sensor nodes as they traverse the sensor network.
In this thesis, we point out that deciding which data collection approach is more energy-efficient depends on application characteristics, includ- ing the mobility patterns of sinks and the desired latency of collected data. We introduce novel adaptive data collection schemes that are able to automatically adjust to changing sink visiting patterns or data requirements, thereby significantly easing the deployment of a WSN.
We illustrate cases where combining proactive and reactive modes of data collection is particularly beneficial. This motivates the design of TwinRoute, a novel hybrid algorithm that can flexibly mix the two col- lection modes at appropriate levels depending on the application sce- nario. Our extensive experimental evaluation, which uses synthetic and real-world sink traces, allows us to identify scenario characteristics that suit proactive, reactive or hybrid data collection schemes. It shows that TwinRoute outperforms the pure approaches in most scenarios, achiev- ing desirable tradeoffs between communication cost and timely delivery of sensor data.